Constitutional mismatch repair deficiency syndrome: Do we know it?

Constitutional mismatch repair deficiency syndrome is a rare autosomal recessive syndrome caused by homozygous mutations in mismatch repair genes. This is characterized by the childhood onset of brain tumors, colorectal cancers, cutaneous manifestations of neurofibromatosis-1 like café au lait spots, hematological malignancies, and occasionally other rare malignancies. Here, we would like to present a family in which the sibling had glioblastoma, and the present case had acute lymphoblastic lymphoma and colorectal cancer. We would like to present this case because of its rarity and would add to literature.     

RNA-binding proteins in plants: the tip of an iceberg?

RNA-binding proteins, which are involved in the synthesis, processing, transport, translation, and degradation of RNA, are emerging as important, often multifunctional, cellular regulatory proteins. Although relatively few RNA-binding proteins have been studied in plants, they are being identified with increasing frequency, both genetically and biochemically. RNA-binding proteins that regulate chloroplast mRNA stability and translation in response to light and that have been elegantly analyzed in Clamydomonas reinhardtii have counterparts with similar functions in higher plants. Several recent reports describe mutations in genes encoding RNA-binding proteins that affect plant development and hormone signaling.     

Systems biology of the secretory pathway: What have we learned so far?

Several RNAi screens were performed in search for regulators of the secretory pathway. These screens were performed in different organisms and cell lines and relied on different readouts. Therefore, they have only little overlap among their hits, leading to the question of what we have learned from this approach so far and how these screens contributed towards an integrative understanding of the endomembrane system. The aim of this review is to revisit these screens and discuss their strengths and weaknesses as well as potential reasons for their failure to overlap with each other. As with secretory trafficking, RNAi screens were also performed on other cellular processes such as cell migration and autophagy, both of which were shown to be intimately linked to secretion. Another aim of this review is to compare the outcome of the RNAi screens on secretion, autophagy and cell migration and ask whether the functional genomic approaches have uncovered potential mechanistic insights into the links between these processes.     

Fanconi's anemia: what have we learned from the genes so far?

Fanconi's anemia (FA) is a rare genetic disorder affecting children at an early age; patients suffer from progressive bone marrow failure and, in many cases, from congenital malformations. As cells from FA patients have an increased sensitivity to DNA-crosslinking agents, FA has been included among the group of DNA repair disorders. However, identification of a specific DNA repair defect in FA has not been firmly established. None the less, this cellular phenotype has allowed the classification of FA patients into eight complementation groups defining eight possible FA genes. Two of these genes have now been cloned and, although they have raised more questions than they have answered, are facilitating the identification of cellular processes implicated in the pathophysiology of FA, and the design of new therapies.     

Fibrillin protein function: the tip of the iceberg?

Fibrillins are nuclear-encoded, plastid proteins associated with chromoplast fibrils and chloroplast plastoglobules, thylakoids, photosynthetic antenna complexes, and stroma. There are 12 sub-families of fibrillins. However, only three of these sub-families have been characterized genetically or functionally. We review evidence indicating that fibrillins are involved in plastoglobule structural development, chromoplast pigment accumulation, hormonal responses, protection of the photosynthetic apparatus from photodamage, and plant resistance to a range of biotic and abiotic stresses. The area of fibrillin research has substantial growth potential and will contribute to better understanding of mechanisms of plant stress tolerance and plastid structure and function.     

Invertebrate models of lysosomal storage disease: what have we learned so far?

The lysosomal storage diseases (LSDs) collectively account for death in 1 in 8,000 children. Although some forms are treatable, they are essentially incurable and usually are lethal in the first decade of life. The most intractable forms of LSD are those with neuronal involvement. In an effort to identify the pathological signaling driving pathology in the LSDs, invertebrate models have been developed. In this review, we outline our current understanding of LSDs and recent findings using invertebrate models. We outline strategies and pitfalls for the development of such models. Available models of LSD in Drosophila and Caenorhabditis elegans are uncovering roles for LSD-related proteins with previously unknown function using both gain-of-function and loss-of-function strategies. These models of LSD in Drosophila and C. elegans have identified potential pathogenic signaling cascades that are proving critical to our understanding of these lethal diseases.     

Prophages and bacterial genomics: what have we learned so far?

Bacterial genome nucleotide sequences are being completed at a rapid and increasing rate. Integrated virus genomes (prophages) are common in such genomes. Fifty-one of the 82 such genomes published to date carry prophages, and these contain 230 recognizable putative prophages. Prophages can constitute as much as 10-20% of a bacterium's genome and are major contributors to differences between individuals within species. Many of these prophages appear to be defective and are in a state of mutational decay. Prophages, including defective ones, can contribute important biological properties to their bacterial hosts. Therefore, if we are to comprehend bacterial genomes fully, it is essential that we are able to recognize accurately and understand their prophages from nucleotide sequence analysis. Analysis of the evolution of prophages can shed light on the evolution of both bacteriophages and their hosts. Comparison of the Rac prophages in the sequenced genomes of three Escherichia coli strains and the Pnm prophages in two Neisseria meningitidis strains suggests that some prophages can lie in residence for very long times, perhaps millions of years, and that recombination events have occurred between related prophages that reside at different locations in a bacterium's genome. In addition, many genes in defective prophages remain functional, so a significant portion of the temperate bacteriophage gene pool resides in prophages.     

Therapy-related myeloid neoplasms - what have we learned so far?

Therapy-related myeloid neoplasms are neoplastic processes arising as a result of chemotherapy, radiation therapy, or a combination of these modalities given for a primary condition. The disease biology varies based on the etiology and treatment modalities patients receive for their primary condition. Topoisomerase Ⅱ inhibitor therapy results in balanced translocations. Alkylating agents, characteristically, give rise to more complex karyotypes and mutations in p53. Other etiologies include radiation therapy, high-dose chemotherapy with autologous stem cell transplantation and telomere dysfunction. Poor-risk cytogenetic abnormalities are more prevalent than they are in de novo leukemias and the prognosis of these patients is uniformly dismal. Outcome varies according to cytogenetic risk group. Treatment recommendations should be based on performance status and karyotype. An in-depth understanding of risk factors that lead to the development of therapyrelated myeloid neoplasms would help developing riskadapted treatment protocols and monitoring patients after treatment for the primary condition, translating into reduced incidence, early detection and timely treatment.     

Advances in cellular technology in the hematology field: What have we learned so far?

Despite the advances in the hematology field, blood transfusion-related iatrogenesis is still a major issue to be considered during such procedures due to blood antigenic incompatibility. This places pluripotent stem cells as a possible ally in the production of more suitable blood products. The present review article aims to provide a comprehensive summary of the state-of-theart concerning the differentiation of both embryonic stem cells and induced pluripotent stem cells to hematopoietic cell lines. Here, we review the most recently published protocols to achieve the production of blood cells for future application in hemotherapy, cancer therapy and basic research.     

Manipulating the genetic code for membrane protein production: What have we learnt so far?

With synthetic gene services, molecular cloning is as easy as ordering a pizza. However choosing the right RNA code for efficient protein production is less straightforward, more akin to deciding on the pizza toppings. The possibility to choose synonymous codons in the gene sequence has ignited a discussion that dates back 50years: Does synonymous codon use matter? Recent studies indicate that replacement of particular codons for synonymous codons can improve expression in homologous or heterologous hosts, however it is not always successful. Furthermore it is increasingly apparent that membrane protein biogenesis can be codon-sensitive. Single synonymous codon substitutions can influence mRNA stability, mRNA structure, translational initiation, translational elongation and even protein folding. Synonymous codon substitutions therefore need to be carefully evaluated when membrane proteins are engineered for higher production levels and further studies are needed to fully understand how to select the codons that are optimal for higher production. This article is part of a Special Issue entitled: Protein Folding in Membranes.     

Proteomic analysis of red blood cells and the potential for the clinic: what have we learned so far?

Introduction: Red blood cells (RBC) are the most abundant host cells in the human body. Mature erythrocytes are devoid of nuclei and organelles and have always been regarded as circulating ‘bags of hemoglobin’. The advent of proteomics has challenged this assumption, revealing unanticipated complexity and novel roles for RBCs not just in gas transport, but also in systemic metabolic homeostasis in health and disease.

Areas covered: In this review we will summarize the main advancements in the field of discovery mode and redox/quantitative proteomics with respect to RBC biology. We thus focus on translational/clinical applications, such as transfusion medicine, hematology (e.g. hemoglobinopathies) and personalized medicine. Synergy of omics technologies – especially proteomics and metabolomics – are highlighted as a hallmark of clinical metabolomics applications for the foreseeable future.

Expert commentary: The introduction of advanced proteomics technologies, especially quantitative and redox proteomics, and the integration of proteomics data with omics information gathered through orthogonal technologies (especially metabolomics) promise to revolutionize many biomedical areas, from hematology and transfusion medicine to personalized medicine and clinical biochemistry.     

Antinuclear antibodies in healthy people: the tip of autoimmunity's iceberg?

Antinuclear antibodies (ANAs) are venerable biomarkers for assessing the diagnosis and prognosis of patients with autoimmunity. While closely associated with diseases such as systemic lupus erythematosus, ANA expression occurs commonly in healthy people. The basis for this expression is unknown, although it may reflect features of the assays for antibody detection or intrinsic immunological disturbances in otherwise normal individuals. Like autoimmunity itself, ANA expression is more common among women than men, pointing to an important determinant of these responses. Future research will clarify the mechanisms of ANA expression and the utility of current assays as antecedent and screening biomarkers.     

The mid-domain effect and species richness patterns:what have we learned so far?

If species' ranges are randomly shuffled within a bounded geographical domain free of environmental gradients, ranges overlap increasingly toward the center of the domain, creating a "mid-domain" peak of species richness. This "mid-domain effect" (MDE) has been controversial both in concept and in application. Empirical studies assess the degree to which the evolutionary, ecological, and historical processes that undeniably act on individual species and clades produce geographical patterns that resemble those produced by MDE models. MDE models that resample empirical range size frequency distributions (RSFDs) balance the risk of underestimating and overestimating the role of MDE, whereas theoretical RSFDs are generally biased toward underestimating MDE. We discuss the inclusion of nonendemic species in MDE models, rationales for setting domain limits, and the validity of one- and two-dimensional MDE models. MDE models, though null models, are not null hypotheses to be simplistically rejected or accepted. They are a means of estimating the expected effect of geometric constraints within the context of multiple causality. We call for assessment of MDE on an equal statistical footing with other candidate explanations for richness gradients. Although some critics have categorically dismissed MDE, an overview of the 21 MDE studies published to date reveals a substantial signature of MDE in natural patterns and justifies continued work.     

Human infections with Dicrocoelium dendriticum in Kyrgyzstan: the tip of the iceberg?

Dicrocoelium dendriticum is the causative agent of a rare food-borne zoonosis of the human biliary tract, dicrocoeliasis, for which few human prevalence data are available. Infection occurs through the ingestion of ants containing metacercariae, whereas pseudo-infections (presence of D. dendriticum eggs in stool in the absence of adult worms) are due to the consumption of infected animal liver. Here, results from a cross-sectional survey carried out among 138 children aged 2-15 yr in a peri-urban area of Kyrgyzstan are reported. Each child provided 1 stool sample that was subjected to the FLOTAC technique. Eggs of D. dendriticum were diagnosed in 11 children (prevalence 8.0%; 95% confidence interval 4.5-13.7%). Although no distinction could be made between true and pseudo-infections, the prevailing animal husbandry system and the diet and hygienic conditions of the study area suggest that the social-ecological system in Kyrgyzstan is conducive for human transmission of D. dendriticum. There is a need to investigate the epidemiology of dicrocoeliasis in Kyrgyzstan, placing emphasis on the distinction between true and pseudo-infections.     

Ten years muscle-bone hypothesis: what have we learned so far?--almost a festschrift--

The importance of mechanical stimuli for bone is widely appreciated. Mechanostat theory proposes a negative feedback system to explain the adaptation of bone by homeostatic control of peak strains. However, no assumption is made as to which forces cause these strains. Biomechanical analyses suggest that the largest forces emerge from muscle contractions, rather than from body weight per se. Hence, the idea of a 'muscle-bone' unit emerged ten years ago, proposing that bones adapt to muscle strength. This muscle-bone hypothesis is well able to account for the accrual of bone mass and strength during childhood, and also to explain why certain types of exercise are able to prevent bone loss during immobilization. However, the hypothesis fails to explain why exercise becomes rather ineffective to increase bone strength after puberty. It is here proposed that joint size as a 'third agent' might solve the conundrum. More specifically, the assumptions are made that the peak forces determine joint size until the end of puberty, and that motor control limits joint reaction forces to critical limits during adulthood in order to prevent joint damage. Providing evidence in favour or against these conjectures will improve our understanding of the musculoskeletal system.     

Lateral gene transfer in eukaryotes: tip of the iceberg or of the ice cube?

Lateral gene transfer (LGT) is the transmission of genes, sometimes across species barriers, outwith the classic vertical inheritance from parent to offspring. LGT is recognized as an important phenomenon that has shaped the genomes and biology of prokaryotes. Whether LGT in eukaryotes is important and widespread remains controversial. A study in BMC Biology concludes that LGT in eukaryotes is neither continuous nor prevalent and suggests a rule of thumb for judging when apparent LGT may reflect contamination.See research article: http://bmcbiol.biomedcentral.com/articles/10.1186/s12915-016-0315-9.     

Current management of the cognitive dysfunction in Parkinson's disease: how far have we come?

Parkinson's disease (PD) clinical features comprise both motor and nonmotor manifestations. Among the nonmotor complications, dementia is the most important. Approximately 40% of PD patients are affected by cognitive impairment. Remarkably, in addition to age, dementia is an independent predictor of mortality, whereas age at onset of PD and severity of neurological symptoms are not. In this review, I summarize the current knowledge of the pathogenesis of the PD cognitive impairment in relation to the therapies presently accessible and those that could become strategic in the near future. It is hypothesized that patients with PD show two components of cognitive dysfunction (CD): a generalized profile of subcortical dementia (PDsCD), and an overlapped pattern suggesting specific prefrontal damage with CD (PDpFCD). PDsCD is associated with structural neocortical/subcortical changes in the brain (in frontal, parietal, limbic, and temporal lobes, as well as in midbrain structures). In PDpFCD cognitive deficits comprise impairments in neuropsychological tests sensitive for frontal lobe function (discrete elements of episodic and working memory for instance), which are considered to be the consequence of dysfunction in neuronal loops connecting the prefrontal cortex and basal ganglia. Drugs reviewed for targeting PDsCD include: cholinesterase inhibitors, agents with mixed cholinergic and dopaminergic properties, antiglutamatergic drugs, mixed antiglutamatergic/dopaminergic agents; antioxidants and enhancers of mitochondrial functions, and anti-COX-2, as well as other anti-inflammatory mediators. Preliminary studies with vehicles that may target PDpFCD include piribedil, tolcapone, amantadine, and farampator. Additional agents (citicoline and neuroimmuniphilines, among others) will be outlined. A brief overview on neuroprotection and promising new biological advances in PD (deep brain stimulation, stem cells, gene therapy) also will be summarized.     

Do we have an internal model of the outside world?

Our phenomenal world remains stationary in spite of movements of the eyes, head and body. In addition, we can point or turn to objects in the surroundings whether or not they are in the field of view. In this review, I argue that these two features of experience and behaviour are related. The ability to interact with objects we cannot see implies an internal memory model of the surroundings, available to the motor system. And, because we maintain this ability when we move around, the model must be updated, so that the locations of object memories change continuously to provide accurate directional information. The model thus contains an internal representation of both the surroundings and the motions of the head and body: in other words, a stable representation of space. Recent functional MRI studies have provided strong evidence that this egocentric representation has a location in the precuneus, on the medial surface of the superior parietal cortex. This is a region previously identified with ‘self-centred mental imagery’, so it seems likely that the stable egocentric representation, required by the motor system, is also the source of our conscious percept of a stable world.