Applied cultural and social studies are needed for a sustainable reduction of genetic disease incidence

While clinical and basic biomedical research focus on diagnoses and cures for common and rare genetic diseases, they are unable to address one of the largest underlying causes for genetic disease: mating within families or other small genetically isolated sub-populations. This interdisciplinary literature study investigates theoretical, moral and practical aspects to solve this major cause for genetic disease from an alternative angle: through cultural change and encouragement of an outbreeding reproductive behavior. Understanding why some communities persist with choosing consanguineous reproductive partners when the modern society has eliminated the economic rationale to do so, and to develop strategies to encourage a cultural change in those communities, is critical for a sustainable long-term solution to reduce the number of new cases of genetic disease and undiagnosed (sub-clinical) but detrimental genetic abnormalities in vulnerable and marginalized groups in modern Western societies

Artistic research in breeding : the Bifrost Eucalyptus project

Genetic signs of domestication of plants and animals date as far back as the oldest known evidence for other artistic expressions like painting, music and sculpture. Breeding is often seen as a science or a craft and is rarely considered art. The Bifrost art project aims to combine the spectacular bark and growth rate of the rainbow gum Eucalyptus deglupta with the cold hardiness of the cider gum Eucalyptus gunnii and possibly other cold-hardy species. The cold hardiness introgression should make it possible to grow amazing rainbow-colored trees in a European or North American climate. The project has been initiated and is expected to continue for decades or centuries in a distributed, participatory, manner. The project explores breeding as an art form, and through extension landscape and ecosystem manipulations that may last beyond the time when human kind has driven itself to its extinction. The project also questions commonly held beliefs about “pristine” and “natural” as being better than “artificial” and “anthropogenic”

Inflammation and NF-κB signaling in prostate cancer : mechanisms and clinical implications

Prostate cancer is a highly prevalent form of cancer that is usually slow-developing and benign. Due to its high prevalence, it is, however, still the second most common cause of death by cancer in men in the West. The higher prevalence of prostate cancer in the West might be due to elevated inflammation from metabolic syndrome or associated comorbidities. NF-κB activation and many other signals associated with inflammation are known to contribute to prostate cancer malignancy. Inflammatory signals have also been associated with the development of castration resistance and resistance against other androgen depletion strategies, which is a major therapeutic challenge. Here, we review the role of inflammation and its link with androgen signaling in prostate cancer. We further describe the role of NF-κB in prostate cancer cell survival and proliferation, major NF-κB signaling pathways in prostate cancer, and the crosstalk between NF-κB and androgen receptor signaling. Several NF-κB-induced risk factors in prostate cancer and their potential for therapeutic targeting in the clinic are described. A better understanding of the inflammatory mechanisms that control the development of prostate cancer and resistance to androgen-deprivation therapy will eventually lead to novel treatment options for patient

Engineering a minimal cloning vector from a pUC18 plasmid backbone with an extended multiple cloning site

Minimal plasmids play an essential role in many intermediate steps in molecular biology. They can for example be used to assemble building blocks in synthetic biology or be used as intermediate cloning plasmids that are ideal for PCR-based mutagenesis methods. A small backbone also opens up for additional unique restriction enzyme cloning sites. Here we describe the generation of pICOz, a 1185 bp fully functional high-copy cloning plasmid with an extended multiple cloning site (MCS). To our knowledge, this is the smallest high-copy cloning vector ever described

MALT1 proteolytic activity suppresses autoimmunity in a T cell intrinsic manner

MALT1 is a central signaling component in innate and adaptive immunity by regulating NF-kappa B and other key signaling pathways in different cell types. Activities of MALT1 are mediated by its scaffold and protease functions. Because of its role in lymphocyte activation and proliferation, inhibition of MALT1 proteolytic activity is of high interest for therapeutic targeting in autoimmunity and certain lymphomas. However, recent studies showing that Mak1 protease-dead knock-in (Malt1-PD) mice suffer from autoimmune disease have somewhat tempered the initial enthusiasm. Although it has been proposed that an imbalance between immune suppressive regulatory T cells (Tregs) and activated effector CD4(+) T cells plays a key role in the autoimmune phenotype of Malt1-PD mice, the specific contribution of MALT1 proteolytic activity in T cells remains unclear. Using T cell-conditional Malt1 protease-dead knock-in (Malt1-PDT) mice, we here demonstrate that MALT1 has a T cell-intrinsic role in regulating the homeostasis and function of thymic and peripheral T cells. T cell-specific ablation of MALT1 proteolytic activity phenocopies mice in which MALT1 proteolytic activity has been genetically inactivated in all cell types. The Malt1-PDT mice have a reduced number of Tregs in the thymus and periphery, although the effect in the periphery is less pronounced compared to full-body Malt1-PD mice, indicating that also other cell types may promote Treg induction in a MALT1 protease-dependent manner. Despite the difference in peripheral Treg number, both T cell-specific and full-body Malt1-PD mice develop ataxia and multi-organ inflammation to a similar extent. Furthermore, reconstitution of the full-body Malt1-PD mice with T cell-specific expression of wild-type human MALT1 eliminated all signs of autoimmunity. Together, these findings establish an important T cell-intrinsic role of MALT1 proteolytic activity in the suppression of autoimmune responses

Engineering a minimal cloning vector from a pUC18 plasmid backbone with an extended multiple cloning site

Minimal plasmids play an essential role in many intermediate steps in molecular biology. For example, they can be used to assemble building blocks in synthetic biology or be used as intermediate cloning plasmids that are ideal for PCR-based mutagenesis methods. A small backbone also opens up for additional unique restriction enzyme cloning sites. Here we describe the generation of pICOz, a 1185-bp fully functional high-copy cloning plasmid with an extended multiple cloning site. We believe that this is the smallest high-copy cloning vector ever described. METHOD SUMMARY: We eliminated all superfluous sequences in a commonly used cloning vector in order to generate as small a cloning plasmid as possible by simple iterative PCR mutagenesis

Mepazine inhibits RANK-induced osteoclastogenesis independent of its MALT1 inhibitory function

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an intracellular cysteine protease (paracaspase) that plays an integral role in innate and adaptive immunity. The phenothiazine mepazine has been shown to inhibit the proteolytic activity of MALT1 and is frequently used to study its biological role. MALT1 has recently been suggested as a therapeutic target in rheumatoid arthritis. Here, we analyzed the effect of mepazine on the receptor activator of nuclear factor κ-B (RANK)-induced osteoclastogenesis. The treatment of mouse bone marrow precursor cells with mepazine strongly inhibited the RANK ligand (RANKL)-induced formation of osteoclasts, as well as the expression of several osteoclast markers, such as TRAP, cathepsin K, and calcitonin. However, RANKL induced osteoclastogenesis equally well in bone marrow cells derived from wild-type and Malt1 knock-out mice. Furthermore, the protective effect of mepazine was not affected by MALT1 deficiency. Additionally, the absence of MALT1 did not affect RANK-induced nuclear factor κB (NF-κB) and activator protein 1 (AP-1) activation. Overall, these studies demonstrate that MALT1 is not essential for RANK-induced osteoclastogenesis, and implicate a MALT1-independent mechanism of action of mepazine that should be taken into account in future studies using this compound

Long-term MALT1 inhibition in adult mice without severe systemic autoimmunity

The protease MALT1 is a key regulator of NF-kappa B signaling and a novel therapeutic target in autoimmunity and cancer. Initial enthusiasm supported by preclinical results with MALT1 inhibitors was tempered by studies showing that germline MALT1 protease inactivation in mice results in reduced regulatory T cells and lethal multi-organ inflammation due to expansion of IFN-gamma-producing T cells. However, we show that long-term MALT1 inactivation, starting in adulthood, is not associated with severe systemic inflammation, despite reduced regulatory T cells. In contrast, IL-2-, TNF-, and IFN-gamma-producing CD4(+) T cells were strongly reduced. Limited formation of tertiary lymphoid structures was detectable in lungs and stomach, which did not affect overall health. Our data illustrate that MALT1 inhibition in prenatal or adult life has a different outcome and that long-term MALT1 inhibition in adulthood is not associated with severe side effects

MALT1-deficient mice develop atopic-like dermatitis upon aging

MALT1 plays an important role in innate and adaptive immune signaling by acting as a scaffold protein that mediates NF-kappa B signaling. In addition, MALT1 is a cysteine protease that further fine tunes proinflammatory signaling by cleaving specific substrates. Deregulated MALT1 activity has been associated with immunodeficiency, autoimmunity, and cancer in mice and humans. Genetically engineered mice expressing catalytically inactive MALT1, still exerting its scaffold function, were previously shown to spontaneously develop autoimmunity due to a decrease in Tregs associated with increased effector T cell activation. In contrast, complete absence of MALT1 does not lead to autoimmunity, which has been explained by the impaired effector T cell activation due to the absence of MALT1-mediated signaling. However, here we report that MALT1-deficient mice develop atopic-like dermatitis upon aging, which is preceded by Th2 skewing, an increase in serum IgE, and a decrease in Treg frequency and surface expression of the Treg functionality marker CTLA-4

Optimising portfolio diversification and dimensionality

A new framework for portfolio diversification is introduced which goes beyond the classical mean-variance approach and portfolio allocation strategies such as risk parity. It is based on a novel concept called portfolio dimensionality that connects diversification to the non-Gaussianity of portfolio returns and can typically be defined in terms of the ratio of risk measures which are homogenous functions of equal degree. The latter arises naturally due to our requirement that diversification measures should be leverage invariant. We introduce this new framework and argue the benefits relative to existing measures of diversification in the literature, before addressing the question of optimizing diversification or, equivalently, dimensionality. Maximising portfolio dimensionality leads to highly non-trivial optimization problems with objective functions which are typically non-convex and potentially have multiple local optima. Two complementary global optimization algorithms are thus presented. For problems of moderate size and more akin to asset allocation problems, a deterministic Branch and Bound algorithm is developed, whereas for problems of larger size a stochastic global optimization algorithm based on Gradient Langevin Dynamics is given. We demonstrate analytically and through numerical experiments that the framework reflects the desired properties often discussed in the literature