A quantitative model of technology transfer and technological "catch-up"

"#2379"--handwritten on coverIncludes bibliographical reference

Evaluation of the Multiplane Method for Efficient Simulations of Reaction Networks

Reaction networks in the bulk and on surfaces are widespread in physical, chemical and biological systems. In macroscopic systems, which include large populations of reactive species, stochastic fluctuations are negligible and the reaction rates can be evaluated using rate equations. However, many physical systems are partitioned into microscopic domains, where the number of molecules in each domain is small and fluctuations are strong. Under these conditions, the simulation of reaction networks requires stochastic methods such as direct integration of the master equation. However, direct integration of the master equation is infeasible for complex networks, because the number of equations proliferates as the number of reactive species increases. Recently, the multiplane method, which provides a dramatic reduction in the number of equations, was introduced [A. Lipshtat and O. Biham, Phys. Rev. Lett. 93, 170601 (2004)]. The reduction is achieved by breaking the network into a set of maximal fully connected sub-networks (maximal cliques). Lower-dimensional master equations are constructed for the marginal probability distributions associated with the cliques, with suitable couplings between them. In this paper we test the multiplane method and examine its applicability. We show that the method is accurate in the limit of small domains, where fluctuations are strong. It thus provides an efficient framework for the stochastic simulation of complex reaction networks with strong fluctuations, for which rate equations fail and direct integration of the master equation is infeasible. The method also applies in the case of large domains, where it converges to the rate equation results

The Effect of Gentamicin-Induced Readthrough on a Novel Premature Termination Codon of CD18 Leukocyte Adhesion Deficiency Patients

Leukocyte adhesion deficiency 1 (LAD1) is an inherited disorder of neutrophil function. Nonsense mutations in the affected CD18 (ITB2) gene have rarely been described. In other genes containing such mutations, treatments with aminoglycoside types of antibiotics (e.g., gentamicin) were reported to partially correct the premature protein termination, by induction of readthrough mechanism.Genetic analysis was performed on 2 LAD1 patients. Expression, functional and immunofluorescence assays of CD18 in the patients were used to determine the in-vivo and in-vitro effects of gentamicin-induced readthrough. A theoretical modeling of the corrected CD18 protein was developed to predict the protein function.We found a novel premature termination codon, C562T (R188X), in exon 6 of the CD18 gene that caused a severe LAD1 phenotype in two unrelated Palestinian children. In-vivo studies on these patients' cells after gentamicin treatment showed abnormal adhesion and chemotactic functions, while in-vitro studies showed mislocalization of the corrected protein to the cytoplasm and not to the cell surface. A theoretical modeling of the corrected CD18 protein suggested that the replacement of the wild type arginine by gentamicin induced tryptophan at the position of the nonsense mutation, although enabled the expression of the entire CD18 protein, this was not sufficient to stabilize the CD18/11 heterodimer at the cell surface.A novel nonsense mutation in the CD18 gene causing a complete absence of CD18 protein and severe LAD1 clinical phenotype is reported. Both in vivo and in vitro treatments with gentamicin resulted in the expression of a corrected full-length dysfunctional or mislocalized CD18 protein. However, while the use of gentamicin increased the expression of CD18, it did not improve leukocyte adhesion and chemotaxis. Moreover, the integrity of the CD18/CD11 complex at the cell surface was impaired, due to abnormal CD18 protein and possibly lack of CD11a expression

Dysregulation of neuronal iron homeostasis as an alternative unifying effect of mutations causing familial Alzheimer's disease

The overwhelming majority of dominant mutations causing early onset familial Alzheimer's disease (EOfAD) occur in only three genes, PSEN1, PSEN2, and APP. An effect-in-common of these mutations is alteration of production of the APP-derived peptide, amyloid ß (Aß). It is this key fact that underlies the authority of the Amyloid Hypothesis that has informed Alzheimer's disease research for over two decades. Any challenge to this authority must offer an alternative explanation for the relationship between the PSEN genes and APP. In this paper, we explore one possible alternative relationship - the dysregulation of cellular iron homeostasis as a common effect of EOfAD mutations in these genes. This idea is attractive since it provides clear connections between EOfAD mutations and major characteristics of Alzheimer's disease such as dysfunctional mitochondria, vascular risk factors/hypoxia, energy metabolism, and inflammation. We combine our ideas with observations by others to describe a "Stress Threshold Change of State" model of Alzheimer's disease that may begin to explain the existence of both EOfAD and late onset sporadic (LOsAD) forms of the disease. Directing research to investigate the role of dysregulation of iron homeostasis in EOfAD may be a profitable way forward in our struggle to understand this form of dementia

Digital Diabetes Care System Observations from a Pilot Evaluation Study in Vietnam

Digital technologies are gaining an important role in the management of patients with diabetes. We assessed clinical outcomes and user satisfaction of incorporating a digital diabetes care system in diabetes clinics of a developing country. The system integrated a wireless blood glucose monitor that communicates data to any smartphone utilizing a patented acoustic data transfer method, a mobile-app, and cloud-based software that stores, analyzes, and presents data. Five hospital endocrinology clinics in Vietnam sequentially recruited all patients willing to join the study, providing they had a smartphone and access to internet connectivity. Face-to-face visits were conducted at baseline and at 12 weeks, with monthly digital visits scheduled in the interim and additional digital visits performed as needed. HbA1c levels were measured at baseline and at 12 weeks (±20 days). The study included 300 patients of whom 279 completed the evaluation. Average glucose levels declined from 170.4 ± 64.6 mg/dL in the first 2 weeks to 150.8 ± 53.2 mg/dL in the last 2 weeks (n = 221; p < 0.001). HbA1c levels at baseline and 12 weeks declined from 8.3% ± 1.9% to 7.6% ± 1.3% (n = 126; p < 0.001). The digital solution was broadly accepted by both patients and healthcare professionals and improved glycemic outcomes. The durability, scalability, and cost-effectiveness of this approach merits further study

Analysis of Chronic Granulomatous Disease in the Kavkazi Population in Israel Reveals Phenotypic Heterogeneity in Patients with the Same NCF1 mutation (c.579G>A)

Chronic granulomatous disease (CGD) is an innate immune deficiency disorder of phagocytes, resulting from mutations in the components of the NADPH oxidase complex that impair the synthesis of oxygen radicals, thus rendering patients susceptible to recurrent infections and excessive hyperinflammatory responses. The most common autosomal recessive form of CGD is p47phox deficiency, which is often clinically milder than the more common X-linked recessive form. Here, we report data on genetics, clinical and biochemical findings in 17 CGD patients of Kavkazi origin with the nonsense mutation c.579G>A in the NCF1 gene, leading to p47phox deficiency. Diagnosis was based on detailed clinical evaluation, respiratory burst activity by cytochrome c reduction and dihydrorhodamine-1,2,3 (DHR) assay by flow cytometry, expression of p47phox by immunoblotting and molecular confirmation by DNA sequence analysis. Twelve male and five female patients with median age at onset of 2.5 years (range 1 day to 9 years) were included in the study. The present cohort displays an encouraging 88% overall long-term survival, with median follow-up of 17 years. Clinical manifestations varied from mild to severe expression of the disease. Correlation between genotype and phenotype is unpredictable, although the Kavkazi patients were more severely affected than other patients with p47phox deficiency. Kavkazi CGD patients harbor a common genetic mutation that is associated with a heterogeneous clinical phenotype. Early diagnosis and proper clinical management in an experienced phagocytic leukocyte center is imperative to ensure favorable patient outcome. New treatment strategies are ongoing, but results are not yet conclusiv

A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease

Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices shows DAM with intracellular/phagocytic Aβ particles. Single-cell analysis of DAM in Tg-AD and triggering receptor expressed on myeloid cells 2 (Trem2)-/- Tg-AD reveals that the DAM program is activated in a two-step process. Activation is initiated in a Trem2-independent manner that involves downregulation of microglia checkpoints, followed by activation of a Trem2-dependent program. This unique microglia-type has the potential to restrict neurodegeneration, which may have important implications for future treatment of AD and other neurodegenerative diseases. Video Abstract: Display Omitted. A new type of microglia associated with restricting neurodegeneration may have important implications for treatment of Alzheimer's and related diseases

Psychosocial, clinical and demographic features related to worry in patients with melanoma

The aim of this study was to investigate clinical, demographic and psychosocial predictors of melanoma-related worry. A questionnaire-based study in a population-ascertained cohort of individuals diagnosed with melanoma in the previous 3-6 months was carried out to identify factors associated with worry about melanoma shortly after diagnosis. A total of 520 patients felt worried about their future with respect to melanoma and 1568 patients felt confident about their future with respect to melanoma. Worry was less likely in men with partners than women with partners [adjusted odds ratio (OR)=0.51, 95% confidence interval (CI) (0.39-0.67)], and increasing age was protective against worry [adjusted OR=0.96 per year, 95% CI (0.95-0.97)]. Worry was more likely for patients with stage III/IV melanoma [adjusted OR=1.90, 95% CI (1.41-2.56) compared with stages IB-IIC], melanoma arising in sun-protected sites (compared with a limb), no occupation (compared with workers), those who reported insufficient emotional support from healthcare providers [adjusted OR=2.20, 95% CI (1.56-3.09) compared with sufficient support], lower knowledge of melanoma [adjusted OR=4.50, 95% CI (2.82-7.18) compared with well informed], perceived financial hardship compared with no financial hardship and over three previous negative life events compared with none/one. Worry about melanoma outcomes after diagnosis is multifactorial in origin