Mitsubishi Corporation (Germany)

AIMS: 1-Methyl-4-phenyl-tetrahydropyridine (MPTP) is among the most widely used neurotoxins for inducing experimental parkinsonism. MPTP causes parkinsonian symptoms in mice, primates, and humans by killing a subpopulation of dopaminergic neurons. Extrapolations of data obtained using MPTP-based parkinsonism models to human disease are common; however, the precise mechanism by which MPTP is converted into its active neurotoxic metabolite, 1-methyl-4-phenyl-pyridinium (MPP(+)), has not been fully elucidated. In this study, we aimed to address two unanswered questions related to MPTP toxicology: (1) Why are MPTP-converting astrocytes largely spared from toxicity? (2) How does MPP(+) reach the extracellular space? RESULTS: In MPTP-treated astrocytes, we discovered that the membrane-impermeable MPP(+), which is generally assumed to be formed inside astrocytes, is almost exclusively detected outside of these cells. Instead of a transporter-mediated export, we found that the intermediate, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP(+)), and/or its uncharged conjugate base passively diffused across cell membranes and that MPP(+) was formed predominately by the extracellular oxidation of MPDP(+) into MPP(+). This nonenzymatic extracellular conversion of MPDP(+) was promoted by O2, a more alkaline pH, and dopamine autoxidation products. INNOVATION AND CONCLUSION: Our data indicate that MPTP metabolism is compartmentalized between intracellular and extracellular environments, explain the absence of toxicity in MPTP-converting astrocytes, and provide a rationale for the preferential formation of MPP(+) in the extracellular space. The mechanism of transporter-independent extracellular MPP(+) formation described here indicates that extracellular genesis of MPP(+) from MPDP is a necessary prerequisite for the selective uptake of this toxin by catecholaminergic neurons.

The decision whether to hire a new CEO from outside the firm or to promote an internal candidate is considered among scholars and practitioners as highly influential for subsequent strategy setting and a firm’s innovativeness. Our empirical investigation shows that internally promoted top managers are associated with significant higher innovative activity compared with their externally hired colleagues. Our findings are consistent with the notion that firm-specific knowledge of inside top managers is relatively more important to facilitate innovative firm activities than experiences from outside the firm. However, we also note that outsiders are often hired for reasons that may not coincide with the objective to promote innovations in first place.

The cases described strongly support the effectiveness of quinine and pyrimethamine therapy when falciparum malaria is diagnosed early and treated promptly. Two thousand and three acute falciparum malaria patients were given quinine sulfate, 650 mg every 8 hr for 14 days, and pyrimethamine, 25 mg base every 12 hr for a total of 6 doses. (A slightly higher pyrimethamine dose was given to the earlier patients in the series.) Response to therapy was seen in all patients, and no deaths occurred. Despite the use of such potent drugs dangerous side-effects were encountered infrequently. Adverse reactions were seen primarily in the hematologic system through hemolysis, or bone marrow depression, or both. Complications in the series included cerebral malaria in 24 patients; anemia requiring transfusion, 18; severe pancytopenia, 11; and malarial hemoglobinuria, 8. Clinical management of malaria and its complications are discussed. Chemoprophylaxis used by units from which these patients were derived included chloroquine, 300 mg base; and primaquine, 45 mg base, weekly; and diophenyldiaminosulfone, 25 mg daily. These drugs along with field mosquito discipline and the existing efficient medical evacuation system contributed to the absence of fatalities in the present series.

Abstract Plant viruses are major contributors to crop losses and induce high economic costs worldwide. For reliable, on-site and early detection of plant viral diseases, portable biosensors are of great interest. In this study, a field-effect SiO 2 -gate electrolyte-insulator-semiconductor (EIS) sensor was utilized for the label-free electrostatic detection of tobacco mosaic virus (TMV) particles as a model plant pathogen. The capacitive EIS sensor has been characterized regarding its TMV sensitivity by means of constant-capacitance method. The EIS sensor was able to detect biotinylated TMV particles from a solution with a TMV concentration as low as 0.025 nM. A good correlation between the registered EIS sensor signal and the density of adsorbed TMV particles assessed from scanning electron microscopy images of the SiO 2 -gate chip surface was observed. Additionally, the isoelectric point of the biotinylated TMV particles was determined via zeta potential measurements and the influence of ionic strength of the measurement solution on the TMV-modified EIS sensor signal has been studied.

Previous studies have shown that MCR peptides possessing the retinoblastoma protein (RB) fragment LFYKKV as the active site are able to inhibit the proliferation of human non-small cell lung cancer (NSCLC) cells in vitro and in vivo. The goal of the present study was to test these compounds against human small cell lung cancer (SCLC) in vivo since this tumor is notoriously resistant to conventional therapy or, respectively, is characterized by rapid relapse after initially successful treatment. We herein report that the MCR peptides MCR-4 and MCR-14 display potent antiproliferative activity against RB-negative H82 SCLC xenograft tumors in nude mice, whereas the chemotherapeutic agent VP-16 tested in parallel in a clinically relevant dose had no anti-tumor effect. These encouraging results warrant accelerating the introduction of MCR peptides into clinical trials in patients with RB-negative tumors such as SCLC in the near future.

In recent years, additive manufacturing, which is more colloquially referred to as three-dimensional (3D) printing, has seen high-impact implementation in manufacturing applications in areas such as aeronautics, robotics, electronics, industrial goods, and even the food industry. This chapter introduces the basic concepts of 3D and four-dimensional (4D) printing technologies as they pertain to biomedical applications. 3D printing typically begins with a computer-aided design file that describes the geometry and size of the objects to be printed. 4D printing is defined as printing of 3D objects with the ability to change the former function under the influence of external stimuli over time. The essential difference between 4D printing and 3D printing is the addition of smart design, or responsive materials, that results in a time-dependent deformation of the object. There are only few major technologies used for biomedical printing. These include extrusion-based, droplet-based, and laser-based systems to print the material.

BACKGROUND: Keratinopathic ichthyoses are a group of hereditary skin disorders caused by pathogenic variants in keratin genes such as KRT1, KRT2 and KRT10, resulting in conditions such as epidermolytic ichthyosis (EI), autosomal-recessive EI, superficial EI and epidermal nevus. Case reports highlight the diversity of clinical manifestations, but only limited information exists regarding the quality of life and burden of disease. OBJECTIVES: The objective of this study was to assess the clinical spectrum, genotype-phenotype correlations and burden of disease in patients with epidermolytic ichthyosis in Germany. METHODS: We conducted an observational study involving 48 patients diagnosed with EI. Evaluations included the severity of skin involvement using the Investigator's Global Assessment (IGA), the modified Ichthyosis Area Severity Index (mIASI) and complications. The burden of disease was evaluated using the Dermatology Life Quality Index (DLQI) or the Children's Dermatology Life Quality Index (cDLQI). RESULTS: Based on clinical features, mIASI and IGA, EI can be categorized into localized, intermediate and severe forms. Patients with keratin 1 mutations tended to have severe EI, while the three forms were evenly distributed in those with keratin 10 mutations. The study highlights that around half of the patients with EI experienced itch and severe pain. Quality of life was affected, with daily life restrictions of 78% due to care and therapies. Reimbursement for moisturizing ointments by health insurance was insufficient for one-quarter of cases. CONCLUSIONS: The results emphasize the need for targeted interventions and comprehensive care strategies to enhance the quality of life for affected individuals.

Immunosorbent turnip vein clearing virus (TVCV) particles displaying the IgG-binding domains D and E of Staphylococcus aureus protein A (PA) on every coat protein (CP) subunit (TVCVPA) were purified from plants via optimized and new protocols. The latter used polyethylene glycol (PEG) raw precipitates, from which virions were selectively re-solubilized in reverse PEG concentration gradients. This procedure improved the integrity of both TVCVPA and the wildtype subgroup 3 tobamovirus. TVCVPA could be loaded with more than 500 IgGs per virion, which mediated the immunocapture of fluorescent dyes, GFP and active enzymes. Bi-enzyme ensembles of cooperating glucose oxidase and horseradish peroxidase were tethered together on the TVCVPA carriers by a single antibody type, with one enzyme conjugated chemically to its Fc region, and the other one bound as target, yielding synthetic multienzyme-complexes. In microtiter plates, the TVCVPA-displayed sugar-sensing system possessed a considerably increased reusability upon repeated testing, compared to the IgG-bound enzyme pair in the absence of the virus. A high coverage of the viral adapters was achieved also on Ta2O5 sensor chip surfaces coated with a polyelectrolyte interlayer, as a prerequisite for durable, TVCVPA-assisted electrochemical biosensing through modularly IgG-assembled sensor enzymes.

Bacillus subtilis is a commensal member of the human oral and gut microbiomes, which can become infectious to immunocompromised patients. It possesses a conjugative transposon, ICEBs1, which includes > 20 genes and can be passed by horizontal gene transfer to other bacteria, including pathogenic Bacillus anthracis and Listeria monocytogenes. ICEBs1 is regulated by the ImmR/ImmA tandem, which are a transcriptional repressor that constitutively blocks transcription and a metallopeptidase that acts as anti-repressor and inactivates ImmR by proteolytic cleavage. We here report the production and purification of 127-residue ImmR from ICEBs1 and the crystal structure of its DNA-binding domain. It features a five-helix bundle centred on a helix-turn-helix motif potentially binding the major grove of double-stranded target DNA. ImmR shows structural and mechanistic similarity with the B. subtilis SinR repressor, which is engaged in sporulation inhibition.

Neuroinflammation is a key feature of Alzheimer’s disease (AD), and stem cell therapies have emerged as promising candidates due to their immunomodulatory properties. Neuro-Cells (NC), a combination of unmodified mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), have demonstrated therapeutic potential in models of central nervous system (CNS) injury and neurodegeneration. Here, we studied the effects of NC in APPswe/PS1dE9 mice, an AD mouse model. Twelve-month-old APPswe/PS1dE9 mice or their wild-type littermates were injected with NC or vehicle into the cisterna magna. Five to six weeks post-injection, cognitive, locomotor, and emotional behaviors were assessed. The brain was stained for amyloid plaque density using Congo red, and for astrogliosis using DAPI and GFAP staining. Gene expression of immune activation markers (Il-1β, Il-6, Cd45, Tnf) and plasticity markers (Tubβ3, Bace1, Trem2, Stat3) was examined in the prefrontal cortex. IL-6 secretion was measured in cultured human monocytes following endotoxin challenge and NC treatment. Untreated APPswe/PS1dE9 mice displayed impaired learning in the conditioned taste aversion test, reduced object exploration, and anxiety-like behavior, which were improved in the NC-treated mutants. NC treatment normalized the expression of several immune and plasticity markers and reduced the density of GFAP-positive cells in the hippocampus and thalamus. NC treatment decreased amyloid plaque density in the hippocampus and thalamus, targeting plaques of <100 μm2. Additionally, NC treatment suppressed IL-6 secretion by human monocytes. Thus, NC treatment alleviated behavioral deficits and reduced amyloid plaque formation in APPswe/PS1dE9 mice, likely via anti-inflammatory mechanisms. The reduction in IL-6 production in human monocytes further supports the potential of NC therapy for the treatment of AD.

Cell-free protein synthesis (CFPS) is one approach to address the increasing demand for complex recombinant proteins in various applications, especially in the pharmaceutical sector. CFPS offers a variety of advantages like the ability to express cytotoxic proteins, no need for transformations or screening of strains and, thus, reduced production times. Often industrially relevant proteins require post-translational modifications (PTM). While disulfide bonds can be obtained with prokaryotic systems, some eukaryotic CFPS systems are able to perform glycosylation to a limited extent. However, scaling the production of a eukaryotic CFPS system and protein production has been a main challenge to enable the manufacturing of complex proteins with these CFPSs. One plant-based system that overcomes these limitations is the Almost Living Cell-free Expression (ALiCE) system, which is based on tobacco BY-2 cells and can produce protein titers of up to 3 µg/µL in batch mode. This study focuses on gaining a deeper understanding of oxygen demand, protein formation and the role of mitochondria in this CFPS system. Online monitoring was established in a combined µRAMOS-BioLector device to investigate the correlation of oxygen transfer, eYFP production and NADH levels during the ALiCE reaction. By varying the maximum oxygen transfer capacity, it was revealed that oxygen availability is tightly coupled to protein formation and that the eYFP production rate decreases with decreasing oxygen availability. Moreover, the mitochondrial inhibitors salicylhydroxamic acid (SHAM) and potassium cyanide (KCN) were added to ALiCE reactions to examine the influence and importance of mitochondrial alternative oxidase and cytochrome c oxidase on the ALiCE reaction. Inhibition of alternative oxidase and cytochrome c oxidase demonstrated that oxygen is consumed in the respiratory chain of intact mitochondria within the ALiCE system. In addition, the NADH balance and eYFP formation are highly dependent on oxygen availability. For the first time, a plant-based cell-free expression system was characterized concerning oxygen demand and the influence of oxygen availability on the kinetics of protein production. The new findings enable the design of ALiCE experiments in mL-scale with optimal oxygen supply for protein formation in the future and provide first insights into the energy metabolism of this plant-based CFPS system.

Abstract Background Women remain underrepresented in transcatheter aortic valve replacement (TAVR) trials, despite well-recognized anatomical differences that necessitate tailored procedural strategies. This study assessed sex-specific differences in baseline characteristics, procedural approaches, hemodynamic outcomes, and their impact on 5-year all-cause mortality. Methods We analyzed data from 20,094 patients in the IMPPACT TAVR registry. Hemodynamic outcomes, including prosthesis-patient mismatch (PPM), were defined according to Valve Academic Research Consortium-3 criteria. Kaplan–Meier and Cox models assessed 5-year all-cause mortality, and logistic regression identified predictors of PPM. Results Women comprised 49.1% of the cohort. They were older (81.4 vs. 80.2 years, p < 0.001), more symptomatic (NYHA ≥ III: 74.4% vs. 67.6%, p < 0.001), and more frequently received self-expanding valves (66.5% vs. 45.7%, p < 0.001). Post-TAVR indexed effective orifice areas were slightly larger in women (1.01 ± 0.28 vs. 0.99 ± 0.27cm 2 /m 2 , p < 0.001). Five-year mortality was lower in women (HR 0.81, 95% CI 0.76–0.86, p < 0.001). Severe PPM occurred less frequently in women (4.0% vs. 4.5%, p < 0.001) and was associated with increased mortality only in men (HR 1.32, 95% CI 1.10–1.59, p = 0.002). Adjustment for comorbidities nullified the association between PPM and mortality in both sexes. Conclusions In this international TAVR cohort, women, despite being older, demonstrated better survival than men, with comparable postprocedural hemodynamic outcomes. Severe PPM was associated with increased mortality only in men, likely reflecting underlying comorbidities and low-flow states. After adjustment for confounders, PPM was no longer associated with survival in either sex. These findings underscore the need for strategies accounting for both procedural and patient-specific risks, beyond prosthesis hemodynamics. Graphical Abstract Sex-Specific Differences in TAVR, ( A ) Kaplan-Meier curves with 95% CI for all-cause mortality stratified by sex. ( B ) TTE-derived non-indexed and BSA-indexed pre-TAVR AVA and post-TAVR EOA stratified by sex. ( C ) Distribution of PPM severity stratified by device type and sex. ( D ) Forest plot showing results of the multivariable Cox proportional hazards model for 5-year all-cause mortality including a comparison of severe PPM against non-severe PPM (no and moderate) in men and women. HR with 95% CI are shown. Study center was included as a random effect in the model. Abbreviations: AVA: aortic valve area; BE: balloon-expandable; CI: confidence interval; EOA: effective orifice area; GFR: glomerular filtration rate; HR: hazard ratio; KM: Kaplan-Meier; LVEF: left ventricular ejection fraction; PPM: prosthesis-patient mismatch; PVL: paravalvular leak; SE: self-expanding

December 01 2000 Brontologik 3.44 Kurt Dahlke Kurt Dahlke Ata Tak, Kölner Str. 226 F, D-40227 Düsseldorf, Germany. E-mail: <kurt@atatak.com>. Website: <http://www.atatak.com>. Search for other works by this author on: This Site Google Scholar Author and Article Information Kurt Dahlke Ata Tak, Kölner Str. 226 F, D-40227 Düsseldorf, Germany. E-mail: <kurt@atatak.com>. Website: <http://www.atatak.com>. Online Issn: 1531-4812 Print Issn: 0961-1215 © 2000 ISAST2000 Leonardo Music Journal (2000) 10: 79. https://doi.org/10.1162/lmj.2000.10.79 Cite Icon Cite Permissions Share Icon Share Twitter LinkedIn Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Search Site Citation Kurt Dahlke; Brontologik 3.44. Leonardo Music Journal 2000; 10 79. doi: https://doi.org/10.1162/lmj.2000.10.79 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsLeonardo Music Journal Search Advanced Search This content is only available as a PDF. © 2000 ISAST2000 Article PDF first page preview Close Modal You do not currently have access to this content.

In his comparative law study, Simon Weise analyses the foundations of German and European state liability. On this basis, he develops specific frameworks governing the respective liability with regard to incorrectly handled merger control.

de Zwifalten; les villes imperiales de Weil, Reutlin- gen, Eslingen, Rothweil, Giengen, Aulen, Hall, Gmeindt et Hailbronn 11 .

Books at home are used for more than reading, such as collecting them, using them as decoration, or expressing personality. In order to get a better understanding of intended and unintended uses of printed books, we conducted seven book tours in different homes followed by semi-structured interviews. This data was complemented with a large-scale online survey with 300 respondents. We describe our findings focusing on storage, sorting, decoration, and self-expressionand how they inspired us to develop a digital bookshelf (ambient display) as a technology probe to explore decoration with eBooks in the home. We argue for a transition from decoration with printed books to eBooks as design inspiration that does not simply replicate a bookshelf as ambient display, but makes eBooks tangible by combining users’ habits with qualities of digital material.

Photorefractive fibers of SBN provide an attractive medium for storing information. The information can be in the form of a 2-D image, called a page, and multiple pages may be stored in a single fiber by holographic recording. The multiple pages are distinguished by angular multiplexing of the reference wave. In this paper we discuss experimental results regarding the number and quality of these pages stored in SBN fibers of different diameters, lengths, and recording arrangements. The data storage capacity of these fibers is calculated taking into account crosstalk and recording resolution.

BACKGROUND: Gunshot deaths due to homicide or military encounters are a major health concern. Noninvasive bullet characterization is of major importance for patients with lodged bullets or in mass disasters with multiple cadavers, which must be prioritized for autopsy. Therefore, the aim of this study was to investigate whether brass and lead bullets can be differentiated using photon-counting CT (PCCT). METHODS: Nine different lead (n = 6) or brass (n = 3) bullets were investigated on a state-of-the-art PCCT using a clinically unavailable research mode. Here, four image sets were reconstructed for different energy thresholds (20, 55, 72, 90 keV). Three circular regions of interest were placed on the 20-keV threshold images by two readers and automatically copied to the three other threshold images. Based on measured HU mean and max values, dual-energy indices (DEI) were calculated for the low/high energy threshold pairs of 20/90, 55/90, and 72/90 keV. RESULTS: Significant differences of DEIs between lead and brass projectiles were observed for the 20/90 keV DEI for HU mean ± standard deviation values (Qr40 kernel, lead: -0.085 ± 0.021, brass: 0.024 ± 0.048) and HU max values (Qr40 kernel, lead: -0.093 ± 0.011, brass: 0.023 ± 0.057) (p < 0.001 for both). Differences decreased for the 55/90 and 72/90 keV DEIs between the two projectile materials but remained statistically significant. CONCLUSION: In this PCCT phantom study, significant differences were observed between lead and brass bullets in the different energy threshold images. RELEVANCE STATEMENT: Photon-counting CT could be a promising tool for bullet identification as significant differences were found in the different energy threshold images for lead and brass bullets, with application in clinical and forensic radiology. KEY POINTS: In emergency settings, noninvasive bullet characterization is of importance for law enforcement. Bullet material characterization can be performed using photon-counting CT. These characteristics can be quantified in the four different energy threshold images.

(1) Background: trays are surgery-specific sets of required materials and medical devices, assembled in consultation between manufacturer and user, and provided in a sterile package. (2) Methods: in a high-volume urological center performing 11,920 operations/procedures annually (2023), we prospectively evaluated the effect of trays compared with the standard approach in a comparative study of 64 operations conducted between 29 October and 30 November 2024. The primary endpoints were the amount of operating room (OR) waste (volume/cm3, weight/g) and setup time (minutes). The secondary endpoint was the workflow assessment by nursing staff, rated on a numerical score (0–10) across seven relevant domains. (3) Results: for endourological procedures, setup time was reduced by 35%, operating room (OR) waste by 34%, and waste volume by 19.0%. Workflow was positively rated with a mean score of 9.75/10. For major open procedures, setup time was reduced by 43%, waste weight by 24.8%, and waste volume by 32%. Workflow was positively rated with a mean score of 8.9/10. (4) Conclusions: Trays have a sustainable and significant impact on reducing OR waste, save nursing staff preparation time, and facilitate improved workflow in the operating room.