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

Dystrophic epidermolysis bullosa in Mexico: 2470insG represents the most common mutation in 21 families

Back in 1973, Dupr e et al. described a new hair shaft abnormality resulting in hair of an unusual texture and appearance. This disorder became known as uncombable hair syndrome (UHS), also known as ‘spun glass hair syndrome’, ‘pili trianguli et canaliculi’ or ‘cheveux incoiffables’. Clinically, the hair often appeared fair, dry, frizzy and resistant to being combed flat, although the phenotype typically improved later in childhood. Some cases occurred sporadically but in others there were autosomal dominant or autosomal recessive inheritance patterns. In 2016, Basmanav et al. used whole exome sequencing to identify the molecular basis of UHS. Looking for rare loss-offunction variants they identified biallelic mutations in three genes: PADI3, TGM3 and TCHH in a total of 11 children. The two enzymes peptidyl arginine deiminase 3 (PADI3) and transglutaminase 3 (TGM3) are responsible for post-translational protein modifications and, along with their target structural protein trichohyalin (TCHH), are involved in hair shaft formation. Of note, PADI3 represents a member of the peptidyl arginine deiminase family of enzymes that catalyse the post-translational deimination of proteins by converting L-arginine residues into citrulline. Supportive cell culture experiments, tri-dimensional protein models and scanning electron microscopy collectively demonstrated clear differences in the structural organization and activity of mutant and wild-type proteins and helped elucidate the molecular genetic causes of UHS and shed light on its pathophysiology and hair physiology. Regarding the process of identifying the three candidate genes in UHS, whole exome sequencing was the ideal investigative method. Whole exome sequencing is a genomic technique for sequencing the protein-coding region of genes in the genome; there are about 180 000 exons which make up ~1% of the human genome. Whole exome sequencing is therefore an efficient way to identify very rare genetic variants that are present in a small number of individuals and that underlie rare Mendelian diseases. Roll on to 2019 and PADI3 mutations have now been implicated in another hair disorder, central centrifugal cicatricial alopecia (CCCA). CCCA represents the most common cause of scarring alopecia, predominantly affecting the central scalp, in women of African descent. In terms of its aetiology, mechanical hair straightening, use of chemical relaxers and heat have all been implicated as possible causative factors in CCCA and the condition is often referred to as ‘hot comb alopecia’. Such trigger factors, however, may be absent in some cases, adding to the complexity of the aetiology of CCCA. Despite the absence of accurate population studies, the incidence of CCCA has been reported to be 2 7–5 6% with an average age of 36 years at presentation. Familial CCCA is very rare and even the reported pedigrees have been mostly limited to two generations, which could simply represent segregation of common variation in a common disease rather than strong supportive evidence for Mendelian inheritance. To investigate a possible genetic basis to CCCA, Malki et al. have used whole exome sequencing in a study of 16 African women with CCCA and identified four heterozygous alleles (one splice site, three missense) in PADI3 in five individuals. Extending the cohort, the authors reported a total of six PADI3 predicted missense and splice disrupting alleles in 14 of 58 patients (24%). Evaluation of whether this observation represents an elevation in protein disrupting alleles, however, was limited to a comparison with observations of PADI3 alleles in 58 control participants of African origin – and herein lies a challenge with the interpretation of these data. Over the past 20 years of genetics research, investigators have developed and applied a rigorous framework for the evaluation of genetic associations. This framework, including control for population stratification and rigorous multiple testing thresholds, has dramatically reduced the reporting of spurious associations in the literature. While the reported PADI3 findings in CCCA are intriguing, further experimentation is required to ensure that this association is robust and not confounded by population stratification. Aside from the genetics, the Malki et al. study also included supportive data showing reduced expression of PADI3 protein in CCCA scalp skin, along with in vitro studies of mutant PADI3 protein aggregation and decreased enzyme activity. These observations cannot be directly connected to the characteristic clinicopathological features of CCCA, including the premature desquamation of the inner root sheath, the dislocation and eventual loss of hair shafts, and perifollicular inflammation and fibrosis leading to the scarring phenotype, but the data do provide fresh insight into the pathobiology of CCCA. Indeed, despite the reservations about the genetic association methodology, the authors may well be correct in highlighting PADI3 as an important protein in CCCA. For most common diseases where there is evidence of heritability, but the majority of affected individuals lack any clear evidence for Mendelian inheritance, association studies provide a framework to identify variants with effect sizes that do not result in clear familial segregation. Such studies require the ascertainment of large numbers of cases and controls to ensure they are sufficiently powered to detect variants robustly with expected moderate effect sizes. A genome-wide association

https://onlinelibrary.wiley.com/doi/epdf/10.1111/bjd.18463

PADI3, hair disorders and genomic investigation.

Solar urticaria is a rare, immunologically-mediated photodermatosis in which activation of cutaneous mast cells is triggered by specific wavelengths of solar electromagnetic radiation. This manifests clinically as the rapid development of cutaneous itch, erythema and wheal formation after several minutes of sun exposure. Disease mechanisms in solar urticaria remain incompletely elucidated and there have been few recent investigations of its pathobiology. Historic passive transfer experiments performed during the twentieth century provide support for a "photoallergy" model of disease pathogenesis, wherein molecular alteration of a putative chromophore by solar electromagnetic radiation produces mast cell activation via an IgE-dependent mechanism. However, this model does not account for several observations made during passive transfer experiments, nor does it explain a range of subsequent clinical and photobiological observations made in solar urticaria patients. Furthermore, increased understanding of the molecular dynamics underpinning cutaneous mast cell responses highlights the need to reformulate our understanding of solar urticaria pathogenesis in the context of this contemporary scientific landscape. In this review, we discuss the current understanding of solar urticaria pathogenesis and, by incorporating recent scientific and clinical observations, develop new hypotheses to drive future investigation into this intriguing disorder.

Pathogenesis of solar urticaria: Classic perspectives and emerging concepts.

ments of currently available therapies. Rightly, the dermatologists surveyed by Taylor et al. identify the need for comparative trials between the various systemic agents and phototherapy as a top priority. Until that evidence is available, practitioners are left to do their best with the available agents and evidence. In the meantime, efforts should be made to bring clinical practice more in line with the currently available evidence.

/pdf/a-new-clinical-diagnostic-matrix-for-epidermolysis-bullosa-43xe3eisp1.pdf

A new clinical diagnostic matrix for epidermolysis bullosa

308 Bone marrow/cord blood transplantation (BMCBT) ameliorates symptoms in some, but not all, subtypes of severe generalized junctional epidermolysis bullosa (JEB)

John A. McGrath

Papers

Dystrophic epidermolysis bullosa in Mexico: 2470insG represents the most common mutation in 21 families

PADI3, hair disorders and genomic investigation.

Pathogenesis of solar urticaria: Classic perspectives and emerging concepts.

A new clinical diagnostic matrix for epidermolysis bullosa

308 Bone marrow/cord blood transplantation (BMCBT) ameliorates symptoms in some, but not all, subtypes of severe generalized junctional epidermolysis bullosa (JEB)