Project description:The S-peptide and S-protein components of bovine pancreatic ribonuclease form a noncovalent complex with restored ribonucleolytic activity. Although this archetypal protein-fragment complementation system has been the object of historic work in protein chemistry, intrinsic limitations compromise its utility. Modern methods are shown to overcome those limitations and enable new applications.
Project description:Data acquisition in (pre)clinical studies is often based on a hypothesis. Numerical algorithms, however, may help to find biomarkers from existing data without formulating any hypothesis. By simply assessing whether a statistical relationship exists between two parameters from a (unlimited) database, every (in)conceivable combination of data becomes a hypothesis. The aim was to create an unbiased and highly automated approach for secondary analysis of (pre)clinical research, including the possibility of a non-linear functional relationship. In our example, an almost homogeneous database was formed by overall 45 parameters (vital, blood and plasma parameters) measured in 11 individual experimental studies at 6 different time points using 57 rats without and 63 rats with systemic inflammation following lipopolysaccharide infusion. For each rat, four group classifiers (treatment, survival, study, ID) were used to get valid samples by a later filtering of the statistical base. Any information about the hypothesis leading to the respective studies was suppressed. In order to assess whether a statistical relationship exists, a total of six different functional prototypes (linear and non-linear) were postulated and examined for their regression. Regression quality, correlation and significance were obtained in form of matrices. In our example, ultimately 510 300 regressions were optimized, automatically evaluated and filtered. The developed algorithm is able to reveal statistical relationships from a nearly crude database with low effort by systematic and unbiased analysis. The finding of well-known correlations proves its reliability, whose validity could be increased by clean aggregation of different studies. In addition, new interesting hints for future research could be gained. Thus, unknown markers can be found which are associated with an increased risk of death during systemic inflammation and sepsis. A further development of the program is planned including multiple regressions (more than two parameters could be related to each other) or cluster analysis.
Project description:Alzheimer's disease is one the major common diseases but so far only with symptomatic treatment options. New insights define the disease as a slowly progressive continuum with very long preclinical and early symptomatic phases. Innovative molecular treatment strategies are based on an improved understanding of the molecular neurobiology of the disease, opening up a variety of therapeutic targets. For the first time, an anti-amyloid antibody has been approved in the USA in 2021 as a disease-modifying treatment for Alzheimer's disease, representing a first highly controversial step towards a molecular, cause-oriented treatment. This review presents the most advanced molecular treatment strategies and discusses the implications of the approved antibody treatment for the clinical practice. The special features of this long-term treatment with i.v. infusions in a particularly vulnerable population and a special side effect profile will impose significant challenges for implementation in the practice and will require a high degree of cooperation within the healthcare system. The future of Alzheimer's treatment with a multimodal therapeutic approach with different classes of drugs will probably reinforce these trends.
Project description:Melanoma is the least common but deadliest type of skin cancer. Melanomagenesis is driven by a series of mutations and epigenetic alterations in oncogenes and tumor suppressor genes that allow melanomas to grow, evolve, and metastasize. Epigenetic alterations can also lead to immune evasion and development of resistance to therapies. Although the standard of care for melanoma patients includes surgery, targeted therapies, and immune checkpoint blockade, other therapeutic approaches like radiation therapy, chemotherapy, and immune cell-based therapies are used for patients with advanced disease or unresponsive to the conventional first-line therapies. Targeted therapies such as the use of BRAF and MEK inhibitors and immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA4 only improve the survival of a small subset of patients. Thus, there is an urgent need to identify alternative standalone or combinatorial therapies. Epigenetic modifiers have gained attention as therapeutic targets as they modulate multiple cellular and immune-related processes. Due to melanoma's susceptibility to extrinsic factors and reversible nature, epigenetic drugs are investigated as a therapeutic avenue and as adjuvants for targeted therapies and immune checkpoint inhibitors, as they can sensitize and/or reverse resistance to these therapies, thus enhancing their therapeutic efficacy. This review gives an overview of the role of epigenetic changes in melanoma progression and resistance. In addition, we evaluate the latest advances in preclinical and clinical research studying combinatorial therapies and discuss the use of epigenetic drugs such as HDAC and DNMT inhibitors as potential adjuvants for melanoma patients.
Project description:On 12 February 1988 (by coincidence Charles Darwin's birthday), a paper published in Science by Katherine Field, Rudy Raff, and colleagues presented the first credible molecular analysis of metazoan phylogeny based on sequences from the small subunit ribosomal RNA gene (SSU). Here I examine the main conclusions reached in this manuscript. I reconstitute their dataset and, by recompiling software available in 1988, I consider how they might have achieved a more accurate tree. I show how three common methods to avoid systematic error - more data, careful taxon sampling and superior models of evolution - overcome the errors that exist in the original paper. This approach illustrates the basis of some of the major advances of the past 25 years resulting in our current understanding of animal phylogeny.
Project description:Two hundred years after the birth of Gregor Mendel, it is an appropriate time to reflect on recent developments in the discipline of genetics, particularly advances relating to the prescient friar's model species, the garden pea (Pisum sativum L.). Mendel's study of seven characteristics established the laws of segregation and independent assortment. The genes underlying four of Mendel's loci (A, LE, I, and R) have been characterized at the molecular level for over a decade. However, the three remaining genes, influencing pod color (GP), pod form (V/P), and the position of flowers (FA/FAS), have remained elusive for a variety of reasons, including a lack of detail regarding the loci with which Mendel worked. Here, we discuss potential candidate genes for these characteristics, in light of recent advances in the genetic resources for pea. These advances, including the pea genome sequence and reverse-genetics techniques, have revitalized pea as an excellent model species for physiological-genetic studies. We also discuss the issues that have been raised with Mendel's results, such as the recent controversy regarding the discrete nature of the characters that Mendel chose and the perceived overly-good fit of his segregations to his hypotheses. We also consider the relevance of these controversies to his lasting contribution. Finally, we discuss the use of Mendel's classical results to teach and enthuse future generations of geneticists, not only regarding the core principles of the discipline, but also its history and the role of hypothesis testing.
Project description:Some alleles of the wtf gene family can increase their chances of spreading by using poisons to kill other alleles, and antidotes to save themselves.
Project description:Mendel and Darwin were contemporaries, with much overlap in their scientifically productive years. Available evidence shows that Mendel knew much about Darwin, whereas Darwin knew nothing of Mendel. Because of the fragmentary nature of this evidence, published inferences regarding Mendel's views on Darwinian evolution are contradictory and enigmatic, with claims ranging from enthusiastic acceptance to outright rejection. The objective of this review is to examine evidence from Mendel's published and private writings on evolution and Darwin, and the influence of the scientific environment in which he was immersed. Much of this evidence lies in Mendel's handwritten annotations in his copies of Darwin's books, which this review scrutinises in detail. Darwin's writings directly influenced Mendel's classic 1866 paper, and his letters to Nägeli. He commended and criticised Darwin on specific issues pertinent to his research, including the provisional hypothesis of pangenesis, the role of pollen in fertilisation, and the influence of "conditions of life" on heritable variation. In his final letter to Nägeli, Mendel proposed a Darwinian scenario for natural selection using the same German term for "struggle for existence" as in his copies of Darwin's books. His published and private scientific writings are entirely objective, devoid of polemics or religious allusions, and address evolutionary questions in a manner consistent with that of his scientific contemporaries. The image that emerges of Mendel is of a meticulous scientist who accepted the tenets of Darwinian evolution, while privately pinpointing aspects of Darwin's views of inheritance that were not supported by Mendel's own experiments.
Project description:Huntington disease (HD) is the most frequent monogenetic neurodegenerative disease and can be unequivocally diagnosed even in the preclinical stage, at least in all individuals in whom the CAG expansion mutation in the huntingtin gene (HTT) is in the range of full penetrance. Therefore, important preconditions for an intervention early in the disease process are met, rendering modification of the course of the disease in a clinically meaningful way possible. In this respect, HD can be viewed as a model disorder for exploring neuroprotective treatment approaches. In the past emphasis was placed on the compensation of a suspected neurotransmitter deficit (GABA) analogous to Parkinson's disease and on classical neuroprotective strategies to influence hypothetical common pathways in neurodegenerative diseases (e.g., excitotoxicity, mitochondrial dysfunction, oxidative stress). With the discovery of the causative HTT mutation in 1993, therapeutic research increasingly focused on intervening as proximally as possible in the chain of pathophysiological events. Currently, an important point of intervention is the HTT mRNA with the aim of reducing the continued production of mutant huntingtin gene products and thus relieving the body of their detrimental actions. To this end, various treatment modalities (single-stranded DNA and RNA, divalent RNA and zinc finger repressor complexes, orally available splice modulators) were developed and are currently in clinical trials (phases I-III) or in late stages of preclinical development. In addition, there is the notion that it may be possible to modify the length of the somatically unstable CAG mutation, i.e. its increase in the brain during the lifetime, thereby slowing the progression of HD.