A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson’s Disease Affects LRRK2 Protein Levels

Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson’s disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant—p.G2294R—located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient’s peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.     

Multifaceted Mechanisms of Action of Metformin Which Have Been Unraveled One after Another in the Long History

While there are various kinds of drugs for type 2 diabetes mellitus at present, in this review article, we focus on metformin which is an insulin sensitizer and is often used as a first-choice drug worldwide. Metformin mainly activates adenosine monophosphate-activated protein kinase (AMPK) in the liver which leads to suppression of fatty acid synthesis and gluconeogenesis. Metformin activates AMPK in skeletal muscle as well, which increases translocation of glucose transporter 4 to the cell membrane and thereby increases glucose uptake. Further, metformin suppresses glucagon signaling in the liver by suppressing adenylate cyclase which leads to suppression of gluconeogenesis. In addition, metformin reduces autophagy failure observed in pancreatic β-cells under diabetic conditions. Furthermore, it is known that metformin alters the gut microbiome and facilitates the transport of glucose from the circulation into excrement. It is also known that metformin reduces food intake and lowers body weight by increasing circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15). Furthermore, much attention has been drawn to the fact that the frequency of various cancers is lower in subjects taking metformin. Metformin suppresses the mechanistic target of rapamycin (mTOR) by activating AMPK in pre-neoplastic cells, which leads to suppression of cell growth and an increase in apoptosis in pre-neoplastic cells. It has been shown recently that metformin consumption potentially influences the mortality in patients with type 2 diabetes mellitus and coronavirus infectious disease (COVID-19). Taken together, metformin is an old drug, but multifaceted mechanisms of action of metformin have been unraveled one after another in its long history.     

Radiophotoluminescence phenomenon in copper-doped aluminoborosilicate glass

Radiophotoluminescence phenomena have been widely investigated on various types of materials for dosimetry applications. We report that an aluminoborosilicate glass containing 0.005 mol% copper exhibits intense photoluminescence in the visible region induced by X-ray and γ-ray irradiation. The luminescence is assigned to the 3d⁹4s¹ → 3d¹⁰ transition of Cu⁺. The proportionality of the intensity of the induced photoluminescence to the irradiation dose was confirmed up to 0.5 kGy using ⁶⁰Co γ-ray irradiation. Based on the spectroscopic results, a potential mechanism was proposed for the enhancement of the photoluminescence. The exposure to the ionizing radiation generates electron-hole pairs in the glass, and the electrons are subsequently captured by the Cu²⁺ ions, which are converted to Cu⁺ and emit the luminescence. For the glass containing 0.01 mol% copper, the pronounced enhancement of the photoluminescence was not observed because the reverse reaction, ie, the capture of the holes by the Cu⁺ ions, becomes prominent. The photoluminescence induced by the irradiation was stably observed for the glasses kept at room temperature and even for the glasses heat-treated at 150°C. However, the induced photoluminescence could be eliminated by the heat treatment at a temperature at 500°C, and the glass returned to the initial pre-irradiation state. The Cu-doped aluminoborosilicate glass is a potential candidate for use in dosimetry applications.     

Cover Image,Volume 69, Issue 3

The cover image is based on the Mini‐Review Well‐defined, environment‐friendly synthesis of polypeptides based on phosgene‐free transformation of amino acids into urethane derivatives and their applications by Takeshi Endo et al., https://doi.org/10.1002/pi.5952 . Cover image © Takeshi Endo Images.

     

Glycoconjugated polymer 6. Synthesis of poly[styrene-<Emphasis Type="Italic">block</Emphasis>-(styrene-<Emphasis Type="Italic">graft</Emphasis>-amylose)] via potato phosphorylase-catalyzed polymerization

Summary The potato phosphorylase-catalyzed polymerization of α-D-glucose-1-phosphate (G-1-P) onto poly[styrene-block-(4-vinylbenzyl maltohexaoside)] (1) was performed at the molar ratios of [G-l-P]₀ and [maltohexaose]₀ of 35, 80, and 250. The product was found to be soluble in dimethyl sulfoxide, which was a good solvent for amylose, and showed the complex-formation with iodine, indicating that the product was assignable to poly[styrene-block-(styrene-graft-amylose)] (2). The quantitative analysis of the liberated phosphoric acid gave the average degree of polymerization o f the glucose unit (n) as 27, 5 1, and 180 for 2-I, 2-II, and 2-III, respectively. Received: 29 November 2002/Accepted: 22 December 2002 Correspondence to Toyoji Kakuchi     

On the one-wayness against chosen-plaintext attacks of the Loidreau's modified McEliece PKC

McEliece public-key cryptosystem (PKC) is one of a few alternatives for the current PKCs that are mostly based on either the integer factoring problem (IFP) or the discrete logarithm problem (DLP) that would be solved in polynomial time after the emergence of quantum computers. The security of the McEliece PKC is based on the decoding problem and it is known that it satisfies, with an appropriate conversion, the strongest security notion, i.e., INDistinguishability of encryption against adaptively Chosen-Ciphertext Attacks (IND-CCA2), in the random oracle model under the assumption that the underlying primitive McEliece PKC satisfies a weak security notion of One-Wayness against Chosen-Plaintext Attacks (OW-CPA). OW-CPA is said to be satisfied if it is infeasible for chosen plaintext attacks to recover the whole plaintext of an arbitrarily given ciphertext. Currently, the primitive McEliece PKC satisfies OW-CPA if a parameter n/spl ges/2048 with optimum t and k is chosen since the binary work factor for (n,k,t)=(2048,1278,70) to break it with the best CPA is around 2/sup 106/, which is infeasible even if world-wide computational power is used. While the binary work factor for the next smaller parameter n=1024 is in a gray level of 2/sup 62/, it will be improved by applying Loidreau's modification that employs Frobenius automorphism in Goppa codes. In this paper, we carefully investigate the one-wayness of the Loidreau's modified McEliece PKC against ever known CPAs and new CPAs we propose, and then show that it certainly improves the one-wayness against ever known CPAs but it is vulnerable against our new CPAs. Thus, it is rather harmful to apply the new modification to the McEliece PKC.     

Apoptosis occurs in granulosa cells but not cumulus cells in the atretic antral follicles in pig ovaries

The porcine antral follicles, 3-6 mm in diameter, were dissected from the ovaries of mature pigs, and then granulosa and cumulus cells were isolated from each follicle. In atretic follicles, high activity of neutral Ca2+/Mg2+-dependent endonuclease and DNA ladder formation, estimated by electrophoresis, were noted in granulosa cells but not in cumulus cells. Extremely low activity of the endonuclease and no DNA ladder formation were observed in both types of cells obtained from healthy follicles. Moreover, apoptotic cells were observed histochemically among granulosa cells only. A good correlation (r = 0.987) between the endonuclease activity of granulosa cells and the progesterone/estradiol ratio of follicular fluid in each follicle was found. These results suggest that apoptosis occurs in granulosa cells but not cumulus cells in the atretic antral follicles in pigs.     

Radiation therapy for stage I-II non-small cell lung cancer in patients aged 75 years and older

Vaccination with peptides that induce a specific immune response is a potential prophylactic or therapeutic strategy against viral infections and tumors. Because of the extensive polymorphism of the HLA loci, synthetic peptide vaccines must consist of a cocktail of peptides that bind specifically to different HLA molecules. Such cocktails should be optimized for the target population as each population has its specific HLA gene frequencies. To achieve maximum population coverage with a minimum number of peptides, information is needed on the ranking of the most frequent HLA phenotypes. We introduce the minimal phenotype panel, which is the smallest combination of HLA antigens selected so that the proportion of individuals in a population that express at least one of the antigens in the panel exceeds a desired minimum value. We developed a method for assembling minimal phenotype panels based on known HLA class I gene frequencies. We give an example based on a set of 2446 well-defined HLA-typed, random, healthy, unrelated, Dutch Caucasoid individuals. In addition, we discuss the possibility of assembling minimal phenotype panels based on two-locus haplotypes, which enables the assembly of phenotype panels from the antigens of both loci.     

Stereoselectivity in cutaneous hydrolysis and transdermal transport of propranolol prodrug

This review is written to evaluate the stereoselectivity in cutaneous hydrolysis and transdermal transport of propranolol prodrug. This discussion will be useful in the development of knowledge about stereoselective cutaneous hydrolysis and its influence on stereoselective transdermal transport of many other chiral prodrugs and drugs. Propranolol prodrugs undergo stereoselective hydrolysis in hairless mouse skin homogenate and in excised skin samples during permeation; the stereoselectivity is markedly biased towards hydrolysis of the (R) isomer. Unlike the liver, the esterase activity of the skin is high in its cytosolic fraction. Most of the lipophilic propranolol prodrugs cause stereoselective permeation across hairless mouse skin. A mechanism of stereoselective permeation of propranolol prodrug across the skin has been proposed, which indicates that the stereoselectivity in permeation is resulted from the stereoselective hydrolysis of lipophilic prodrug during permeation.