The present invention relates to immunogenic but non-depositing-forming polypeptides or peptides homologous to amyloid β, prion, amylin or α-synuclein which can be used alone or conjugated to an immunostimulatory molecule in an immunizing composition for inducing an immune response to amyloid β peptides and amyloid deposits, to prion protein and prion deposits, to amylin and amylin deposits, to α-synuclein and deposits containing α-synuclein, or to polyglutamine repeats and deposits of proteins containing polyglutamine repeats. Described are also antibodies directed against such peptides, their generation, and their use in methods of passive immunization to such peptides and deposits.

1. Field of the Invention
The present invention relates to the field of amyloid β peptides, prion protein, amylin, α-synuclein, and polyglutamine repeats and methods for inducing an immune response to amyloid β peptides and amyloid deposits, prion proteins and deposits, amylin and amylin fibrils, filaments and fibrils containing α-synuclein, or protein aggregates containing polyglutamine repeats. The invention also relates to a method of treating or preventing amyloid plaque forming diseases or amyloidosis by the use of a synthetic immunogenic but not deposit forming polypeptide homologous to the protein which forms the amyloid plaque.
2. Description of the Background Art
Amyloid β
Alzheimer's disease (AD) is the most common form of late-life dementia in adults (Soto et al., 1994), constituting the fourth leading cause of death in the United States. Approximately 10% of the population over 65 years old is affected by this progressive degenerative disorder that is characterized by memory loss, confusion and a variety of cognitive disabilities. Neuropathologically, AD is characterized by four major lesions: a) intraneuronal, cytoplasmic deposits of neurofibrillary tangles (NFT), b) parenchymal amyloid deposits called neuritic plaques, c) cerebrovascular amyloidosis, and d) synaptic and neuronal loss. One of the key events in AD is the deposition of amyloid as insoluble fibrous masses (amyloidogenesis) resulting in extracellular neuritic plaques and deposits around the walls of cerebral blood vessels. The major constituent of the neuritic plaques and congophilic angiopathy is amyloid β (Aβ), although these deposits also contain other proteins such as glycosaminoglycans and apolipoproteins.
Aβ is a 4.1-4.3 kDa hydrophobic peptide that is codified in chromosome 21 as part of a much longer amyloid precursor protein APP (Muller-Hill et al., 1989). The APP starts with a leader sequence (signal peptide), followed by a cysteine-rich region, an acidic-rich domain, a protease inhibitor motif, a putative N-glycosylated region, a transmembrane domain, and finally a small cytoplasmic region. The Aβ sequence begins close to the membrane on the extracellular side and ends within the membrane. Two-thirds of Aβ faces the extracellular space, and the other third is embedded in the membrane (Kang et al., 1987 and Dyrks et al., 1988). Several lines of evidence suggest that amyloid may play a central role in the early pathogenesis of AD.
Evidence that amyloid may play an important role in the early pathogenesis of AD comes primarily from studies of individuals affected by the familial form of AD (FAD) or by Down's syndrome. Down's syndrome patients have three copies of the APP gene and develop AD neuropathology at an early age (Wisniewski et al., 1985). Genetic analysis of families with hereditary AD revealed mutations in chromosome 21, near or within the Aβ sequence (Forsell et al., 1995), in addition to mutations within the presenilin 1 and 2 genes. Moreover, it was reported that transgenic mice expressing high levels of human mutant APP progressively develop amyloidosis in brain (Games et al., 1995). These findings appear to implicate amyloidogenesis in the pathophysiology of AD. In addition, Aβ fibrils are toxic in neuronal culture (Yankner et al., 1989) and to some extent when injected into animal brains (Sigurdsson et al., 1996 and 1997).
Furthermore, several other pieces of evidence suggest that the deposition of Aβ is a central triggering event in the pathogenesis of AD, which leads subsequently to NFT formation and neuronal loss. The amyloid deposits in AD share a number of properties with all the other cerebral amyloidoses, such as the prion related amyloidoses, as well as the systemic amyloidoses. These characteristics are: 1) being relatively insoluble; 2) having a high β-sheet secondary structure, which is associated with a tendency to aggregate or polymerize; 3) ultrastructurally, the deposits are mainly fibrillary; 4) presence of certain amyloid-associated proteins such as amyloid P component, proteoglycans and apolipoproteins; 5) deposits show a characteristic apple-green birefringence when viewed under polarized light after Congo red staining.
The same peptide that forms amyloid deposits in AD brain was also found in a soluble form (sAβ) normally circulating in the human body fluids (Seubert et al., 1992 and Shoji et al., 1992). Zlokovic et al. (1994), reported that the blood-brain barrier (BBB) has the capability to control cerebrovascular sequestration and transport of circulating sAβ, and that the transport of the sAβ across the BBB was significantly increased when sAβ was perfused in guinea pigs as a complex with apolipoprotein J (apoj). The sAβ-apoJ complex was found in normal cerebrospinal fluid (CSF; Ghiso et al., 1994) and in vivo studies indicated that sAβ is transported with apoJ as a component of the high density lipoproteins (HDL) in normal human plasma (Koudinov et al., 1994). It was also reported by Zlokovic et al. (1996), that the transport of sAβ across the BBB was almost abolished when the apoJ receptor gp330 was blocked. It is believed that the conversion of sAβ to insoluble fibrils is initiated by a conformational modification of the 2-3 amino acid longer soluble form. It has been suggested that the amyloid formation is a nucleation-dependent phenomena in which the initial insoluble "seed" allows the selective deposition of amyloid (Jarrett et al., 1993).
Peptides containing the sequence 1-40 or 1-42 of Aβ and shorter derivatives can form amyloid-like fibrils in the absence of other protein (Soto et al., 1994), suggesting that the potential to form amyloid resides mainly in the structure of Aβ. The relation between the primary structure of Aβ and its ability to form amyloid-like fibrils was analyzed by altering the sequence of the peptide. Substitution of hydrophilic residues for hydrophobic ones in the internal Aβ hydrophobic regions (amino acids 17-21) impaired fibril formation (Hilbich et al., 1992), suggesting that Aβ assembly is partially driven by hydrophobic interactions. Indeed, larger Aβ peptides (Aβ1-42/43) comprising two or three additional hydrophobic C-terminal residues are more amyloidogenic (Jarrett et al., 1993). Secondly, the conformation adopted by Aβ peptides is crucial in amyloid formation. Aβ peptides incubated at different pH, concentrations and solvents can have either a mainly α-helical, random coil, or a β-sheet secondary structure (Barrow et al., 1992; Burdick et al., 1992 and Zagorski et al., 1992). The Aβ peptide with α-helical or random coil structure aggregates slowly; Aβ with β-sheet conformation aggregates rapidly (Zagorski et al., 1992; Soto et al., 1995 and Soto et al., 1996). The importance of hydrophobicity and β-sheet secondary structure on amyloid formation also is suggested by comparison of the sequence of other amyloidogenic proteins.
Analysis of Aβ aggregation by turbidity measurements indicates that the length of the C-terminal domain of Aβ influences the rate of Aβ assembly by accelerating nucleus formation (Jarrett et al., 1993). Thus, the C-terminal domain of Aβ may regulate fibrillogenesis. However, in vitro modulators of Aβ amyloid formation, such as metal cations (Zn, Al) (Bush et al., 1994 and Exley et al., 1993) heparin sulfate proteoglycans, and apoliprotein E (Strittmatter et al., 1993) interact with the 12-28 region of Aβ. Moreover, mutations in the APP gene within the N-terminal Aβ domain yield analogs more fibrillogenic (Soto et al., 1995 and Wisniewski et al., 1991). Finally, while the C-terminal domain of Aβ invariably adopts a β-strand structure in aqueous solutions, environmental parameters determine the existence of alternative conformation in the Aβ N-terminal domain (Barrow et al., 1992; Soto et al., 1995 and Burdick et al., 1992). Therefore, the N-terminus may be a potential target site for inhibition of the initial random coil to β-sheet conformational change.
The emerging picture from studies with synthetic peptides is that Aβ amyloid formation is dependent on hydrophobic interactions of Aβ peptides adopting an antiparallel β-sheet conformation and that both the N- and C-terminal domains are important for amyloid formation. The basic unit of fibril formation appears to be the conformer adopting an antiparallel β-sheet composed of strands involving the regions 10-24 and 29-40/42 of the peptide (Soto et al., 1994). Amyloid formation proceeds by intermolecular interactions between the β-strands of several monomers to form an oligomeric β-sheet structure precursor of the fibrillar β-cross conformation. Wood et al., (1995) reported the insertion of aggregation-blocking prolines into amyloid proteins and peptides to prevent aggregation of such proteins and peptides. In this manner, the authors suggest that novel proteins can be designed to avoid the problem of aggregation as a barrier to their production without affecting the structure or function of the native protein. Thus, Wood et al. seek to produce novel proteins that would not aggregate during recombinant protein production and purification by inserting aggregation/blocking prolines into these novel peptides.
To date there is no cure or effective therapy for reducing a patient's amyloid burden or preventing amyloid deposition in AD, and even the unequivocal diagnosis of AD can only be made after postmortem examination of brain tissues for the hallmark neurofibrillary tangles (NFT) and neuritic plaques. However, there are an increasing number of publications outlining strategies for the treatment of Alzheimer's disease. Amyloid-related therapeutic strategies include the use of compounds that affect processing of the amyloid-β precursor protein (APP; Dovey et al., 2001), that interfere with fibril formation or that promote fibril disassembly (Soto et al., 1998; Sigurdsson et al., 2000; and Findeis, 2000).
Heparin sulfate (glycosoaminoglycan) or the heparin sulfate proteoglycan, perlecan, has been identified as a component of all amyloids and has also been implicated in the earliest stages of inflammation-associated amyloid induction. Kisilevsky et al. (1995) describes the use of low molecular weight (135-1,000 Da) anionic sulfonate or sulfate compounds that interfere with the interaction of heparin sulfate with the inflammation-associated amyloid precursor and the β-peptide of AD. Heparin sulfate specifically influences the soluble amyloid precursor (SAA2) to adopt an increased β-sheet structure characteristic of the protein-folding pattern of amyloids. These anionic sulfonate or sulfate compounds were shown to inhibit heparin-accelerated Alzheimer's Aβ fibril formation and were able to disassemble preformed fibrils in vitro as monitored by electron micrography. Moreover, when administered orally at relatively high concentrations (20 or 50 mM), these compounds substantially arrested murine splenic inflammation-associated amyloid progression in vivo in acute and chronic models. However, the most potent compound, poly-(vinylsulfonate), was acutely toxic.
Anthracycline 4′-iodo-4′-deoxy-doxorubicin (IDOX) has been observed clinically to induce amyloid resorption in patients with immunoglobin light chain amyloidosis (AL). Merlini et al. (1995), elucidated its mechanism of action. IDOX was found to bind strongly via hydrophobic interactions to two distinct binding sites (Scatchard analysis) in five different tested amyloid fibrils, inhibiting fibrillogenesis and the subsequent formation of amyloid deposits in vitro. Preincubation of IDOX with amyloid enhancing factor (AEF) also reduced the formation of amyloid deposits. Specific targeting of IDOX to amyloid deposits in vivo was confirmed in an acute murine model. This binding is distinct from heparin sulfate binding as removal of the glycosaminoglycans from extracted amyloid fibrils with heparinases did not modify IDOX binding. The common structural feature of all amyloids is a β-pleated sheet conformation. However, IDOX does not bind native amyloid precursor light chains which suggests that the β-pleated sheet backbone alone is not sufficient to form the optimal structure for IDOX binding, and that it is the fibril cross-β-sheet quaternary structure that is required for maximal IDOX binding. Tt has been found that the amount of IDOX extracted from spleens is correlated with amyloid load and not circulating serum precursor amyloid levels. IDOX, however, is also extremely toxic.
The regulation and processing of amyloid precursor protein (APP) via inhibition or modulation of phosphorylation of APP control proteins has also been investigated in U.S. Pat. No. 5,385,915 and WO 9427603. Modulating proteolytic processing of APP to nucleating forms of AD has also been examined in AU 9338358 and EP569777. WO 95/046477 discloses synthetic peptides of composition X-X-N-X coupled to a carrier, where X is a cationic amino acid and N is a neutral amino acid, which inhibit Aβ binding to glycosoaminoglycan. Peptides containing Alzheimer's Aβ sequences that inhibit the coupling of α-1-antichymotrypsin and Aβ are disclosed in WO 92/03474.
From experiments conducted at the laboratory of the present inventors, WO 96/39834 discloses that peptides capable of interacting with a hydrophobic portion on a protein or peptide, such as Aβ, involved in amyloid-like deposit formation can be used to inhibit and structurally block the abnormal folding of such proteins and peptides into amyloid or amyloid-like deposits. The peptides which block abnormal folding of Aβ into amyloid deposits have a hydrophobic portion containing β-sheet breaking amino acid residue(s), such as proline, that reduces the propensity of the peptide for adopting a β-sheet conformation. The laboratory of the present inventors, in later reports, have demonstrated that LeuProPhePheAsp (SEQ ID NO:14), a non-amyloidogenic peptide with sequence homology to Aβ blocks fibril formation (Soto et al., 1998), and induces in vivo disassembly of fibrillar Aβ deposits (Sigurdsson et al., 2000).
Recently, the coupling of lysine residues to peptides was proposed by Pallitto et al. (1999), in the design of anti-β sheet peptides or Aβ fibrillogenesis inhibitors that have an Aβ-binding recognition sequence and a hexameric lysine aggregation disrupting element.
In vitro studies have shown that monoclonal antibodies raised against the N-terminal region of Aβ can disaggregate Aβ fibrils, maintain Aβ solubility, and prevent Aβ toxicity in cell culture (Solomon et al., 1996 and 1997).
WO 96/25435 discloses the potential for using a monoclonal antibody, which is end-specific for the free C-terminus of the Aβ1-42 peptide, but not for the Aβ1-43 peptide, in preventing the aggregation of Aβ1-42. The administration of such an Aβ end-specific monoclonal antibody is further disclosed to interact with the free C-terminal residue of Aβ1-42, thereby interfering with and disrupting aggregation that may be pathogenic in AD.
WO 98/44955 takes a different approach to avoiding the problems associated with repeated administration of pharmacological agent and discloses a method for preventing the onset of Alzheimer's Disease or for inhibiting progression of Alzheimer's Disease through the stable ectopic expression in the brain of recombinant antibodies end-specific for amyloid-β peptides.
Recently, Schenk et al. (1999) demonstrated that immunization with amyloid-β attenuated Alzheimer's disease-like pathology in PDAPP transgenic mice serving as an animal model for amyloid-β deposition and Alzheimer's disease-like neuropathologies. They reported that immunization of young animals prior to the onset of Alzheimer's disease-type neuropathologies essentially prevented the development of β-amyloid plaque formation, neuritic dystrophy and astrogliosis, whereas treatment in older animals after the onset of Alzheimer's disease-type neuropathologies was observed to reduce the extent and progression of these neuropathologies. This effect is thought to be mediated by antibodies, since peripherally administered antibodies against Aβ have been shown to reduce brain parenchymal amyloid burden (Bard et al., 2000). In addition, intranasal immunization with freshly solubilized Aβ1-40 reduces cerebral amyloid burden (Weiner et al., 2000). Two recent studies demonstrated that a vaccination-induced reduction in brain amyloid deposits resulted in cognitive improvements (Morgan et al., 2000; Janus et al., 2000).
Although the results reported by Schenk et al. provides promise for using immunomodulation as a general approach to treat Alzheimer's disease, immunization with intact amyloid-β according to Schenk et al. presents problems that make it inappropriate for human use. First, Schenk et al's experiments used transgenic mice which express a mutated human protein that is foreign to them and that has no physiological function in mice (the mouse and human Aβ peptide sequences are significantly different). However, in humans, the precursor protein (βAPP) is an endogenous protein that has a normal function. Hence, using this approach in humans with a human Aβ peptide may well lead to development of an autoimmune disorder or disease that could make matters worse not better. Second, Martel et al. (1996) and the present inventors have results which demonstrate that Aβ peptides, Aβ1-42 and Aβ1-40, can cross the blood brain barrier in experimental animals. Therefore, in humans, it is expected that Aβ1-42, which is used for immunization in Schenk et al., can cross the blood brain barrier and co-deposit on any existing amyloid plaques leading to increased toxicity, and may actually promote plaque formation. This has not been a problem in the PDAPP transgenic mouse model for AD because human Aβ1-42 is less toxic for the mouse; even with massive deposition of human Aβ1-42, none of the transgenic mice show significant neuronal loss. Thirdly, Schenk et al. use a toxic adjuvant to induce an immune response.
Prion
From a mechanistic point of view, the best understood of the conformational disorders are the prion related diseases (or prionoses). The etiology of these diseases is the conversion of the normal prion protein, PrPC, into its infectious and pathogenic form, PrPSc (Prusiner et al., 1998; Horwich and Weismann, 1997). PrPC and PrPSc are thought to differ only in their conformation, with PrPSc having a greater β-sheet content.
The first of these disorders to be described was scrapie, a disease of sheep recognized for over 250 years. This illness manifested by hyper-excitability, itching and ataxia, leads to paralysis and death. It is called scrapie because of the tendency of affected animals to rub against the fences of their pens in order to stay upright, reflecting their cerebellar dysfunction. The transmission of this disease was demonstrated first in 1943 when a population of Scottish sheep was accidentally inoculated against a common virus using a formalin extract of lymphoid tissue from an animal with scrapie (Gordon, 1946). After an incubation period of two years about 10% of the inoculated animals developed scrapie.
The first human prionosis was described some years later and is called kuru (Gajdusek and Zigas, 1957; Gajdusek and Zigas, 1959). This is an illness of the Fore people living in the highlands of New Guinea, that is thought to be linked to ritualistic cannibalism. Presumably this illness originated with the accidental consumption of an initial patient with sporadic Creutzfeldt-Jacob disease (CJD). Kuru was once the major cause of death among Fore women; however, the disease has virtually disappeared with the end of cannibalistic rituals. Rather similar to scrapie, patients clinically present with difficulty walking and develop progressive signs of cerebellar dysfunction. Death occurs approximately 1 year following onset of symptoms. The neuropathology of kuru, in common with all prionoses to a variable extent, includes widespread spongiform change and astrocytosis, as well as neuronal loss affecting the cerebral hemispheres and cerebellum. In about 70% of cases, amyloid plaques are found, with amyloid deposition being a common but not invariable accompaniment of the prionoses. It was Gajdusek's detailed description of this illness that lead Hadlow to suggest that kuru might be the human representation of scrapie (Hadlow, 1959). This in turn suggested to Gajdusek and his team to test whether kuru was also transmissible. They first showed kuru was transmissible to chimpanzees, after a long incubation, in 1966 (Gajdusek et al., 1966); this work led to Gajdusek being awarded the Nobel Prize in 1976.
Other human prionoses include Gerstamann-Sträussler-Scheinker disease (GSS), described in a large kindred in 1936 (Gerstmann et al., 1936). This illness presents with a slowly progressive limb and truncal ataxia, as well as dementia, with death occurring from 6 to 10 years following presentation. The pattern of inheritance is autosomal dominant; it is now known that all cases of GSS are associated with mutations of the PrP gene. The neuropathology of GSS is remarkable in that there is extensive and invariable amyloid deposition, in addition to the typical spongiform change, gliosis and neuronal loss. Interestingly, in several kindreds of GSS, extensive neurofibrillary tangle (NFT) formation is found (Ghetti et al., 1994). NFTs are an essential feature of AD. Another variation of autosomal dominantly inherited human prionosis has been termed prion protein-congophilic angiopathy (PrP-CAA), which is characterized by cerebral vessel PrP amyloid deposition and the presence of NFT (Ghetti et al., 1996). CAA is also an essential feature of AD. Both these variants of prionoses further link the pathogenesis of AD and the prion related diseases.
Creutzfeldt-Jacob disease (CJD) was initially described by Jacob in 1921 (Jacob, 1921); ironically, the case reported by Creutzfeldt a year earlier is probably unrelated to the disease which carries his name. Clinically CJD is characterized by a rapidly progressive dementia, associated with myoclonic jerks, as well as a variable constellation of pyramidal, extrapyramidal and cerebellar signs. The EEG typically shows distinctive changes of high voltage, slow (1 to 2 Hz) and sharp wave complexes on an increasingly slow and low-voltage background. CJD is found throughout the world with an incidence of about 1 per million. In addition to extensive cortical spongiosis, gliosis and neuronal loss, 10% of CJD cases have amyloid plaques (Prusiner et al., 1998).
Fatal familial insomnia (FFI) is a disorder presenting with intractable insomnia, dysautonomia, a variety of endocrine abnormalities and motor paralysis (Medori et al., 1992). Neuropathologically, there is marked atrophy of the anterior ventral and mediodorsal thalamic nuclei, due to neuronal loss and gliosis. Unlike other prionoses, spongiform change can be a minor feature or be absent altogether. All patients with FFI have a missense mutation at codon 178 of the PrP gene where Asn is replaced by Asp, coupled with a Met at the polymorphic codon 129 (Goldfarb et al., 1992). The somewhat divergent clinical and neuropathological features of FFI, in comparison to other human prionoses, highlight the wide spectrum of disease associated with PrP dysfunction and suggests that there may be other human illnesses which have yet to be recognized as prionoses.
There has been a recent epidemic of a new prionosis, bovine spongiform encephalopathy (BSE), that has led to more than 160,000 cattle deaths in the UK (Collinge, 1997). This new disease is thought to be caused by meat and bone meal dietary supplements to cattle that were contaminated with scrapie infected sheep and other cattle with BSE. Some evidence suggests that BSE also has led to a new type of CJD, called new variant CJD (vCJD) (Collinge et al., 1996a). The first cases of vCJD were reported in 1995, when two cases of CJD were found in 2 British teenagers (Bateman et al., 1995; Britton et al., 1995). Only 4 cases of sporadic CJD have been reported previously among teenagers; the peak onset of sporadic CJD being between ages 60 to 65 years. In addition to the early age, these cases had distinctive neuropathology that included so-called "florid" amyloid plaques which are reminiscent of kuru associated PrP amyloid plaques (Collee and Bradley, 1997; Will et al., 1997). Since the original reports, there have been 14 cases with these distinctive features; all were in the UK except for one French case. The emergence of vCJD has raised the specter of an epidemic of prion related disease among the British population similar to that of BSE in cattle.
Highly divergent hypotheses have been put forward regarding the etiology of the prionoses, including that they consist of nucleic acid only, protein only, are lacking both protein and nucleic acid or are a polysaccharide. The most widely accepted hypothesis, first put forward by Griffith (Griffith, 1967) and more explicitly by Pruisner is the "protein only" hypothesis (Prusiner et al., 1998). Pruisner introduced the term "prion" to indicate that scrapie is related to a proteinous infectious particle (Prusiner, 1982). This hypothesis was initially greeted with great scepticism in the scientific community; now it represents the current dogma with Dr. Pruisner being honored with the 1998 Noble Prize for Science. This hypothesis suggests that prions contain no nucleic acid and are referred to as PrPSc. The latter represents a conformationally modified form of a normal cellular PrPC, which is a normal host protein found on the surface of many cells, in particular neurons. PrPSc when introduced into normal, healthy cells causes the conversion of PrPC into PrPSc, initiating a self-perpetuating vicious cycle (Prusiner et al., 1998).
Other hypotheses for prion have included the "virino hypothesis" (Weissmann, 1996). Here it is suggested that the infectious agent consists of a nucleic acid with host derived PrPSc serving as a coat. The latter would explain the lack of an immunological and inflammatory response, while the presence of a nucleic acid provides an explanation for the numerous strains of scrapie, each with distinctive features. Other investigators have also suggested that the scrapie agent is a conventional virus with highly atypical properties. However, despite extensive searches, no nucleic acid associated with prion infection has been detected so far. The unusual nature of the scrapie agent first became apparent during the early transmission studies, where it first was found that infectivity was filterable, consistent with the presence of a virus, but differing from viruses in that formalin treatment did not abolish this infectivity (Gordon, 1946). Later Alper et al. showed that the scrapie agent was resistant to inactivation by UV at 254 nm unlike nucleic acid (Alper et al., 1967), but sensitive to irradiation at 237 nm, suggestive of the presence of a protein (Latarjet et al., 1970). The possibility that a protein was involved was furthered by the pioneering work of Pruisner et al. with the biochemical partial purification of infectious activity (Prusiner, 1982). These workers reported a 1000 fold increase in infectivity compared to homogenates of infectious brain by a series of steps involving polyethylene glycol precipitation, nuclease digestion, partial proteinase K (PK) digestion and density gradient centrifugation. The enriched infectious activity was inactivitated or reduced by extensive PK digestion, diethyl pyrocarbonate, urea, chaotropes, phenol and/or SDS. However, it was unaffected by nuclease digestion or UV irradiation. Pruisner et al. identified a protein within this enriched infectious material which they termed PrP that was resistant to partial PK digestion and was found only in infected hamster brains. This protein migrated on SDS-PAGE at 27-30 kDa and ultrastructurally had the appearance of rods, which were first identified by Merz et al. (Merz et al., 1981). Fractions enriched for these rods were found to be highly infectious. This PrPSc is thought to differ from the normal cellular PrPC by conformation alone. FT-IR and CD studies have identified that PrPC is about 40% α-helical with little β-sheet, while PrPSc is ˜30% α-helical and ˜45% β-sheet (Pan et al., 1993; Caughey et al., 1997; Safar et al., 1993). So far, no post-translational modifications have been found that distinguish PrPSc from PrPC despite numerous studies. However, a remaining major problem is that even with current techniques, the ratio of PrPSc molecules to infectious units is on the order of 10,000 to one (Horwich and Weismann, 1997). Hence, with such a ratio it is very difficult to completely rule out that other essential components are not part of the infectious agent or that some covalent or other post-translational modifications do not occur as part of the PrPC to PrPSc conversion. Indeed, the pattern of glycosylation has been shown to be distinctive among differing human PrPSc types, indicating that this post-translational modification may influence strain specificity (Collinge et al., 1996b). For the final proof of the "protein only" hypothesis it will be necessary to produce infectious particles in vitro from purified PrPC or from recombinant protein.
With the purification of PrP27-30 it was possible to obtain its amino terminal sequence and subsequently cDNA clones encoding the PrP protein (Liao et al., 1986; Oesch et al., 1985). The human PrP gene is found on chromosome 20. It spans 20 kb and consists of a short, non-coding first exon, a 10-15 kb intron and a second exon that contains the entire 759 bp open reading frame and 1.64 kb of 3′ non-translated sequence, with the translation product being 253 amino acids long. The PrP gene is highly conserved across mammalian species and is constitutively expressed in both neuronal and non-neuronal tissue (Kretzschmar et al., 1986). The highest mRNA levels are found in neurons, in particular in the hippocampus; however, substantial amounts are also found in the heart and skeletal muscle. The primary structure of PrP from normal animals was found to be identical to that found from scrapie infected animals and the levels of mRNA were comparable in both settings (Oesch et al., 1985; Chesebro et al., 1985). Cell culture studies have indicated that PrPC is transported in secretory vesicles to the external cell surface, where it is anchored via a GPI moiety (Taraboulos et al., 1992). Most of this PrPC is internalized into an endocytic compartment; however, some can be released into the extracellular space by cleavage of the GPI anchor(Shyng et al., 1993). The endocytic PrPC is recycled intact to the cell surface or cleaved at the N-terminus and externalized (Harris et al., 1993; Shyng et al., 1993). The identification of the PrP gene, designated PRNP in humans, also allowed for the characterization of numerous mutations associated with familial prionoses (Prusiner et al., 1998). Three mutations in the first putative α-helical domains of PrP at codons 102, 105 and 117, with a fourth at codon 145, which is at the carboxyl end of the second putative helical domain, are associated with a GSS phenotype. The codon 145 mutation produces a stop codon and the synthesis of a truncated PrP (Kitamoto et al., 1993). Other GSS linked mutations occur at codons 198 and 217 (Dlouhy et al., 1992; Hsiao et al., 1992). Interestingly, these two mutations are associated with widespread NFT similar to that seen in AD. Conversely, a familial CJD picture, with little or no amyloid deposition, has been identified among kindreds with insertions of variable octarepeats in the amino terminal domain of PrP and mutations at codons 178, 180, 200, 210 and 232; all these are in the third and fourth putative helical domains of PrP (Prusiner et al., 1998). A particularly interesting mutation occurs at codon 178, resulting in a substitution of Asn for Asp. This point mutation can result in either the clinical picture of CJD or FFI depending on a polymorphism at codon 129 (Medori et al., 1992; Goldfarb et al., 1992). The codon 178 mutation, plus Met at codon 129 results in FFI whereas if there is a Val at codon 129 a CJD picture is seen. This demonstrates the importance of the 129 codon polymorphism on the distribution of disease, since in FFI the neuropathology is largely confined to the thalamus while in CJD there is widespread spongiform change in the cerebral cortex and in subcortical nuclei.
Two critical genetic studies provide strong evidence for the requirement of endogenous PrPC for PrPSc infection. The first of these used PrP knockout mice designated Prnp0/0. In two such lines of Prnp0/0 mice, there were little or no differences found from controls (Bueler et al., 1992; Manson et al., 1994); however, altered sleep-wake cycles and abnormal synaptic behavior in brain slices have been reported (Tobler et al., 1996; Collinge et al., 1994). The synaptic changes could not be confirmed by one other group (Liedo et al., 1996). One line of Prnp0/0 mice showed ataxia and Purkinje cell loss at about 70 weeks of age (Sakaguchi et al., 1996). Importantly, during transmission studies all of these different lines of Prnp0/0 mice have all been shown to be highly resistant to prion infection (Bueler et al., 1993; Prusiner et al., 1993). Prnp0/0 mice sacrificed at 4, 60, 120 and 315 days after inoculation with prions showed no infectivity with the exception of residual infectivity from the inoculum detected at five day following inoculation.
The second set of genetic mouse experiments showing the need for endogenous PrP used mice expressing PrP with a GSS linked mutation. These mice spontaneously express prion disease which could be transferred when inoculated into transgenic mice expressing low levels of the same mutant PrP protein, but which otherwise would not develop disease (Telling et al., 1996; Hsiao et al., 1994). These transgenic mouse experiments combined with the Prnp0/0 mice, clearly show the need for endogenous PrPC for expression of disease.
A ligand which interacts with PrPC in the production of PrPSc has also been suggested and has been called "protein X" (Prusiner et al., 1998). The existence of protein X is indicated by a number of transmission studies by Pruisner's team. They found the transmission of human CJD prions to transgenic mice expressing human PrPC, Tg(HuPrP), occurred in only about 10% of inoculated mice, which is similar to the rate seen in wild-type mice (Telling et al., 1994). This situation was very different when transgenic mice were used that express a chimeric human/mouse (Hu/Mo) transgene (MH2M). The PrPC encoded by MH2M differed from Mo PrPC by nine amino acids within residues 96 to 167, while there are 28 amino acid differences between the entire mouse and human PrP sequences. All these mice, when inoculated with human PrPSc become sick with fairly short incubation periods of 202 to 249 days (Telling et al., 1995). The much higher frequency of human CJD PrPSc transmission to Tg(MHu2M) mice versus the Tg(HuPrP) shows the importance of the mouse PrP sequence and may suggest that participation of a cellular factor that recognizes some epitopes that are specific for mouse PrP versus the human PrP. It is this cellular factor that has been designated protein X.
Given our increasing knowledge of the factors involved in the PrPC to PrPSc conversion, its conceivable to design effective therapeutic agents. Currently, no such therapeutic agents exist. So far only a limited number of approaches have been attempted. Experimental treatment approaches that have been reported for prion diseases include the use of amphotericin B (Pocchiari et al., 1987), Congo red (Caughey and Race, 1992), sulphated polyanions (Ladogana et al., 1992), anthracyclines (Tagliavini et al., 1997), β-sheet breaker peptides (Soto et al., 2000), porphyrin and phthalocyanine compounds (Priola et al., 2000). Some of these compounds delay the incubation time of animals infected with PrPSc but all have limitations in terms of toxicity and/or pharmacokinetics. Other approaches would be the development of agents that either modify the action of protein X or inhibit the conformational change of PrPC to PrPSc.
Amylin
Type-2 diabetes mellitus is characterized by defects in the action of insulin and/or its secretion (Hoppener et al., 2000). Usually both abnormalities are present but to a varying degree, depending on the patient and the course of the disease. Islet amyloid is found in about 90% of patients with type 2 diabetes, and there is a good correlation between the extent of amyloid deposition and a reduction in insulin-producing β-cells, suggesting that these deposits may lead to β-cell failure (Howard, Jr., 1986). Identical deposits are found in other species that develop this disease (Westermark et al., 1990), but are absent in rodents (Westermark et al., 1990; Johnson et al., 1989; Moriarty and Raleigh, 1999).
The islet amyloid fibrils are composed of a 37 amino acid peptide known as islet amyloid polypeptide or amylin (Johnson et al., 1989). The nucleotide sequence of the amylin gene is identical in normal subjects compared to diabetes patients indicating that a change in amino acid sequence is not the cause of amyloid fibril formation. An amyloidogenic region (amino acids 20-29) has been identified in the human amylin peptide by in viLro studies and by comparing the amino acid sequences of various species in some of which amylin is not deposited, such as rats, mice and hamsters (Westermark et al., 1990; Johnson et al., 1989; Moriarty and Raleigh, 1999).
Amylin fibrils are formed intracellularly and are also found extracellularly. The mechanism of toxicity of these fibrils has not been thoroughly investigated although integration of aggregates into cell membranes, which can then function as calcium permeable ion channels, has been implicated (Mirzabekov et al., 1996). Subsequent increase in intracellular calcium may lead to cytotoxcity. Disruption of intracellular membranes by amyloid fibrils may also have a role in their toxicity (Janson et al., 1999).
Potential therapeutic targets for Type-2 diabetes involve:
A) Reducing the production of amylin or inhibiting fibrillogenesis with: 1) drugs blocking amylin generating enzymes; 2) drugs affecting the interaction between amylin and its chaperones (Kisilevsky, 1996); 3) the use of antibodies against amylin; and 4) compounds that bind to amylin and prevent fibril formation and/or lead to fibril disassembly, an approach used for other amyloid diseases (Soto et al., 1998; Sigurdsson et al., 2000; Soto et al., 2000).
B) Reducing the demand for endogenous insulin by providing insulin therapy early in the course (Lindstrom et al., 1997).
C) Lowering glucose production (Zapecka-Dubno et al., 1999).
D) Increasing peripheral glucose disposal (Inzucchi et al., 1998).
α-Synuclein
Parkinson's disease (PD) is the second most common neurodegenerative disease and the most common movement disorder (Goedert, 2001). It affects 1-2% of the population over 65 years. PD is primarily characterized by muscle rigidity, bradykinesia and resting tremor. Lewy bodies, found to the greatest extent in the substantia nigra, are the defining neuropathological characteristics of all cases of PD and are mainly composed of α-synuclein (Spillantini et al., 1997). The substantia nigra is rich in dopaminergic neuronal cell bodies and is the main site of cell loss in PD. Subsequent effects on the dopaminergic system are primarily responsible for the clinical symptoms. Cell loss is also seen in the motor nucleus of the vagus nerve, the hypothalamus, the nucleus basalis of Meynert, the locus coeruleus, the cerebral cortex, the olfactory bulb and the autonomic nervous system. Most of PD cases are idiopathic although a missense mutation in the α-synuclein gene is a rare genetic cause of PD (Polymeropoulos et al., 1997). Filamentous inclusions of this protein are also found in multiple system atrophy (MSA), such as olivopontocerebellar atropy, striatonigral degeneration, and Shy-Drager syndrome (Goedert, 2001). In MSA, glial cytoplasmic inclusions are observed instead of Lewy bodies. Another disease characterized by Lewy bodies and Lewy neurites is dementia with Lewy bodies (DLB), a common form of late onset dementia that often overlaps with Alzheimer's disease. Unlike PD, DLB has numerous Lewy bodies and Lewy neurites in the cerebral cortex (Kosaka, 1978), although the substantia nigra is also affected as in PD. Lewy bodies are also found in numerous rare diseases (Goedert, 2001).
Synuclein proteins are abundant in the brain although their physiological function is not understood. The family consists of α-, β- and γ-synuclein ranging from 127 to 140 amino acids, which are 55-62% identical in amino acid sequences (Goedert, 2001). Of these three, only α-synuclein is associated with diseases containing Lewy bodies and MSA with pathology primarily in neurons and glia, respectively. Inactivation of the α-synuclein gene does not lead to a severe neurological phenotype, suggesting that loss of function of the protein does
not lead to the neurodegeneration observed in PD (Abeliovich et al., 2000).
The accumulation of intracellular aggregates of α-synuclein has been implicated in the pathogenesis of these diseases although the mechanism of toxicity remains to be determined. Assembly of α-synuclein is accompanied by the conversion of a random coil formation to a β-pleated sheet (Serpell et al., 2000; Conway et al., 2000; Biere et al., 2000), and occurs through the repeats in the amino-terminal region, whereas the carboxy-terminal regions inhibits assembly (Goedert, 2001). At least one of the α-synuclein mutations (A53T) leads to generation of an altered α-synuclein with an increased rate of filament formation. Although α-synuclein aggregates do not stain with typical stains used to detect amyloid they have been shown by electron diffraction to have the conformation characteristics of amyloid fibrils (Serpell et al., 2000). β- and γ-synuclein do not assemble into filaments (Serpell et al., 2000; Biere et al., 2000; Giasson et al., 2001), which may explain why these forms have not been implicated in any diseases.
Although various treatment options are available for PD, most of them affect the dopaminergic system or deal with the side effects of those drugs (Hely et al., 2000). This is a symptomatic treatment but does not address the cause of the disease. Presently, there are no reports on experimental α-synuclein based therapy.
Polyglutamine
There are eight neurodegenerative disorders caused by expansion of a CAG trinucleotide repeat coding for polyglutamine (Kaytor and Warren, 1999). These diseases are Spinocerebellar Ataxia Type 1 (39-83 glutamine repeats), Type 3 (55-84 repeats), Type 6 (21-30 repeats), Type 7 (34 to over 200 repeats), Huntington's disease (HD; 38-180 repeats), Spinal and Bulbar Muscular Atrophy (38-65 repeats), and Dentatorubral-Pallidoluysian Atropy (49-88 repeats). Protein aggregates have been found in most of these diseases (Kaytor and Warren, 1999). Their common features are progressive neuronal loss and decline in motor and cognitive functions (Zoghbi and Orr, 2000). The mechanism of pathogenesis has not been elucidated but the polyglutamine repeats are important because longer repeats lead to earlier onset and more severe phenotype (Kaytor and Warren, 1999; Hughes and Olson, 2001).
Huntington's disease has been the most extensively investigated of these diseases. Nuclear inclusions of huntingtin are found both in neurons and in non-neuronal tissue outside the brain (Gutekunst et al., 1999). The striatum is predominantly affected in HD, although it contains far fewer protein aggregates than the cortex (Gutekunst et al., 1999), suggesting that some cell types are more vulnerable to the toxicity of the inclusions. There is a good correlation between the lengths of a truncated hutingtin protein and the size of the CAG repeat with the frequency and localization of aggregates (Rubinsztein et al., 1999). Huntingtin aggregation can be inhibited in vitro by antibodies and with compounds that bind to the β-sheet conformation of amyloid fibrils such as Congo red, thioflavin S, chrysamine G and Direct fast yellow (Heiser et al., 2000). Although HD is not considered an amyloid disease, these findings suggest that a similar therapy approach as is being developed for amyloid diseases may be effective for these diseases as well because the aggregates have a high β-sheet content. Other drug candidates include excitatory amino acid receptor antagonists, glutamate release inhibitors and mitochondrial agents (Hughes and Olson, 2001). Presently, no effective treatments have been developed for HD or the other polyglutamine diseases (Hughes and Olson, 2001).
In these diseases, the aggregates are found intra- and/or extracellularily. Antibody mediated clearance of extracellular Aβ deposits has already been observed by others and us. With regard to the intracellular deposits, there are several reports of cellular uptake of antibodies. It has been demonstrated that a monoclonal antibody markedly inhibits rabies virus RNA transcription following its cellular internalization (Dietzschold et al., 1992). Also, motor neurons of the CNS in rats that project outside the BBB seem capable of picking up IgG from serum by retrograde transport (Fabian and Petroff, 1987). Furthermore, extraction of IgG from the CSF by dendrites of Purkinje cells has been demonstrated both in the rat (Borges et al., 1985) and the guinea pig (Graus et al., 1991). In human necropsy studies normal IgG has been detected in large amounts in the cytoplasm of Purkinje cells (Fishman et al., 1990), and anti-neuronal antibodies have been found in the human dorsal root ganglia and Purkinje cells (Drlicek et al., 1992). Given these reports, the antibodies may gain access into affected cells where they may facilitate disassembly of the aggregates and/or prevent their formation.
Citation of any document herein is not intended as an admission that such document is pertinent prior art, or considered material to the patentability of any claim of the present application. Any statement as to content or a date of any document is based on the information available to applicant at the time of filing and does not constitute an admission as to the correctness of such a statement.

Synthetic immunogenic but non-deposit-forming polypeptides and peptides homologous to amyloid β, prion protein, amylin, α-synuclein, or polyglutamine repeats for induction of an immune response thereto


A method for streaming audio data in a network, the audio data having a sequence of samples, includes encoding the sequence of samples into a plurality of coded base bitstreams, generating a plurality of enhancement streams, and transmitting the coded base bitstreams and the enhancement bitstreams to a receiver for decoding. Each of the enhancement bitstreams is generated from one of a plurality of non-overlapping portions of the sequence of samples.

The recent advances in networking technologies and mobile devices is allowing more and more mobile users to receive multimedia contents over wireless networks. Real-time delivery of multimedia data is called streaming. Streaming, which is typically server-based, allows users to consume contents while they download them. Recently, peer-to-peer (P2P) streaming has become popular as a potentially cost-effective alternative to server-based streaming.
In P2P systems, peers not only consume media contents, but also contribute their uplink bandwidth and/or local storage. Thus the system can scale well as users bring resources to the system. Mobile devices often connect to the network via wireless channels. But, the downlink of the wireless channel (e.g., the cellular access network) tends to be limited in throughput. The wireless channel may also suffer from channel fading or unexpected interferences, which results in throughput fluctuation. Thus, it is desirable to adjust the bitrate of the audio stream over time to adapt to channel conditions. In addition, it is desirable to adapt the audio signal to individual mobile users depending on the requirements of applications and the hardware limitations of the mobile devices (e.g., low-end built-in speaker).
The change in the bitrate or in the quality of the audio signal can be achieved by transcoding. When a mobile device connects to a peer in the P2P system, the fixed peer transcodes the original audio signal according to the unique requirements of the mobile device, including its wireless channel condition and/or its multimedia capability. However, peers in the systems are unreliable because they can leave the system anytime. When peers leave the system without prior notice, mobile users connected to the departing peers may experience temporary disruption in downloading the audio and/or unwanted disconnection from a P2P system.

Method and system for distributed audio transcoding in peer-to-peer systems

The Board of Trustees of the Leland Stanford Junior University


An electrostatic liquid-ejection actuation mechanism includes a membrane, a frame, and one or more deformable beams. The frame has two sides and a number of cross members that are non-parallel to the two sides. The two sides and the cross members define one or more areas individually corresponding to one or more liquid chambers. The deformable beams are disposed between the membrane and the frame. The deformable beams individually correspond to the liquid chambers, and define a number of slits. Each slit is adjacent to one of the two sides of the frame. The deformable beams have a width that is less than a width of the liquid chambers, due at least to the slits.

Inkjet-printing devices, such as inkjet printers, are devices that are able to form images on sheets of media like paper by ejecting ink onto the media sheets. Drop-on-demand inkjet-printing devices primarily include actuation mechanisms based on heat generation, piezoelectric work, or electrostatic attraction. A thermal inkjet printing device ejects ink by heating the ink, which causes formation of a bubble within the ink and results in ink to be ejected. A piezoelectric inkjet printing device ejects ink by deforming a piezoelectric plate, which forces ink to be ejected. An electrostatic inkjet-printing device operates by deforming a membrane with an electrostatic charge between two electrodes. When the electrostatic charge is released, the membrane forcibly ejects ink from the device.

Electrostatic liquid-ejection actuation mechanism

Hewlett-Packard Development Company, L.P.


A bar code reading terminal includes a cordless optical reader. The optical reader includes a microprocessor, a scan engine coupled to the microprocessor, a hand held housing supporting the scan engine, program memory coupled to the microprocessor, a decode processor circuit coupled to the microprocessor, and a short-cycle energy storage device coupled to the microprocessor. The energy storage device has high power density and low energy density. In one embodiment, the short-cycle energy storage device comprises a power density greater than 1 kW/kg. The bar code reading terminal further includes a base unit having a housing that includes a socket for receiving the hand held housing. The socket has a connector to facilitate transfer of bar code data messages from the hand held optical reader to the base unit. The connector also transfer powers from the base unit to the short-cycle energy storage device.

In various commercial and industrial environments, the use of optical indicia, such as bar code symbols, has become the norm for identifying products and inventory. Typically, each item is marked with optical indicia associated with a description of the item and other attributes (for example, price) that are stored in a database of a host device or network system. Optical readers are used to read the optical indicia and provide that reading as input information to host devices. In some cases, the data is provided to the host devices via base units, which communicate with the optical reader. Examples of host devices include a computer (fixed or portable), a personal digital assistant (PDA), a portable data terminal (PDT), a point of sale (POS) terminal, a transaction terminal, cash register, or similar device. Checkout stations in retail settings typically employ stationary presentation-type optical readers, mobile hand held optical readers hardwired to a base unit, mobile wireless hand held optical readers that communicate wirelessly with a linked base unit, or some combination of the above to read optical indicia such as bar code symbols, or bar codes.
Stationary presentation-type optical readers, such as flat bed scanners, typically require a cashier to manually move an item bearing optical indicia into the field of view of the optical reader and orient the item such that the optical reader can scan the information and communicate this information to the cash register. While stationary presentation-type optical readers may be adequate for scanning encoded optical indicia on small items that are easily moved through their field of view by a cashier or other operator, these types of optical readers are not well suited for scanning large or heavy items that need to be repositioned by the cashier or customer so the scanner can read the optical indicia. This movement of large and/or heavy objects is inherently risky and undesirable. Furthermore, since stationary presentation-type optical readers require that the cashier position the item to be scanned somewhat precisely into the field of view of the optical reader so that the optical reader can scan the optical indicia, multiple attempts are often required to achieve a successful scan. This can lead to frustration by the cashier and customer and thus detract from customer satisfaction.
An advance upon the stationary presentation-type optical scanner is the use of a mobile hand held optical reader hardwired to a linked base unit. This configuration permits the cashier to manually move the hand held optical reader into position to scan an item's optical indicia, rather than having to move the item into the field of view of the optical reader as in the stationary presentation-type optical scanner. The scanned information from the optical indicia is then transmitted to the hand held optical reader's linked base unit via the hardwired connection between the two components. The base unit then communicates this information to the cash register. Alternatively, the hand held optical reader can be connected directly to the cash register. Unfortunately, this approach does not eliminate the problems associated with scanning items that are out of reach of the hardwired hand held optical reader and must be repositioned into the field of view of the optical reader so that the optical reader can scan the optical indicia. One approach to solve this access problem was to provide longer cords to the hardwired optical reader. However, the extra length must be stowed when not in use, which delays the time between scans, and may further detract from customer satisfaction.
In order to eliminate the limitations imposed by hardwiring the hand held optical reader to its base unit, another approach is the use of a wireless optical reader that can communicate wirelessly with its linked base unit. In this approach, the wireless hand held optical reader is held in a base unit or docking cradle until needed to read optical indicia that are out of the view of a stationary presentation-type optical reader. The wireless optical reader houses a battery to power the optical reader's internal electronics. The cashier can manually move the hand held optical reader into position to scan an item's optical indicia as long as the optical reader is within a distance where it can communicate wirelessly with its linked base unit. The scanned information is then transmitted to the hand held optical reader's linked base unit over the wireless connection. The base unit then communicates this bar code information to the cash register.
One noted problem with wireless mobile hand held optical readers that communicates wirelessly with its individual base unit is that the power requirements to transmit the data is substantial. Accordingly, the batteries in the hand held unit were large, heavy, and recharged very slowly. The batteries made the hand held optical reader difficult to wield, and caused wrist fatigue over the course of a working day.

Short-charge cordless scanner for retail terminals


A semiconductor structure that includes a semiconductor fin comprising an III-V compound semiconductor material. A functional gate structure straddles a portion of the semiconductor fin. A semiconductor channel material having an electron mobility greater than silicon and comprising a different semiconductor material than the semiconductor fin and is located beneath the functional gate structure. The semiconductor channel material is present on at least each vertical sidewall of the semiconductor fin. A dielectric spacer is located on each vertical sidewall surface of the functional gate structure. A doped semiconductor is located on each side of the functional gate structure and underneath each dielectric spacer. A portion of the doped semiconductor material located beneath each dielectric spacer directly contacts a sidewall surface of semiconductor channel material located on each vertical sidewall of the semiconductor fin.

The present application relates to a semiconductor structure and a method of forming the same. More particularly, the present application relates to a fin field effect transistor (finFET) containing an III-V compound semiconductor fin and an undercut extension region located beneath a dielectric spacer that is present on each vertical sidewall of a functional gate structure and a method of forming the same.
Throughout the evolution and advancement of semiconductor devices, reducing the size and power consumption of the devices, while maintaining or improving a high processing capacity have long been design goals. Planar field-effect transistor (FET) devices, which have been widely used in integrated circuits for the past several decades, have been found to be increasingly inefficient on the nanometer scale. Reducing the size of the channel between the terminals of planar transistors to this scale leads to an inefficient leakage of current in the off-state of the transistor, resulting in an increase in power consumption in its idle state.
Multi-gate field-effect transistors (MuGFET) have been developed to address this problem, as such transistors incorporate several gates that surround the channel between a source and drain terminal of the transistor on a plurality of surfaces, thereby enabling the suppression of leakage current in the off-state. There are several different types of multi-gate devices. FinFET and Trigate devices are two examples. FinFET devices include a thin fin, which can be made of silicon, that provides the channel between a source and a drain. The fin can be overlaid with one or more pairs of gates, where the gates in a pair are on opposing sides of the fin.

This patent is subject to a terminal disclaimer.

Overlapped III-V finFET with doped semiconductor extensions

International Business Machines Corporation


An insulating resin layer (30) is formed on a metal substrate (20), and a wiring is formed on the insulating resin layer (30). A circuit composed of a circuit element (50) and a passive element (60) is formed on the wiring (40), and the metal substrate (20) is covered with an over coat (80) and a sealing resin member (90). The insulating resin layer (30) is provided with an opening (31) so that a part of the metal substrate (20) is exposed therefrom. The exposed part of the metal substrate (20) is connected to one terminal of a capacitor (62) through a conductive wire (42), and the other terminal of the capacitor (62) is connected to the ground potential.

In recent years, the power module has been in growing demand for smaller size and better heat release in order to achieve improved space efficiency. Also, there has been demand for lower energy cost and reduced environmental load of the power module. Developed to meet these demands are intelligent power modules (IPMs), which are circuit devices having both a control unit and a power device mounted on a single metal substrate.
FIG. 11 is a cross-sectional view schematically illustrating a structure of a conventional circuit device. An insulating resin layer 510 is formed on a metal substrate 500 made of aluminum or the like. Wirings 520 made of copper, for instance, are formed on the insulating resin layer 510. Further, circuit elements 530, such as transistors and ICs, and passive elements 540, such as resistors and capacitors, are mounted on the wirings 520 through the medium of solder 551, thereby realizing a predetermined circuit. When the circuit elements 530 are to be mounted face-up, the electrodes of the circuit elements 530 are connected to the wirings 520 by wire bonding using gold wire 532. An external lead 550 is connected to an external electrode terminal 552 through the medium of solder 551, and a part of the external lead 550 is exposed outside from a sealing resin member 580 to be described later.
Note that the insulating resin layer 510 is provided with an opening which allows a part of the metal substrate 500 to be exposed. The exposed part of the metal substrate 500 is connected to a wiring 520a which is connected to ground potential. As a result, the metal substrate 500 functions as a shield even when the circuit elements 530 are in operation, so that malfunction of the circuit and occurrence of noise are being suppressed.
An overcoat 560 is formed to cover solder joints, gold wires 532, circuit elements 530, and passive elements 540.
The sealing resin member 580 includes a support 582 and a sealing resin layer 584. The support 582 and the sealing resin layer 584 are both made of a thermoplastic resin. The sealing resin 580 is formed by injection molding in which the metal substrate 500 placed on the support 582 is coated with the sealing resin layer 584. This produces a circuit device of a full-molded structure.
[Patent Document 1] Japanese Patent Application Publication No. 2005-277174.


Systems and methods for delivery of therapeutic and/or diagnostic compositions to an interventional site having diseased or newly treated tissue are provided. Integrated interventional catheter systems incorporating surfaces coated with a therapeutic composition, or tissue penetration members for scoring or disrupting tissue prior to or during administration of a therapeutic composition are provided. Infusion of therapeutic composition(s) may also be provided.

Angioplastic techniques for creating and enlarging openings in obstructed or partially obstructed blood vessels by inflating a balloon or another device at or near the site of an occlusion using an interventional catheter are well known and commonly employed. Material forming the obstruction is typically compressed during angioplasty as the vessel wall is stretched to enlarge the vessel lumen. An implantable device, such as a stent, may be placed at the site to maintain or improve vessel patency. Restenosis of vessels following angioplasty and stent placement procedures is common and may require additional interventions. Drug-eluting stents were developed to retard or reduce the incidence and severity of restenosis and have been effective in many circumstances.
Removal of diseased tissue, such as atherosclerotic plaque, thrombus and other types of obstructions and partial obstructions from internal body lumens or cavities is also a well-established interventional technique. Numerous interventional catheters have been conceived and developed. Most of these systems require placement of a guiding catheter and guide wire prior to introduction of the interventional catheter and placement of the interventional catheter near the target operating site. Advanceable, rotating operating heads have been used to cut and/or abrade and/or ablate obstructions. Plaque excision devices that incorporate cutting or scraping structures operating through a window or port, or having coring or helical screw structures that operate in a recessed opening, are also used. Aspirating catheters have been used to remove diffuse material, such as thrombus. Many of these prior art systems incorporate aspiration or mechanical withdrawal systems to remove the obstructive material from the site. Some systems incorporate or are used in conjunction with mechanisms such as distal filters for preventing obstructive material from circulating in the blood stream.
Other types of material removal systems, such as excimer lasers, high intensity focused ultrasound systems, RF systems, and the like have also been devised and used. Although mechanical devices such as cutter-based and mechanical removal devices and laser and ultrasound-based systems are effective in removing diseased tissue from and opening lumens through blood vessels, it is difficult to prevent restenosis of the vessel following material removal. Thus, despite the many and varied techniques used to prevent blood vessels from becoming occluded and the successful removal of material and placement of implantable devices such as stents, prevention of restenosis following the intervention remains problematic.
Many interventional devices have infusion systems that infuse liquids such as saline, imaging compositions, or therapeutic and/or diagnostic compositions to a site of intervention prior to or during operation of the device. Delivery of therapeutic and/or diagnostic compositions in solution using conventional infusion protocols generally isn't effective for treatment of tissue at interventional sites in blood vessels because the infusate is rapidly diluted and carried away in the bloodstream. For effective therapy or diagnosis, the composition must generally remain in contact with and have an opportunity to interact with the diseased or affected tissue. Delivery of therapeutic and diagnostic compositions to interventional sites in the blood stream thus remains challenging.
Many systems have been conceived and developed for delivery of therapeutic compositions to an interventional site. U.S. Patent Publication No. US 2005/0250672 describes a composition for restenosis prevention including an antihyperplastic composition. The composition may be applied to the outer surface of a catheter for delivery. U.S. Patent Publication No. US 2006/0020243 discloses balloon catheters coated with lipophilic drugs. U.S. Pat. No. 6,939,320 discloses a medical device including an expandable substrate, such as a balloon catheter, coated with a drug, and an expandable sheath positioned over the substrate, the expandable sheath having at least one perforation that is substantially closed when the substrate and the sheath are in a compressed state and substantially open when the substrate and sheath are expanded. The drug is thus able to pass through the sheath following expansion of the substrate and sheath.
U.S. Pat. No. 6,997,898 discloses a catheter provided with multiple inflatable balloons that, when inflated, create closed delivery pockets for delivery of compositions to a defined space. PCT International Publication No. WO 2005/055800 provides a method for exposing the luminal wall of a blood vessel to a substance by deploying a drug-eluting polymer film inside the lumen of the blood vessel during or following angioplasty.
U.S. Pat. No. 5,843,033 discloses an inflatable balloon catheter having a plurality of conduits in fluid communication with a plurality of apertures on the outer surface of the balloon, whereby medications are transferred from the conduits into a surrounding vessel following inflation of the balloon. U.S. Pat. No. 6,210,392 provides a device including an inflatable balloon mounted on a catheter, the balloon having a plurality of dispensers that extend outwardly from the balloon and are in fluid communication with a fluid source. Following delivery of the balloon to a treatment area in a vessel, the balloon is inflated to embed the dispensers in the vessel wall and fluid is introduced into the treatment area. U.S. Patent Publication No. US 2004/0098014 discloses a balloon angioplasty device having a plurality of cutting elements, such as microneedles, provided on the outer surface of the balloon. The microneedles enhance dilation of an artery and may be employed to deliver a drug to a cutting region.
U.S. Pat. No. 5,196,024 discloses a balloon catheter having cutting edges located parallel to the longitudinal axis of the balloon that make longitudinal cuts in a vessel wall. During delivery, the cutting edges are covered by folds of the deflated balloon, thereby minimizing injury to the vessel wall. U.S. Pat. No. 5,320,634 describes an angioplasty device comprising an inflatable balloon having a plurality of atherotomes mounted on its outer surface, the balloon being mounted on a catheter.

Delivery and administration of compositions using interventional catheters


Described are techniques for servicing data requests in a data storage system. One or more data requests from an application executing on the host are received. The data storage system allocates a first amount of resources for use in servicing data requests from the application. Behavior of the host is monitored for occurrences of I/O failure. In accordance with criteria and the occurrences of I/O failure, it is determined whether at least one of the host or the application is in a state of pending failure. If it is determined that at least one of the host or the application is in a state of pending failure, a second amount of resources larger than the first amount are allocated for a time period when servicing data requests from the application. After the time period, data requests from the application are serviced in accordance with the first amount of resources.

1. Technical Field
This application generally relates to servicing requests, and more particularly to techniques used in connection with prioritizing requests.
2. Description of Related Art
Computer systems may include different resources used by one or more host processors. Resources and host processors in a computer system may be interconnected by one or more communication connections. These resources may include, for example, data storage devices such as those included in the data storage systems manufactured by EMC Corporation. These data storage systems may be coupled to one or more host processors and provide storage services to each host processor. Multiple data storage systems from one or more different vendors may be connected and may provide common data storage for one or more host processors in a computer system.
A host processor may perform a variety of data processing tasks and operations using the data storage system. For example, a host processor may perform basic system I/O operations in connection with data requests, such as data read and write operations.
Host processor systems may store and retrieve data using a storage device containing a plurality of host interface units, disk drives, and disk interface units. Such storage devices are provided, for example, by EMC Corporation of Hopkinton, Mass. and disclosed in U.S. Pat. No. 5,206,939 to Yanai et al., U.S. Pat. No. 5,778,394 to Galtzur et al., U.S. Pat. No. 5,845,147 to Vishlitzky et al., and U.S. Pat. No. 5,857,208 to Ofek. The host systems access the storage device through a plurality of channels provided therewith. Host systems provide data and access control information through the channels to the storage device and storage device provides data to the host systems also through the channels. The host systems do not address the disk drives of the storage device directly, but rather, access what appears to the host systems as a plurality of logical disk units. The logical disk units may or may not correspond to the actual disk drives. Allowing multiple host systems to access the single storage device unit allows the host systems to share data stored therein.
In a computing environment, multiple storage devices, hosts, and perhaps other computing devices service requests that may be initiated from many independent other devices. For example, a number of independent hosts and other storage devices may request I/Os from a particular storage system. The data storage system may store the data from multiple applications executing on multiple hosts. The resource may service requests in accordance with an appropriate priority level or quality of service (QOS) selected for each of the different requesters. For example, the data storage system may service I/O requests from the different applications using different QOS levels. A QOS level may be associated with servicing an application's I/O requests in accordance with the particular priority objectives of the application.
One problem that may occur in connection with servicing requests is that the lower priority requests may not always be serviced within a reasonable or acceptable amount of time adversely affecting the requester. For example, an I/O request not serviced within a defined time period may cause the host and/or application to experience a timeout. The host may wait a defined amount of time for the I/O request to be serviced. If the I/O request is not serviced within the defined amount of time, the host may assume that the data storage system is unable to service the I/O request resulting in the timeout. Repeated occurrences of such timeouts may cause the requester, such as the application, to be unable to meet its performance objectives and may also have other adverse affects on the requester. For example, repeated I/O timeouts may cause the application and/or host to crash (e.g., taking the host and/or application offline and cease performing its operations.)

Techniques for adjusting priorities associated with servicing requests


A portable shelter comprises a pair of base members pivotally supporting a plurality of support arches spanning therebetween. Each support arch is hinged at an apex thereof to permit folding of the arch support in half for storage. The support arches are coupled to the base members for pivotal movement about respective pivot axes in which ends portions of the support arches are offset both axially and radially relative to the respective pivot axes from the other support arches to permit the support arches to be nested within one another flat against the ground prior to folding to enhance the compactness of the shelter in storage.

Various types of portable shelters are known in which the shelter is permitted to be collapsed for storage when not in use. Examples of portable shelters include U.S. Pat. No. 6,349,732 to Cooper, U.S. Pat. No. 4,116,206 to Warner et al., U.S. Pat. No. 5,746,237 to Arnic and U.S. Pat. No. 4,425,929 to Von Mosshaim. In each instance the shelter generally comprises a plurality of support arches which are pivotally coupled at opposing free ends thereof for relative pivotal movement between a collapsed position in which the support arches are all positioned adjacent one another and a domed structure in which the support arches are angularly offset from one another to form a dome structure with a suitable cover spanning the arches. Typical prior art shelters have limited collapsibility as the arches, even when positioned adjacent one another, are still sufficiently larger to fully span the width of the assembled shelter that the collapsed shelter remains cumbersome for storage.
U.S. Pat. No. 5,842,495 to Egnew et al. discloses a shelter including a plurality of support arches pivotal relative one another in which each arch is hinged at an apex thereof to permit the arches to be folded in half to further collapse the shelter for storage. The support arches are pivotally supported on respective base members in a manner so that when the support arches are pivoted against one another for collapsing, the apexes of the arches lie in a common plane which is perpendicular to the desired direction of folding. Awkward manipulation of the hinges is thus required as the outermost support arch when folding at the apex must stretch across the combined width of all of the arches stacked against one another. In addition to the awkward manipulation of the hinges, the stacked arrangement of the apexes still has considerable bulk.


In a battery-powdered system, a first integrated circuit provides a secondary power supply to a second integrated circuit, and also provides data signals in a serial protocol. The first integrated circuit steps down the secondary power supply when the reset-bar signal is being driven high. The second chip goes active whenever its reset-bar input exceeds its battery-voltage input.

The present invention relates to battery-powered systems or subsystems in which multiple integrated circuits must sustain data communications.
The power efficiency requirements of battery-powered modules can be extremely stringent. For best reliability, neither battery recharging nor user detection of imminent failure should be relied on. Therefore, to reliably meet the design battery lifetime of a module, extreme care must be taken to identify and control the worst-case battery-drain scenarios.
Battery lifetime management can be particularly difficult where several complex integrated circuits are included in a battery-powered module. Where significant control interactions, or even data exchange, may occur, the demands of such transactions must also be allowed for.
The present invention provides a battery-powered module architecture which is particularly advantageous where a serial data interface is used to link two (or more) integrated circuits within the module. Among the teachings of the present invention is a battery-powered system, where a first integrated circuit provides a secondary power supply to a second integrated circuit, and also provides data signals in a serial protocol. The first integrated circuit steps down the secondary power supply when the reset-bar signal is being driven high. The second chip goes active whenever its reset-bar input exceeds its battery-voltage input.
Preferably a scaled supply voltage output is provided by a data converter chip to downstream chips (including an access control chip, in the presently preferred embodiment). The access control chip (in the presently preferred embodiment) goes active whenever its RST* input exceeds its V.sub.BAT input. Since RST* can be driven only to the positive power supply level, the converter chip provides the access control with a reference voltage level which is lower than the power supply level. (However, to minimize power consumption, this reference voltage level is lowered only when necessary, i.e. when the RST* line is being driven high.) This reference voltage is connected to the V.sub.BAT input of the access control chip.
A further feature is that the switching transistors are arranged in a configuration such that two transistors would have to fail before the battery could receive uncontrolled charging current. This provides improved safety.

Power supply intercept with reference output


In an access management method in a network including at least one end system, a packet communication unit for routing, and an access management server including an authentication function, a communication partner is authenticated for each session and a communication permitted by a communication partner is permitted by the access management server. A packet meeting a condition of a denied packet being denied by the communication partner is discarded by the packet communication unit.

1. Field of the Invention
The present invention generally relates to access management methods and access management servers, and more particularly to an access management method in a network system including a packet communication apparatus for conducting a routing and an access management server having an authentication function, and the access management server.
2. Description of the Related Art
Recently, a personal computer has been widely used, and functions and performance of the personal computer and a network have been improved. In an organization, as a tool to smoothly operate a business, the network becomes more important and also important data are transmitted through the network. In order to secure the data, a security device such as a firewall system is provided against attacks of illegal access and viruses.
Japanese Laid-open Patent Application No. 2003-249944 discloses that an organization secures safety of a new base station arranged by a general user by conducting an authentication mutually between an authentication server and the new base station and the authentication is mutually conducted between the base station and a new radio terminal. In addition, Japanese Laid-open Patent Application No. 2003-249944 discloses that the base station first when the new radio terminal accesses and the base station does not transmit a packet being sent by the new radio terminal to a network at an organization side until the authentication succeeds mutually between the base station and the radio terminal, so as to prevent from a DoS (Denial of Service) attack which pretends an authentication.
Japanese Laid-open Patent Application No. 2003-8660 discloses that a permission list of IP addresses is provided to a router after a user is authenticated.
Recently, since it has been desired to provide means against problems such as a data leak, an attack by a virus to the network, various methods are proposed. However, those methods are not sufficient to solve the problems.
In the invention disclosed in Japanese Laid-open Patent No. 2003-8660, the permission list of IP addresses is provided to the router after the user is authenticated. Accordingly, the list of IP addresses is just one way of managing the list of IP addresses. In addition, since information showing a communication permission is set to an access management server and the information is just one way of managing the communication permission, it is impossible to manage the communication permission on a case-by-case basis in that one communication partner temporarily denies a communication with another communication partner or it is impossible to flexibly manage the communication permission in a case of determining a communication permission corresponding to a detail condition such a condition for each session. Since the communication permission cannot be dynamically managed, when a communication partner being regularly permitted infects with a virus and attacks to other communication partners, it is impossible to prevent from the attack. Moreover, when the number of terminals is increased, the list of IP addresses becomes greater and then performance of the router is degraded. Accordingly, it is difficult to realize a larger scale.
As the authentication for each session, a technology such as SSL (Secure Socket Layer) can be generally used. However, since this technology is used at an end system, it is impossible to prevent from an attack such as the attack by DoS passing through a regular procedure.
The above-described problems in a conventional system can be summarized as follows:    (1) Since only a member can-be authenticated, it is impossible to authenticate a user over a different network being managed by another manager.    (2) Since the communication permission is managed based on information showing the communication permission for each communication partner, which is fixed, it is impossible to prevent from an attack by a terminal when the terminal temporarily becomes an attacker.    (3) Even if a session authentication is conducted at the end system and a filter is provided, when the attack of DoS, the attack achieves the end system. Accordingly, it is not sufficient to prevent from the attack.

Access management method and access management server


The pre-polygon scanning path length of a raster output scanning system is reduced by replacing a required cylinder lens, or lenses, with two cylindrical mirrors. One mirror with a negative, concave surface and a second positive cylindrical mirror. The first mirror directs the light beam to the second mirror. The second mirror directs the light onto the facets of a rotating polygon to form a focused beam in the vertical axis of the polygon. The function of the two cylindrical mirrors is to act as a telephoto lens to properly focus the image of the laser at the polygon facet while reducing the total pre-polygon path length.

The present invention relates to a Raster Output Scanner (ROS) and, more particularly, to a ROS having a compact optical system design.
Printing systems utilizing lasers to reproduce information are well known in the art. Typically, such systems include a laser for generating a laser beam, a modulator, such as an acousto-optic modulator or laser diode driver electronics, for modulating the laser beam in accordance with input information to be reproduced, a multifaceted polygon scanner for scanning the modulated laser beam across a medium on a line to line basis, and various optical components to focus and align the laser beam at the medium.
In some printing systems it is required that a cylindrical lens be interposed between the modulated laser beam and the polygon scanner to shape the laser beam to optically correct for motor-polygon induced sagittal beam position errors, commonly referred to as wobble errors. The optical system disclosed in U.S. Pat. No. 3,750,189 illustrates the general utility of such a lens. The cylindrical lens is preferably aligned with the laser beam to redistribute the energy of the modulated laser beam in a manner whereby the energy distribution of the laser beam incident on the recording medium is substantially symmetrical about the start of scan and end of scan positions of the medium, and focused to a small spot. This is particularly important in those systems which utilize a xerographic recording medium.
A compact design for the scanning optics of these prior art type of ROS printers is desirable to make the machine itself as compact as possible and to enable extendability of the same ROS design into many machine architectures.
One well known technique is to introduce folding mirrors to fold the optical path and allow the optical components to be positioned in a more compact area. Another concept disclosed in U.S. Pat. No. 5,142,403, is to replace both a folding mirror and a cylindrical lens in the pre-polygon optics with a single cylindrical mirror. This technique has been found useful for ROS systems which utilize either an underfilled facet design; e.g. the light beam directed against the rotating polygon illuminates only a portion of each facet or in an overfilled facet design; e.g. the light beam directed against the rotating polygon completely illuminates each facet and a portion of adjacent facets. Each design, overfilled and underfilled, has advantages and disadvantages. One of the disadvantages of the overfilled design is that a longer pre-polygon optical path is required to properly image the larger spot at the overfilled facets. A cylindrical lens is required to focus the collimated beam on the facet in the cross scan plane; however, two cylinder lenses may be used in a telephoto configuration which allows for a more compact pre-polygon optical path length. U.S. Pat. No. 4,941,721 illustrates the use of two cylindrical lenses between the beam collimator and the polygon in an overfilled system. According to the present invention, the two cylinder lenses of the prior art are replaced by two cylindrical mirrors so as to approximate a telephoto lens. The first cylindrical mirror must be tilted at a small angle in either the cross scan direction (sagittal plane) or the fast scan direction (tangential plane) in order to eliminate locational interferences between the elements and the beam of light. The second cylindrical mirror may also be tilted the same amount in the opposite direction to aim the beam incident on the polygon facet to be parallel to the plane of the polygon disk. This tilt angle should not be large because abberations may be greater at larger angles. The smaller the mirror, the smaller the angle can be. This design, as will be seen, results in a shortening of the pre-polygon mechanical path length enabling a more compact design which requires no additional elements. Although, technically this idea would work in either an underfilled or an overfilled ROS system, the greatest benefit would result from an overfilled system where the pre-polygon path length is usually much longer than in an underfilled system. More particularly, the present invention relates to a raster output scanner (ROS) imaging system comprising:
a light source for generating a coherent collimated light beam output along an optical path, PA1 a photosensitive image plane, PA1 a rotatable multifaceted polygon interposed in the optical path between the light source and the photosensitive image plane for scanning light beams directed onto the facets of said polygon in a fast scan and slow scan direction across the photosensitive image plane, PA1 a post polygon optical system to focus reflected light beams from said polygon in said fast scan and slow scan directions, and
a pre-polygon optical system including a first cylindrical mirror positioned in the optical path between said light source and said polygon, said first cylindrical mirror reflecting light onto a second cylindrical mirror, the second cylindrical mirror reflecting the beams to said polygon, said first and second cylindrical mirrors creating a focused beam in the cross scan axis of the polygon while maintaining the collimation of the beam in the perpendicular or scanning axis.


The present disclosure describes techniques and apparatuses for clone-resistant logic. In some aspects, this clone-resistant logic enables computing-device manufacturers to better protect their devices against use of inauthentic accessories.

The background description provided herein is for the purpose of generally presenting the context of the disclosure. Unless otherwise indicated herein, the approaches described in this section are not prior art to the claims in the present disclosure and are not admitted to be prior art by inclusion in this section.
More and more, users wish to accessorize their computing devices. A user may wish to play music on his or her tablet computer using peripheral speakers or video on an auxiliary display. Manufacturers of these computing devices often wish to maintain the highest-quality experience for those using their devices by offering tested and proven accessories. In contrast, third parties may instead wish to sell accessories that the manufacturer has not tested or proven.
In an attempt to ensure that only tested and proven accessories are used by their computing devices, many manufacturers require their computing devices to authenticate accessories before use. Accessories can be authenticated through secure communication between the computing device and the accessory, generally using a secret stored on the accessory.
This secret, however, can be discovered by third parties. In some cases, for example, accessories include a chip that stores the secret in read-only memory within the chip. The chip uses this secret to establish secure communications to authenticate the accessory. A third party, however, may reverse engineer the chip, layer-by-layer, and, using sophisticated image-processing techniques, discover the secret within the read-only memory on the chip. With the secret, the third party can duplicate the functionality of the chip with an inauthentic chip, also called a "clone." This clone can then be used to fool the computing device into authorizing use of inauthentic accessories.


A glove box assembly incorporated into a vehicle instrument panel, along which extends a reinforcing bar. The assembly includes a three-dimensional and interiorly open receptacle fixedly mounted within the instrument panel. The receptacle includes one or more integrally formed structural projections extending from a rear side thereof and in a direction towards the reinforcing bar, typically spaced a slight distance from the receptacle structure. A bin secures within the glove box receptacle and includes a door exposed to adjoining surfaces of the instrument panel. Upon experiencing a collision event resulting in a passenger's knees impacting the door, inward deformation of the receptacle transfers forces both to the instrument panel and through deforming the reinforcing bar.

1. Field of the Invention
The present invention relates generally to a passenger side located glove box assembly exhibiting specific impact deforming and force transferring properties. More specifically, the present invention discloses a glove box assembly including a three-dimensional recessed component mounted within the vehicle dash/instrument panel assembly.
Upon experiencing forward directed forces, associated with the passenger's knees impacting a door of the glove box, these forces are initially transferred to the surrounding and supporting instrument panel structure. Additional forwardly directed impact forces are transferred from extending structural portions associated with the glove box inner receptacle, upon the same being forwardly deformed into abutting contact with the vehicle's laterally extending structural reinforcing bar.
In this manner, the structural projections associated with the glove box's fixed inner receptacle serve to transfer significant load during a crash situation to non-critical vehicle locations supporting the reinforcing bar, such as the doors, steering column support and the like. A further advantage of this design is that it provides balance between the counter-forces exerted by a passenger actuating airbag (upper torso forces) and those responsible for the controlled deformation and lower collapse of the glove box door and inner assembly (lower body forces).
2. Description of the Prior Art
The prior art is well documented with various occupant knee impact assemblies, these typically associated with a passenger side of a vehicle and calculated to transfer lower body forces associated with a frontal impact event. The objective of such designs is to transfer as much force as possible away from the occupant to the vehicle, in as controlled a fashion as possible and in order to minimize injury.
Conventional bracket structures have been utilized in an attempt to transfer impact forces from the glove box assembly to the IP/dash structure and associated crosswise extending reinforcing bar. Such have included striker brackets and other connecting flange assemblies, the shortcomings of which include the requirement of installing additional hardware as well as the unsatisfactory force deformation and redirection results associated with such designs.
Another example selected from the prior art is disclosed in U.S. Patent Application Publication No. 2004/0124623, to Yamazaki, and which teaches an occupant protection apparatus exhibiting a panel constituting part of a passenger compartment side of an instrument panel, and which is separatable from the IP (instrument panel). The panel is constructed to move (deform) when at least a knee load of an occupant is inputted.
A pair of bracket shaped support members extend in inwardly spaced apart arrangement and between transverse end portions of the panel and a crosswise extending reinforcement. The support members exhibit a rigidity greater than that of the panel and, upon experiencing forward forces associated with a frontal impact, provide additional controlled deformation following inward collapse of the panel, and relative to the rigid extending reinforcing support.
A further example from the prior art is disclosed in U.S. Pat. No. 6,783,156, issued to Chickmenahalli et al., and which teaches a passenger restraint including a knee bolster having receptacles for receiving knee blockers. The knee blockers are multi-celled elements which absorb kinetic energy attributed to collisions of a motor vehicle.
U.S. Pat. No. 5,431,442, issued to Tomita et al., teaches a passenger restraint structure for an automotive vehicle which has a glove box in which at least one face is able to be opened to a passenger compartment and which is attached to an instrument panel so as to be opposed to the knees of a passenger. The glove box includes an intermediate wall connecting a front wall and a rear wall of the glove box. A stiffener member is located between the glove box and a part of a vehicle body and is stiffer than the glove box for absorbing crash energy generated between the passenger and the vehicle body in the running direction of the vehicle. Upon impact, the weaker intermediate wall of the glove box is compressed, deformed and broken, thereby absorbing the crash energy.
U.S. Pat. No. 4,662,649, issued to Ikeda et al., teaches a knee protector in an automobile and which includes an instrument panel arranged in front of a seat within a passenger compartment of the automobile and exiting widthwise of the automobile. The IP includes an opening defined therein, a lid similar in shape to the contour of the opening is supported by the instrument panel for selective closing and opening. A first protector member is provided inside the lid, a pair of pin members being spaced a distance from each other in a direction widthwise of the automobile and secured to the first protector member so as to protrude in a direction close towards the instrument panel. A second protector member is provided inside the instrument panel and includes separate engagement regions defined therein for engagement with the respective pin members when a load acting in a direction frontwardly of the automobile acts on the lid.
Finally, U.S. Pat. No. 5,071,162, issued to Takagawa, teaches a knee bolster including a lid for covering the surface of a glove box mounted in an opening made in a surface of an instrument panel opposed to a passenger's knees and which includes a plate-like shock absorbing member mounted thereon. A reinforcing plate is disposed along the peripheral edge of the opening and opposed to an outer edge of the back of the shock absorbing member. A load bearing member is fixed at one end thereof to a vehicle body and opposed at the other end to the back of the reinforcing plate.

Glove box assembly exhibiting knee impact force transferring structure with respect to an associated vehicle dash/instrument panel and reinforcing bar

Toyota Motor Engineering & Manufacturing North America, Inc.