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Homicide by electrocution is rare in forensics, and the identification of the cause of death can be quite difficult when the electric device is removed from the scene. We present an instance where the police were unsure of homicide in the initial investigation. The offender used hand-made electrode plates for electrocution, which produced unique electric marks different from those produced by common electric devices such as electric wires. To the best of our knowledge, this is the first report of homicide by electrocution with electrode plates. We believe that the macroscopic and microscopic findings in this instance are quite valuable for forensic practitioners.

Ischemic stroke is one of the leading causes of death and disability worldwide. The inhibition of cerebral blood flow triggers intertwined pathological events, resulting in cell death and loss of brain function. Interestingly, animals pre-exposed to short-term ischemia can tolerate subsequent severe ischemia. This phenomenon is called ischemic tolerance and is also triggered by other noxious stimuli. However, whether short-term exposure to non-noxious stimuli can induce ischemic tolerance remains unknown. Recently, we found that pre-exposing mice to an enriched environment for 40 min is sufficient to facilitate cell survival after a subsequent stroke. The neuroprotective process depends on the neuronal activity soon before stroke, of which the activity-dependent transcription factor Npas4 is essential. Excessive Ca

Significance Stroke is the second leading cause of death and the most frequent cause of disability in adults. After stroke, most ischemic neurons die and a few neurons live, leading to brain dysfunction; yet, genes involved in both neuronal survival and death remain poorly understood. Here, we found that the activity-dependent transcription factor Npas4 is essential for acquisition of neuronal tolerance to ischemia. Moreover, a systematic search for Npas4-downstream genes identified Gem, which encodes Ras-related small GTPase that mediates neuroprotective effects of Npas4. Gem suppresses the membrane localization of voltage-gated Ca2+ channels to inhibit excess Ca2+ influx, thereby protecting neurons from excitotoxic death. Our findings suggest that Gem expression via Npas4 promotes neuroprotection and neuroplasticity in injured and healthy brains, respectively., Ischemic stroke, which results in loss of neurological function, initiates a complex cascade of pathological events in the brain, largely driven by excitotoxic Ca2+ influx in neurons. This leads to cortical spreading depolarization, which induces expression of genes involved in both neuronal death and survival; yet, the functions of these genes remain poorly understood. Here, we profiled gene expression changes that are common to ischemia (modeled by middle cerebral artery occlusion [MCAO]) and to experience-dependent activation (modeled by exposure to an enriched environment [EE]), which also induces Ca2+ transients that trigger transcriptional programs. We found that the activity-dependent transcription factor Npas4 was up-regulated under MCAO and EE conditions and that transient activation of cortical neurons in the healthy brain by the EE decreased cell death after stroke. Furthermore, both MCAO in vivo and oxygen-glucose deprivation in vitro revealed that Npas4 is necessary and sufficient for neuroprotection. We also found that this protection involves the inhibition of L-type voltage-gated Ca2+ channels (VGCCs). Next, our systematic search for Npas4-downstream genes identified Gem, which encodes a Ras-related small GTPase that mediates neuroprotective effects of Npas4. Gem suppresses the membrane localization of L-type VGCCs to inhibit excess Ca2+ influx, thereby protecting neurons from excitotoxic death after in vitro and in vivo ischemia. Collectively, our findings indicate that Gem expression via Npas4 is necessary and sufficient to promote neuroprotection in the injured brain. Importantly, Gem is also induced in human cerebral organoids cultured under an ischemic condition, revealing Gem as a new target for drug discovery.

INTRODUCTION: Spinal cord injury (SCI) is a major direct cause of accidental death. Cervical SCI can lead to death in a short time period by neurogenic shock. Prompt vasopressor administration is recommended for patients with SCI accompanied by hypotension (systolic blood pressure 90 mmHg without vasopressor agents. High fever occurred 7 days after the accident and he died in the next morning. Autopsy revealed segmental intestinal necrosis from the ileum to the ascending colon, without mesenteric embolism, or severe arteriosclerosis. DISCUSSION: This case implies that maintenance of >90-mmHg systolic blood pressure can insufficiently keep the blood flow to prevent NOMI, and the mean arterial blood pressure of >85 mmHg can be more plausible as suggested in the guideline. Monitoring the mean arterial blood pressure in acute SCI is useful not only for neurological recovery but also for the maintenance of vital intestinal perfusion.

Background: Multicellular taste buds located within taste papillae on the tongue mediate taste sensation. In taste papillae, taste bud cells (TBCs), such as taste receptor cells and taste precursor cells, and the surrounding lingual epithelium including epithelial progenitors (also called taste stem/progenitor cells) are maintained by continuous cell turnover throughout life. However, it remains unknown how the cells constituting taste buds proliferate and differentiate to maintain taste bud tissue. Based on in situ hybridization (ISH) screening, we demonstrated that the oncofetal antigen 5T4 (also known as trophoblast glycoprotein: TPBG) gene is expressed in the adult mouse tongue. Results: In immunohistochemistry of coronal tongue sections, 5T4 protein was detected at a low level exclusively in the basal part of the lingual epithelium in developing and adult mice, and at a high level particularly in foliate papillae and circumvallate papillae (CVPs). Furthermore, immunohistochemistry of the basal part of CVPs indicated that the proliferation marker PCNA (proliferating cell nuclear antigen) co-localized with 5T4. 5T4 was strongly expressed in Krt5+ epithelial progenitors and Shh+ taste precursor cells, but weakly in mature taste receptor cells. The number of proliferating cells in the CVP was higher in 5T4-knockout mice than in wild-type (WT) mice, while neither cell differentiation nor the size of taste buds differed between these two groups of mice. Notably, X-ray irradiation enhanced cell proliferation more in 5T4-knockout mice than in WT mice. Conclusion: Our results suggest that 5T4, expressed in epithelial progenitors (taste stem/progenitor cells), and taste precursor cells, may influence the maintenance of taste papillae under both normal and injury conditions.

The filament perforation model (FPM) in mice is becoming increasingly popular to elucidate the molecular pathogenesis of neuronal injury after subarachnoid hemorrhage (SAH). We evaluated brain MRI in a mouse FPM. A total of 28 male C57Bl/6J mice were used. Seventeen animals underwent SAH induction by FPM. In two animals, transient middle cerebral artery occlusion (MCAo) was induced. Nine mice served as controls. T1-weighted images (T1WI), T2-weighted images (T2WI), T2(∗)-weighted images (T2*WI) and apparent diffusion coefficient maps were acquired at day 0 and at various time points following SAH (range: day 1-6 after SAH). Cerebral blood flow (CBF) analysis by (14)C-iodoamphetamine ((14)C-IMP) autoradiography was conducted in nine animals. Hemorrhage could be best confirmed using T2*WI. The degree of hemorrhage varied. All animals evaluated for ⩾2days were hydrocephalic, which was best seen on T2WI. T2-hyperintensity of the corpus callosum and external capsule, indicating white matter (WM) injury, was present after SAH. Ventricle and WM injury volumes were statistically significantly higher at day 3 compared to day 0. Territorial ischemia was detectable in MCAo but not in SAH. Markedly hypointense cortical veins were visible in the hyperacute and delayed phase after SAH on T2*WI. The (14)C-IMP analysis indicated decreased CBF after SAH. MRI is feasible and useful in evaluating pathophysiological changes over time. T2*WI seems best for SAH detection and grading. The chronological change of hydrocephalus and WM injury could be analyzed. T2*WI illustrated specific signal changes of cortical veins, possibly caused by increased oxygen extraction fraction due to decreased CBF.

It has been shown in a variety of mammalian species that sensory experience can regulate the development of various structures, including the retina, cortex, hippocampus, and olfactory bulb (OB). In the mammalian OB, the development of dendrites in excitatory projection neurons, such as mitral and tufted cells, is well known to be dependent on odor experience. Odor experience is also involved in the development of another OB population, a subset of inhibitory interneurons that are generated in the ventricular-subventricular zone throughout life and differentiate into granule cells (GCs) and periglomerular cells. However, the roles that each type of interneuron plays in the control of olfactory behaviors are incompletely understood. We recently found that among the various types of OB interneurons, a subtype of GCs expressing the oncofetal trophoblast glycoprotein 5T4 gene is required for odor detection and discrimination behaviors. Our results suggest that embryonic-born OB interneurons, including 5T4-positive GCs, play a crucial role in fundamental olfactory responses such as simple odor detection and discrimination behaviors. By contrast, postnatal- and adult-born OB interneurons are important in the learning of more complicated olfactory behaviors. Here, we highlight the subtypes of OB GCs, and discuss their roles in olfactory processing and behavior, with a particular focus on the relative contributions of embryonically and postnatally generated subsets of GCs in rodents.

In Japan, most sudden deaths occurring during bathing happen in the winter, and predominantly to elderly people. One can infer a relation to physical conditions that are specific to aging. Atrial fibrillation, an arrhythmia, increases with age. This study examined histological changes in the pulmonary vein myocardial sleeves of sudden bathtub death victims and compared them with those of control individuals. We investigated 35 sudden deaths that occurred during bathing and 34 accidental deaths or deaths caused by diseases unrelated to cardiopathies. Pulmonary veins were excised cross-sectionally from the hilar side to the venoatrial junction. Then they were stained with hematoxylin and eosin, resorcin-fuchsin van Gieson, and Congo-red stains. Amyloid deposits in the pulmonary vein myocardial sleeves, as well as the range and severity of scarring, were graded microscopically on a scale of 0-3. In the sudden bathtub death victims, severe scarring was found in the myocardial sleeves of the four pulmonary veins (mean score, 2.0), which was significantly different (p < 0.05) from the control subjects (mean score, 1.4). Cardiomegaly was found in 28 out of the autopsied individuals. In subjects with cardiomegaly, the mean value of pulmonary vein myocardial sleeve scarring was 2.1. In subjects without cardiomegaly, the mean value was 1.8. Comparison revealed that cardiomegaly was associated significantly with scarring progression and degeneration of the myocardial sleeves. Scarring of the pulmonary vein myocardial sleeves was more advanced in victims of sudden bathtub death than in controls without heart disease. Elderly people with scarring of the pulmonary vein myocardial sleeves are likely to develop degenerative variations in their intra-atrial excitation conduction. These results demonstrate that taking hot baths might induce supraventricular arrhythmias such as atrial fibrillation.

A male in his 70s was found lying dead in the living room of his house. A gunshot entrance wound was observed in the left orbit, with a lead slug and wadding left in the skull, which exhibited fatal cranio-cerebral trauma. A cartridge had been discharged from a handmade launcher, or zip gun, that had been fixed to a spare gun barrel on a pipe chair, by heating the launcher from the side using a gas burner. The deceased had owned guns for hunting in the past and had returned the license, but he had retained a spare barrel and live cartridges at home. In this unique case of suicide, a zip gun was discharged by heating with a gas burner.

Olfaction plays a fundamental role in the various behaviors such as feeding, mating, nursing, and avoidance in mice. Behavioral tests that characterize abilities of odor detection and recognition using genetically modified mice reveal the contribution of target genes to the olfactory processing. Here, we describe the olfactory habituation-dishabituation test for investigating the odor detection threshold in mice.

Sudden death in a hot bathtub occurs frequently in Japan, particularly among elderly people. This retrospective report describes the epidemiologic circumstances and physical findings at autopsy. In total, 268 victims were found unconscious or dead during tub bathing. After postmortem examination, the manner of death was judged as natural cause in 191 (71.2%) and accidental drowning in 63 (23.5%) cases. Mean age (SD) was 72.1 (15.2) years with no significant difference between males and females. A seasonal difference was evident: the winter displayed the highest frequency. Drowning water inhalation, which was confirmed in 72% of victims, was absent in the others. The most common observations on postmortem examination were cardiac ischemic changes and cardiomegaly. Water inhalation signs were evident in a significantly fewer victims exhibiting these factors. In contrast, inhalational findings were observed more frequently in victims with other backgrounds such as alcohol intake, mobility disturbance, and history of epilepsy. Annual mortality in Japan from accidental drowning in persons aged older than 75 years is 33 deaths per 100,000 population. However, this number may be considerably underestimated as pathologists tend to regard lack of water inhalation as indicating a natural cause of death. Confusion in diagnosis remains consequent to the accidental and natural aspects of "dead in hot bathtub" phenomenon.

Pairs of enantiomeric odor ligands are difficult to resolve by instrumental analyses because compounds with mirror-image molecular structures have almost identical physicochemical properties. The olfactory system, however, discriminates (–)-forms of enantiomers from their (+)-forms within seconds. To investigate key olfactory receptors for enantiomer discrimination, we compared behavioral detection and discrimination thresholds of wild-type mice with those of ΔD mice that lack all dorsal olfactory receptors. Surprisingly, wild-type mice displayed an exquisite “supersensitivity” to enantiomeric pairs of wine lactones and carvones in both detection and discrimination tasks using odor plume-like flows in a Y-maze. In contrast, ΔD mice showed >10 10 -fold reductions in enantiomer discrimination sensitivity compared to wild-type mice. ΔD mice detected one or both of the (–)- and (+)-enantiomers over a wide concentration range, but were unable to discriminate them. This “enantiomer odor discrimination paradox” indicates that the most sensitive dorsal receptors play a critical role in hierarchical odor coding for enantiomer identification. In addition, to identify residues responsible for the rapid and robust response of murine olfactory receptor S6 ( mOR-S6 ) via chimeric Gα 15_olf , mutations of the C-terminal helix 8 were analyzed in a heterologous functional expression system. The N-terminal hydrophobic core between helix 8 and TM1−2 of mOR-S6 is important for Gα activation. A point mutation of a helix 8 N-terminal acidic residue eliminated the improved response dynamics via the chimeric Gα 15_olf . This result suggests that an N-terminal acidic residue of helix 8 is responsible for rapid Gα activation. Supersensitive odor discrimination is thus largely governed by signals from the most sensitive dorsal olfactory receptors with the shortest onset latencies, which are controlled in part by initial transient interactions between the receptor C-terminal helix 8 and the Gα C-terminal region.

Biological objects are composed of submicrometer structures such as cells and organelles that are essential for their functions. Here, we report on three-dimensional X-ray visualization of cells and organelles at resolutions up to 100 nm by imaging microtomography (micro-CT) equipped with Fresnel zone plate optics. Human cerebral tissue, fruit fly cephalic ganglia, and Escherichia coli bacteria labeled with high atomic-number elements were embedded in epoxy resin and subjected to X-ray microtomography at the BL37XU and BL47XU beamlines of the SPring-8 synchrotron radiation facility. The obtained results indicated that soft tissue structures can be visualized with the imaging microtomography.

Inhibitory interneurons in the olfactory bulb are generated continuously throughout life in the subventricular zone and differentiate into periglomerular and granule cells. Neural circuits that undergo reorganization by newborn olfactory bulb interneurons are necessary for odor detection, odor discrimination, olfactory memory, and innate olfactory responses. Although sensory experience has been shown to regulate development in a variety of species and in various structures, including the retina, cortex, and hippocampus, little is known about how sensory experience regulates the dendritic development of newborn olfactory bulb interneurons. Recent studies revealed that the 5T4 oncofetal trophoblast glycoprotein and the neuronal Per/Arnt/Sim domain protein 4 (Npas4) transcription factor regulate dendritic branching and dendritic spine formation, respectively, in olfactory bulb interneurons. Here, we summarize the molecular mechanisms that underlie the sensory input-dependent development of newborn interneurons and the formation of functional neural circuitry in the olfactory bulb.

Long-term WT1 peptide vaccination for patients with acute myeloid leukemia with minimal residual disease

A case of suicide, a male shot in the abdomen using a homemade weapon, is described herein. Postmortem examination revealed bleeding into the thoracic and abdominal cavities, a collapsed liver and other organs with numerous pellets. The contact-shot wound was not noticed during the initial investigation at the scene, but it was elucidated during autopsy. A simple launcher had been assembled from pipes of a clothes rack frame made for home use. The deceased had once owned a shotgun, but his firearm license had been relinquished 5 years prior. A shotgun shell that he had kept was used. Presumably, the injuries from the homemade weapon were not noticed initially because of strict gun control rules in Japan.

Since the discovery of odorant receptors (ORs) in rodents, most ORs have remained orphan receptors. Even for deorphanized ORs in vitro, their in vivo properties are largely unknown. Here, we report odor response profiles of two highly homologous mouse ORs, MOR29A and MOR29B, both in vivo and in vitro. The BAC transgenic mouse was generated, in which olfactory sensory neurons (OSNs) expressing the transgenes MOR29A and MOR29B were differently tagged with IRES-gapECFP and IRES-gapEYFP, respectively. MOR29A- and MOR29B-expressing OSN axons converged on separate but nearby loci on the dorsal surface of the olfactory bulb (OB). Optical imaging of intrinsic signals in the OB identified five different phenyl ethers as candidate ligands for MOR29B. Based on in vitro calcium imaging with the isolated OSNs and luciferase assay with heterologous cells, only guaiacol and vanillin were found to be potent agonists for MOR29A and MOR29B. Because of its accessible glomerular locations in the dorsal OB and defined odor response profiles both in vivo and in vitro, the MOR29A/29B tagging mouse will serve as an excellent tool for studying both odor-signal processing and neural circuitry in the OB.

Recent evidence shows that olfactory sensory neurons expressing a given odorant receptor (OR) are not necessarily confined to one of four zones, rather arranged in an overlapping manner in the olfactory epithelium (OE). In this study, in situ hybridization of OE sections with the OR probes indicated that the OR genes, the mRNAs of which were detected in an array of glomeruli on olfactory bulb (OB) along the anterodorsal/posteroventral (AD/PV) axis, are expressed in subareal zones within the most ventral zone, zone 4, along the dorsomedial/ventrolateral (DM/VL) axis. We also found that Neuropilin-2 (Nrp2) is expressed in a DM-low to VL-high gradient within zone 4 of OE. Furthermore, in Nrp2 mutant mice, we observed multiple glomeruli for zone 4 ORs in OB. These results suggest that the graded expression of Nrp2 in OE is required for the proper targeting of ventral glomeruli along the AD/PV axis in OB.

The paper provides evidence for the existence of a multi-center hydrogen bonding network of trifluorolactate, the structure of which was elucidated by single crystal X-ray diffraction analysis, in the liquid state. We reported that the trifluorolactate experienced discrimination of its enantiomeric excess by distillation. X-ray crystallographic analyses of the single crystals of the trifluorolactates suggested that the phenomenon could be caused by a homo-chiral recognizing hydrogen bonding system. Low-angle X-ray diffraction measurement of the trifluorolactate in the liquid state showed a ca. 5 A repeated, which indicates the existence of the hydrogen bonding network in the liquid state. Here, the chiral recognition could be caused by the electrostatic repulsion of the negative charges on trifluoromethyl groups.

The Wilms' tumor gene WT1 is overexpressed in most of human leukemias regardless of disease subtypes. To characterize the expression pattern of WT1 during normal and neoplastic hematopoiesis, we generated a knock-in reporter green fluorescent protein (GFP) mouse (WT1(GFP/+)) and assayed for WT1 expression in normal and leukemic hematopoietic cells. In normal hematopoietic cells, WT1 was expressed in none of the long-term (LT) hematopoietic stem cells (HSC) and very few (1%) of the multipotent progenitor cells. In contrast, in murine leukemias induced by acute myeloid leukemia 1 (AML1)/ETO+TEL/PDGFbetaR or BCR/ABL, WT1 was expressed in 40.5 or 38.9% of immature c-kit(+)lin(-)Sca-1(+) (KLS) cells, which contained a subset, but not all, of transplantable leukemic stem cells (LSCs). WT1 expression was minimal in normal fetal liver HSCs and mobilized HSCs, both of which are stimulated for proliferation. In addition, overexpression of WT1 in HSCs did not result in proliferation or expansion of HSCs and their progeny in vivo. Thus, the mechanism by which expansion of WT1-expressing cells occurs in leukemia remains unclear. Nevertheless, our results demonstrate that the WT1(GFP/+) mouse is a powerful tool for analyzing WT1-expressing cells, and they highlight the potential of WT1, as a specific therapeutic target that is expressed in LSCs but not in normal HSCs.

Enantiomeric pairs of mirror-image molecular structures are difficult to resolve by instrumental analyses. The human olfactory system, however, discriminates (−)-wine lactone from its (+)-form rapidly within seconds. To gain insight into receptor coding of enantiomers, we compared behavioural detection and discrimination thresholds of wild-type mice with those of ΔD mice in which all dorsal olfactory receptors are genetically ablated. Surprisingly, wild-type mice displayed an exquisite “supersensitivity” to enantiomeric pairs of wine lactones and carvones. They were capable of supersensitive discrimination of enantiomers, consistent with their high detection sensitivity. In contrast, ΔD mice showed selective major loss of sensitivity to the (+)-enantiomers. The resulting 108-fold differential sensitivity of ΔD mice to (−)- vs. (+)-wine lactone matched that observed in humans. This suggests that humans lack highly sensitive orthologous dorsal receptors for the (+)-enantiomer, similarly to ΔD mice. Moreover, ΔD mice showed >1010-fold reductions in enantiomer discrimination sensitivity compared to wild-type mice. ΔD mice detected one or both of the (−)- and (+)-enantiomers over a wide concentration range, but were unable to discriminate them. This “enantiomer odour discrimination paradox” indicates that the most sensitive dorsal receptors play a critical role in hierarchical odour coding for enantiomer identification.

Sensory experience regulates the development of various brain structures, including the cortex, hippocampus, and olfactory bulb (OB). In the OB, the regulation of the neuronal development by sensory experience is well-studied in mitral and tufted cells, but little is known about how morphological changes depending on a neuronal activity occur in OB interneurons, such as granule cells and periglomerular cells. OB interneurons are a useful model for studying the modifi cation of neural circuits by sensory inputs from the external world during postnatal stages. Interestingly, OB interneurons are generated and integrated into preexisting neural circuits in rodents even at the adult stage. Thus, an effi cient method of gene transfer into newborn neurons would allow a better understanding of adult neurogenesis in the OB. In this chapter, we describe a basic method for in vivo electroporation of DNA into OB interneurons in postnatal mice, without the need for complex surgery. Delivery of electric pulses following microinjection of plasmid DNA into the lateral ventricle enabled effi cient gene transfer into newborn OB interneurons. Utilizing a fl uorescent protein gene, labeling appears in various classes of OB interneurons and persists into adulthood with no adverse side effects. Collectively, postnatal electroporation is a powerful tool to understand adult neurogenesis, and compares favorably in terms of time and cost to other genetic manipulation techniques.

We report an autopsy case of sudden death in a 36-year-old craftsman with idiopathic scoliosis. The doctor identified his scoliosis at the age of thirteen, and he was under medical care for three years until he stopped consulting the doctor. He collapsed while walking at the station and was sent to an emergency room in cardiopulmonary arrest state, where he was declared dead in spite of more than an hour of CPR. Numbers of petechiae were seen on the bilateral palpebral conjunctivae and the lips were cyanotic. There were no particular injuries except for small abrasions observed on the face. The back showed right rib hump owing to midthoracic scoliosis (with 73 degrees of Cobb's angle) and right hemithorax was deformed showing an appearance of pectus excavatum in the front. The volume of the right thoracic cavity was significantly decreased. In the right lung, there was extensive stromal fibrosis, leaving almost no normal alveolar structures, and medial hypertrophy of pulmonary arteriolar walls. Hypertrophy of the right heart ventricle due to these pulmonary changes and the congestion of other organs suggested that the cause of death in this case was cor pulmonale due to pulmonary hypertension. This was a rare case of fatal outcome of advanced idiopathic scoliosis without medical care in spite of early detection through mass screening.

Infinite dilution activity coefficients (γ∞) have been determined by using a gas−liquid chromatography (GLC) technique for benzene, toluene, methanol, ethanol, 2-propanol, and acetaldehyde in ethylene glycol and ethylene carbonate in a range of temperatures from 50 to 110 °C. In the literature, there were no reported data for γ∞ for any of the studied solutes in ethylene carbonate or for acetaldehyde in ethylene glycol. A few γ∞ data were available for benzene, toluene, methanol, and 2-propanol in ethylene glycol, but they were limited to a low-temperature range (

Genomic analysis was performed for the murine odorant receptor (OR) genes. The MOR28 cluster on chromosome 14 was extensively studied. It contains six OR genes, MOR28, 10, 83, 29A, 29B and 30. The human homolog of this cluster is located on the human chromosome 14, and contains five OR genes, HOR28/10, 83, 29A, 29B and 30. Sequence comparison of these OR gene paralogs and orthologs suggests that the coding homologies are accounted for not only by recent gene duplication, but also by gene conversion among the coding sequences within the cluster. A possible role of gene conversion in the olfactory system is discussed in the context of the olfactory map.

The presence of solvents is essential in all steps of pharmaceutical processes (reaction, separation, and formulation). For toxicological reasons, drug manufacturers are increasingly required to minimize the number of solvents employed in pharmaceutical processes. In practice, the selection of solvents and antisolvents for pharmaceuticals mostly relies on experience, analogy and experimental testing. Our work aims to systematically investigate the solubility of pharmaceutical compounds and their intermediates in a wide range of solvents. We describe the development of solubility databases of mono- and bifunctional compounds that are based on the core molecular fragments of common drugs and contain substituents of gradually increasing polarity. The core fragments can be identified by a classification of drugs into pharmaceutical categories. Each of the solutes is studied in a series of pharmaceutical solvents of varying polarity and hydrogen bonding tendency. The utility of an example database is shown which uses the benzene ring as the core fragment and contains activity coefficient data of 13 monofunctional benzene derivatives in 17 solvents. The database was analyzed by the Modified UNIFAC (Dortmund) group contribution method and quantum-mechanical/COSMO-RS calculations. The testing shows the importance of polarization effects which are common between drug-like molecules and small polar solvents. The proposed approach can be useful to provide a systematic insight into solvent–solute interactions and for testing of new methods of solubility prediction.

Activity coefficients and diffusivities of small molecules in phenol resin were determined by using inverse gas chromatography (IGC) technique with packed column. The Romdhane-Danner approach was used to measure the diffusivities for solvents in phenol resin. Since the thickness of the polymer film on the support materials has a significant effect on the value of diffusivity, it was determined by using a more accurate method based on Braun-Guillet approach. The experimental data of activity coefficients and diffusivity at infinite dilution for three systems have been determined. The PolyNRTL model was adopted to represent the measured activity coefficient data. Also, the elution model of the packed columns and the estimations of model parameters were evaluated to obtain the diffusivity. (C) 2002 Elsevier Science B.V. All rights reserved.

WT1 peptide vaccination following allogeneic stem cell transplantation in pediatric leukemic patients with high risk for relapse: successful maintenance of durable remission

The Wilms' tumor gene WT1 is overexpressed in leukemia and solid tumors and has an oncogenic role in leukemogenesis and tumorigenesis. However, precise regulatory mechanisms of WT1 overexpression remain undetermined. In the present study, microRNA-125a (miR-125a) was identified as a miRNA that suppressed WT1 expression via binding to the WT1-3'UTR. MiR-125a knockout mice overexpressed WT1, developed myeloproliferative disorder (MPD) characterized by expansion of myeloid cells in bone marrow (BM), spleen and peripheral blood, and displayed urogenital abnormalities. Silencing of WT1 expression in hematopoietic stem/progenitor cells of miR-125a knockout MPD mice by short-hairpin RNA inhibited myeloid colony formation in vitro. Furthermore, the incidence and severity of MPD were lower in miR-125a (-/-) mice than in miR-125a (+/-) mice, indicating the operation of compensatory mechanisms for the complete loss of miR-125a. To elucidate the compensatory mechanisms, miRNA array was performed. MiR-486 was occasionally induced in compete loss of miR-125a and inhibited WT1 expression instead of miR-125a, resulting in the cancellation of MPD occurrence. These results showed for the first time the post-transcriptional regulatory mechanisms of WT1 by both miR-125a and miR-486 and should contribute to the elucidation of mechanisms of normal hematopoiesis and kidney development.

Transport and thermodynamic properties of electrolyte solutions are very essential for development and design of lithium ion or lithium polymer batteries. An electrolyte database for lithium battery, which includes a quite number of organic solvents, lithium electrolytes and possible by-products (e.g. CO2), has been compiled. Appropriate models have been evaluated for representing the variety of properties for solvents and electrolyte solutions, such as, conductivity, transference number, diffusivity, dissociation constant and so on. particular attention has been given on conductivity in this paper, considering its essential importance for battery; several typical examples have been presented and discussed. (C) 2001 Elsevier Science B.V. All rights reserved.

We have previously generated transgenic mice carrying the murine odourant receptor gene, MOR28, tagged with lacZ. In this animal, the endogenous MOR28 is differently tagged with GFP. It was found that the transgenic and endogenous MOR28 genes are expressed in a mutually exclusive manner and that the two sets of olfactory sensory neurones (OSNs), each expressing either the transgenic or the endogenous MOR28, project their axons to separate glomeruli. Our fluorescent in situ hybridization (FISH) revealed that the two endogenous alleles of MOR28 are also mutually excluded for their transcriptional activation. Therefore, we studied whether there would be any segregation in the projection of the two subsets of OSNs: one set expressing the paternal and the other expressing the maternal allele. It was found that the OSNs for both alleles shared the same glomerulus for their projection, but the projection targets were segregated within the glomerular structure. Two subsets of neurones expressing either the transgenic or the endogenous MOR28 target their axons to two separate glomeruli based on the differences in the genetic backgrounds, nature of tagging, and chromosomal locations. In contrast, neurones expressing a maternal or paternal allele share the same glomeruli, but tend to target to segregated areas within the glomerular structure. The segregation was more prominent with increased differences in the genetic background between the two alleles.

Vapor–liquid equilibrium ratios (Kw1∞ values) for hexane at infinite dilution in propylene+impact polypropylene copolymer (ICP–PP) and ethylene+ICP–PP systems were measured at temperatures 323.2, 343.2 and 363.2 K and pressures up to 2.4 MPa using a chromatographic technique. The solubilities of propylene in polypropylene and those of propylene, ethylene, and hexane in ICP–PP were measured. The PVT properties of the polypropylene and ICP–PP were also studied. These data were used to determine the pure component and binary interaction parameters for the Sanchez–Lacombe equation of state (S–L EOS). The Kw1∞ values were predicted by using the S–L EOS with binary parameters evaluated by correlation of phase-equilibrium data of binary systems. Good agreement between the experimental and calculated Kw1∞ values was obtained by optimizing the equation parameters.

Henry's law coefficients and partial molar volumes of 34 penetrants (5 inert gases, 6 inorganic gases, 17 hydrocarbon gases, 5 fluorinated gases, and CCl4 vapor) dissolved in poly(dimethylsiloxane) and low-density polyethylene were determined at 25 °C by measuring sorption of the gases and the concomitant dilation of the polymers. From the Henry's law coefficients and the partial molar volumes, Flory−Huggins parameters for polymer/gas interactions were estimated. The partial molar volumes were correlated with critical molar volumes of gases, and the interaction parameters were found to depend on the partial molar volumes. These relationships for the fluorinated gases were clearly different from those of all other gases. For CO2 and CH4 in poly(dimethylsiloxane), partial molar volumes and interaction parameters were obtained as a function of temperature over a range −30 to 95 °C. Thermal expansivities of these dissolved molecules were estimated to be 2 × 10-3 °C-1 from the temperature dependence of partial...

During the development of lymphocytes, expression of the Ig genes is strictly regulated in a tissue-specific manner and in a time-ordered fashion. We have previously shown that the PU.1 binding motif in the Igkappa 3' enhancer (kappaE3') and a novel Ets family protein other than PU.1 may be possibly involved in the control of V(kappa)-J(kappa) joining. In the attempt to isolate the novel Ets family protein, we have screened cDNA libraries with the yeast one-hybrid method and identified a new PU.1-related factor, Prf. This novel Ets family protein is shown to interact with the PU.1 binding sequences in various promoters and enhancers, including kappaE3'. It was found that expression of the prf gene is predominant in the B-lineage cells, with the exception of immature B cells. Since Prf does not exhibit functions of transcriptional activity, this novel protein may act as an antagonist against other Ets family proteins, e.g. PU.1 and Spi-B. Possible roles of Prf with respect to the B cell differentiation are discussed.