Polymorphism in sexual versus non-sexual disease transmission

Pathogens causing sexually transmitted diseases (STDs) often consist of related strains that cause non-sexually transmitted, or ''ordinary infectious'', diseases (OIDs). We use differential equation models of single populations to derive conditions under which a genetic variant with one (e.g. sexual) transmission mode can invade and successfully displace a genetic variant with a different (e.g. non-sexual) transmission mode. Invasion by an STD is easier if the equilibrium population size in the presence of an OID is smaller; conversely an OID can invade more easily if the equilibrium size of the population with the STD is larger. Invasion of an STD does not depend on the degree of sterility caused by the infection, but does depend on the added mortality caused by a resident OID. In contrast, the ability of an OID to invade a population at equilibrium with an STD decreases as the degree of sterility caused by the STD increases. When equilibrium population sizes for a population infected with an STD are above the point at which non-sexual contacts exceed sexual contacts (the sexual–social crossover point) and when equilibrium population sizes for an OID are below this point, there can be a stable genetic polymorphism for transmission mode. This is most likely when the STD is mildly sterilizing, and the OID causes low or intermediate levels of added mortality. Because we assume the strains are competitively equivalent and there are no heterogeneities associated with the transmission process, the polymorphism is maintained by density-dependent selection brought about by pathogen effects on population size.     

载脂蛋白E研究进展

载脂蛋白E在脂质代谢中发挥重要作用 ,三种亚型 (apoE2 ,apoE3和apoE4 )只有二个部位的氨基酸发生变化 ,呈现出不同的生理作用。apoE4与老年痴呆、心血管疾病的高发性相关 ,而且对各种脑外伤功能的恢复具有负面影响。apoE2则对老年痴呆具有防护作用 ,并与高脂蛋白血症有关。apoE3对机体正常生理功能的发挥起关键作用。体外及动物实验研究表明 ,血浆中的apoE多态性与人体的冠心病、高脂蛋白血症、动脉粥样硬化相关。而脑中的apoE是一种多功能分子 ,在淀粉样蛋白沉积与清除、稳定微管蛋白结构、细胞内信号传导等细胞过程中发挥重要作用 ,其多态性与老年痴呆相关。因此 ,从分子水平研究其结构与功能之间的构效关系 ,对探索相关疾病的发病机制、诊断及治疗具有重要意义。     

Neurodegenerative disease-specific induced pluripotent stem cell research

Neurodegenerative disease-specific induced pluripotent stem cell (iPSC) research contributes to the following 3 areas; “Disease modeling”, “Disease material” and “Disease therapy”.“Disease modeling”, by recapitulating the disease phenotype in vitro, will reveal the pathomechanisms. Neurodegenerative disease-specific iPSC-derived non-neuronal cells harboring disease-causative protein(s), which play critical roles in neurodegeneration including motor neuron degeneration in amyotrophic lateral sclerosis, could be “Disease material”, the target cell(s) for drug screening. These differentiated cells also could be used for “Disease therapy”, an autologous cellular replacement/neuroprotection strategy, for patients with neurodegenerative disease.Further progress in these areas of research can be made for currently incurable neurodegenerative diseases.     

Indices of Disease Severity in Diseases that Cause Abscesses in Target Organs

Some animal diseases cause variable numbers of abscesses of varying severity in target organs. In assessing the efficacy of vaccines developed to combat these diseases it is necessary to devise indices of disease severity that incorporate the number of abscesses in an animal and the severity scores of the abscesses. Three indices are defined and their relative merits are discussed. Some of the distributional properties of the indices are examined and their relevance to statistical analyses are discussed.     

Compensatory up-regulation of behavioral disease avoidance in immuno-compromised people with rheumatoid arthritis

Disgust and disease-related cues can activate the immune system. Here, we test whether immuno-suppression is associated with an up-regulation of cognitions and behaviors that assist in disease avoidance. People with rheumatoid arthritis (RA), who have a heightened risk of infection-related morbidity and mortality, were compared to age, gender and demographically matched healthy controls on a range of disease avoidance tasks. People with RA scored higher on reports of behavior likely to control infection, were more accurate in spotting individuals who were sick, and showed disease-specific ethnocentrism, ascribing a greater risk of contracting disease to non-Caucasians, although having no overall propensity for greater racism on the Modern Racism Scale. Contrary to predictions, disgust sensitivity (DS) did not differ between groups, however among people with RA, DS was found to be lower in those taking drugs that can increase infection risk. While more explicit disease avoidance behaviors are clearly up-regulated in people with RA, changes in DS may have a different and perhaps more biological casual basis.     

Applications of patient-specific induced pluripotent stem cells; focused on disease modeling, drug screening and therapeutic potentials for liver disease

The recent advances in the induced pluripotent stem cell (iPSC) research have significantly changed our perspectives on regenerative medicine by providing researchers with a unique tool to derive disease-specific stem cells for study. In this review, we describe the human iPSC generation from developmentally diverse origins (i.e. endoderm-, mesoderm-, and ectoderm- tissue derived human iPSCs) and multistage hepatic differentiation protocols, and discuss both basic and clinical applications of these cells including disease modeling, drug toxicity screening/drug discovery, gene therapy and cell replacement therapy.     

Periodontal defects of pulpal origin: evidence in early man

False assumptions have led to the widespread opinion that periodontitis of gingival origin is a ubiquitous disease and a common cause of tooth loss among ancient populations. Evaluation of dry skulls reveals that horizontal loss of crestal alveolar bone was unusual and of minor severity. Localized vertical bone defects of pulpal etiology were common and severe, often resulting in tooth mortality. The present paper identifies a number of factors that have contributed to the development of some important misconceptions about the nature of periodontal disease, its incidence, and its etiology.     

Amyloid-β Peptide-specific DARPins as a Novel Class of Potential Therapeutics for Alzheimer Disease

Passive immunization with anti-amyloid-β peptide (Aβ) antibodies is effective in animal models of Alzheimer disease. With the advent of efficient in vitro selection technologies, the novel class of designed ankyrin repeat proteins (DARPins) presents an attractive alternative to the immunoglobulin scaffold. DARPins are small and highly stable proteins with a compact modular architecture ideal for high affinity protein-protein interactions. In this report, we describe the selection, binding profile, and epitope analysis of Aβ-specific DARPins. We further showed their ability to delay Aβ aggregation and prevent Aβ-mediated neurotoxicity in vitro. To demonstrate their therapeutic potential in vivo, mono- and trivalent Aβ-specific DARPins (D23 and 3×D23) were infused intracerebroventricularly into the brains of 11-month-old Tg2576 mice over 4 weeks. Both D23 and 3×D23 treatments were shown to result in improved cognitive performance and reduced soluble Aβ levels. These findings demonstrate the therapeutic potential of Aβ-specific DARPins for the treatment of Alzheimer disease.     

Application of Statistical Classification Technique to the Forecasting of Outcomes of Diseases

A probabilistic statistical model based on statistical classification is proposed for disease outcome forecasting. In particular, cardiac infarction outcome is forecasted and a table of the forecasting results is given. A conclusion of theoretical character is made about the preferable use of a non-uniform band width in the construction of a general histogram for unknown distribution density estimation.     

Corruption and Spread of Pathogenic Proteins in Neurodegenerative Diseases

With advancing age, the brain becomes increasingly susceptible to neurodegenerative diseases, most of which are characterized by the misfolding and errant aggregation of certain proteins. The induction of aggregation involves a crystallization-like seeding mechanism by which a specific protein is structurally corrupted by its misfolded conformer. The latest research indicates that, once formed, proteopathic seeds can spread from one locale to another via cellular uptake, transport, and release. Impeding this process could represent a unified therapeutic strategy for slowing the progression of a wide range of currently intractable disorders.     

Map-based cloning of the tomato genomic region that spans the Sw-5 tospovirus resistance gene in tomato

Two yeast artificial chromosomes (YACs) containing genomic DNA from tomato have been isolated using CT220, an RFLP marker which is tightly linked to the tomato spotted wilt virus resistance gene, Sw-5. High-resolution mapping of the YAC ends and internal YAC probes demonstrated that one of the YAC clones, TY257 (400 kb), spans Sw-5. By chromosome walking in a cosmid library, the position of Sw-5 has been delimited within the YAC to a maximal chromosomal segment of 100 kb, spanned by nine overlapping cosmid clones. Received: 13 March 1997 / Accepted: 11 may 1997     

Interaction with Polyglutamine Aggregates Reveals a Q/N-rich Domain in TDP-43

The identification of pathologic TDP-43 aggregates in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, followed by the discovery of dominantly inherited point mutations in TDP-43 in familial ALS, have been critical insights into the mechanism of these untreatable neurodegenerative diseases. However, the biochemical basis of TDP-43 aggregation and the mechanism of how mutations in TDP-43 lead to disease remain enigmatic. In efforts to understand how TDP-43 alters its cellular localization in response to proteotoxic stress, we found that TDP-43 is sequestered into polyglutamine aggregates. Furthermore, we found that binding to polyglutamine aggregates requires a previously uncharacterized glutamine/asparagine (Q/N)-rich region in the C-terminal domain of TDP-43. Sequestration into polyglutamine aggregates causes TDP-43 to be cleared from the nucleus and become detergent-insoluble. Finally, we observed that sequestration into polyglutamine aggregates led to loss of TDP-43-mediated splicing in the nucleus and that polyglutamine toxicity could be partially rescued by increasing expression of TDP-43. These data indicate pathologic sequestration into polyglutamine aggregates, and loss of nuclear TDP-43 function may play an unexpected role in polyglutamine disease pathogenesis. Furthermore, as Q/N domains have a strong tendency to self-aggregate and in some cases can function as prions, the identification of a Q/N domain in TDP-43 has important implications for the mechanism of pathologic aggregation of TDP-43 in ALS and other neurodegenerative diseases.     

Microtubule affinity-regulating kinase 2 (MARK2) turns on phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) at Thr-313, a mutation site in Parkinson disease: effects on mitochondrial transport

The kinase MARK2/Par-1 plays key roles in several cell processes, including neurodegeneration such as Alzheimer disease by phosphorylating tau and detaching it from microtubules. In search of interaction partners of MARK2, we identified phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1), which is important for the survival of neurons and whose mutations are linked to familial Parkinson disease (PD). MARK2 phosphorylated and activated the cleaved form of PINK1 (ΔN-PINK1; amino acids 156-581). Thr-313 was the primary phosphorylation site, a residue mutated to a non-phosphorylatable form (T313M) in a frequent variant of PD. Mutation of Thr-313 to Met or Glu in PINK1 showed toxic effects with abnormal mitochondrial distribution in neurons. MARK2 and PINK1 were found to colocalize with mitochondria and regulate their transport. ΔN-PINK1 promoted anterograde transport and increased the fraction of stationary mitochondria, whereas full-length PINK1 promoted retrograde transport. In both cases, MARK2 enhanced the effects. The results identify MARK2 as an upstream regulator of PINK1 and ΔN-PINK1 and provide insights into the regulation of mitochondrial trafficking in neurons and neurodegeneration in PD.     

Prions and Prion-like Proteins

Prions are self-replicating protein aggregates and are the primary causative factor in a number of neurological diseases in mammals. The prion protein (PrP) undergoes a conformational transformation leading to aggregation into an infectious cellular pathogen. Prion-like protein spreading and transmission of aggregates between cells have also been demonstrated for other proteins associated with Alzheimer disease and Parkinson disease. This protein-only phenomenon may therefore have broader implications in neurodegenerative disorders. The minireviews in this thematic series highlight the recent advances in prion biology and the roles these unique proteins play in disease.     

Reproduction numbers and sub-threshold endemic equilibria for compartmental models of disease transmission

A precise definition of the basic reproduction number, , is presented for a general compartmental disease transmission model based on a system of ordinary differential equations. It is shown that, if , then the disease free equilibrium is locally asymptotically stable; whereas if , then it is unstable. Thus, is a threshold parameter for the model. An analysis of the local centre manifold yields a simple criterion for the existence and stability of super- and sub-threshold endemic equilibria for near one. This criterion, together with the definition of , is illustrated by treatment, multigroup, staged progression, multistrain and vector–host models and can be applied to more complex models. The results are significant for disease control.     

Tumor necrosis factor receptor-associated factor 6 (TRAF6) associates with huntingtin protein and promotes its atypical ubiquitination to enhance aggregate formation

Huntington disease (HD) is a neurodegenerative disorder caused by an expansion of polyglutamines in the first exon of huntingtin (HTT), which confers aggregation-promoting properties to amino-terminal fragments of the protein (N-HTT). Mutant N-HTT aggregates are enriched for ubiquitin and contain ubiquitin E3 ligases, thus suggesting a role for ubiquitination in aggregate formation. Here, we report that tumor necrosis factor receptor-associated factor 6 (TRAF6) binds to WT and polyQ-expanded N-HTT in vitro as well as to endogenous full-length proteins in mouse and human brain in vivo. Endogenous TRAF6 is recruited to cellular inclusions formed by mutant N-HTT. Transient overexpression of TRAF6 promotes WT and mutant N-HTT atypical ubiquitination with Lys(6), Lys(27), and Lys(29) linkage formation. Both interaction and ubiquitination seem to be independent from polyQ length. In cultured cells, TRAF6 enhances mutant N-HTT aggregate formation, whereas it has no effect on WT N-HTT protein localization. Mutant N-HTT inclusions are enriched for ubiquitin staining only when TRAF6 and Lys(6), Lys(27), and Lys(29) ubiquitin mutants are expressed. Finally, we show that TRAF6 is up-regulated in post-mortem brains from HD patients where it is found in the insoluble fraction. These results suggest that TRAF6 atypical ubiquitination warrants investigation in HD pathogenesis.     

Focus: Allergic Diseases and Type II Immunity: Amlexanox: A Novel Therapeutic for Atopic,Metabolic, and Inflammatory Disease

Amlexanox, a small molecule targeted therapy which has been used in the treatment of atopic conditions was previously but is not currently available in the United States. Amlexanox has also been legally utilized and administered in Japan as a treatment for asthma, a chronic pulmonary disease characterized by inflammation of the lower respiratory tract. Amlexanox’s immune modulatory effects have been the subject of studies which have repurposed the drug for potential therapeutic applications in metabolic and inflammatory disease. Because amlexanox inhibits TANK-binding kinase1 (TBK1) and nuclear factor kB kinase epsilon (IKKε), several studies have demonstrated its usefulness through its evidence downregulation of the immune system and attenuation of downstream TBK1 signaling. Novel therapies, such as amlexanox, for inflammatory conditions such as asthma will continue to be of value in clinical management. This report summarizes key applications of the drug based on animal and human studies and explores its potential in treatment of metabolic and inflammatory diseases.     

Seeded Aggregation and Toxicity of α-Synuclein and Tau: CELLULAR MODELS OF NEURODEGENERATIVE DISEASES*

The deposition of amyloid-like filaments in the brain is the central event in the pathogenesis of neurodegenerative diseases. Here we report cellular models of intracytoplasmic inclusions of α-synuclein, generated by introducing nucleation seeds into SH-SY5Y cells with a transfection reagent. Upon introduction of preformed seeds into cells overexpressing α-synuclein, abundant, highly filamentous α-synuclein-positive inclusions, which are extensively phosphorylated and ubiquitinated and partially thioflavin-positive, were formed within the cells. SH-SY5Y cells that formed such inclusions underwent cell death, which was blocked by small molecular compounds that inhibit β-sheet formation. Similar seed-dependent aggregation was observed in cells expressing four-repeat Tau by introducing four-repeat Tau fibrils but not three-repeat Tau fibrils or α-synuclein fibrils. No aggregate formation was observed in cells overexpressing three-repeat Tau upon treatment with four-repeat Tau fibrils. Our cellular models thus provide evidence of nucleation-dependent and protein-specific polymerization of intracellular amyloid-like proteins in cultured cells.     

Conophylline Protects Cells in Cellular Models of Neurodegenerative Diseases by Inducing Mammalian Target of Rapamycin (mTOR)-independent Autophagy

Macroautophagy is a cellular response that leads to the bulk, nonspecific degradation of cytosolic components, including organelles. In recent years, it has been recognized that autophagy is essential for prevention of neurodegenerative diseases, including Parkinson disease (PD) and Huntington disease (HD). Here, we show that conophylline (CNP), a vinca alkaloid, induces autophagy in an mammalian target of rapamycin-independent manner. Using a cellular model of PD, CNP suppressed protein aggregation and protected cells from cell death caused by treatment with 1-methyl-4-phenylpyridinium, a neurotoxin, by inducing autophagy. Moreover, in the HD model, CNP also eliminated mutant huntingtin aggregates. Our findings demonstrate the possible use of CNP as a therapeutic drug for neurodegenerative disorders, including PD and HD.