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

At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

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Free Radicals in the Physiological Control of Cell Function

I have developed "tennis elbow" from lugging this book around the past four weeks, but it is worth the pain, the effort, and the aspirin. It is also worth the (relatively speaking) bargain price. Including appendixes, this book contains 894 pages of text. The entire panorama of the neural sciences is surveyed and examined, and it is comprehensive in its scope, from genomes to social behaviors. The editors explicitly state that the book is designed as "an introductory text for students of biology, behavior, and medicine," but it is hard to imagine any audience, interested in any fragment of neuroscience at any level of sophistication, that would not enjoy this book. The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or

Principles of Neural Science

Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death

The discovery that mammalian cells generate nitric oxide, a gas previously considered to be merely an atmospheric pollutant, is providing important information about many biologic processes. Nitric oxide is synthesized from the amino acid L-arginine by a family of enzymes, the nitric oxide synthases, through a hitherto unrecognized metabolic route -- namely, the L-arginine-nitric oxide pathway1–8. The synthesis of nitric oxide by vascular endothelium is responsible for the vasodilator tone that is essential for the regulation of blood pressure. In the central nervous system nitric oxide is a neurotransmitter that underpins several functions, including the formation of memory. . . .

The L-Arginine-Nitric Oxide Pathway

Described are methods of inhibiting neurodegeneration in a subject by administering to the subject an agent that prevents (alpha)-syn PFF from binding to its receptor. The agent may be a small molecule chemical compound, antibody, nucleic acid molecule, or polypeptide. Drug screening methods are also provided.

THERAPEUTIC USES OF LAG3 THE (alpha)-SYNUCLEIN TRANSMISSION RECEPTOR

Dystrophin and nnos double knockout mice maintain dystrophic phenotype

Although the failure of the UPS has been implicated in both sporadic and familial forms of PD, it is unclear as to whether it is involved in the initiation or progression (or both) of the disease. It is hypothesized that mutations in parkin impair its normal ubiquitination activity, leading to an accumulation of proteins that overload the UPS and result in the selective death of neurons in the substantia nigra by a mechanism that is largely unknown. The paucity of Lewy bodies and therefore a lack of normal cellular defenses against excess levels of toxic proteins may manifest as early onset and severe neurodegeneration in parkin-associated PD. The pathogenic connection between the ubiquitination pathway and parkin-related PD has been established — the thrust should now be on understanding the mechanisms that cause and contribute to the development of disease.

Ubiquitination by Parkin — Implications in Parkinson’s Disease

Poly(ADP-ribose) (PAR) is a protein implicated in numerous neurodegenerative disease states including Parkinson's disease (PD). To date, no routine laboratory test has been developed to diagnosis, assess or monitor patients suffering from PD. Disclosed herein a novel method to assess the PAR concentration in the cerebral spinal fluid (CSF) of a patient and correlate that concentration to the medical condition of a patient with PD. Also disclosed is the use of PAR as a biomarker for PD.

Detection of par in the csf of patients with parkinson's disease

Toxic cellular insults activate the nuclear protein poly (ADP-ribose) (PAR) polymerase-1 (PARP-1) to initiate parthanatos, a regulated cell death program. PAR acts as a death signal by translocating from the nucleus to the cytosol, where it activates the next steps in the parthanatic cell death cascade. How PAR translocates from the nucleus to the cytosol is not known. Here we show that PARylation and PAR binding to histone H1.2 enables it to act as a carrier, transporting PAR out of the nucleus to the cytosol. Knocking down the expression of histone H1.2 via CRISPR/Cas9 and knockout of histone H1.2 reduces the translocation of PAR to the cytosol after treatment of human cortical neurons with N-methyl-D-aspartate (NMDA) or following oxygen-glucose deprivation (OGD). The PAR-dependent E3 ubiquitin ligase, Iduna (RNF146) ubiquitinates PARylated H1.2. Overexpression of Iduna reduces the expression levels of cytosolic histone H1.2, preventing the translocation of PAR following NMDA or OGD exposure, similar to inhibition of PAR formation by the PARP inhibitor, DPQ. Whereas, the catalytically null variant Iduna C60A, or the PAR binding mutant Iduna Y156A and R157A (YRAA) was ineffective in ubiquitinating histone H1.2 and preventing the reduction in cytosolic histone H1.2 levels and PAR translocation from the nucleus to the cytosol. Histone H1.2 heterozygote and homozygote knockout mice exhibited reduced infarct volume 24 hrs post middle cerebral artery occlusion (MCAO) and showed better recovery in motor deficits than wildtype littermates at day 3 and/or day 7 post MCAO. Collectively, these findings reveal histone H1.2 as the key carrier of PAR out of the nucleus to the cytosol where it participates in the next step of the parthanatic cell death cascade.

https://www.biorxiv.org/content/biorxiv/early/2023/06/18/2023.06.18.545460.full.pdf

Valina L. Dawson

Papers

THERAPEUTIC USES OF LAG3 THE (alpha)-SYNUCLEIN TRANSMISSION RECEPTOR

Dystrophin and nnos double knockout mice maintain dystrophic phenotype

Ubiquitination by Parkin — Implications in Parkinson’s Disease

Detection of par in the csf of patients with parkinson's disease

Histone H1.2 Dependent Translocation of Poly (ADP-ribose) Initiates Parthanatos