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In this paper we present μSAXS and TEM investigations on the local microstructure of an experimental W-rich single crystal Ni-base γ/γ′-superalloy. Using the ID13(ESRF) X-ray microfocus beam we scanned a small sample area and were able to distinguish between different precipitate phases (γ′/σ). The σ phase could be unambiguously identified by comparing the data to numerical two-dimensional simulations on similar alloys, e.g. SCA, SC16. The low concentrated detrimental platelet TCP σ phase, which was not detectable in SANS on the same alloy, seems to be ordered in stacks with a preferential orientation perpendicular to the [3 2 0]-direction. [Copyright &y& Elsevier]

Mitochondrial DNA (mtDNA) mutations are frequent in cancer, yet their precise role in cancer progression remains debated. To functionally evaluate the impact of mtDNA variants on tumor growth and metastasis, we developed an enhanced cytoplasmic hybrid (cybrid) generation protocol and established isogenic human melanoma cybrid lines with wild-type mtDNA or pathogenic mtDNA mutations with partial or complete loss of mitochondrial oxidative function. Cybrids with homoplasmic levels of pathogenic mtDNA reliably established tumors despite dysfunctional oxidative phosphorylation. However, these mtDNA variants disrupted spontaneous metastasis from primary tumors and reduced the abundance of circulating tumor cells. Migration and invasion of tumor cells were reduced, indicating that entry into circulation is a bottleneck for metastasis amid mtDNA dysfunction. Pathogenic mtDNA did not inhibit organ colonization following intravenous injection. In heteroplasmic cybrid tumors, single-cell analyses revealed selection against pathogenic mtDNA during melanoma growth. Collectively, these findings experimentally demonstrate that functional mtDNA is favored during melanoma growth and supports metastatic entry into the blood.

For over a century, fasting regimens have improved health, lifespan and tissue regeneration in diverse organisms, including humans 1-6 . However, how fasting and post-fast refeeding affect adult stem cells and tumour formation has yet to be explored in depth. Here we demonstrate that post-fast refeeding increases intestinal stem cell (ISC) proliferation and tumour formation; post-fast refeeding augments the regenerative capacity of Lgr5 + ISCs, and loss of the tumour suppressor gene Apc in post-fast-refed ISCs leads to a higher tumour incidence in the small intestine and colon than in the fasted or ad libitum-fed states, demonstrating that post-fast refeeding is a distinct state. Mechanistically, we discovered that robust mTORC1 induction in post-fast-refed ISCs increases protein synthesis via polyamine metabolism to drive these changes, as inhibition of mTORC1, polyamine metabolite production or protein synthesis abrogates the regenerative or tumorigenic effects of post-fast refeeding. Given our findings, fast-refeeding cycles must be carefully considered and tested when planning diet-based strategies for regeneration without increasing cancer risk, as post-fast refeeding leads to a burst in stem-cell-driven regeneration and tumorigenicity., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Liver metastasis (LM) confers poor survival and therapy resistance across cancer types, but the mechanisms of liver-metastatic organotropism remain unknown. Here, through in vivo CRISPR-Cas9 screens, we found that Pip4k2c loss conferred LM but had no impact on lung metastasis or primary tumor growth. Pip4k2c-deficient cells were hypersensitized to insulin-mediated PI3K/AKT signaling and exploited the insulin-rich liver milieu for organ-specific metastasis. We observed concordant changes in PIP4K2C expression and distinct metabolic changes in 3,511 patient melanomas, including primary tumors, LMs and lung metastases. We found that systemic PI3K inhibition exacerbated LM burden in mice injected with Pip4k2c-deficient cancer cells through host-mediated increase in hepatic insulin levels; however, this circuit could be broken by concurrent administration of an SGLT2 inhibitor or feeding of a ketogenic diet. Thus, this work demonstrates a rare example of metastatic organotropism through co-optation of physiological metabolic cues and proposes therapeutic avenues to counteract these mechanisms., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Cobalt-Rhenium (Co-Re)-based alloys are currently investigated as potential high-temperature materials with melting temperatures beyond those of nickel-based superalloys. Their attraction stems from the binary Co-Re phase diagram, exhibiting complete miscibility between Co and Re, whereby the melting temperature steadily increases with the Re-content. Thus, depending on the Re-content, one can tune the melting temperature between that of pure Co (1495 °C) and that of pure Re (3186 °C). Current investigations focus on Re-contents of about 15 at.%, which makes melting with standard equipment still feasible. In addition to solid solution strengthening due to the mixture of Co- and Re-atoms, particle strengthening by tantalum carbide (TaC) and titanium carbide (TiC) precipitates turned out to be promising in recent studies. Yet, it is currently unclear which of the two particle types is the best choice for high temperature applications nor has the strengthening mechanism associated with the monocarbide (MC)-precipitates been elucidated. To address these issues, we perform compression tests at ambient and elevated temperatures on the particle-free base material containing 15 at.% of rhenium (Re), 5 at.% of chromium (Cr) and cobalt (Co) as balance (Co-15Re-5Cr), as well as on TaC- and TiC-containing variants. Additionally, transmission electron microscopy is used to analyze the shape of the precipitates and their orientation relationship to the matrix. Based on these investigations, we show that TiC and TaC are equally suited for precipitation strengthening of Co-Re-based alloys and identify climb over the elongated particles as a rate controlling particle strengthening mechanism at elevated temperatures. Furthermore, we show that the Re-atoms are remarkably strong obstacles to dislocation motion, which are overcome by thermal activation at elevated temperatures.

Column purchasing cost is an important issue for an analyst to analyze complex sample matrices. Here, we report the development of an amino acid (β-alanine)-derived stationary phase (Sil-Ala-C12) with strategic and effective interaction sites (amide and urea as embedded polar groups with C12 alkyl chain) able to separate various kinds of analytes. Owing to the balanced hydrophobicity and hydrophilicity of the phase, it showed exceptional separation abilities in both reversed-phase high-performance liquid chromatography (RP-HPLC) as a hydrophobic phase and hydrophilic interaction chromatography (HILIC) as a hydrophilic phase. Remarkably, the baseline separation was achieved for the challenging β- and γ-isomers of tocopherol. Usually, three columns such as pentafluorophenyl or C30, C18, and sulfobetaine HILIC are required for the analysis of vitamin E, capsaicinoids, and vitamin C in chili peppers ( Capsicum spp.), respectively. However, only Sil-Ala-C12 was able to separate these analytes. A single column can serve 3-4 purposes, which suggests that Sil-Ala-C12 had the potential to reduce column purchasing costs.

Laser powder bed fusion (LPBF) of titanium or titanium alloys allows fabrication of geometrically more complex and, possibly, individualized implants or osteosynthesis products and could thus improve the outcome of medical treatments considerably. However, insufficient LPBF process parameters can result in substantial porosity, decreasing mechanical properties and requiring post-treatment. Furthermore, texturized parts with anisotropic properties are usually obtained after LPBF processing, limiting their usage in medical applications. The present study addresses both: first, a design of experiments is used in order to establish a set of optimized process parameters and a process window for LPBF printing of small commercially pure (CP) titanium parts with minimized volume porosity. Afterward, the first results on the development of a biocompatible titanium alloy designed for LPBF processing of medical implants with improved solidification and more isotropic properties are presented on the basis of conventionally melted alloys. This development was performed on the basis of Ti-0.44O-0.5Fe-0.08C-0.4Si-0.1Au, a near-α alloy presented by the authors for medical applications and conventional manufacturing, with yttrium and boron additions as additional growth restriction solutes. In terms of LPBF processing of CP titanium grade 1 powder, a high relative density of approximately 99.9% was obtained in the as-printed state of the volume of a small cubical sample by using optimized laser power, scanning speed, and hatch distance in combination with a rotating scanning pattern. Moreover, tensile specimens processed with these volume settings and tested in the as-printed milled state exhibited a high average yield and ultimate tensile strength of approximately 663 and 747 N/mm 2 , respectively, combined with a high average ductility of approximately 24%. X-ray diffraction results suggest anisotropic mechanical properties, which are, however, less pronounced in terms of the tested specimens. Regarding alloy development, the results show that yttrium additions lead to a considerable microstructure refinement but have to be limited due to the occurrence of a large amount of precipitations and a supposed higher propensity for the formation of long columnar prior β-grains. However, phase/texture and microstructure analyses indicate that Ti-0.44O-0.5Fe-0.08C-0.4Si-0.1Au-0.1B-0.1Y is a promising candidate to achieve lower anisotropy during LPBF processing, but further investigations on LPBF printing and Y 2 O 3 formation are necessary., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Haase, Siemers and Rösler.)

This study reassesses the optimum matrix composition of Co-Re-Cr-based alloys for strengthening by MC-type carbides. It is found that the composition of Co-15Re-5Cr is ideally suited for this purpose as it allows the solution of the carbide-forming elements such as Ta, Ti, Hf, and C within a matrix consisting entirely of fcc-phase (typically at 1450 °C), having a high solubility for these elements, while precipitation heat treatment (typically at 900-1100 °C) occurs in a hcp-Co matrix, displaying a much lower solubility. In the case of the monocarbides TiC and HfC, this was investigated and achieved for the first time in Co-Re-based alloys. TaC and TiC emerged as suitable particles in Co-Re-Cr alloys for creep applications due to a large population of nano-sized particle precipitation, which is not the case for the mainly coarse HfC. Both Co-15Re-5Cr-xTa-xC and Co-15Re-5Cr-xTi-xC exhibit a formerly unknown maximum solubility close to x = 1.8 at.%. Therefore, further research on the particle-strengthening effect and the governing creep mechanisms of carbide-strengthened Co-Re-Cr alloys should focus on alloys with the following compositions: Co-15Re-5Cr-1.8Ta-1.8C and Co-15Re-5Cr-1.8Ti-1.8C.

The pore size of nanoporous superalloy membranes produced by directional coarsening is directly related to the γ-channel width after creep deformation, since the γ-phase is removed subsequently by selective phase extraction. The continuous network of the γ'-phase thus remaining is based on complete crosslinking of the γ'-phase in the directionally coarsened state forming the subsequent membrane. In order to be able to achieve the smallest possible droplet size in the later application in premix membrane emulsification, a central aspect of this investigation is to minimize the γ-channel width. For this purpose, we use the 3 w 0 -criterion as a starting point and gradually increase the creep duration at constant stress and temperature. Stepped specimens with three different stress levels are used as creep specimens. Subsequently, the relevant characteristic values of the directionally coarsened microstructure are determined and evaluated using the line intersection method. We show that the approximation of an optimal creep duration via the 3w0-criterion is reasonable and that coarsening occurs at different rates in dendritic and interdendritic regions. The use of staged creep specimens shows significant material and time savings in determining the optimal microstructure. Optimization of the creep parameters results in a γ-channel width of 119 ± 43 nm in dendritic and 150 ± 66 nm in interdendritic regions while maintaining complete crosslinking. Furthermore, our investigations show that unfavorable stress and temperature combinations favor undirectional coarsening before the rafting process is completed.

Background: Although of high individual and socioeconomic relevance, a reliable prediction model for the prognosis of juvenile stroke (18-55 years) is missing. Therefore, the study presented in this protocol aims to prospectively validate the discriminatory power of a prediction score for the 3 months functional outcome after juvenile stroke or transient ischemic attack (TIA) that has been derived from an independent retrospective study using standard clinical workup data., Methods: PREDICT-Juvenile-Stroke is a multi-centre (n = 4) prospective observational cohort study collecting standard clinical workup data and data on treatment success at 3 months after acute ischemic stroke or TIA that aims to validate a new prediction score for juvenile stroke. The prediction score has been developed upon single center retrospective analysis of 340 juvenile stroke patients. The score determines the patient's individual probability for treatment success defined by a modified Rankin Scale (mRS) 0-2 or return to pre-stroke baseline mRS 3 months after stroke or TIA. This probability will be compared to the observed clinical outcome at 3 months using the area under the receiver operating characteristic curve. The primary endpoint is to validate the clinical potential of the new prediction score for a favourable outcome 3 months after juvenile stroke or TIA. Secondary outcomes are to determine to what extent predictive factors in juvenile stroke or TIA patients differ from those in older patients and to determine the predictive accuracy of the juvenile stroke prediction score on other clinical and paraclinical endpoints. A minimum of 430 juvenile patients (< 55 years) with acute ischemic stroke or TIA, and the same number of older patients will be enrolled for the prospective validation study., Discussion: The juvenile stroke prediction score has the potential to enable personalisation of counselling, provision of appropriate information regarding the prognosis and identification of patients who benefit from specific treatments., Trial Registration: The study has been registered at https://drks.de on March 31, 2022 ( DRKS00024407 )., (© 2023. The Author(s).)

A silicon-stereogenic aminosilanol was isolated in excellent diastereomeric ratio and the absolute configuration was determined. The silanol is configurative and condensation stable in solution and shows stereoselective transformations with a clean stereospecific pathway in follow-up reactions, which leads to the isolation of a silicon-stereogenic zinc complex and siloxane compounds. Investigations with 18 O-labelled water and mass spectrometry analysis revealed an otherwise hidden exchange of oxygen atoms of silanol and water in solution that proceeds with retention of the configuration at the silicon center. This novel combination of a stereochemical probe and isotopic labeling in a silicon-stereogenic compound opens new analytic possibilities to study stereochemical courses of reactions with the aid of chiral silanols mechanistically., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

The utilization of fluorescein-guided biopsies has recently been discussed to improve and expedite operative techniques in the detection of tumor-positive tissue, as well as to avoid making sampling errors. In this study, we aimed to report our experience with fluorescein-guided biopsies and elucidate distribution patterns in different histopathological diagnoses in order to develop strategies to increase the efficiency and accuracy of this technique. We report on 45 fluorescence-guided stereotactic biopsies in 44 patients (15 female, 29 male) at our institution from March 2016 to March 2021, including 25 frame-based stereotactic biopsies and 20 frameless image-guided biopsies using VarioGuide ® . A total number of 347 biopsy samples with a median of 8 samples (range: 4-18) per patient were evaluated for intraoperative fluorescein uptake and correlated to definitive histopathology. The median age at surgery was 63 years (range: 18-87). Of the acquired specimens, 63% were fluorescein positive. Final histopathology included glioblastoma (n = 16), B-cell non-Hodgkin lymphoma (n = 10), astrocytoma, IDH-mutant WHO grade III (n = 6), astrocytoma, IDH-mutant WHO grade II (n = 1), oligodendroglioma, IDH-mutant and 1p/19q-codeleted WHO grade II (n = 2), reactive CNS tissue/inflammation (n = 4), post-transplantation lymphoproliferative disorder (PTLD; n = 2), ependymoma (n = 1), infection (toxoplasmosis; n = 1), multiple sclerosis (n = 1), and metastasis (n = 1). The sensitivity for high-grade gliomas was 85%, and the specificity was 70%. For contrast-enhancing lesions, the specificity of fluorescein was 84%. The number needed to sample for contrast-enhancing lesions was three, and the overall number needed to sample for final histopathological diagnosis was five. Interestingly, in the astrocytoma, IDH-mutant WHO grade III group, 22/46 (48%) demonstrated fluorescein uptake despite no evidence for gadolinium uptake, and 73% of these were tumor-positive. In our patient series, fluorescein-guided stereotactic biopsy increases the likelihood of definitive neuropathological diagnosis, and the number needed to sample can be reduced by 50% in contrast-enhancing lesions.

Colloidal emulsions for lipophilic drugs can be fabricated using premix membrane emulsification. The state of the art is the application of membranes made from, for example, polycarbonate or polyester, which, however, are prone to fouling and cause waste, due to the low number of cycles. With the use of metallic membranes made from the nickel based single crystalline superalloy CMSX-4, these key disadvantages are eliminated. However, instead, the pore size and the resulting droplet size distribution need to be adjusted and improved. This can be realized by tailoring the size of the γ'-particles, which is controllable by the time and temperature used during precipitation heat treatment and the quenching method after homogenization heat treatment. Therefore, we utilized different heat treatment protocols, varying the cooling rate (water quenching and air cooling) after homogenization heat treatment and the holding time and temperature during precipitation heat treatment. Then, we investigated the γ/γ'-microstructure, including the γ'-morphology and γ'-particle size. We show that water quenching has a significant impact on the γ/γ'-microstructure and often leads to irregular-shaped and poorly aligned γ'-particles after precipitation heat treatment. In comparison, air cooling, followed by a subsequent precipitation heat treatment, results in well-aligned and cubic shaped γ'-particles and is, therefore, favorable for membrane fabrication. A reduction in precipitation temperature leads to morphology changes to the γ'-particles. A reduction of the holding time during precipitation heat treatment diminishes the γ'-particle growth, resulting in smaller γ'-particles. Additionally, a suitable heat treatment protocol for membrane fabrication was identified with a γ'-edge length of 224 ± 52 nm and well-aligned, cubic shaped γ'-particles.

Exoscopic surgery promises alleviation of physical strain, improved intraoperative visualization and facilitation of the clinical workflow. In this prospective observational study, we investigate the clinical usability of a novel 3D4K-exoscope in routine neurosurgical interventions. Questionnaires on the use of the exoscope were carried out. Exemplary cases were additionally video-documented. All participating neurosurgeons (n = 10) received initial device training. Changing to a conventional microscope was possible at all times. A linear mixed model was used to analyse the impact of time on the switchover rate. For further analysis, we dichotomized the surgeons in a frequent (n = 1) and an infrequent (n = 9) user group. A one-sample Wilcoxon signed rank test was used to evaluate, if the number of surgeries differed between the two groups. Thirty-nine operations were included. No intraoperative complications occurred. In 69.2% of the procedures, the surgeon switched to the conventional microscope. While during the first half of the study the conversion rate was 90%, it decreased to 52.6% in the second half (p = 0.003). The number of interventions between the frequent and the infrequent user group differed significantly (p = 0.007). Main reasons for switching to ocular-based surgery were impaired hand-eye coordination and poor depth perception. The exoscope investigated in this study can be easily integrated in established neurosurgical workflows. Surgical ergonomics improved compared to standard microsurgical setups. Excellent image quality and precise control of the camera added to overall user satisfaction. For experienced surgeons, the incentive to switch from ocular-based to exoscopic surgery greatly varies., (© 2021. The Author(s).)

Background: Augmented reality (AR) has the potential to support complex neurosurgical interventions by including visual information seamlessly. This study examines intraoperative visualization parameters and clinical impact of AR in brain tumor surgery., Methods: Fifty-five intracranial lesions, operated either with AR-navigated microscope (n = 39) or conventional neuronavigation (n = 16) after randomization, have been included prospectively. Surgical resection time, duration/type/mode of AR, displayed objects (n, type), pointer-based navigation checks (n), usability of control, quality indicators, and overall surgical usefulness of AR have been assessed., Results: AR display has been used in 44.4% of resection time. Predominant AR type was navigation view (75.7%), followed by target volumes (20.1%). Predominant AR mode was picture-in-picture (PiP) (72.5%), followed by 23.3% overlay display. In 43.6% of cases, vision of important anatomical structures has been partially or entirely blocked by AR information. A total of 7.7% of cases used MRI navigation only, 30.8% used one, 23.1% used two, and 38.5% used three or more object segmentations in AR navigation. A total of 66.7% of surgeons found AR visualization helpful in the individual surgical case. AR depth information and accuracy have been rated acceptable (median 3.0 vs. median 5.0 in conventional neuronavigation). The mean utilization of the navigation pointer was 2.6 × /resection hour (AR) vs. 9.7 × /resection hour (neuronavigation); navigation effort was significantly reduced in AR (P < 0.001)., Conclusions: The main benefit of HUD-based AR visualization in brain tumor surgery is the integrated continuous display allowing for pointer-less navigation. Navigation view (PiP) provides the highest usability while blocking the operative field less frequently. Visualization quality will benefit from improvements in registration accuracy and depth impression., German Clinical Trials Registration Number: DRKS00016955., (© 2021. The Author(s).)

The neurophysiology of the subjective sensation of being conscious is elusive; therefore, it remains controversial how consciousness can be recognized in patients who are not responsive but seemingly awake. During general anesthesia, a model for the transition between consciousness and unconsciousness, specific covariance matrices between the activity of brain regions that we call patterns of global brain communication reliably disappear when people lose consciousness. This functional magnetic imaging study investigates how patterns of global brain communication relate to consciousness and unconsciousness in a heterogeneous sample during general anesthesia and after brain injury. First, we describe specific patterns of global brain communication during wakefulness that disappear during propofol ( n = 11) and sevoflurane ( n = 14) general anesthesia. Second, we search for these patterns in a cohort of unresponsive wakeful patients ( n = 18) and unmatched healthy controls ( n = 20) in order to evaluate their potential use in clinical practice. We found that patterns of global brain communication characterized by high covariance in sensory and motor areas or low overall covariance and their dynamic change were strictly associated with intact consciousness in this cohort. In addition, we show that the occurrence of these two patterns is significantly related to activity within the frontoparietal network of the brain, a network known to play a crucial role in conscious perception. We propose that this approach potentially recognizes consciousness in the clinical routine setting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Golkowski, Willnecker, Rösler, Ranft, Schneider, Jordan and Ilg.)

Objective: Current literature debates the role of newly developed three-dimensional (3D) Exoscopes in the daily routine of neurosurgical practice. So far, only a small number of cadaver lab studies or case reports have examined the novel Aesculap Aeos Three-Dimensional Robotic Digital Microscope. This study aims to evaluate the grade of satisfaction and intraoperative handling of this novel system in neurosurgery., Methods: Nineteen neurosurgical procedures (12 cranial, 6 spinal and 1 peripheral nerve) performed over 9 weeks using the Aeos were analyzed. Ten neurosurgeons of varying levels of training were included after undergoing device instruction and training. Following every surgery, a questionnaire consisting of 43 items concerning intraoperative handling was completed. The questionnaires were analyzed using descriptive statistics., Results: No intraoperative complications occurred. Surgical satisfaction was ranked high (78.95%). In total, 84.21% evaluated surgical ergonomics as satisfactory, while 78.95% of the surgeons would like to use this system frequently. Image quality, independent working zoom function and depth of field were perceived as suboptimal by several neurosurgeons., Conclusion: The use of Aeos is feasible and safe in microsurgical procedures, and surgical satisfaction was ranked high among most neurosurgeons in our study. The system might offer advanced ergonomic conditions in comparison to conventional ocular-based microscopes.

Objective: The utilization of fluorescein-guided biopsies and resection has been recently discussed as a suitable strategy to improve and expedite operative techniques for the resection of central nervous system (CNS) tumors. However, little is known about the optical properties of sodium fluorescein (NaFl) in human tumor tissue and their potential impact on ex vivo analyses involving fluorescence-based methods., Methods: Tumor tissue was obtained from a study cohort of an observational study on the utilization of fluorescein-guided biopsy and resection (n=5). The optical properties of fluorescein-stained tissue were compared to the optical features of the dye in vitro and in control samples consisting of tumor tissue of high-grade glioma patients (n=3) without intravenous (i.v.) application of NaFl. The dye-exposed tumor tissues were used for optical measurements to confirm the detectability of NaFl emission ex vivo . The tissue samples were fixed in 4%PFA, immersed in 30% sucrose, embedded in Tissue-Tek OCT compound, and cut to 10 μm cryosections. Spatially resolved emission spectra from tumor samples were recorded on representative slides with a Confocal Laser Scanning Microscope FV1000 (Olympus GmbH, Hamburg, Germany) upon excitation with λ exc = 488 nm., Results: Optical measurements of fluorescein in 0.9% sodium chloride (NaCl) under in vitro conditions showed an absorption maximum of λ max abs = 479 nm as detected with spectrophotometer Specord 200 and an emission peak at λ max em = 538 nm recorded with the emCCD detection system of a custom-made microscope-based single particle setup using a 500 nm long-pass filter. Further measurements revealed pH- and concentration-dependent emission spectra of NaFl. Under ex vivo conditions, confocal laser scanning microscopy of fluorescein tumor samples revealed a slight bathochromic shift and a broadening of the emission band., Conclusion: Tumor uptake of NaFl leads to changes in the optical properties - a bathochromic shift and broadening of the emission band - possibly caused by the dye's high pH sensitivity and concentration-dependent reabsorption acting as an inner filter of the dye's emission, particularly in the short wavelength region of the emission spectrum where absorption and fluorescence overlap. Understanding the ex vivo optical properties of fluorescein is crucial for testing and validating its further applicability as an optical probe for intravital microscopy, immunofluorescence localization studies, and flow cytometry analysis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer JG declared a past co-authorship with the authors to the handling editor., (Copyright © 2021 Xu, Teich, Frenzel, Hoffmann, Radke, Rösler, Faust, Blank, Brandenburg, Misch, Vajkoczy, Onken and Resch-Genger.)

Purpose: Spinal diseases requiring urgent surgical treatment are rare during pregnancy. Evidence is sparse and data are only available in the form of case reports. Our aim is to provide a comprehensive guide for spinal surgery on pregnant patients and highlight diagnostic and therapeutic aspects., Methods: The study included a cohort of consecutive pregnant patients who underwent spinal surgery at five high-volume neurosurgical centers between 2010 and 2017. Perioperative and perinatal clinical data were derived from medical records., Results: Twenty-four pregnant patients were included. Three underwent a preoperative cesarean section. Twenty-one patients underwent surgery during pregnancy. Median maternal age was 33 years, and median gestational age was 13 completed weeks. Indications were: lumbar disk prolapse (n = 14; including cauda equina, severe motor deficits or acute pain), unstable spine injuries (n = 4); intramedullary tumor with paraparesis (n = 1), infection (n = 1) and Schwann cell nerve root tumor presenting with high-grade paresis (n = 1). Two patients suffered transient gestational diabetes and 1 patient presented with vaginal bleeding without any signs of fetal complications. No miscarriages, stillbirths, or severe obstetric complications occurred until delivery. All patients improved neurologically after the surgery., Conclusion: Spinal surgical procedures during pregnancy seem to be safe. The indication for surgery has to be very strict and surgical procedures during pregnancy should be reserved for emergency cases. For pregnant patients, the surgical strategy should be individually tailored to the mother and the fetus.

Nanoporous superalloy membranes are a functional extension of the use of nickel-based alloys. The material, which is usually used for high-temperature applications, consists mainly of the two phases γ and γ'. Through coarsening of the precipitates and thus forming of a bicontinuous γ/γ' network, membranes can be produced by removing either of these phases. From the single-crystalline alloy CMSX-4, the bicontinuous network can be formed either thermo-mechanically by directional coarsening of coherent precipitates or by load-free coalescence of incoherent precipitates. Recent investigations have shown that membranes also can be produced from polycrystalline starting material in both ways. In this article, the process route for membranes by load-free coarsening of incoherent γ' precipitates from a carbon-free version of the polycrystalline alloy Nimonic 115 is presented. This manufacturing method has the advantage of its simplicity and in comparison to single-crystalline membranes it can be realized in larger scales. We discuss the microstructure and show the mechanical properties by means of tensile tests. Despite the grain boundaries as a mechanical weak link, polycrystalline membranes show promising mechanical properties. Their strength even exceeds that of the single-crystalline membranes despite the significantly higher pore volume content.

Objective: Surgical treatment of convexity meningiomas is usually considered a low-risk procedure. Nevertheless, the risk of postoperative motor deficits is higher (7.1%-24.7% of all cases) for lesions located in the rolandic region, especially when an arachnoidal cleavage plane with the motor pathway is not identifiable. The authors analyzed the possible role of navigated transcranial magnetic stimulation (nTMS) for planning resection of rolandic meningiomas and predicting the presence or lack of an intraoperative arachnoidal cleavage plane as well as the postoperative motor outcome., Methods: Clinical data were retrospectively collected from surgical cases involving patients affected by convexity, parasagittal, or falx meningiomas involving the rolandic region, who received preoperative nTMS mapping of the motor cortex (M1) and nTMS-based diffusion tensor imaging (DTI) fiber tracking of the corticospinal tract before surgery at 2 different neurosurgical centers. Surgeons' self-reported evaluation of the impact of nTMS-based mapping on surgical strategy was analyzed. Moreover, the nTMS mapping accuracy was evaluated in comparison with intraoperative neurophysiological mapping (IONM). Lastly, we assessed the role of nTMS as well as other pre- and intraoperative parameters for predicting the patients' motor outcome and the presence or absence of an intraoperative arachnoidal cleavage plane., Results: Forty-seven patients were included in this study. The nTMS-based planning was considered useful in 89.3% of cases, and a change of the surgical strategy was observed in 42.5% of cases. The agreement of nTMS-based planning and IONM-based strategy in 35 patients was 94.2%. A new permanent motor deficit occurred in 8.5% of cases (4 of 47). A higher resting motor threshold (RMT) and the lack of an intraoperative arachnoidal cleavage plane were the only independent predictors of a poor motor outcome (p = 0.04 and p = 0.02, respectively). Moreover, a higher RMT and perilesional edema also predicted the lack of an arachnoidal cleavage plane (p = 0.01 and p = 0.03, respectively). Preoperative motor status, T2 cleft sign, contrast-enhancement pattern, and tumor volume had no predictive value., Conclusions: nTMS-based motor mapping is a useful tool for presurgical assessment of rolandic meningiomas, especially when a clear cleavage plane with M1 is not present. Moreover, the RMT can indicate the presence or absence of an intraoperative cleavage plane and predict the motor outcome, thereby helping to identify high-risk patients before surgery.

Background: We introduce a user-friendly, standardized protocol for tractography of the major language fiber bundles., Method: The introduced method uses dMRI images for tractography whereas the ROI definition is based on structural T1 MPRAGE MRI templates, without normalization to MNI space. ROIs for five language-relevant fiber bundles were visualized on an axial, coronal, or sagittal view of T1 MPRAGE images. The ROIs were defined based upon the tracts' obligatory pathways, derived from literature and own experiences in peritumoral tractography., Results: The resulting guideline was evaluated for each fiber bundle in ten healthy subjects and ten patients by one expert and three raters. Overall, 300 ROIs were evaluated and compared. The targeted language fiber bundles could be tracked in 88% of the ROI pairs, based on the raters' result blinded ROI placements. The evaluation indicated that the precision of the ROIs did not relate to the varying experience of the raters., Conclusions: Our guideline introduces a standardized language tractography method for routine preoperative workup and for research contexts. The ROI placement guideline based on easy-to-identify anatomical landmarks proved to be user-friendly and accurate, also in inexperienced test persons.

As a reaction to the increasing noise pollution, caused by the expansion of airports close to residential areas, porous trailing edges are investigated to reduce the aeroacoustic noise produced by flow around the airframe. Besides mechanical and acoustical investigations of porous materials, the fouling behavior of promising materials is an important aspect to estimate the performance in long-term use. For this study, two sintered fiber felts were selected for a long-term fouling experiment where the development of the flow resistivity and accumulation of dirt was observed. Based on 3D structural characterizations obtained from X-ray tomography of the initial materials, acoustic models (Biot and Johnson-Champoux-Allard) in the frame of the transfer matrix method were applied to the sintered fiber felts. Flow resistivity measurements and the measurements of the absorption coefficient in an impedance tube are the basis for a fouling model for sintered fiber felts. The contribution will conclude with recommendations concerning the modeling of pollution processes of porous materials.

Objective: To explore plasticity in patients scheduled for extra-intracranial bypass surgery due to unilateral symptomatic occlusive cerebrovascular disease via navigated transcranial magnetic stimulation., Methods: In this observational study, patients were allocated to different substudies and examined before and 3 months after operation. (1) Corticospinal excitability was determined via identification of the resting motor threshold. (2) Intracortical inhibition and facilitation were tested by paired pulse transcranial magnetic stimulation. (3) Area of cortical representation of the first dorsal interosseous muscle was identified., Results: (1) Resting motor thresholds were higher in the affected hemispheres with impaired cerebrovascular reserve capacity compared to the unaffected hemispheres (45.7% ± 2.2% compared to 39.2% ± 1.4%, n = 39, p < 0.05). Reduced excitability normalized 3 months after revascularization (51% ± 2.6% → 45% ± 1.9%, n = 21, p < 0.05). (2) In paired pulse paradigms, there was a motor disinhibition in the operated hemispheres. (3) There was a reduction of the cortical representation areas of the first dorsal interosseous muscle (2.3 ± 0.5 cm(2) → 0.9 ± 0.6 cm(2), n = 9, p < 0.05) after operation., Conclusions: Our data demonstrate a reversibly impaired motor cortical function in the chronically ischemic brain. In carefully selected patients, cerebral revascularization leads to improved motor output indicated by a lower resting motor threshold, intracortical disinhibition, and more focused motor cortical representation., (© 2016 American Academy of Neurology.)

Background: Neurological and oncological outcomes of motor eloquent brain-tumor patients depend upon the ability to localize functional areas and the respective proposed therapy. We set out to determine whether the use of navigated transcranial magnetic stimulation (nTMS) had an impact on treatment and outcome in patients with brain tumors in motor eloquent locations., Methods: We enrolled 250 consecutive patients and compared their functional and oncological outcomes to a matched pre-nTMS control group (n = 115)., Results: nTMS mapping results disproved suspected involvement of primary motor cortex in 25.1% of cases, expanded surgical indication in 14.8%, and led to planning of more extensive resection in 35.2% of cases and more restrictive resection in 3.5%. In comparison with the control group, the rate of gross total resections increased significantly from 42% to 59% (P < .05). Progression-free-survival for low grade glioma was significantly better in the nTMS group at 22.4 months than in control group at 15.4 months (P < .05). Integration of nTMS led to a nonsignificant change of postoperative deficits from 8.5% in the control group to 6.1% in the nTMS group., Conclusions: nTMS provides crucial data for preoperative planning and surgical resection of tumors involving essential motor areas. Expanding surgical indications and extent of resection based on nTMS enables more patients to undergo surgery and might lead to better neurological outcomes and higher survival rates in brain tumor patients. The impact of this study should go far beyond the neurosurgical community because it could fundamentally improve treatment and outcome, and its results will likely change clinical practice., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: This paper describes the shaping of freestanding objects out of metallic structures in the nano- and submicron size. The technique used, called nanoforging, is very similar to the macroscopic forging process., Results: With spring actuated tools produced by focused ion beam milling, controlled forging is demonstrated. With only three steps, a conical bar stock is transformed to a flat- and semicircular bent bar stock., Conclusion: Compared with other forming techniques in the reduced scale, nanoforging represents a beneficial approach in forming freestanding metallic structures, due to its simplicity, and supplements other forming techniques.

Clinical and genetic heterogeneity renders confirmation or exclusion of autoimmune lymphoproliferative syndrome difficult. To re-evaluate and improve the currently suggested diagnostic approach to patients with suspected FAS mutation, the most frequent cause of autoimmune lymphoproliferative syndrome, we prospectively determined 11 biomarkers in 163 patients with splenomegaly or lymphadenopathy and presumed or proven autoimmune cytopenia(s). Among 98 patients sequenced for FAS mutations in CD3(+)TCRα/β(+)CD4(-)CD8(-) "double negative" T cells, 32 had germline and six had somatic FAS mutations. The best a priori predictor of FAS mutations was the combination of vitamin B12 and soluble FAS ligand (cut-offs 1255 pg/mL and 559 pg/mL, respectively), which had a positive predictive value of 92% and a negative predictive value of 97%. We used these data to develop a web-based probability calculator for FAS mutations using the three most discriminatory biomarkers (vitamin B12, soluble FAS ligand, interleukin-10) of the 11 tested. Since more than 60% of patients with lymphoproliferation and autoimmune cytopenia(s) in our cohort did not harbor FAS mutations, 15% had somatic FAS mutations, and the predictive value of double-negative T-cell values was rather low (positive and negative predictive values of 61% and 77%, respectively), we argue that the previously suggested diagnostic algorithm based on determination of double-negative T cells and germline FAS sequencing, followed by biomarker analysis, is not efficient. We propose vitamin B12 and soluble FAS ligand assessment as the initial diagnostic step with subsequent decision on FAS sequencing supported by a probability-calculating tool.

Background: Navigated transcranial magnetic stimulation (nTMS) is increasingly used in presurgical brain mapping. Preoperative nTMS results correlate well with direct cortical stimulation (DCS) data in the identification of the primary motor cortex. Repetitive nTMS can also be used for mapping of speech-sensitive cortical areas., Objective: The current cohort study compares the safety and effectiveness of preoperative nTMS with DCS mapping during awake surgery for the identification of language areas in patients with left-sided cerebral lesions., Methods: Twenty patients with tumors in or close to left-sided language eloquent regions were examined by repetitive nTMS before surgery. During awake surgery, language-eloquent cortex was identified by DCS. nTMS results were compared for accuracy and reliability with regard to DCS by projecting both results into the cortical parcellation system., Results: Presurgical nTMS maps showed an overall sensitivity of 90.2%, specificity of 23.8%, positive predictive value of 35.6%, and negative predictive value of 83.9% compared with DCS. For the anatomic Broca's area, the corresponding values were a sensitivity of 100%, specificity of 13.0%, positive predictive value of 56.5%, and negative predictive value of 100%, respectively., Conclusion: Good overall correlation between repetitive nTMS and DCS was observed, particularly with regard to negatively mapped regions. Noninvasive inhibition mapping with nTMS is evolving as a valuable tool for preoperative mapping of language areas. Yet its low specificity in posterior language areas in the current study necessitates further research to refine the methodology.

Fluorescent fusion proteins together with transient transformation techniques are commonly used to investigate intracellular protein localisation in vivo. Biolistic transfection is reliable, efficient and avoids experimental problems associated with producing and handling fragile protoplasts. Onion epidermis pavement cells are frequently used with this technique, their excellent properties for microscopy resulting from their easy removal from the underlying tissues and large size. They also have advantages over mesophyll cells for fluorescence microscopy, as they are devoid of chloroplasts whose autofluorescence can pose problems. The arrested plastid development is peculiar to epidermal cells, however, and stands in the way of studies on protein targeting to plastids. We have developed a system enabling studies of in vivo protein targeting to organelles including chloroplasts within a photosynthetically active plant cell with excellent optical properties using a transient transformation procedure. We established biolistic transfection in epidermal pavement cells of the lawn daisy (Bellis perennis L., cultivar "Galaxy red") which unusually contain a moderate number of functional chloroplasts. These cells are excellent objects for fluorescence microscopy using current reporters, combining the advantages of the ease of biolistic transfection, the excellent optical properties of a single cell layer and access to chloroplast protein targeting. We demonstrate chloroplast targeting of plastid-localised heme oxygenase, and two further proteins whose localisation was equivocal. We also demonstrate unambiguous targeting to mitochondria, peroxisomes and nuclei. We thus propose that the Bellis system represents a valuable tool for protein localisation studies in living plant cells.

Porous metal membranes are produced from a two phase system in which the discrete cubic gamma'-precipitates connect during self assembly. In the so called rafting process the cubic particles start to coarsen and finally create a network within the gamma-matrix. In a following electrochemical leaching process one of the phases can be removed leaving the nanoporous membrane. So far, single crystalline alloys have been used for producing thin nanoporous membranes. Now research is in progress to produce the nanoporous membranes from polycrystalline alloys in a creep process. A modification of the commercially available alloy Nimonic 115 was used for these membranes. The permeability of these membranes was proven in a gas-flow test.

Phytochrome photoperception is a common mechanism for the detection of red and far-red light in bacteria, cyanobacteria, fungi and plants. However, the responses following phytochrome activation appear to be quite diverse between species. Lower plants, such as mosses, show phytochrome-mediated directional responses, namely phototropism and polarotropism. These cannot be explained by nuclear gene regulation and are thought to be triggered by phytochromes in the cytoplasm or at the plasma membrane. In higher plants, similar directional responses are mediated via phototropin, a blue light receptor, with phytochromes mainly controlling morphogenetic responses through gene regulation. However, cytoplasmic phytochrome responses exist in higher plants too, which appear to be intertwined with directional blue light perception. By summarizing the respective findings, a possible conservation of cytoplasmic phytochrome function in higher and lower plants is addressed here.

Titanium alloys like Ti6Al4V are widely used in medical engineering. However, the mechanical and chemical properties of titanium alloys lead to poor machinability, resulting in high production costs of medical products. To improve the machinability of Ti6Al4V, 0.9% of the rare earth element lanthanum (La) was added. The microstructure, the mechanical, and the corrosion properties were determined. Lanthanum containing alloys exhibited discrete particles of cubic lanthanum. The mechanical properties and corrosion resistance were slightly decreased but are still sufficient for many applications in the field of medical engineering. In vitro experiments with mouse macrophages (RAW 264.7) and human bone-derived cells (MG-63, HBDC) were performed and revealed that macrophages showed a dose response below and above a LaCl3 concentration of 200 microM, while MG-63 and HBDC tolerated three times higher concentrations without reduction of viability. The viability of cells cultured on disks of the materials showed no differences between the reference and the lanthanum containing alloy. We therefore propose that lanthanum containing alloy appears to be a good alternative for biomedical applications, where machining of parts is necessary.

There is increasing demand to functionalize meso- and nanoporous materials by coating and make the porous substrate biocompatible or environmentally friendly. However, coating on a meso-porous substrate poses great challenges, especially if the pore aspect ratio is high. We adopted the pulsed laser deposition (PLD) method to coat Ni(3)Al-based meso-porous membranes, which were fabricated from a single-crystal Ni-based superalloy by a unique selective phase dissolution technique. These membranes were about 250 µm thick and had channel-like pores (∼200 nm wide) with very high aspect ratio. Two different coating materials, i.e. diamond-like carbon (DLC) and titanium, were used to coat these membranes. High energy C or Ti ions, produced in the plasma plume by the PLD process, penetrated the channel-like pores and deposited coatings on the pore walls deep inside the membrane. The thickness and the quality of coatings on the pore walls were examined using the dual-beam system. The coating thickness, of the order of 50 nm, was adherent to the pore walls and was quite uniform at different depths. The carbon and the Ti deposition behaved quite similarly. The preliminary experiments showed that the PLD is an adequate method for coating fine open cavities of complex geometry. Simulations based on stopping and the range of ions in matter (SRIM) calculations helped in understanding the deposition processes on pore walls at great depths.

Phytochrome A (phyA) plays an important role during germination and early seedling development. Because phyA is the primary photoreceptor for the high-irradiance response and the very-low-fluence response, it can trigger development not only in red and far-red (FR) light but also in a wider range of light qualities. Although phyA action is generally associated with translocation to the nucleus and regulation of transcription, there is evidence for additional cytoplasmic functions. Because nuclear accumulation of phyA has been shown to depend on far-red-elongated hypocotyl 1 (FHY1) and FHL (FHY1-like), investigation of phyA function in a double fhl/fhy1 mutant might be valuable in revealing the mechanism of phyA translocation and possible cytoplasmic functions. In fhl/fhy1, the FR-triggered nuclear translocation of phyA could no longer be detected but could be restored by transgenic expression of CFP:FHY1. Whereas the fhl/fhy1 mutant showed a phyA phenotype in respect to hypocotyl elongation and cotyledon opening under high-irradiance response conditions as well as a typical phyA germination phenotype under very-low-fluence response conditions, fhl/fhy1 showed no phenotype with respect to the phyA-dependent abrogation of negative gravitropism in blue light and in red-enhanced phototropism, demonstrating clear cytoplasmic functions of phyA. Disturbance of phyA nuclear import in fhl/fhy1 led to formation of FR-induced phyA:GFP cytoplasmic foci resembling the sequestered areas of phytochrome. FHY1 and FHL play crucial roles in phyA nuclear translocation and signaling. Thus the double-mutant fhl/fhy1 allows nuclear and cytoplasmic phyA functions to be separated, leading to the novel identification of cytoplasmic phyA responses.

cDNA clones for all enzymes of the prechorismate pathway of higher plants have previously been cloned, with the exception of the second enzyme of the pathway, 3-dehydroquinate synthase. Here we describe the isolation of a cDNA encoding a 3-dehydroquinate synthase from tomato which was identified by complementing a 3-dehydroquinate synthase-deficient Escherichia coli strain with a tomato cDNA library. The deduced amino acid sequence contains a putative N-terminal plastid-specific transit peptide, and the sequence of the mature enzyme resembles those of the corresponding bacterial enzymes more than of the fungal enzymes. Sequence identity was even higher between the tomato and E. coli sequences than between the E. coli and other known bacterial sequences. The abundance of 3-dehydroquinate synthase transcripts differ in the organs of tomato plants analyzed. In cultured tomato cells, the abundance of 3-dehydroquinate synthase transcripts increased 9-fold within 4 to 5 h of elicitor treatment.

The Authors evaluate the risk of lung cancer and mesothelioma among asbestos workers in Germany. 3,988 workers (3,372 male and 616 female) were included in the study, which took into consideration the branch of the asbestos industry in which they had worked, the duration of their employment and also their smoking habits. At the end of the 12 year follow-up, 3,315 workers were alive and 673 dead. The analysis of cause of death showed an increased risk of dying from lung cancer and pleural and peritoneal mesothelioma, in men as well as in women. The risk was shown to be greatest among workers in the asbestos textile industry and among insulators. A probable multiplicative effect of asbestos exposure and smoking on lung cancer causation was noted.

A cohort study was conducted of 616 German female workers with a history of exposure to asbestos. Standardized proportionate mortality analysis was done except for mesothelioma, for which proportionate mortality was computed based on best evident cause of death. Mortality from lung cancer was increased three times over expected value. Death rates due to mesothelioma were 340 times higher than in the general population. Female mortality rates surpassed those observed in men twofold for lung cancer and fourfold for mesothelioma. In comparison with published data from international cohort studies, the observed mortality for mesothelioma in our female cohort appeared higher than that previously reported. German women with a history of asbestos exposure are considered a high-risk group for developing mesothelioma and lung cancer. They should be a target group for intervention strategies (eg, chemoprevention, smoking cessation, early cancer detection).