Facile synthesis of sulfinate esters from aryl iodides via direct oxidation of thioesters.

A practical method to synthesize sulfinate esters from aryl iodides is disclosed. Direct oxidation of thioesters prepared by copper-catalyzed C-S formation of aryl iodides realized the efficient synthesis of sulfinate esters. Due to the good accessibility of aryl iodides, a wide variety of sulfinate esters were prepared from easily available starting materials such as carboxylic acids and anilines.

Perturbation of monoamine metabolism and enhanced fear responses in mice defective in the regeneration of tetrahydrobiopterin.

Increasing evidence suggests the involvement of peripheral amino acid metabolism in the pathophysiology of neuropsychiatric disorders, whereas the molecular mechanisms are largely unknown. Tetrahydrobiopterin (BH4) is a cofactor for enzymes that catalyze phenylalanine metabolism, monoamine synthesis, nitric oxide production, and lipid metabolism. BH4 is synthesized from guanosine triphosphate and regenerated by quinonoid dihydropteridine reductase (QDPR), which catalyzes the reduction of quinonoid dihydrobiopterin. We analyzed Qdpr-/- mice to elucidate the physiological significance of the regeneration of BH4. We found that the Qdpr-/- mice exhibited mild hyperphenylalaninemia and monoamine deficiency in the brain, despite the presence of substantial amounts of BH4 in the liver and brain. Hyperphenylalaninemia was ameliorated by exogenously administered BH4, and dietary phenylalanine restriction was effective for restoring the decreased monoamine contents in the brain of the Qdpr-/- mice, suggesting that monoamine deficiency was caused by the secondary effect of hyperphenylalaninemia. Immunohistochemical analysis showed that QDPR was primarily distributed in oligodendrocytes but hardly detectable in monoaminergic neurons in the brain. Finally, we performed a behavioral assessment using a test battery. The Qdpr-/- mice exhibited enhanced fear responses after electrical foot shock. Taken together, our data suggest that the perturbation of BH4 metabolism should affect brain monoamine levels through alterations in peripheral amino acid metabolism, and might contribute to the development of anxiety-related psychiatric disorders. Cover Image for this issue: https://doi.org/10.1111/jnc.15398.

Diagnostic yield of seizure recordings and neuroimaging in patients with focal epilepsy without interictal epileptiform discharges.

OBJECTIVE: Repeated routine electroencephalography (EEG) or even long-term video-EEG monitoring (VEM) does not always record interictal epileptiform discharges (IEDs) in some patients with epilepsy. The present study investigated whether focal seizures detected by VEM and focal abnormalities on neuroimaging are useful for the diagnosis of patients with focal epilepsy without IEDs. METHODS: We retrospectively reviewed 409 consecutive patients with focal epilepsy (207 men, aged 9 to 76 years) who underwent 4- or 5-day VEM, magnetic resonance imaging (MRI), and fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) for diagnosis to identify patients without IEDs. The occurrence of focal seizures during VEM and the presence of focal abnormalities on neuroimaging were investigated in those patients. The occurrence rate of seizures during VEM was investigated in patients with daily, weekly, monthly, and yearly seizure frequency based on history-taking. RESULTS: Ninety-five (23.2%) of 409 patients with focal epilepsy did not have IEDs. Fifty-five (57.9%) of the 95 patients had focal seizures during VEM. Fifty-four patients (56.8%) showed focal abnormalities compatible with seizure semiology on neuroimaging investigations. Neither seizure recordings nor neuroimaging abnormalities were seen in 16 (16.8%) of the 95 patients. The occurrence rate of seizures during VEM depended on the seizure frequency at history-taking. However, 28 (45.9%) of 61 patients with monthly and yearly seizure frequency had focal seizures during 4- or 5-day VEM with seizure induction. CONCLUSIONS: Video-EEG monitoring can detect focal seizures in patients with focal epilepsy but no IEDs. Comprehensive assessment including VEM and neuroimaging study is important for the diagnosis.

Identifying a possible factor for the increased newborn size in singleton pregnancies after assisted reproductive technology using cryopreserved embryos, in comparison with fresh embryos.

PURPOSE: To determine whether the cycle regimens that are used for endometrial preparation are associated with the birthweight (BW) after assisted reproductive technology (ART) using frozen-thawed embryo transfer (FET). METHODS: The BW of singletons who were born by ART using FET was compared retrospectively, according to whether a FET was conducted in a hormone replacement therapy cycle (HRT, n = 403) or an ovulatory cycle (OVL, n = 117). The BW after timed intercourse (NAT, n = 162) also was investigated. RESULTS: There were no significant differences in the age of the mothers, percentage of primiparas, gestational periods, Body Mass Index, and sex ratio between the HRT and OVL cycles. The average BW from HRT was significantly greater than that of OVL. The BW from HRT was also greater, compared with NAT, while statistical significance was not achieved between OVL and NAT. The putative factors affecting the BW, such as ovarian stimulation protocols, endometrial thickness, and the stage and quality of embryos, could not explain the difference in the BW between the HRT and OVL cycles. CONCLUSION: An increased BW from ART using FET seems to be ascribable to conditions of the endometrium, but not cryopreservation procedures per se, which might provide a mechanistic framework for understanding heavier neonates who are born by FET.

Synthesis of 1,2,3-triazoles using Grignard reactions through the protection of azides.

An efficient method to prepare organomagnesium intermediates having a protected azido group is reported. Protection of azido groups with di-(tert-butyl)(4-(dimethylamino)phenylphosphine (amphos) and following iodine-magnesium exchange realized the preparation of organomagnesium intermediates, which served in the synthesis of diverse azides by transformation with various electrophiles followed by deprotection with elemental sulfur. Furthermore, click reactions of azides with alkynes enabled synthesizing a wide variety of 1,2,3-triazoles.

Palladium-Catalyzed Sulfinylation of Aryl- and Alkenylborons with Sulfinate Esters.

An efficient, direct sulfinylation of organoborons catalyzed by palladium is disclosed. Treatment of organoborons and sulfinate esters in the presence of a palladium precatalyst provided a broad range of sulfoxides. Various organosulfur compounds having oxidizable functional groups were successfully prepared through the sulfoxide synthesis.

LRRK2 phosphorylates tubulin-associated tau but not the free molecule: LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth.

Leucine-rich repeat kinase 2 (LRRK2), a large protein kinase containing multi-functional domains, has been identified as the causal molecule for autosomal-dominant Parkinson's disease (PD). In the present study, we demonstrated for the first time that (i) LRRK2 interacts with tau in a tubulin-dependent manner; (ii) LRRK2 directly phosphorylates tubulin-associated tau, but not free tau; (iii) LRRK2 phosphorylates tau at Thr181 as one of the target sites; and (iv) The PD-associated LRRK2 mutations, G2019S and I2020T, elevated the degree of tau-phosphorylation. These results provide direct proof that tau is a physiological substrate for LRRK2. Furthermore, we revealed that LRRK2-mediated phosphorylation of tau reduces its tubulin-binding ability. Our results suggest that LRRK2 plays an important role as a physiological regulator for phosphorylation-mediated dissociation of tau from microtubules, which is an integral aspect of microtubule dynamics essential for neurite outgrowth and axonal transport.

Stimulatory effect of α-synuclein on the tau-phosphorylation by GSK-3ß.

Hyperphosphorylation of tau protein (tau) causes neurodegenerative diseases such as Alzheimer's disease (AD). Recent studies of the physiological correlation between tau and α-synuclein (α-SN) have demonstrated that: (a) phosphorylated tau is also present in Lewy bodies, which are cytoplasmic inclusions formed by abnormal aggregation of α-SN; and (b) the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) increases the phosphorylation of tau as well as the protein level of α-SN in cultured neuronal cells, and also in mice. However, the molecular mechanism responsible for the α-SN-mediated hyperphosphorylation of tau remains to be elucidated. In this in vitro study, we found that: (a) α-SN directly stimulates the phosphorylation of tau by glycogen synthase kinase-3ß (GSK-3ß), (b) α-SN forms a heterotrimeric complex with tau and GSK-3ß, and (c) the nonamyloid beta component (NAC) domain and an acidic region of α-SN are responsible for the stimulation of GSK-3ß-mediated tau phosphorylation. Thus, it is concluded that α-SN functions as a connecting mediator for tau and GSK-3ß, resulting in GSK-3ß-mediated tau phosphorylation. Because the expression of α-SN is promoted by oxidative stress, the accumulation of α-SN induced by such stress may directly induce the hyperphosphorylation of tau by GSK-3ß. Furthermore, we found that heat shock protein 70 (Hsp70) suppresses the α-SN-induced phosphorylation of tau by GSK-3ß through its direct binding to α-SN, suggesting that Hsp70 acts as a physiological suppressor of α-SN-mediated tau hyperphosphorylation. These results suggest that the cellular level of Hsp70 may be a novel therapeutic target to counteract α-SN-mediated tau phosphorylation in the initial stage of neurodegenerative disease.

Preliminary survey of taxonomical problems, pharmacognostical characteristics, and chloroplast DNA polymorphisms of the folk medicinal herb Artemisia campestris from the Ryukyu Islands, Japan.

Artemisia campestris L. (Compositae) occurs naturally along the coastline of the Ryukyu Islands and has been traditionally used as a folk medicine for the treatment of liver and kidney disorders. The authors obtained specimens from the Ishigaki and Kume Islands of the Ryukyu Islands, Japan, and from the USA. A survey of the literature revealed that the Japanese name for A. campestris is Niitaka-yomogi or Riukiu-yomogi. Two distinct overall plant-form phenotypes were identified: an erect phenotype with long, upright, and straight main axis and assurgent branches; and a prostrate phenotype, having branches that are longer than the main axis and which grow along the ground. Except for the number of ray flowers, most of the flower head characters in the erect phenotypes were significantly larger than those in the prostrate phenotypes. In this experiment, the flower heads contained only small amounts of either capillarisin (<0.01-0.11 of the dry weight, % DW) and 6,7-dimethylesculetin (<0.01-0.30% DW), or none at all. DNA polymorphisms at two sites of the rpl16-rpl14 spacer region (nucleotide position 181-189 and 291-300 from the 5' end) revealed the existence of four different haplotypes. The number of adenines at nucleotide positions 291-300 appeared to be polymorphic within A. campestris from the Ryukyu Islands. Conversely, geographic differences between specimens from the Ryukyu Islands and USA manifested as a nine-base deletion at nucleotide positions 181-189. From a pharmacognostical context, the use of A. campestris flower heads as a substitute for Artemisiae capillaris Flos is not effective.