抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.

Mitochondrial Membrane Permeabilization in Cell Death

Reported values in the literature on the number of cells in the body differ by orders of magnitude and are very seldom supported by any measurements or calculations. Here, we integrate the most up-to-date information on the number of human and bacterial cells in the body. We estimate the total number of bacteria in the 70 kg "reference man" to be 3.8·1013. For human cells, we identify the dominant role of the hematopoietic lineage to the total count (≈90%) and revise past estimates to 3.0·1013 human cells. Our analysis also updates the widely-cited 10:1 ratio, showing that the number of bacteria in the body is actually of the same order as the number of human cells, and their total mass is about 0.2 kg.

/pdf/revised-estimates-for-the-number-of-human-and-bacteria-cells-4fb3y5elnx.pdf

Revised Estimates for the Number of Human and Bacteria Cells in the Body.

https://www.cell.com/molecular-cell/pdf/S1097-2765(08)00292-X.pdf

Oxygen Sensing by Metazoans: The Central Role of the HIF Hydroxylase Pathway

http://basicmed.med.ncku.edu.tw/admin/up_img/1007-2.pdf

Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases

Of all the topics the BJD has covered over the last 125 years, genetic skin diseases have certainly been an integral part of the journal. Over its existence, the BJD has published close to 2000 manuscripts on inherited skin conditions, encompassing a variety of known and unknown clinical entities and a spectrum of developmental, chromosomal or other inherited disorders with skin anomalies. Approximately 85% of these genetic skin disease manuscripts have made it to press within the last 25 years of BJD publishing, probably reflecting what has become technically possible in the modern era of molecular biological dissection of disease and functional genomics. Of course, many other dermatology journals have also published an increasing number of papers on genetic skin diseases in recent years, which raises the question of whether the BJD has managed to create a special home for genodermatology? The answer has to be a resounding yes! For clinical academics working in genetics, there has always been a professional tendency to try to publish new gene discoveries and first mutation reports in the highest impact genetics journals, perhaps offering accounts of the second or third mutations for a particular condition to journals like the BJD. Nevertheless, the recent surge in the impact factor of the BJD (currently 3 759) puts it on a par with genetics journals like the European Journal of Human Genetics, Heredity and Human Genetics, which therefore makes the BJD a very competitive journal to which to submit those primary genetic findings. However, the willingness of the BJD to publish the follow-on papers for monogenic disorders still has considerable value, both to the readership and the journal, in furthering understanding of the molecular basis of inherited skin diseases and in helping to expand genotype–phenotype correlation. But the track record of the BJD has been so much more substantial than this, notably in showing the impact of genetics on common diseases that dermatologists see every day. For example, since mutational analysis of the FLG gene, encoding the skin barrier component filaggrin, became feasible in 2006, the BJD has published more than 60 articles on FLG mutations allied to diseases such as atopic, contact or irritant dermatitis, as well as hand eczema, skin infections, atopy and ichthyosis vulgaris. These reports include data from 12 different countries, demonstrating that for genetics, as for the rest of dermatology, the BJD is truly a global journal in which to publish. Although approximately 35% of all reports on monogenic skin diseases in the BJD have been case reports, including case series, several predominantly clinical papers published over the last 125 years have offered beautiful descriptive accounts of observations on genetic skin diseases that have withstood the test of time. Rereading these original papers in the BJD also demonstrates just how careful and detailed these clinical descriptions tended to be before analysis of genes became the focus of most modern-day reports. The 1950s, for example, saw several landmark clinical reports of novel genodermatoses. Notably, two eponymous syndromes were described in backto-back issues of the BJD in 1954. These are an autosomal dominant form of trauma-induced skin fragility, which subsequently became known as Dowling–Meara epidermolysis bullosa simplex (OMIM 131760), and an autosomal recessive skin fragility and poikilodermatous disorder, which thereafter has been known as Kindler syndrome (OMIM 173650). Both of these genodermatoses have become established as distinct clinicopathological entities and, in modern times, when eponymous syndrome names have tended to be replaced by more descriptive or mechanistic disease titles, it is interesting to note that the latest classification of epidermolysis bullosa published in 2008 retained Dowling–Meara as one of the few eponymous types of epidermolysis bullosa simplex and inserted Kindler syndrome as a distinct fourth major category of epidermolysis bullosa. Other novel clinical descriptions of genetic skin diseases published in the BJD have also led to designation as eponymous syndromes, including a 1976 publication of an autosomal dominant form of ectodermal dysplasia, subsequently known as Hay–Wells syndrome (OMIM 106240), although this disorder has now been rebranded as ankyloblepharon–ectodermal defects–clefting syndrome, with perhaps synonymous overlap with another type of ectodermal dysplasia, Rapp–Hodgkin syndrome (OMIM 129400), first published in 1968. Aside from these historical focal points, one of the major attractions of the BJD and genetics has been that the journal has offered a home for detailed reviews, many of which have relevance to clinical practice, providing pointers to making accurate clinical diagnoses. The journal has also reported innovative laboratory tests, guidelines for treatment and interventions such as prenatal diagnosis that may benefit families at risk of recurrence of inherited skin diseases. Few journals can match the BJD for the clinical significance of its genetics publications. Nevertheless, more than 40% of the BJD publications on genetic skin diseases in the last 5 years have centred on mutation data, perhaps indicative of the current focus of laboratory work to investigate patients. Worthy as such publications may be, times are changing and the advent of next-generation sequencing is definitely moving the emphasis from mutation detection to skin genetics with more clinical relevance. Once efficient clinical service platforms are established for next-generation sequencing, automation with whole-genome or whole-exome sequencing and bioin-

https://onlinelibrary.wiley.com/doi/pdf/10.1111/bjd.12889

Genodermatoses and 125 years of the BJD

MBTPS2 mutation in a family with keratosis follicularis spinulosa decalvans

Background Epidermolysis bullosa pruriginosa (EBP) is rare a clinical variant of dystrophic epidermolysis bullosa characterized by trauma-induced bullae formation, milia and nail dystrophy accompanied by severe pruritus. Treatment pruritus of EBP focuses on immunosuppressive treatment with limited efficacy. Treatment strategies are not well-established. Aim To provide the genetic characterization of a multi-generational EBP family and discuss the efficacy of intravenous immunoglobulin treatment in EBP. Materials & methods The clinical characteristics of patients diagnosed with EBP in three consecutive generations were determined. The mutation is analyzed in the index patient's genomic DNA by Sanger sequencing, and this mutation was confirmed in other affected members of the family. Index case with severe phenotype was treated with intravenous immunoglobulin (IVIG). Results A heterozygous single nucleotide transition, c.6127G>A, in exon 73 of COL7A1 was identified in all affected members. Physical examination of patients revealed lichenoid papules on extensor surfaces of extremities, excoriations, milia formation and nail dystrophy. Majority of patients had elevated serum IgE levels (%86 (6/7)) without a medical history for atopy. Female patients had generalized involvement and severe phenotype. The skin lesions of the index case were refractory to high dose systemic steroids and cyclosporine treatment. Lesions improved significantly with intravenous immunoglobulin therapy. Conclusion In severe cases, unresponsive to other therapies, IVIG may be a preferable therapeutic approach to modulate the inflammatory response in patients with EBP.

John A. McGrath

Papers

Genodermatoses and 125 years of the BJD

MBTPS2 mutation in a family with keratosis follicularis spinulosa decalvans

Promising effect of intravenous immunoglobulin therapy for epidermolysis bullosa pruriginosa.

Two phase III trials of baricitinib for alopecia areata: a critically appraised research paper.

Whole-exome sequencing diagnosis of two autosomal recessive disorders in one family