SMiPoly: Generation of a Synthesizable Polymer Virtual Library Using Rule-Based Polymerization Reactions.

Recent advances in machine learning have led to the rapid adoption of various computational methods for de novo molecular design in polymer research, including high-throughput virtual screening and inverse molecular design. In such workflows, molecular generators play an essential role in creation or sequential modification of candidate polymer structures. Machine learning-assisted molecular design has made great technical progress over the past few years. However, the difficulty of identifying synthetic routes to such designed polymers remains unresolved. To address this technical limitation, we present Small Molecules into Polymers (SMiPoly), a Python library for virtual polymer generation that implements 22 chemical rules for commonly applied polymerization reactions. For given small organic molecules to form a candidate monomer set, the SMiPoly generator conducts possible polymerization reactions to generate an exhaustive list of potentially synthesizable polymers. In this study, using 1083 readily available monomers, we generated 169,347 unique polymers forming seven different molecular types: polyolefin, polyester, polyether, polyamide, polyimide, polyurethane, and polyoxazolidone. By comparing the distribution of the virtually created polymers with approximately 16,000 real polymers synthesized so far, it was found that the coverage and novelty of the SMiPoly-generated polymers can reach 48 and 53%, respectively. Incorporating the SMiPoly library into a molecular design workflow will accelerate the process of de novo polymer synthesis by shortening the step to select synthesizable candidate polymers.

Exciton diffusion in amorphous organic semiconductors: Reducing simulation overheads with machine learning.

Simulations of exciton and charge hopping in amorphous organic materials involve numerous physical parameters. Each of these parameters must be computed from costly ab initio calculations before the simulation can commence, resulting in a significant computational overhead for studying exciton diffusion, especially in large and complex material datasets. While the idea of using machine learning to quickly predict these parameters has been explored previously, typical machine learning models require long training times, which ultimately contribute to simulation overheads. In this paper, we present a new machine learning architecture for building predictive models for intermolecular exciton coupling parameters. Our architecture is designed in such a way that the total training time is reduced compared to ordinary Gaussian process regression or kernel ridge regression models. Based on this architecture, we build a predictive model and use it to estimate the coupling parameters which enter into an exciton hopping simulation in amorphous pentacene. We show that this hopping simulation is able to achieve excellent predictions for exciton diffusion tensor elements and other properties as compared to a simulation using coupling parameters computed entirely from density functional theory. This result, along with the short training times afforded by our architecture, shows how machine learning can be used to reduce the high computational overheads associated with exciton and charge diffusion simulations in amorphous organic materials.

Corpus callosotomy in pediatric patients with non-lesional epileptic encephalopathy with electrical status epilepticus during sleep.

Epileptic encephalopathy with electrical status epilepticus during sleep (ESES) is often refractory to medical treatment and leads to poor cognitive outcomes. Corpus callosotomy may be an effective treatment option for drug-resistant ESES with no focal etiology. We retrospectively identified three patients who underwent corpus callosotomy for drug-resistant ESES in our institution. Electroencephalography (EEG) findings and cognitive functions were evaluated before surgery, at 3 months, 6 months, 1 year, and 2 years after surgery. Age at surgery was 6 years 10 months, 7 years 9 months, and 8 years 4 months, respectively. Period between the diagnosis of ESES and surgery ranged from 7 to 25 months. All patients had no obvious structural abnormalities and presented with cognitive decline despite multiple antiseizure medications and steroid therapies. One patient showed complete resolution of ESES and an improvement of intelligence quotient after surgery. Epileptiform EEG was lateralized to one hemisphere after surgery and spike wave index (SWI) was decreased with moderate improvement in development and seizures in the other 2 patients. SWI re-exacerbated from 6 months after surgery, but without subsequent developmental regression in these 2 patients. Corpus callosotomy may become an important treatment option for drug-resistant ESES in patients with no structural abnormalities.

Y chromosome analysis for common surnames in the Japanese male population.

For many years of Japan's long history, Japanese surnames have been handed down patrilineally. This study investigated relations between major surnames and Y chromosomal polymorphism among the Japanese male population. To analyze genetic phylogeny in namesakes, the Y-single nucleotide polymorphism (SNP) plus Y-short tandem repeat (STR) approach was employed. A haplogroup based on SNPs and haplotypes at 17 STR loci were typed in 567 unrelated volunteers recruited in Kanagawa, Japan. Samples covered 27 common surnames such as Satoh and Suzuki, each name having 10-55 bearers. Significant difference was found for SNP haplogroup compositions and a multidimensional scaling plot using STR haplotypes in several surname groups. By contrast, these common surnames displayed wide diversity with phylogenetic networks, suggesting that no genetic drift event has occurred in their history. In all, 22 descent clusters were found, as judgcriteria ed by ad hoc of groups within five mutational steps in the 15 STR loci with the same haplogroup. The times of the most recent common ancestor ranged from 279 to over 2577 years. According to the approximate millennium span of Japanese surname history, descent criteria are expected to be reasonable for grouping within four step-neighbors. High heterogeneity of common surnames resembles that observed for England and Spain, but not for Ireland. Our results highlight that common Japanese surnames consist of descent clusters and many singletons, reflecting a mixture of long-term bearers and short-term bearers among the population. The genetic study of this population revealed characteristic features of Japanese surnames.

Diapause hormone directly stimulates the prothoracic glands of diapause larvae under juvenile hormone regulation in the bamboo borer, Omphisa fuscidentalis Hampson.

Larval diapause in many lepidopteran insects is induced and maintained by high juvenile hormone (JH). In the case of the bamboo borer, Omphisa fuscidentalis, the effect of JH is the opposite: The application of juvenile hormone analog (JHA: S-methoprene) terminates larval diapause, unlike in other insect species. Here, we analyzed the expression of JH-receptor Met, DH-PBAN, and Kr-h1 in the subesophageal ganglion (SG) from October to April using semi-quantitative polymerase chain reaction (PCR). The results show that OfMet and OfDH-PBAN messenger RNA in the SG are mainly expressed during the larval diapause stage, while OfKr-h1 increases during the pupal stage. Using tissue culture techniques and an enzyme-linked immunosorbent assay (ELISA), diapause hormone (DH) was found to induce ecdysteroidogenesis in the culture medium of the prothoracic gland (PG) after incubation for 30 min with 25 ng and 50 ng of DH. Thus, DH is a novel stimulator for the PG. We identified a DHR homolog in the bamboo borer and confirmed that it is expressed in the PG. In addition, for in vitro experiments, DH increased the expression levels of OfDHR, OfEcR-A, and ecdysone-inducible genes in the PG. These results demonstrate that DH can function as a prothoracicotropic factor, and this function of DH might be through of DHR expressed on PG cells. Consequently, DH is one of the key factors in larval diapause break which is triggered by JH in the bamboo borer, O. fuscidentalis.

Remission of light chain proximal tubulopathy in IgG λ-type multiple myeloma by lenalidomide and dexamethasone therapy.

Light chain proximal tubulopathy is a rare manifestation of monoclonal gammopathy. A 73-year-old Japanese woman was noted to have urinary protein and hypertension on health examination and visited the regional clinic. She was noted to have IgG λ M protein and suspected of multiple myeloma. She was referred to us with massive proteinuria (7.5 g/g creatinine) and Bence Jones proteinuria without renal dysfunction. A renal biopsy revealed no glomerular abnormalities, but a tubular cast was observed partially in tubules without tubular atrophy or a crystalline structure. Direct Fast Scarlet staining was absent both in glomerulus and vascular wall. Immunofluorescence revealed λ light chain (LC) staining in the proximal tubules. Electron microscopy revealed nonspecific findings including increased lysosomes with irregular contours and mottled appearance. A bone marrow biopsy revealed plasma cell proliferation (35%) and multiple myeloma immunoglobulin G λ type. She showed progressive anemia and decrease of eGFR with elevated level of urinary ß-2 microglobulin. She was treated with lenalidomide + dexamethasone (Ld). With Ld therapy, she achieved hematologic and nephrologic remission reducing the free LC, λ/κ ratio, urinary protein level, and urinary ß-2 microglobulin level.

Intractable epilepsy due to a rosette-forming glioneuronal tumor with a dysembryoplastic neuroepithelial background.

A rosette-forming glioneuronal tumor (RGNT) was initially reported as an infratentorial tumor that comprised both small neurocytic rosettes and astrocytic components. However, a few studies have reported supratentorial RGNTs arising in the cerebral hemispheres. Here, we report an unusual case involving a 9-year-old boy with a supratentorial RGNT who presented with intractable epilepsy and behavioral changes. Brain MRI revealed a well-circumscribed space-occupying lesion with septae in the right inferomedial parietal lobe. Electroencephalography showed multifocal spikes over the right frontal, temporal and parietal regions. The seizure frequency decreased dramatically after tumorectomy. Histopathological examination revealed prominent neurocytic rosette formation appearing with the specific glioneuronal element of a dysembryoplastic neuroepithelial tumor (DNT). Although the pathogenesis has not been elucidated, a supratentorial RGNT presenting with epilepsy may exhibit a rosette component, which is the major feature of this tumor, against the background of a specific glioneuronal element mimicking DNT. However, RGNT arising in regions other than the fourth ventricle is rare, and the pathogenesis of epilepsy due to RGNT has not been fully elucidated. Further clinical and histological studies are required to understand the pathology underlying epilepsy caused by RGNT.

[A Case of Severe Legionella longbeachae Pneumonia and Usefulness of LAMP Assay].

Urinary antigen test is frequently used as a routine laboratory test for early diagnosis of Legionella infection, which is especially suitable for ordinary Legionella pneumophila serogroup 1, but not for other types of Legionella. We report a case of severe pneumonia caused by Legionella longbeachae, where a method of loop-mediated isothermal amplification (LAMP) assay contributed an important role for the early detection. This case involved an 83-year-old man who developed fever, dyspnea, and productive cough. Since the medication of prescribed ceftriaxone had not been effective, he visited the emergency room of our hospital, where an X-ray revealed a severe pneumonia harboring a consolidation with air bronchogram in his right lower lung. His sputum and urine were subjected to the routine bacterial culture or the urinary antigen test for Legionella, which initially brought negative results. However, a positive result of LAMP assay enabled early diagnosis of Legionella pneumonia. Later, the bacterial cultures of sputum made some progress and 16S rRNA sequencing provided a proof of L. longbeachae. This LAMP assay may bring a benefit for the patients with Legionella pneumonia by enabling early detection of not only specific L. pneumophila serogroup 1, but also of the other Legionella species.

Larval diapause termination in the bamboo borer, Omphisa fuscidentalis.

In insects, juvenile hormone (JH) and 20-hydroxyecdysone (20E) regulate larval growth and molting. However, little is known about how this cooperative control is terminating larval diapause especially in the bamboo borer, Omphisa fuscidentalis. In both in vivo and in vitro experiments, we here measured the expression levels of genes which were affected by juvenile hormone analogue (JHA: S-methoprene) and 20-hydroxyecdysone (20E) in diapausing O. fuscidentalis larvae. Corresponding mRNA expression changes in the subesophageal ganglion (SG) and prothoracic gland (PG) were evaluated using qRT-PCR. The data showed similar response patterns of JH receptor gene (OfMet), diapause hormone gene (OfDH-PBAN), ecdysone receptor genes (OfEcR-A and OfEcR-B1) and ecdysone inducible genes (OfBr-C, OfE75A, OfE75B, OfE75C and OfHR3). JHA induced the expressions of OfMet and OfDH-PBAN in both SG and PG, whereas ecdysone receptor genes and ecdysone inducible genes were induced by JHA only in PG. For 20E treatment group, expressions of ecdysone receptor genes and ecdysone inducible genes in both SG and PG were increased by 20E injection. In addition, the in vitro experiments showed that OfMet and OfDH-PBAN were up-regulated by JHA alone, but ecdysone receptor genes and ecdysone inducible genes were up-regulated by JHA and 20E. However, OfMet and OfDH-PBAN in the SG was expressed faster than OfMet and OfDH-PBAN in the PG and the expression of ecdysone receptor genes and ecdysone inducible genes induced by JHA was much later than observed for 20E. These results indicate that JHA might stimulate the PG indirectly via factors (OfMet and OfDH-PBAN) in the SG, which might be a regulatory mechanism for larval diapause termination in O. fuscidentalis.

Comparison of hard tissues that are useful for DNA analysis in forensic autopsy.

Forensic analysis of DNA from hard tissues can be important when investigating a variety of cases resulting from mass disaster or criminal cases. This study was conducted to evaluate the most suitable tissues, method and sample size for processing of hard tissues prior to DNA isolation. We also evaluated the elapsed time after death in relation to the quantity of DNA extracted. Samples of hard tissues (37 teeth, 42 skull, 42 rib, and 39 nails) from 42 individuals aged between 50 and 83 years were used. The samples were taken from remains following forensic autopsy (from 2 days to 2 years after death). To evaluate the integrity of the nuclear DNA isolated, the percentage of allele calls for short tandem repeat profiles were compared between the hard tissues. DNA typing results indicated that until 1 month after death, any of the four hard tissue samples could be used as an alternative to teeth, allowing analysis of all of the loci. However, in terms of the sampling site, collection method and sample size adjustment, the rib appeared to be the best choice in view of the ease of specimen preparation. Our data suggest that the rib could be an alternative hard tissue sample for DNA analysis of human remains.

Allatotropin inhibits juvenile hormone biosynthesis by the corpora allata of adult Bombyx mori.

Juvenile hormone (JH) synthesis by the corpora allata (CA) does not occur during the pupal stage in both male and female Bombyx mori but begins shortly before adult ecdysis and thereafter only in females. JH biosynthesis in female adults was prevented by allatotropin (AT) through the corpora cardiaca (CC) and the tightly attached oesophagus before adult ecdysis, but after ecdysis, removal of the CC had little effect and only the oesophagus was necessary for AT to prevent JH synthesis. AT could not prevent JH synthesis by the CA alone in either stage. Short neuropeptide F (sNPF) acted directly on the CA, preventing JH biosynthesis without preventing the JH biosynthetic enzymes before adult ecdysis, but had little effect after ecdysis, indicating that the action of AT was not via sNPF. The inhibition of JH synthesis by AT was indirect. Both AT and a factor(s) from the AT-stimulated oesophagus through the CC were necessary for the inhibitory action, which was due to the prevention of some of the JH biosynthetic enzymes. These results clearly show that AT prevents JH synthesis in adult CA in B. mori, although AT stimulates JH biosynthesis by the CA in several insect species.

Short neuropeptide F (sNPF) is a stage-specific suppressor for juvenile hormone biosynthesis by corpora allata, and a critical factor for the initiation of insect metamorphosis.

Molting and metamorphosis are essential events for arthropod development, and juvenile hormone (JH) and its precursors play critical roles for these events. We examined the regulation of JH biosynthesis by the corpora allata (CA) in Bombyx mori, and found that intact brain-corpora cardiaca (CC)-CA complexes produced a smaller amount of JH than that in CC-CA complexes and CA alone throughout the 4th and 5th (last) instar stadium. The smaller amount of synthesis was due to allatostatin-C (AST-C) produced by the brain. The CC synthesized short neuropeptide F (sNPF) that also suppressed the JH synthesis, but only in day 3 4th stadium and after the last larval ecdysis. For the suppression, both peptides prevented the expression of some of the distinct JH biosynthetic enzymes in the mevalonate pathway. Allatotropin (AT) stimulated sNPF expression in the CC of day 1 5th instar stadium, not of day 3 4th; therefore the stage-specific inhibition of JH synthesis by sNPF was partly due to the stimulative action of AT on the sNPF expression besides the stage-specific expression of the sNPF receptors in the CA, the level of which was high in day 2 4th and day 0 5th instar larvae. The cessation of JH biosynthesis in the last instar larvae is a key event to initiate pupal metamorphosis, and both sNPF and AST-C are key factors in shutting down JH synthesis, along with the decline of ecdysone titer and dopamine.

Surgical management of cortical dysplasia in infancy and early childhood.

PURPOSE: To describe operative procedures, seizure control and complications of surgery for cortical dysplasia (CD) causing intractable epilepsy in infancy and early childhood. METHODS: Fifty-six consecutive children (less than 6years old) underwent resective epilepsy surgery for CD from December 2000 to August 2011. Age at surgery ranged from 2 to 69months (mean 23months) and the follow-up was from 1 to 11years (mean 4years 4months). RESULTS: Half of the children underwent surgery during infancy at an age less than 10months, and the majority (80%) of these infants needed extensive surgical procedures, such as hemispherotomy and multi-lobar disconnection. Seizure free (ILAE class 1) outcome was obtained in 66% of the cases (class 1a; 55%): 85% with focal resection (n=13), 50% with lobar resection (n=18), 71% with multilobar disconnection (n=7) and 67% with hemispherotomy (n=18). Peri-ventricular and insular structures were resected in 23% of focal and 61% of lobar resections. Repeated surgery was performed in 9 children and 5 (56%) became seizure free. Histological subtypes included hemimegalencephaly (16 patients), polymicrogyria (5 patients), and FCD type I (6 patients), type IIA (19 patients), type IIB (10 patients). Polymicrogyria had the worst seizure outcome compared to other pathologies. Surgical complications included 1 post-operative hydrocephalus, 1 chronic subdural hematoma, 2 intracranial cysts, and 1 case of meningitis. No mortality or severe morbidities occurred. CONCLUSIONS: Early surgical intervention in children with CD and intractable seizures in infancy and early childhood can yield favorable seizure outcome without mortality or severe morbidities although younger children often need extensive surgical procedures.

The reaction mechanism of Claisen rearrangement obtained by transition state spectroscopy and single direct-dynamics trajectory.

Chemical bond breaking and formation during chemical reactions can be observed using "transition state spectroscopy". Comparing the measurement result of the transition state spectroscopy with the simulation result of single direct-dynamics trajectory, we have elucidated the reaction dynamics of Claisen rearrangement of allyl vinyl ether. Observed the reaction of the neat sample liquid, we have estimated the time constants of transformation from straight-chain structure to aromatic-like six-membered ring structure forming the C¹-C6 bond. The result clarifies that the reaction proceeds via three steps taking longer time than expected from the gas phase calculation. This finding provides new hypothesis and discussions, helping the development of the field of reaction mechanism analysis.

Hormonal regulation of insect metamorphosis with special reference to juvenile hormone biosynthesis.

Ecdysteroids and juvenile hormones (JHs) are key hormones that are responsible for insect molting and metamorphosis. JH maintains the larval state and the decline of its level in the hemolymph is crucial to elicit transformation to the pupal stage; therefore, the precise control of JH biosynthesis is necessary for normal development and the initiation of metamorphosis. This chapter summarizes mechanisms of the regulation of JH biosynthesis by the corpora allata and shows that several factors such as ecdysteroids, neurotransmitters, and peptides act together in the stage-specific manner to guarantee the accurate production of JH in each stage, in particular, in the last larval stage when metamorphosis is initiated with the transformation of the larva to the pupa. In addition, recent progress in understanding the JH signaling pathway is briefly discussed, including the identification of a long elusive JH receptor.

High gamma activity of 60-70 Hz in the area surrounding a cortical tuber in an infant with tuberous sclerosis.

PURPOSE: To detect the epileptogenic region causing epileptic spasms in an infant with tuberous sclerosis (TS). METHODS: We applied a multiple band frequency analysis to video electroencephalographic (EEG) recordings of the infant's scalp. We also performed computed tomography (CT), magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), and magnetoencephalography (MEG) of the brain in order to ascertain the epileptic focus. RESULTS: During the periodic spasms, we identified fast ictal activity with frequencies of 60-70 Hz in the right centroparietal region. This region was part of the area surrounding the largest cortical tuber that was identified on CT and MRI and was located in the right frontal lobe. An area of increased blood perfusion that was observed with SPECT and dipole sources that were determined with interictal MEG were also located in this area. In addition, ictal frequency oscillations (FOs) with high gamma activity were identified over the cortex surrounding the largest tuber. After a lesionectomy of this tuber, the periodic spasms disappeared, and no FOs were detected over this area. CONCLUSIONS: Scalp EEG, which identified the ictal onset zone by detecting fast activity that was suggestive of FOs, was useful for detecting the epileptogenic region in an infant with TS.

8p deletion and 9p duplication in two children with electrical status epilepticus in sleep syndrome.

We describe two individuals with the same chromosomal aberrations derived from an unbalanced translocation between chromosomes 8p and 9p, who presented with intellectual disabilities, dysmorphic features, and localization-related epilepsy. Several years after the onset of epilepsy, aggravation of widespread epileptic discharges during sleep resulted in the emergence of absence and/or atonic seizures in both patients; one patient additionally presented with psychomotor deterioration. These symptoms completely disappeared after treatment with ethosuximide and benzodiazepines, and marked improvement was observed in electroencephalographic findings. We review the clinical features of der(8)t(8;9) with particular focus on epileptic complications. We conclude that particular types of chromosomal aberrations may have a propensity to develop the condition categorized as electrical status epilepticus in sleep.

Larval fat body cells die during the early pupal stage in the frame of metamorphosis remodelation in Bombyx mori.

In holometabolus insects, morphology of the larval fat body is remodeled during metamorphosis. In higher Diptera, remodeling of the fat body is achieved by cell death of larval fat body cells and differentiation of the adult fat body from primordial cells. However, little is known about remodeling of the fat body at pupal metamorphosis in Lepidoptera. In this study, we found that cell death of the larval fat body in Bombyx mori occurs at shortly after pupation. About 30% of the fat body cells underwent cell death on days 1 and 2 after pupation. The cell death involved genomic DNA fragmentation, a characteristic of apoptosis. Surgical manipulation and in vitro culture of fat body cells revealed that 20-hydroxyecdysone and juvenile hormone had no effect on either initiation or progression of cell death. During cell death, a large increase in activity of caspase-3, a key enzyme of cell death, was observed. Western blot analysis of the active form of caspase-3-like protein revealed that the length of caspase-3 of B. mori was much larger than that of caspase-3 in other species. The results suggest that larval fat body cells of B. mori are removed through cell death, which is mediated by a caspase probably categorized in a novel family.

An anti-juvenile hormone agent, ethyl 4-(2-benzylhexyloxy)benzoate, inhibits juvenile hormone synthesis through the suppression of the transcription of juvenile hormone biosynthetic enzymes in the corpora allata in Bombyx mori.

Ethyl 4-[(S)-2-benzylhexyloxy)]benzoate (KF-13S), derived from ethyl 4-[2-(tert-butylcarbonyloxy)butoxy]benzoate (ETB), has strong anti-juvenile hormone (JH) activity which causes precocious metamorphosis in Bombyx mori, and the mode of action of this compound was studied. Application of KF-13S inhibited JH biosynthesis by the corpora allata (CA) in a reversible manner, and in vitro culture experiments showed that this inhibition was due to the direct action of this compound on the CA. When mRNA expression of the JH biosynthetic enzymes were studied, KF-13S strongly suppressed those of HMG Co-A synthase and HMG Co-A reductase. mRNA levels of other mevalonate enzymes and JH acid O-methyltransferase were also suppressed but were less sensitive to the compound. These studies showed that KF-13S prevents the transcription of many of the JH biosynthetic enzymes so that JH synthesis is suppressed.

Stage-specific regulation of juvenile hormone biosynthesis by ecdysteroid in Bombyx mori.

In the penultimate (4th) instar larvae of Bombyx mori, juvenile hormone (JH) synthesis by corpora allata (CA) fluctuates. When diet containing 20-hydroxyecdysone (20E) was fed, JH synthetic activity of the CA was first stimulated as the ecdysteroid titer increased, then suppressed slightly by the higher molting concentration of ecdysteroids (>250 ng/ml). The overall JH biosynthetic activity was modulated by the expression of JH biosynthetic enzymes in the CA: primarily JH acid O-methyltransferase (JHAMT), isopentenyl diphosphate isomerase, and farnesyl diphosphate synthase 1. After the last (5th) larval ecdysis, the artificially increased high ecdysteroid level due to the 20E diet activated JH synthesis by the CA, which required intact nervous connections with the brain. A factor(s) from the 20E-activated brain controls mainly JHAMT and HMG Co-A reductase expression to stimulate the JH synthesis. In the normal last instar larvae, the ecdysteroid titer declines so that these activation mechanisms are absent; therefore the decline of the ecdysteroid titer after the final larval ecdysis is one of the factors which induces the cessation of the JH synthesis by CA.