For better or worse: Immune system involvement in Alzheimer's Disease.

In this issue of the Biomedical Journal, we explore the key role of the immune system in the development of Alzheimer's disease. We also learn more about the link between two disorders related to metabolic imbalances, with findings that could help to inform future screening programs. Finally, we would like to highlight some big news for our journal: the Biomedical Journal will be indexed in the Science Citation Index and receive its first official impact factor from this year.

Antiviral Properties of Chemical Inhibitors of Cellular Anti-Apoptotic Bcl-2 Proteins.

Viral diseases remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral diseases, new treatments are urgently needed. Here we show that small-molecules, which inhibit cellular anti-apoptotic Bcl-2 proteins (Bcl-2i), induced the premature death of cells infected with different RNA or DNA viruses, whereas, at the same concentrations, no toxicity was observed in mock-infected cells. Moreover, these compounds limited viral replication and spread. Surprisingly, Bcl-2i also induced the premature apoptosis of cells transfected with viral RNA or plasmid DNA but not of mock-transfected cells. These results suggest that Bcl-2i sensitizes cells containing foreign RNA or DNA to apoptosis. A comparison of the toxicity, antiviral activity, and side effects of six Bcl-2i allowed us to select A-1155463 as an antiviral lead candidate. Thus, our results pave the way for the further development of Bcl-2i for the prevention and treatment of viral diseases.

Perturbing purinergic signaling: A pathogen's guidebook to counteracting inflammatory responses.

In this issue of the Biomedical Journal, we learn how bacteria and parasites alike counteract inflammatory signaling by manipulating purinergic signaling. We also focus on an original article shedding light on the role of an Epstein-Barr virus encoded gene in metastasis in nasopharyngeal carcinoma. Finally, we learn about a possible link between Trichomonas vaginalis and recurrent urinary tract infection.

On the road to epigenetic therapy.

In this issue of the Biomedical Journal, we examine how far the explosion of epigenetic studies in recent years has translated to benefits for patients in the clinic, and we highlight an original study suggesting that increased vegetable intake protects against osteoporotic fractures. We also hear several opinions on the use, or perhaps misuse, of Impact Factor and what the future should hold for this publication metric.

From mishap to model: The origins and utility of experimental autoimmune encephalomyelitis.

This special edition of the Biomedical Journal focuses on experimental autoimmune encephalomyelitis, and includes three reviews showing how this model has greatly facilitated our understanding of the pathophysiology of multiple sclerosis. We also highlight a small single center study which suggests that the use of calcium bone substitutes during core decompression surgery may do more harm than good. Finally, we see how policy changes affect the management of fungal infections in immunocompromised patients and we learn about antibiotic resistance among strains of Streptococcus agalactiae circulating in Taiwan.

The surprising activities of APOBEC3B and 5-fluorouracil.

In this mini-special issue on cancer, we learn how DNA editing enzymes can accelerate the development of cancer and we discover some remarkable effects of the chemotherapeutic agent, 5-fluorouracil, on the immune system. We also discuss a study revealing the continuing problem of vitamin B deficiencies in children in developing countries, and we determine how to distinguish two near-identical forms of necrotizing fasciitis.

The two faces of invariant natural killer T cells.

In this issue of the Biomedical Journal, we take a look at some of the immune system's most peculiar cells, invariant natural killer T cells, which have features of both innate and adaptive cells. We also highlight a clinical study revealing that high serum phosphate levels could show that it's time to start dialysis in patients with chronic kidney diseases. Finally, this issue also includes some case reports, including an unusual case of aspergillosis related to long-term inhaler use.

Buried treasure: Unlocking the secrets of medicinal mushrooms.

In this issue of the Biomedical Journal, we investigate the potential of plants and fungi as a source of beneficial molecules for human health. We explore the weird and wonderful world of the mushroom and examine how Western medicine still has a lot to learn from Eastern practices dating back thousands of years. We also discuss a study further supporting claims that flaxseed, the plant kingdom's richest source of omega-3 fatty acids, can have lipid-lowering and fat-busting properties in the right physiological context. Finally, this issue also includes several validation studies of medical procedures or devices that define optimal conditions for their use in Asian populations.

Dnmt3b Prefers Germ Line Genes and Centromeric Regions: Lessons from the ICF Syndrome and Cancer and Implications for Diseases.

The correct establishment and maintenance of DNA methylation patterns are critical for mammalian development and the control of normal cell growth and differentiation. DNA methylation has profound effects on the mammalian genome, including transcriptional repression, modulation of chromatin structure, X chromosome inactivation, genomic imprinting, and the suppression of the detrimental effects of repetitive and parasitic DNA sequences on genome integrity. Consistent with its essential role in normal cells and predominance at repetitive genomic regions, aberrant changes of DNA methylation patterns are a common feature of diseases with chromosomal and genomic instabilities. In this context, the functions of DNA methyltransferases (DNMTs) can be affected by mutations or alterations of their expression. DNMT3B, which is involved in de novo methylation, is of particular interest not only because of its important role in development, but also because of its dysfunction in human diseases. Expression of catalytically inactive isoforms has been associated with cancer risk and germ line hypomorphic mutations with the ICF syndrome (Immunodeficiency Centromeric instability Facial anomalies). In these diseases, global genomic hypomethylation affects repeated sequences around centromeric regions, which make up large blocks of heterochromatin, and is associated with chromosome instability, impaired chromosome segregation and perturbed nuclear architecture. The review will focus on recent data about the function of DNMT3B, and the consequences of its deregulated activity on pathological DNA hypomethylation, including the illicit activation of germ line-specific genes and accumulation of transcripts originating from repeated satellite sequences, which may represent novel physiopathological biomarkers for human diseases. Notably, we focus on cancer and the ICF syndrome, pathological contexts in which hypomethylation has been extensively characterized. We also discuss the potential contribution of these deregulated protein-coding and non-coding transcription programs to the perturbation of cellular phenotypes.

Germline genes hypomethylation and expression define a molecular signature in peripheral blood of ICF patients: implications for diagnosis and etiology.

BACKGROUND: Immunodeficiency Centromeric Instability and Facial anomalies (ICF) is a rare autosomal recessive disease characterized by reduction in serum immunoglobulins with severe recurrent infections, facial dysmorphism, and more variable symptoms including mental retardation. ICF is directly related to a genomic methylation defect that mainly affects juxtacentromeric heterochromatin regions of certain chromosomes, leading to chromosomal rearrangements that constitute a hallmark of this syndrome upon cytogenetic testing. Mutations in the de novo DNA methyltransferase DNMT3B, the protein ZBTB24 of unknown function, or loci that remain to be identified, lie at its origin. Despite unifying features, common or distinguishing molecular signatures are still missing for this disease. METHOD: We used the molecular signature that we identified in a mouse model for ICF1 to establish transcriptional biomarkers to facilitate diagnosis and understanding of etiology of the disease. We assayed the expression and methylation status of a set of genes whose expression is normally restricted to germ cells, directly in whole blood samples and epithelial cells of ICF patients. RESULTS: We report that DNA hypomethylation and expression of MAEL and SYCE1 represent robust biomarkers, easily testable directly from uncultured cells to diagnose the most prevalent sub-type of the syndrome. In addition, we identified the first unifying molecular signatures for ICF patients. Of importance, we validated the use of our biomarkers to diagnose a baby born to a family with a sick child. Finally, our analysis revealed unsuspected complex molecular signatures in two ICF patients suggestive of a novel genetic etiology for the disease. CONCLUSIONS: Early diagnosis of ICF syndrome is crucial since early immunoglobulin supplementation can improve the course of disease. However, ICF is probably underdiagnosed, especially in patients that present with incomplete phenotype or born to families with no affected relatives. The specific and robust biomarkers identified in this study could be introduced into routine clinical immunology or neurology departments to facilitate testing of patients with suspected ICF syndrome. In addition, as exemplified by two patients with a combination of molecular defects never described before, our data support the search for new types of mutations at the origin of ICF syndrome.

Maintenance of DNA methylation: Dnmt3b joins the dance.

DNA methylation mostly occurs within the context of CpG dinucleotides and is essential for embryonic development and gene repression. It is generally accepted that DNA methyltransferases carry out specific and non-overlapping functions, Dnmt3a and Dnmt3b being responsible for the establishment of methylation around the time of implantation and Dnmt1 ensuring that methylation is faithfully copied to daughter cells via what has come to be known as "maintenance methylation." This longstanding view has been challenged over the years with the observation that Dnmt1 alone is incapable of perfect maintenance methylation. A new model is emerging that takes into account a contribution of the de novo enzymes Dnmt3a and Dnmt3b in the maintenance of the DNA methylation. We recently showed that certain germ line genes are specific targets of Dnmt3b, and that Dnmt3b remains bound to their promoter regions in somatic cells via interaction with the transcriptional repressor E2F6. It is tempting to consider an ongoing role for Dnmt3b in the methylation of germ line genes in somatic cells. We propose here observations in support of the hypothesis that the maintenance of methylation and subsequent silencing of a handful of germ line genes requires Dnmt3b but not Dnmt1. In addition to suggesting a new role for Dnmt3b in the protection of somatic cells against the promiscuous expression of the germ line program, these observations are of particular interest in the field of carcinogenesis, given that the expression of catalytically inactive Dnmt3b isoforms and aberrant expression of germ line genes are commonly observed in cancer cells.