211At on gold nanoparticles for targeted radionuclide therapy application.

Targeted alpha therapy (TAT) is a methodology that is being developed as a promising cancer treatment using the α-particle decay of radionuclides. This technique involves the use of heavy radioactive elements being placed near the cancer target area to cause maximum damage to the cancer cells while minimizing the damage to healthy cells. Using gold nanoparticles (AuNPs) as carriers, a more effective therapy methodology may be realized. AuNPs can be good candidates for transporting these radionuclides to the vicinity of the cancer cells since they can be labeled not just with the radionuclides, but also a host of other proteins and ligands to target these cells and serve as additional treatment options. Research has shown that astatine and iodine are capable of adsorbing onto the surface of gold, creating a covalent bond that is quite stable for use in experiments. However, there are still many challenges that lie ahead in this area, whether they be theoretical, experimental, and even in real-life applications. This review will cover some of the major developments, as well as the current state of technology, and the problems that need to be tackled as this research topic moves along to maturity. The hope is that with more workers joining the field, we can make a positive impact on society, in addition to bringing improvement and more knowledge to science.

Mother/offspring co-administration of the traditional herbal remedy yokukansan during the nursing period influences grooming and cerebellar serotonin levels in a rat model of neurodevelopmental disorders.

Neurodevelopmental impairment in the serotonergic system may be involved in autism spectrum disorder. Yokukansan is a traditional herbal remedy for restlessness and agitation in children, and mother-infant co-administration (MICA) to both the child and the nursing mother is one of the recommended treatment approaches. Recent studies have revealed the neuropharmacological properties of Yokukansan (YKS), including its 5-HT1A (serotonin) receptor agonistic effects. We investigated the influence of YKS treatment on behavior in a novel environment and on brain monoamine metabolism during the nursing period in an animal model of neurodevelopmental disorders, prenatally BrdU (5-bromo-2'-deoxyuridine)-treated rats (BrdU-rats). YKS treatment did not influence locomotor activity in BrdU-rats but reduced grooming in open-field tests. YKS treatment without MICA disrupted the correlation between locomotor behaviors and rearing and altered levels of serotonin and its metabolite in the cerebellum. These effects were not observed in the group receiving YKS treatment with MICA. These data indicate a direct pharmacological effect of YKS on the development of grooming behavior and profound effects on cerebellar serotonin metabolism, which is thought to be influenced by nursing conditions.

Tailor-made TALEN system for highly efficient targeted gene replacement in the rice blast fungus.

Genetic manipulation is key to unraveling gene functions and creating genetically modified strains of microbial organisms. Recently, engineered nucleases that can generate DNA double-strand breaks (DSBs) at a specific site in the desired locus within genome are utilized in a rapidly developing genome editing technology via DSBs repair. However, the use of engineered nucleases in filamentous fungi has not been validated. In this study, we demonstrated that tailor-made transcriptional activator-like effector nucleases (TALENs) system, Platinum-Fungal TALENs (PtFg TALENs), could improve the efficiency of homologous recombination-mediated targeted gene replacement by up to 100% in the rice blast fungus Pyricularia oryzae. This high-efficiency PtFg TALEN has great potential for basic and applied biological applications in filamentous fungi.

Tailor-made CRISPR/Cas system for highly efficient targeted gene replacement in the rice blast fungus.

CRISPR/Cas-derived RNA-guided nucleases (RGNs) that can generate DNA double-strand breaks (DSBs) at a specific sequence are widely used for targeted genome editing by induction of DSB repair in many organisms. The CRISPR/Cas system consists of two components: a single Cas9 nuclease and a single-guide RNA (sgRNA). Therefore, the system for constructing RGNs is simple and efficient, but the utilization of RGNs in filamentous fungi has not been validated. In this study, we established the CRISPR/Cas system in the model filamentous fungus, Pyricularia oryzae, using Cas9 that was codon-optimized for filamentous fungi, and the endogenous RNA polymerase (RNAP) III U6 promoter and a RNAP II fungal promoter for the expression of the sgRNA. We further demonstrated that RGNs could recognize the desired sequences and edit endogenous genes through homologous recombination-mediated targeted gene replacement with high efficiency. Our system will open the way for the development of various CRISPR/Cas-based applications in filamentous fungi.

Second thresholds in BEC-BCS-laser crossover of exciton-polariton systems.

The mechanism of second thresholds observed in several experiments is theoretically revealed by studying the BEC-BCS-laser crossover in exciton-polariton systems. We find that there are two different types of second thresholds: one is a crossover within quasiequilibrium phases and the other is into nonequilibrium (lasing). In both cases, the light-induced band renormalization causes gaps in the conduction and valence bands, which indicates the existence of bound electron-hole pairs in contrast to earlier expectations. We also show that these two types can be distinguished by the gain spectra.

Excitons and biexcitons in symmetric electron-hole bilayers.

Symmetric electron-hole bilayer systems have been studied at zero temperature using the diffusion quantum Monte Carlo method. A flexible trial wave function is used that can describe fluid, excitonic, and biexcitonic phases. We calculate condensate fractions and pair correlation functions for a large number of densities r(s) and layer separations d. At small d we find a one-component fluid phase, an excitonic fluid phase, and a biexcitonic fluid phase, and the transitions among them appear to be continuous. At d=0, excitons appear to survive down to about r(s)=0.5 a.u., and biexcitons form at r(s)>2.5 a.u.

Transcriptomics and proteomics analyses of the PACAP38 influenced ischemic brain in permanent middle cerebral artery occlusion model mice.

INTRODUCTION: The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is considered to be a potential therapeutic agent for prevention of cerebral ischemia. Ischemia is a most common cause of death after heart attack and cancer causing major negative social and economic consequences. This study was designed to investigate the effect of PACAP38 injection intracerebroventrically in a mouse model of permanent middle cerebral artery occlusion (PMCAO) along with corresponding SHAM control that used 0.9% saline injection. METHODS: Ischemic and non-ischemic brain tissues were sampled at 6 and 24 hours post-treatment. Following behavioral analyses to confirm whether the ischemia has occurred, we investigated the genome-wide changes in gene and protein expression using DNA microarray chip (4x44K, Agilent) and two-dimensional gel electrophoresis (2-DGE) coupled with matrix assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS), respectively. Western blotting and immunofluorescent staining were also used to further examine the identified protein factor. RESULTS: Our results revealed numerous changes in the transcriptome of ischemic hemisphere (ipsilateral) treated with PACAP38 compared to the saline-injected SHAM control hemisphere (contralateral). Previously known (such as the interleukin family) and novel (Gabra6, Crtam) genes were identified under PACAP influence. In parallel, 2-DGE analysis revealed a highly expressed protein spot in the ischemic hemisphere that was identified as dihydropyrimidinase-related protein 2 (DPYL2). The DPYL2, also known as Crmp2, is a marker for the axonal growth and nerve development. Interestingly, PACAP treatment slightly increased its abundance (by 2-DGE and immunostaining) at 6 h but not at 24 h in the ischemic hemisphere, suggesting PACAP activates neuronal defense mechanism early on. CONCLUSIONS: This study provides a detailed inventory of PACAP influenced gene expressions and protein targets in mice ischemic brain, and suggests new targets for thereaupetic interventions.

What determines the wave function of electron-hole pairs in polariton condensates?

The ground state of a microcavity polariton Bose-Einstein condensate is determined by considering experimentally tunable parameters such as excitation density and detuning. During a change in the ground state of Bose-Einstein condensate from excitonic to photonic, which occurs as the excitation density is increased, the origin of the binding force of electron-hole pairs changes from Coulomb to photon-mediated interactions. The change in the origin gives rise to the strongly bound pairs with a small radius, like Frenkel excitons, in the photonic regime. The phase diagram obtained provides valuable information that can be used to build theoretical models for each regime.

Predictors of antidepressant adherence: results of a Japanese Internet-based survey.

AIM: The purpose of the present study was to identify the psychosocial/pharmacological predictors of antidepressant (AD) adherence. METHODS: An Internet-based survey was conducted among 1151 Japanese individuals with major depressive disorder. Subjects were asked to report their degree of non-adherence for each AD taken using a 5-point Likert scale: 0, never forget; 1, rarely forget; 2, occasionally forget; 3, sometimes forget; and 4, often forget. The highest number reported among each subject was assigned as their low adherence index (LAI). Individuals with an LAI > or = 3 were defined as members of the low adherence (LA) group. Predictors of LA was analyzed using bivariate and multivariate models, both among the total number of subjects and single AD subgroup (n = 657). RESULTS: Nearly one-third of subjects (n = 381, 33.1%) reported LA. On bivariate analysis, LA was associated with lower age, worker or student status (vs unemployed or housewife), higher daily dosing frequency (DDF), low drug satisfaction, and a neutral/negative doctor-patient relationship (DPR; P < 0.001). In a multivariate model, LA was predicted by age (< or =34 years: odds ratio [OR], 1.64), worker or student status (OR, 1.87), higher DDF (> or =twice daily: OR, 1.61), and neutral/negative DPR (OR, 1.54; P < 0.01). Among the single-AD subgroup, adherence was similar between those on selective serotonin reuptake inhibitors/serotonin-noradrenaline reuptake inhibitors and tricyclics. Use of neither medication was associated with adherence in a multivariate model. CONCLUSION: LA was predicted by lower age, worker or student status, higher DDF, and neutral/negative DPR. Adherence was not significantly different between subjects on newer agents and tricyclics.

Modified electroconvulsive therapy for recurrent major depressive disorder in a meningioma patient: a case report of clinical experience.

Electroconvulsive therapy (ECT) is primarily indicated for mood disorders and schizophrenia. Clinicians may encounter cases in which ECT is administered to patients with various kinds of complications. However, to our knowledge, no detailed medical guideline is available about the indications for ECT in psychiatric illness complicated with a concomitant brain tumor, which is one of the most likely physical complications that can directly affect ECT. We report a case in which 3 courses of modified ECT (m-ECT) were successfully administered without any neurological deterioration to a patient, who was frequently hospitalized for recurrent depressive disorder with stupor. We did not undertake any additional measures for reducing adverse events derived from the meningioma during m-ECT. In this report, we discuss the relation between brain tumor and depression.

Characteristic behavioral anomalies in rats prenatally exposed to 5-bromo-2'-deoxyuridine.

The aim of the present study was to characterize behavioral anomalies in rats prenatally exposed to 5-bromo-2'-deoxyuridine, a useful model of hyperactive disorder. Rats were treated with BrdU at 50mg/kg IP or carboxymethylcellulose, its vehicle, on gestational Days 9 through 15, and their offsprings were subjected to behavioral tests. Rats prenatally exposed to 5-bromo-2'-deoxyuridine showed higher locomotor activity levels when the lights were turned off, and these levels kept increasing throughout the dark cycle. In an elevated plus maze, the rats prenatally exposed to 5-bromo-2'-deoxyuridine exhibited decreased anxiety-related behavior, including higher open arm entries and a longer time spent per one open arm entry when compared with rats prenatally exposed to carboxymethylcellulose. Methylphenidate, a psychostimulant that suppresses hyperactivity in humans with attention-deficit hyperactivity disorder, increased locomotor activity in both rats, with a greater sensitivity in rats prenatally exposed to 5-bromo-2'-deoxyuridine. Desipramine, a specific noradrenaline uptake inhibitor, normalized the hyperactivity of rats prenatally exposed to 5-bromo-2'-deoxyuridine. Paroxetine, a selective serotonin reuptake inhibitor, also normalized the hyperactivity and the low anxiety-related behavior in the elevated plus maze. These results suggest that rats prenatally exposed to 5-bromo-2'-deoxyuridine are hyperactive and exhibit a lower anxiety level. Dysfunctional monoaminergic neurons may be, at least in part, the cause of the behavioral anomalies.

Induction of a thoracolumbar supernumerary rib in rat developmental toxicity studies: A short discussion on the critical window.

Thoracolumbar supernumerary ribs (TSRs) are classified as less severe skeletal anomalies in rat developmental toxicity studies, although their incidence is relatively high in rodent studies. To investigate the characteristics of the critical window for chemically-induced TSR, in this study, rats were administered 5-fluorocytocine (5-FC) or sodium salicylate (SAL) at one of three time periods on gestational day (GD) 9, early morning (7:00 am), midday (12:00 pm to 1:00 pm), or late afternoon (4:00 pm or 7:00 pm). The incidence of TSR and other anomalies were assessed in GD20 fetuses. A single treatment with both chemicals on GD9-induced TSR, with the incidence highest when administered at 7:00 Am, decreasing gradually when administered later. This trajectory was clearer in rats treated with 5-FC than with SAL. The critical period of TSR induction is shorter in rats administered 5-FC than SAL. The characteristics of the critical window may cause variability in the incidence of TSR observed in developmental toxicity studies.

Lithium-induced Hashimoto's encephalopathy: a case report.

OBJECTIVE: To report on a patient with Hashimoto's encephalopathy induced by lithium. PATIENT AND INTERVENTIONS: A 61-year-old woman with a type II bipolar disorder and a history of lithium-induced thyrotoxicosis associated with silent thyroiditis was hospitalized to treat a severe major depressive episode. Given long-term treatment with levothyroxine for hypothyroidism that had resulted from silent thyroiditis, endogenous hormone in thyroid follicles was assumed to be minimized by the negative feedback, decreasing risk of recurrent thyrotoxicosis if lithium were restarted. RESULTS: Lithium clearly relieved the patient's depressive symptoms, but after 40 days encephalopathy developed. Thyrotoxicosis was ruled out, and serum antithyroid antibody titers were elevated. In the cerebrospinal fluid, protein content was substantially elevated and antithyroid antibodies were detected. Encephalopathy resolved dramatically after course of intravenous pulse therapy with methylprednisolone. CONCLUSIONS: We believe that autoantibodies against antigens shared by the thyroid gland and the brain were induced by exposure to lithium, causing the patient to develop Hashimoto's encephalopathy.

Alcohol exposure alters cell cycle and apoptotic events during early neurulation.

BACKGROUND: Fetal alcohol exposure causes growth deficits, microencephaly, and neurological abnormalities. Although the effects of alcohol on developmental delay and growth-related deficits have been hypothesized, little is understood about how alcohol alters, in particular, the cyclin pathway within the cell cycle, which is critical to proliferation and apoptotic control. In this study, we examined cell cycle proteins pertinent to the G1-S phase transition and apoptosis, to determine if cell cycle misregulation can be attributed to apoptotic induction and growth defects. METHODS: We examined cell cycle regulation during G1 and S-phase, and DNA fragmentation damage, using E14 dorsal root ganglia neural stem cells (DRG-NC), and cultured mouse embryos exposed to 200 and 400 mg/dl ethanol. RESULTS: Alcohol-exposed DRG-NC demonstrated a dose-dependent increase in cells expressing increased cyclin D1 protein, and increased DNA fragmentation. Western blot analysis, using embryos, demonstrated an overexpression of cyclin D1, D2, and E2F1, key G1 to S-phase cell cycle regulatory components, and increases in p53, linking the cell cycle and apoptotic pathways. Bromodeoxyuridine incorporation indicated reduced DNA synthesis and growth in several embryonic regions. Propidium iodide staining demonstrated decreases in DNA content and increases in DNA fragmentation in several embryonic tissues. CONCLUSIONS: This study indicated that retarded growth of DRG-NC and embryos, induced by alcohol, is associated with altered expression of cell cycle and apoptotic proteins and concurrent inhibition of proliferation and increased DNA fragmentation. We suggest that alcohol induces an increase in cyclin D1 expression, premature S-phase entry, and disjointed DNA synthesis with increased apoptosis.

The evaluation of early embryonic neurogenesis after exposure to the genotoxic agent 5-bromo-2'-deoxyuridine in mice.

Developmental neurotoxicity (DNT) is an important issue in children's health. Neurogenesis occurs throughout the early fetal to the postnatal period. The proliferation of embryonic stem cells can be a target for toxicants, especially genotoxic compounds. 5-Bromo-2'-deoxyuridine (BrdU), a thymidine analogue, has been used as a marker for proliferating cells. However, we reported that prenatal BrdU exposure induced behavioral abnormalities such as hyperactivity in rat and mouse offspring. In this study, to further clarify the toxic effect of BrdU on the early neurogenesis and to examine the usefulness of the evaluation of this process in DNT, C57BL/6 mice were exposed to 100 mg/kg of BrdU once on gestational day (GD) 9 or 11, and serial sections from a wide variety of areas of the embryonic brains 24 h after the exposure were examined. BrdU exposure on GD11 induced cell death in some specific areas, such as the neocortex and striatum, but not in the substantia nigra, raphe and pons, even though BrdU was incorporated into those cells. BrdU decreased the number of cells positive for phosphorylated histone 3 (phospho-histone 3), a marker for proliferating cells at metaphase of mitosis, in the cortex, mammillary body and cerebellum, suggesting that BrdU affected the proliferation of neural stem cells. Exposure on GD9 did not induce cell death in the fetal brain. These results indicate that BrdU actually impaired the early neurogenesis, supporting the postnatal results, and demonstrated that embryonic neurogenesis has heterogeneous sensitivity to the genotoxic agents BrdU that differs according to the area and developmental stage. The evaluation of events in early neurogenesis such as the proliferation of neural stem cells shortly after chemical exposure will be one of the valuable endpoints for studying postnatal neurodevelopmental disorders.

Valproate-induced developmental neurotoxicity is affected by maternal conditions including shipping stress and environmental change during early pregnancy.

Prenatal stress is known to affect the development of the brain, and exaggerate the developmental toxicity of chemicals. Many studies of developmental neurotoxicity (DNT) use pregnant rodents mated at the supplier, which consequently suffer from the stress of shipping and of environmental changes. Here, we demonstrated differences in the developmental neurotoxicity induced by valproate (VPA) between pregnant rats mated at our own animal facility (in-house group) and rats purchased pregnant (supplier group). Rats were treated with VPA (800mg/kg) orally on gestation day (GD) 9 or 11 (VPAE9 or VPAE11), and the fetal brain was examined at embryonic day 14 using immunohistochemistry for TuJ1 (a marker for immature neurons). The size of the fetal brain was also measured. The treatment decreased fetal live viability and fetal body weight only in the supplier group. VPA treatment on either day impaired the development of TuJ1-positive neurons in the cerebral cortex. The size of the forebrain was also affected by VPA. The supplier group was much more sensitive to these toxic effects. Therefore, difference in mating place (one's own animal facility or supplier) takes part in reproducibility of valproate-induced DNT.

Quantum condensation in electron-hole systems: excitonic BEC-BCS crossover and biexciton crystallization.

Quantum condensation of electron-hole (e-h) systems in photoexcited semiconductors is reviewed from a theoretical viewpoint, stressing the exciton Bose-Einstein condensation (BEC), the e-h BCS-type condensed state, the exciton Mott transition, and the biexciton crystallization. First, we discuss the crossover between the exciton BEC and the e-h BCS states at low temperature using the self-consistent t-matrix and local approximations, applied to the high-dimensional two-band Hubbard model with both repulsive and attractive on-site interactions. We also study the metal-insulator transition (called the 'exciton Mott transition') at zero and finite temperatures, investigated with the dynamical mean-field theory. Away from half-filling we find excitonic/biexcitonic insulating phases and the first-order transition between metallic and insulating states. Second, in a one-dimensional e-h system, we employ the exciton bosonization and renormalization-group techniques to clarify quantum orders at zero temperature. The most probable ground state exhibits the biexciton crystallization, which reflects the Tomonaga-Luttinger liquid properties, the e-h backward scattering, and the long-range Coulomb interaction. The one-dimensional e-h system is insulating even at the high-density limit, hence the exciton Mott transition never occurs at zero temperature in one dimension.

Decomposition of radiation energy into work and heat.

We investigate energy transfer by the radiation from a cavity quantum electrodynamics system in the context of quantum thermodynamics. We propose a method of decomposing it into work and heat within the framework of quantum master equations. We find that the work and heat correspond, respectively, to the coherent and incoherent parts of the radiation. In the derivation of the method, it is crucial to investigate the dynamics of the system that receives the radiation from the cavity.

Markovian quantum master equation beyond adiabatic regime.

By introducing a temporal change time scale τ_{A}(t) for the time-dependent system Hamiltonian, a general formulation of the Markovian quantum master equation is given to go well beyond the adiabatic regime. In appropriate situations, the framework is well justified even if τ_{A}(t) is faster than the decay time scale of the bath correlation function. An application to the dissipative Landau-Zener model demonstrates this general result. The findings are applicable to a wide range of fields, providing a basis for quantum control beyond the adiabatic regime.