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Purpose This paper aims to study the internationalization path of emerging market multinational enterprises (EMNEs) in their international expansion through the global cities (GCs) phenomenon. Design/methodology/approach The authors used a quantitative approach to identify the most used ownership and entry modes, the preferred economic sectors and the level of interconnectedness of GCs. Findings The manuscript identified the predominance of the tertiary sector in the selection of GCs as foreign direct investment destinations. Second, the acquisition is the preferred entry mode regardless of the connectivity of the GC and the country of origin of the EMNE. The third is the use of wholly-owned subsidiaries as the preferred ownership mode. Finally, market-seeking is the main driver for the internationalization of Latin American EMNE. Consequentially, some GCs-specific advantages remain untapped by Latin American EMNE. Research limitations/implications This manuscript considered each investment into a global city as a single step, although some acquisitions occurred incrementally through several small investments. Practical implications The authors developed a road map for the internationalization of Latin American EMNEs through GCs, acquisitions and wholly-owned subsidiaries. Finally, service-oriented EMNEs, such as IT and financial services, target locations with high interconnectedness to maximize the benefits of GCs-specific advantages. Originality/value The authors pointed out that market-seeking, not resource-seeking or efficiency-seeking is the primary driver of the internationalization of EMNE into global cities.

This article aims to present the differences between the profile of plants and the global value chains (GVC) of two aircraft manufacturers, Embraer and Boeing. After, literature review about the theories of internationalization, global value chains, and internationalization of manufacturing. It is concluded that Embraer leads a value chain called Relational. At the same time, Boeing opted for the type called Hierarchy after a failed experience with the Relational type of value chain during the development of the 787 Dreamliner model.

Tissue clearing and fluorescent microscopy are powerful tools for unbiased organ-scale protein expression studies. Critical for interpreting expression patterns of large imaged volumes are reliable quantification methods. Here, we present DELiVR a deep learning pipeline that uses virtual reality (VR)-generated training data to train deep neural networks, and quantify c-Fos as marker for neuronal activity in cleared mouse brains and map its expression at cellular resolution. VR annotation significantly accelerated the speed of generating training data compared to conventional 2D slice based annotation. DELiVR detects cells with much higher precision than current threshold-based pipelines, and provides an extensive toolbox for data visualization, inspection and comparison. We applied DELiVR to profile cancer-related mouse brain activity, and discovered a novel activation pattern that distinguishes between weight-stable cancer and cancer-associated weight loss. Thus, DELiVR provides a robust mouse brain analysis pipeline at cellular scale that can be used to study brain activity patterns in health and disease.The DELiVR software, Fiji plugin and documentation can be found athttps://www.DISCOtechnologies.org/DELiVR/.Graphical AbstractHighlightsDELiVR detects labelled cells in cleared brains with deep learningDELiVR is trained by annotating ground-truth data in virtual reality (VR)DELiVR is launched via a FIJI plugin anywhere from PCs to clustersUsing DELiVR, we found new brain activity patterns in weight-stable vs. cachectic cancerSupplementary Videos can be seen at:https://www.DISCOtechnologies.org/DELiVR/

Background Parallel to the growth of the oral healthcare market, there is a constantly increasing demand for natural products as well. Many customers prefer products that contain fewer toxic agents, therefore providing an environmentally friendly solution with the benefit of smaller risk to the user. Medieval and early modern medicinal knowledge might be useful when looking for natural, herbal-based components to develop modern products. Along with these considerations we created, tested, and compared an entirely natural mouthwash, named Herba Dei. Methods The manufacturing procedure was standardized, and the created tincture was evaluated by GC/MS analysis for active compounds, experimentally tested in cell-based cytotoxicity, salivary protein integrity, cell-free antioxidant activity, anti-bacterial and anti-viral assays, and compared with three market-leading mouthwashes. Results Our tincture did not show significant damage in the cytotoxicity assays to keratinocyte and Vero E6 cells and did not disrupt the low molecular weight salivary proteins. Its radical scavenging capacity surpassed that of two tested, partly natural, and synthetic mouthwashes, while its antibacterial activity was comparable to the tested products, or higher in the bacterial aerobic respiratory assay. The active compounds responsible for the effects include naturally occurring phenylpropanoids, terpenes, and terpenoids. Our mouthwash proved to be effective in vitro in lowering the copy number of SARS-CoV-2 in circumstances mimicking the salivary environment. Conclusions The developed product might be a useful tool to impede the transmission and spread of SARS-CoV-2 in interpersonal contact and aerosol-generating conditions. Our mouthwash can help reduce the oral bacterial flora and has an antioxidant activity that facilitates wound healing and prevents adverse effects of smoke in the oral cavity.

Background The optimal surgical staging procedure of the axilla in patients who convert from a clinically positive (cN+) to a clinically negative node status (ycN0) through neoadjuvant chemotherapy is still controversial. Widely diverse techniques such as full Axillary Lymph Node Dissection (ALND), Targeted Axillary Dissection (TAD), Targeted Lymph Node Biopsy (TLNB) and Sentinel Lymph Node Biopsy alone (SLNB) are given preference in different international guidelines. So far, no comparative data on the oncological outcome or the morbidity of the different procedures are available. Further research is needed to safely de-escalate the extent of axillary surgery in this patient group. Trial design The AXSANA study is an international prospective cohort study including cN+ patients converting to ycN0 status and treated with different axillary staging techniques according to the standard at their treating institution. The study is initiated by the EUBREAST network. The trial includes patients with cT1-4c tumors, who present initially with axillary lymph node metastasis and are scheduled for neoadjuvant chemotherapy. According to an amendment in 2020 the inclusion of patients with highly suspicious nodes without minimally invasive biopsy is allowed. All patients converting to ycN0 status undergo follow-up for 5 years irrespectively of the ypN status. Primary endpoints: Invasive disease-free survival, axillary recurrence rate and health-related quality of life (HRQoL). HRQoL are evaluated using four standardized questionnaires (EORTC QLQ-C 30, EORTC QLQ BR 23, Lymph ICF and SOC-13) at baseline and after 1, 3 and 5 years after surgery. Secondary endpoints are the feasibility and performance of different axillary staging techniques (detection rate, number of removed lymph nodes and association with complications, arm morbidity and quality of life, operating time and use of clinical and economic resources); impact of learning curve, and the detailed mapping of surgical and oncological treatment standards in different countries. The impact on different regional treatment strategies (radiotherapy, ALND) in patients with ypN0(i+), ypN1(mi) and ypN1 is assessed. Current status of the study: On June 30th 157 study sites from 15 countries are open for recruitment (Austria 2, Czech Republic 1, Finland 1, Germany 112, Greece 3, Italy 1, Norway 1, Poland 3, Portugal 5, Romania 2, Russia 1, Sweden 4, Switzerland 4, Spain 6, Turkey 11). 620 patients have been included in the study. Among patients who converted to ycN0 status, 144 have been scheduled for ALND, 157 for TAD and 49 for SLNB. The study is still open for further international study sites. Funding: AGO-B, Claudia-von Schilling Foundation, Ehmann Foundation, AWOgyn, Merit Medical, Endomagnetics, Mammotome Target accrual: 3000 patients worldwide Citation Format: Thorsten Kühn, Steffi Hartmann, Elmar Stickeler, Jana de Boniface, Oreste Gentilini, Sarah Fröhlich, Franziska Ruf, Marc Thill, Michael Hauptmann, Guldeniz Karadeniz Cakmak, Isabel Rubio, Maria Luisa Gasparri, Michaelis Kontos, Eduard-Alexandru Bonci, Laura Niinikoski, Rosa Di Micco, Dawid Murawa, David Pinto, Florentia Peintinger, Christine Solbach, Matilda Appelgren, Jens-Uwe Blohmer, Michael Weigel, Gabriele Kaltenecker, Michael Schrauder, Janine Simons, Marjolein Smidt, Ellen Schlichting, Lukas Dostalek, Alexander Sergeevich Emelyanov, Elisabeth Thiemann, Semra Gunay, Sybille Loibl, Maggie Banys-Paluchowski. AXSANA - EUBREAST 3 (axillary surgery after neoadjuvant treatment): An international prospective multicenter cohort study of the EUBREAST study group to evaluate different surgical methods of axillary staging (sentinel lymph node biopsy, targeted axillary dissection, axillary dissection) in clinically node-positive breast cancer patients treated with neoadjuvant chemotherapy (NCT04373655) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-04-04.

Sodium glucose co-transporter-2 inhibitors (SGLT-2i) improve cardiorenal outcomes in patients with chronic kidney disease (CKD), with and without type 2 diabetes. The molecular mechanisms underlying these pleiotropic effects remain unclear, yet it is speculated that SGLT-2i elicit a neurohormonal modulation resulting in renin-angiotensin system (RAS) activation. We hypothesized that combined SGLT-2 and angiotensin-converting enzyme inhibition (ACEi) favours RAS regulation towards the beneficial angiotensin-(1-7)-driven axis.This randomized controlled prospective study investigated the effect of 12 weeks treatment with the SGLT-2i empagliflozin on top of ACEi on the molecular RAS dynamics in 24 diabetic and 24 non-diabetic patients with CKD. Systemic RAS peptides were quantified by mass spectrometry.In patients with type 2 diabetes, combined SGLT-2i and ACEi significantly upregulated plasma renin activity [pre-treatment median and interquartile range 298.0 (43.0-672.0) pmol/L versus post-treatment 577.0 (95.0-1543.0) pmol/L; p = .037] and angiotensin I levels [pre-treatment 289.0 (42.0-668.0) pmol/L versus post-treatment 573.0 (93.0-1522.0) pmol/L; p = .037], together with a significant increase of angiotensin-(1-7) levels [pre-treatment 14.0 (2.1-19.0) pmol/L versus post-treatment 32.0 (5.7-99.0) pmol/L; p = .012]. Empagliflozin treatment resulted in a 1.5 to 2-fold increase in main RAS peptides in patients with diabetes compared with placebo. No significant effect of empagliflozin on top of ACEi on RAS peptides was found in patients with CKD without diabetes.A distinct RAS modulation by SGLT-2i occurs in diabetic kidney disease reflected by enhancement of the beneficial angiotensin-(1-7) providing a molecular background for this renoprotective therapeutic approach.

The research followed a three-step methodology to determine the intertwining between innovation and internationalization in elite business schools. First, linear regression (OLS) to understand the ...

Background Cancer cachexia (CCx) is a multifactorial wasting disorder characterized by involuntary loss of body weight that affects many cancer patients and implies a poor prognosis, reducing both tolerance to and efficiency of anticancer therapies. Actual challenges in management of CCx remain in the identification of tumour‐derived and host‐derived mediators involved in systemic inflammation and tissue wasting and in the discovery of biomarkers that would allow for an earlier and personalized care of cancer patients. The aim of this study was to identify new markers of CCx across different species and tumour entities. Methods Quantitative secretome analysis was performed to identify specific factors characteristic of cachexia‐inducing cancer cell lines. To establish the subsequently identified phospholipase PLA2G7 as a marker of CCx, plasma PLA2G7 activity and/or protein levels were measured in well‐established mouse models of CCx and in different cohorts of weight‐stable and weight‐losing cancer patients with different tumour entities. Genetic PLA2G7 knock‐down in tumours and pharmacological treatment using the well‐studied PLA2G7 inhibitor darapladib were performed to assess its implication in the pathogenesis of CCx in C26 tumour‐bearing mice. Results High expression and secretion of PLA2G7 were hallmarks of cachexia‐inducing cancer cell lines. Circulating PLA2G7 activity was increased in different mouse models of CCx with various tumour entities and was associated with the severity of body wasting. Circulating PLA2G7 levels gradually rose during cachexia development. Genetic PLA2G7 knock‐down in C26 tumours only partially reduced plasma PLA2G7 levels, suggesting that the host is also an important contributor. Chronic treatment with darapladib was not sufficient to counteract inflammation and tissue wasting despite a strong inhibition of the circulating PLA2G7 activity. Importantly, PLA2G7 levels were also increased in colorectal and pancreatic cancer patients with CCx. Conclusions Overall, our data show that despite no immediate pathogenic role, at least when targeted as a single entity, PLA2G7 is a consistent marker of CCx in both mice and humans. The early increase in circulating PLA2G7 levels in pre‐cachectic mice supports future prospective studies to assess its potential as biomarker for cancer patients.

Purpose This study aims to examine the relationship between cultural distances between countries and their scores in the Corruption Perception Index (CPI), which is the most commonly used measure of corruption in international business (IB) research. Design/methodology/approach The authors applied fixed-effect (generalized least squares) statistical modeling technique to analyze 1,580 year-country observations. Findings The authors found that the CPI score is determined to a large extent by cultural distances between countries, specifically the distance to the USA and to Denmark. Research limitations/implications CPI is often used as a sole measure of state-level corruption in IB research. The results show that the measure is significantly influenced by cultural differences and hence it should be applied with great caution, preferably augmented with other measures. Originality/value To the best of the authors’ knowledge, this is the first study to look at cultural distances as determinants of CPI score. The authors empirically test whether the CPI is culturally biased.

Background: The primary objective of the prospective, non-interventional study (NIS) AkyPRO was the evaluation of quality of life (QoL) in adult cancer patients (pts) receiving NEPA as antiemetic prophylaxis. Secondary endpoints were efficacy and safety of NEPA. NEPA is administered as an oral fixed dose combination of 300 mg of the neurokinin-1-receptor antagonist - (NK1RA) netupitant and 0,5 mg of the 5-hydroxytryptamin-3-receptor antagonist (5-HT3RA) palonosetron once per chemotherapy cycle as primary prophylaxis for chemotherapy-induced nausea and vomiting (CINV) associated with moderately (MEC) or highly (HEC) emetogenic chemotherapy. In modern antiemetic guidelines, anthracycline/ cyclophosphamide (AC) - containing chemotherapy (AC-CT) is classified as HEC requiring triple antiemetic prophylaxis with a 5-HT3RA, a NK1RA and dexamethasone. Pts with breast cancer (BC) have additional risk factors for nausea and vomiting, like female sex and younger age, thus representing a high-risk group for CINV. Here, we present a post-hoc analysis of quality of life data and effectiveness of NEPA in the subgroup of BC pts in two age groups ≥ and < 60 years (y), who were treated with AC-CT in the AkyPRO NIS. Methods: The AkyPRO NIS has been conducted to evaluate quality of life and effectiveness of antiemetic prophylaxis with NEPA in cancer pts with various cancer entities receiving single day or two day MEC or HEC in a real life situation. Quality of life (QoL) was recorded by FLIE questionnaires. Effectiveness of NEPA as indicated by complete response (CR: no vomiting, no rescue medication), additional medication, and adverse events were recorded in patient diaries over three consecutive chemotherapy cycles. Patients and physicians documented overall antiemetic control on a 4-point scale (very good, good, satisfactory, poor). Results: In total, the AkyPro NIS enrolled 2,427 pts. 1,428 pts (65.7 %) had breast cancer. In this post hoc analysis 1,197 BC pts receiving AC-CT (83 % of all BC pts) were evaluated. 782 pts (65%) were Conclusion: This real-life study confirmed the effectiveness of NEPA in preventing CINV in the subgroup of BC pts receiving AC-chemotherapy. Pts ≥ 60y experienced less CINV compared to pts Citation Format: Joerg Schilling, Steffi Busch, Martin Hollaender, Gabriele Kaltenecker, Eberhard Müller, Thomas Resch, Angelika Till, Meinholf Karthaus. Evaluation of age as a risk factor for CINV in breast cancer patients: Post-hoc analysis of the German real-world AkyPRO study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-35.

Background Cancer cachexia (CCx) is a multifactorial energy‐wasting syndrome reducing the efficiency of anti‐cancer therapies, quality of life, and survival of cancer patients. In the past years, most studies focused on the identification of tumour and host‐derived proteins contributing to CCx. However, there is still a lack of studies addressing the changes in bioactive lipids. The aim of this study was to identify specific lipid species as a hallmark of CCx by performing a broad range lipid analysis of plasma from well‐established CCx mouse models as well as cachectic and weight stable cancer patients. Methods Plasma from non‐cachectic (PBS‐injected mice, NC26 tumour‐bearing mice), pre‐cachectic and cachectic mice (C26 and LLC tumour‐bearing mice, ApcMin/+ mutant mice), and plasma from weight stable and cachectic patients with gastrointestinal cancer, were analysed using the Lipidyzer™ platform. In total, 13 lipid classes and more than 1100 lipid species, including sphingolipids, neutral and polar glycerolipids, were covered by the analysis. Correlation analysis between specific lipid species and readouts of CCx were performed. Lipidomics data were confirmed by gene expression analysis of metabolic organs to analyse enzymes involved in sphingolipid synthesis and degradation. Results A decrease in several lysophosphatidylcholine (LPC) species and an increase in numerous sphingolipids including sphingomyelins (SMs), ceramides (CERs), hexosyl‐ceramides (HCERs) and lactosyl‐ceramides (LCERs), were mutual features of CCx in both mice and cancer patients. Notably, sphingolipid levels gradually increased during cachexia development. Key enzymes involved in ceramide synthesis were elevated in liver but not in adipose, muscle, or tumour tissues, suggesting that ceramide turnover in the liver is a major contributor to elevated sphingolipid levels in CCx. LPC(16:1), LPC(20:3), SM(16:0), SM(24:1), CER(16:0), CER(24:1), HCER(16:0), and HCER(24:1) were the most consistently affected lipid species between mice and humans and correlated negatively (LPCs) or positively (SMs, CERs and HCERs) with the severity of body weight loss. Conclusions High levels of sphingolipids, specifically ceramides and modified ceramides, are a defining feature of murine and human CCx and may contribute to tissue wasting and skeletal muscle atrophy through the inhibition of anabolic signals. The progressive increase in sphingolipids during cachexia development supports their potential as early biomarkers for CCx.

The Marabou Stork Leptoptilos crumenifer is a large wading bird that occurs extensively throughout sub-Saharan Africa in savanna and wetland habitats. Despite its widespread occurrence in southern Africa, the number of known breeding localities and the numbers of nests are limited. We report on large, dispersed nesting colonies in the greater Gorongosa landscape in central Mozambique. We counted the number of active Marabou nests in Gorongosa National Park and adjoining areas by conducting annual aerial (helicopter) surveys between 2016 and 2019. The Muaredzi colony within Gorongosa National Park has been expanding annually from 82 active nests in 2016 up to 258 nests in 2019. Similarly, the Mussicadzi colony has increased from five nests in 2016 to 81 nests in 2019. A total of 373 active nests were recorded in 2019 in Gorongosa National Park. Since 2017, a small number of additional nests were also observed in the Coutada 11 and Coutada 12 hunting areas, adjacent to Gorongosa. The total count for the greater Gorongosa landscape was 380 active nests in 2019. This represents the first formal record of what appears to be the single largest breeding assembly of Marabou Storks south of the Zambezi and Cunene Rivers. The observation of a significant number of active Marabou nests in the greater Gorongosa landscape has important conservation implications. French Title: Le Marabout d’Afrique Leptoptilos crumenifer se reproduisent dans le grand paysage de Gorongosa, Mozambique Le Marabout d’Afrique Leptoptilos crumenifer est un grand echassier qui se trouve partout en Afrique subsaharienne dans des habitats de savane et de zones humides. Malgre sa presence etendue en Afrique australe, le nombre de localites de reproduction connues et le nombre de nids sont limites. Nous faisons etat de grandes colonies de nidification dispersees dans le grand paysage de Gorongosa, au centre du Mozambique. Nous avons recense le nombre de nids de Marabouts actifs dans le parc national de Gorongosa et les zones adjacentes en effectuant des releves aeriens annuels (par helicoptere) entre 2016 et 2019. La colonie de Muaredzi dans le parc national de Gorongosa s’est developpee chaque annee, passant de 82 nids actifs en 2016 a 258 nids en 2019. De meme, la colonie de Mussicadzi est passee de 5 nids en 2016 a 81 nids en 2019. Un total de 373 nids actifs a ete enregistre en 2019 dans le parc national de Gorongosa. Depuis 2017, un petit nombre de nids supplementaires a egalement ete observe dans les zones de chasse Coutada 11 et Coutada 12, adjacentes a Gorongosa. Le nombre total de nids actifs dans le grand paysage de Gorongosa etait de 380 en 2019. Il s›agit du premier enregistrement officiel de ce qui semble etre le plus grand rassemblement de Cigognes Marabouts nicheuses au sud des rivieres Zambeze et Cunene. L›observation d›un nombre important de nids de Marabouts actifs dans le grand paysage de Gorongosa a des implications importantes pour la conservation de la nature. Keywords: breeding colony, conservation importance. scavenger, Southern Africa

Artificial intelligence has gained considerable momentum in software engineering, but there are major challenges that make this domain special. We review recent advances, raise awareness of the distinctiveness of software configuration spaces, and provide practical guidelines for modeling, predicting, and optimizing performance.

Background: Protroca evaluated the efficacy and safety of primary and secondary prophylaxis of neutropenia with lipegfilgrastim (Lonquex®) in breast cancer patients receiving neoadjuvant or adjuvant chemotherapy (CT). Patients and Methods: Of the 255 patients enrolled, 248 patients were evaluable for the intent-to-treat (ITT) and 194 patients for the per-protocol set. Primary and secondary end points after lipegfilgrastim treatment were assessed. Results: Nine patients of the ITT set receiving lipegfilgrastim as primary prophylaxis (n = 222) had febrile neutropenia of grade 3–4 (5 patients) or infection of grade 3–4 (4 patients); 1/26 of those receiving secondary prophylaxis had an event. Dose reductions were performed in 9.5% of the patients. Postponement of cancer CT cycles for >3 days occurred in Conclusions: Application of lipegfilgrastim was effective as primary and secondary prophylaxis in the prevention of CT-induced neutropenia in breast cancer.

Seasonal migration is a dynamic natural phenomenon that allows organisms to exploit favourable habitats across the annual cycle. While the morphological, physiological and behavioural changes associated with migratory behaviour are well characterized, the genetic basis of migration and its link to endogenous biological time-keeping pathways are poorly understood. Historically, genome-wide research has focused on genes of large effect, whereas many genes of small effect may work together to regulate complex traits like migratory behaviour. Here, we explicitly relax stringent outlier detection thresholds and, as a result, discover how multiple biological time-keeping genes are important to migratory timing in an iconic raptor species, the American kestrel ( Falco sparverius ). To validate the role of candidate loci in migratory timing, we genotyped kestrels captured across autumn migration and found significant associations between migratory timing and genetic variation in metabolic and light-input pathway genes that modulate biological clocks ( top1, phlpp1, cpne4 and peak1) . Further, we demonstrate that migrating individuals originated from a single panmictic source population, suggesting the existence of distinct early and late migratory genotypes (i.e. chronotypes). Overall, our results provide empirical support for the existence of a within-population-level polymorphism in genes underlying migratory timing in a diurnally migrating raptor.

Supplement 1, with additional experimental and fitting details, the derivation of the model and additional measurements.

Supplementary Figures S1 to S8, and Supplementary Tables S1 to S2

The subwavelength confinement of surface plasmon polaritons (SPPs) makes them attractive for various applications such as sensing, light generation and solar energy conversion. Near-field microscopy associated with interferometric detection allows to visualize both the amplitude and phase of SPPs. However, their full quantitative characterization in a reflection configuration is challenging due to complex wave patterns arising from the interference between several excitation channels. Here, we present near-field measurements of SPPs on large monocrystalline gold platelets in the visible spectral range. We study systematically the influence of the incident angle of the exciting light on the SPPs launched by an atomic force microscope tip. We find that the amplitude and phase signals of these SPPs are best disentangled from other signals at grazing incident angle relative to the edge of the gold platelet. Furthermore, we introduce a simple model to explain the phase shift observed between the SPP amplitude and phase profiles. Using this model, the wavelength and propagation length of the tip-launched plasmons are retrieved by isolating and fitting their signals far from the platelets edges. Our experimental results are in excellent agreement with theoretical models using gold refractive index values. The presented method to fully characterize the SPP complex wavevector could enable the quantitative analysis of polaritons occurring in different materials at visible wavelengths., Comment: 36 pages, 8 figures

Spatial molecular profiling of complex tissues is essential to investigate cellular function in physiological and pathological states. However, methods for molecular analysis of large biological specimens imaged in 3D are lacking. Here, we present DISCO-MS, a technology that combines whole-organ/whole-organism clearing and imaging, deep-learning-based image analysis, robotic tissue extraction, and ultra-high-sensitivity mass spectrometry. DISCO-MS yielded proteome data indistinguishable from uncleared samples in both rodent and human tissues. We used DISCO-MS to investigate microglia activation along axonal tracts after brain injury and characterized early- and late-stage individual amyloid-beta plaques in a mouse model of Alzheimer's disease. DISCO-bot robotic sample extraction enabled us to study the regional heterogeneity of immune cells in intact mouse bodies and aortic plaques in a complete human heart. DISCO-MS enables unbiased proteome analysis of preclinical and clinical tissues after unbiased imaging of entire specimens in 3D, identifying diagnostic and therapeutic opportunities for complex diseases. VIDEO ABSTRACT.

SUMMARYSpatial molecular profiling of complex tissues is essential to investigate cellular function in physiological and pathological states. However, methods for molecular analysis of biological specimens imaged in 3D as a whole are lacking. Here, we present DISCO-MS, a technology combining whole-organ imaging, deep learning-based image analysis, and ultra-high sensitivity mass spectrometry. DISCO-MS yielded qualitative and quantitative proteomics data indistinguishable from uncleared samples in both rodent and human tissues. Using DISCO-MS, we investigated microglia activation locally along axonal tracts after brain injury and revealed known and novel biomarkers. Furthermore, we identified initial individual amyloid-beta plaques in the brains of a young familial Alzheimer’s disease mouse model, characterized the core proteome of these aggregates, and highlighted their compositional heterogeneity. Thus, DISCO-MS enables quantitative, unbiased proteome analysis of target tissues following unbiased imaging of entire organs, providing new diagnostic and therapeutic opportunities for complex diseases, including neurodegeneration.Graphical AbstractHighlightsDISCO-MS combines tissue clearing, whole-organ imaging, deep learning-based image analysis, and ultra-high sensitivity mass spectrometryDISCO-MS yielded qualitative and quantitative proteomics data indistinguishable from fresh tissuesDISCO-MS enables identification of rare pathological regions & their subsequent molecular analysisDISCO-MS revealed core proteome of plaques in 6 weeks old Alzheimer‘s disease mouse model Supplementary Video can be seen at: http://discotechnologies.org/DISCO-MS/

Although relevant pieces of literature discuss innovation in management education and the importance of internationalization of business schools, there is a lack of scholarly articles analyzing the mutual influence between internationalization and innovation in business schools, particularly when considering the types of programs and their location. Henceforth, to fill the identified theoretical gap, this article pursues the following research question: Are innovation and internationalization intertwined in elite business schools? The study follows a two-step methodology in its investigation and experiments. First, we performed a correlational analysis using linear regression (OLS) to determine if there is a relationship between internationalization and innovation of business schools by considering two types of programs: the Global MBA, and the Executive MBA. The results of the OLS method show that there is no correlation between Innovation and Internationalization in the Global MBA programs (p=.546) whereas, there exists a positive correlation between Innovation and Internationalization in Executive MBA (p=.00). Second, we conducted a One-way multivariate analysis of variance (MANOVA) to evaluate the impact of the location of the MBA programs on internationalization and innovation. We found that location presented no significant relationship with internationalization and innovation in the Global MBA program (as their significance levels were p=.483 and p=.490, respectively) and Executive MBA programs (p=.222 and p=.654, respectively). In both cases, these results mean that internationalized or highly innovative programs such as Global MBA and Executive MBA programs can be found all over the world. Thus, we reached two main sets of conclusions. First, innovation and internationalization are uncorrelated in Global MBA programs, whereas both variables (innovation and internationalization) are correlated in Executive MBA programs. For the second set of conclusions, we note that the location of business schools does not impact their internationalization and innovation. Keywords: Educational Innovation, Internationalization, Executive Educatio

INTRODUCTION AND OBJECTIVE:Since the introduction of rsRARP in 2010 three prospective RCTs comparing rsRARP and cRARP have been published. To further evaluate the results published until now we con...

We investigate single-cycle terahertz (THz) field-induced nonlinear absorption in doped silicon carbide. We find that the nonlinear response is ultrafast, and we observe up to 20% reduction of transmission of single THz pulses at peak field strengths of 280 kV/cm. We model the field and temperature dependence of the nonlinear response by a finite-difference time-domain simulation that incorporates the temporally nonlocal nonlinear conductivity of the silicon carbide. Nonlinear two-dimensional THz spectroscopy reveals that the nonlinear absorption has an ultrafast subpicosecond recovery time, with contributions from both sum-frequency generation and four-wave mixing, in the form of a photon-echo signal. The ultrafast nonlinearity with its equally fast recovery time makes silicon carbide an interesting candidate material for extremely fast nonlinear THz modulators.

This paper aims at giving an overview of Ramon Lazkano’s musical universe, focussing on four of his recent works: Ortzi Isilak (2005), two pieces from the cycle Chalk Laboratory (2001–11), and the ...

We report a breakthrough in observing living cells with infrared s-SNOM (scattering near-field microscope).(1, 2) To keep cells "happy" it is mandatory to avoid evaporation, oxygen attack, and mechanical distortion. We reported at IRMMW-THz 2019 that we successfully analyzed E. coli cells protected by graphene, but later had to realize that strong van der Waals forces squeeze cells and thus impair their metabolic functions.Here we demonstrate a new, satisfactory method of letting cells in nutrient broth adhere weakly to a biocompatible surface, SiN, where they can develop freely. We choose this material in form of an extremely thin (10 nm), free-standing membrane so that the s-SNOM tip can work on and probe through it from the other side at atmospheric conditions, while the tip-confined infrared near field reaches through this membrane largely unaffected.

Infrared fingerprint spectra can reveal the chemical nature of materials down to 20-nm detail, far below the diffraction limit, when probed by scattering-type scanning near-field optical microscopy (s-SNOM). But this was impossible with living cells or aqueous processes as in corrosion, due to water-related absorption and tip contamination. Here, we demonstrate infrared s-SNOM of water-suspended objects by probing them through a 10-nm thick SiN membrane. This separator stretches freely over up to 250 µm, providing an upper, stable surface to the scanning tip, while its lower surface is in contact with the liquid and localises adhering objects. We present its proof-of-principle applicability in biology by observing simply drop-casted, living E. coli in nutrient medium, as well as living A549 cancer cells, as they divide, move and develop rich sub-cellular morphology and adhesion patterns, at 150 nm resolution. Their infrared spectra reveal the local abundances of water, proteins, and lipids within a depth of ca. 100 nm below the SiN membrane, as we verify by analysing well-defined, suspended polymer spheres and through model calculations. SiN-membrane based s-SNOM thus establishes a novel tool of live cell nano-imaging that returns structure, dynamics and chemical composition. This method should benefit the nanoscale analysis of any aqueous system, from physics to medicine.

The aim of this study was to investigate whether the lack of signal transducer and activator of transcription 5 (STAT5) in mature adipocytes of obese mice (Stat5Adipoq mice) improves glucose and lipid metabolism as previously observed in lean mice. Male Stat5Adipoq mice and their wild type (WT) littermates were fed high-fat diet (HFD). Effects of adipocyte STAT5 deficiency on adiposity as well as on glucose and lipid metabolism were determined under ad libitum feeding and after weight loss induced by calorie restriction. Compared to WT mice, obese Stat5Adipoq mice showed modestly accelerated weight gain and blunted depletion of fat stores under calorie restriction (reduction in % body fat after 3 weeks: WT, -9.3±1.1, vs Stat5Adipoq, -5.9±0.8, p = 0.04). No differences were observed between Stat5Adipoq and WT mice with regard to parameters of glucose and lipid metabolism including basal glycaemia, glucose tolerance, and plasma triglycerides. In conclusion, STAT5 deficiency in the adipocyte of HFD-fed obese mice was associated with increased fat accumulation. In contrast to previous findings in lean mice, however, lipid accumulation was not associated with any improvement in glucose and lipid metabolism. Our results do not support adipocyte STAT5 as a promising target for the treatment of obesity-associated metabolic derangements.

BACKGROUND: Recent studies proved that metabolic changes in malignant disorders have an impact on protein glycosylation, however, only a few attempts have been made so far to use O-GlcNAc analysis as a prognostic tool. Glucose metabolism is reported to be altered in hematological malignancies thus, we hypothesized that monitoring intracellular O-GlcNAc levels in Rai stage 0-I (Binet A) CLL patients could give deeper insights regarding subtle metabolic changes of progression which are not completely detected by the routine follow-up procedures. OBJECTIVE: In this proof of concept study we established a flow cytometric detection method for the assessment of O-GlcNAcylation as a possible prognostic marker in CLL malignancy which was supported by fluorescence microscopy. METHODS: Healthy volunteers and CLL patients were recruited for this study. Lymphocytes were isolated, fixed and permeabilised by various methods to find the optimal experimental condition for O-GlcNAc detection by flow cytometry. O-GlcNAc levels were measured and compared to lymphocyte count and various blood parameters including plasma glucose level. RESULTS: The protocol we developed includes red blood cell lysis, formalin fixation, 0.1% Tween 20 permeabilisation and employs standardized cell number per sample and unstained controls. We have found significant correlation between O-GlcNAc levels and WBC (R2= 0.8535, p< 0.0029) and lymphocyte count (R2= 0.9225, p< 0.0006) in CLL patients. Interestingly, there was no such correlation in healthy individuals (R2= 0.05664 for O-GlcNAc vs WBC and R2= 0.04379 for O-GlcNAc vs lymphocytes). CONCLUSION: Analyzing O-GlcNAc changes in malignant disorders, specifically in malignant hematologic diseases such as CLL, could be a useful tool to monitor the progression of the disease.

Background Renin–angiotensin–aldosterone system (RAAS) blockade with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) is the cornerstone of antihypertensive treatment in patients with chronic kidney disease (CKD) and diabetes mellitus. Mineralocorticoid receptor antagonists (MRA) on top of conventional RAAS blockade confer cardio- and renoprotective effects. Yet, the detailed effects of this therapeutic approach on key RAAS effectors have not been elucidated to date. Methods In this exploratory placebo-controlled study, 15 patients with CKD stages 2–3 and albuminuria due to diabetic kidney disease (DKD) were randomized to receive the MRA eplerenone or placebo in addition to ACEi therapy. Employing mass-spectrometry, we quantified plasma angiotensin levels [Ang I, Ang II, Ang-(1–7), Ang-(1–5), Ang III, Ang IV], renin and aldosterone in patients before and after 8 weeks of MRA treatment. Results While blood pressure and kidney function were similar in the placebo and eplerenone treatment group during the study period, distinct differences in RAAS regulation occurred: eplerenone treatment resulted in an increase in plasma renin activity, Ang I and aldosterone concentrations, indicating global RAAS activation. In addition, eplerenone on top of ACEi profoundly upregulated the alternative RAAS effector Ang-(1–7). Conclusions Combined eplerenone and ACEi therapy increases Ang-(1–7) levels in patients with CKD indicating a unique nephroprotective RAAS pattern with considerable therapeutic implications. Supplementary Information The online version contains supplementary material available at 10.1007/s13300-021-01118-7.

In scientific computing, researchers often use feature-rich software frameworks to simulate physical, chemical, and biological processes. Commonly, researchers follow a clone-and-own approach: Copying the code of an existing, similar simulation and adapting it to the new simulation scenario. In this process, a user has to select suitable artifacts (e.g., classes) from the given framework and replaces the existing artifacts from the cloned simulation. This manual process incurs substantial effort and cost as scientific frameworks are complex and provide large numbers of artifacts. To support researchers in this area, we propose a lightweight API-based analysis approach, called VORM, that recommends appropriate artifacts as possible alternatives for replacing given artifacts. Such alternative artifacts can speed up performance of the simulation or make it amenable to other use cases, without modifying the overall structure of the simulation. We evaluate the practicality of VORM—especially, as it is very lightweight but possibly imprecise—by means of a case study on the DUNE numerics framework and two simulations from the realm of physical simulations. Specifically, we compare the recommendations by VORM with recommendations by a domain expert (a developer of DUNE). VORM recommended 34 out of the 37 artifacts proposed by the expert. In addition, it recommended 2 artifacts that are applicable but have been missed by the expert and 32 artifacts not recommended by the expert, which however are still applicable in the simulation scenario with slight modifications. Diving deeper into the results, we identified an undiscovered bug and an inconsistency in DUNE, which corroborates the usefulness of VORM.

Many software systems can be tuned for multiple objectives (e.g., faster runtime, less required memory, less network traffic or energy consumption, etc.). Optimizers built for different objectives suffer from "model disagreement"; i.e., they have different (or even opposite) insights and tactics on how to optimize a system. Model disagreement is rampant (at least for configuration problems). Yet prior to this paper, it has barely been explored. This paper shows that model disagreement can be mitigated via VEER, a one-dimensional approximation to the N-objective space. Since it is exploring a simpler goal space, VEER runs very fast (for eleven configuration problems). Even for our largest problem (with tens of thousands of possible configurations), VEER finds as good or better optimizations with zero model disagreements, three orders of magnitude faster (since its one-dimensional output no longer needs the sorting procedure). Based on the above, we recommend VEER as a very fast method to solve complex configuration problems, while at the same time avoiding model disagreement., Comment: 27 pages, 7 figures, 4 tables, accepted by EMSE

Objective This study aimed to investigate the feasibility and accuracy of non-radioactive target lymph node (TLN) biopsy and targeted axillary dissection (TAD) in routine clinical practice. Background data TAD involves TLN biopsy (TLNB) and sentinel lymph node biopsy (SLNB) and was recently introduced as a new standard for less invasive axillary staging in breast cancer (BC) patients undergoing neoadjuvant systemic therapy (NST); however, clinical evidence is limited. Methods The SenTa study is a prospective registry study conducted at 50 centers. Patients with invasive BC who underwent clip insertion into the most suspicious axillary lymph node (LN) were eligible. Axillary surgery was performed with or without SLNB, TLNB, and/or axillary lymph node dissection (ALND). Main endpoints were the detection rate (DR) and false-negative rate (FNR) of TLNB and TAD after NST. Results Between 2017 and 2018, 548 consecutive BC patients underwent clip placement into biopsy-confirmed positive LNs. After NST (n = 473), the clipped TLN was intraoperatively resected in 329 of 423 patients (77.8%, 95% confidence interval [CI]: 74.0 to 82.0). TAD was successful in 199 of 229 patients (DR: 86.9%, 95% CI: 81.8 to 91.0), the SLN and TLN were identical in 129 patient (64.8%). FNRs were 7.2% (8 of 111, 95% CI: 3.1 to 13.6) for TLNB followed by ALND (n = 203) and 4.3% (2 of 46, 95% CI: 0.5 to 14.8) for TAD followed by ALND (n = 77). Conclusions The SenTa study demonstrates the feasibility of TAD in a real-world cohort of BC patients. Our findings are of great importance for de-escalation of surgical strategies.

Drawing on Hegel and Foucault, Rimbaud and Wordsworth, Martin Kaltenecker engages conventional historical reading of the progression of Western music. Beyond this important context, Kaltenecker draws attention to a recent, noteworthy development: a certain tendency of recent music to devote itself to its own medium, to the materiality of sound devoid of any structuring principle.

Rationale: Kidney homeostasis is critically determined by the coordinated activity of the renin-angiotensin system (RAS), including the balanced synthesis of its main effector peptides Ang (angiotensin) II and Ang (1–7). The condition of enzymatic overproduction of Ang II relative to Ang (1–7) is termed RAS dysregulation and leads to cellular signals, which promote hypertension and organ damage, and ultimately progressive kidney failure. ACE2 (angiotensin-converting enzyme 2) and NEP (neprilysin) induce the alternative, and potentially reno-protective axis by enhancing Ang (1–7) production. However, their individual contribution to baseline RAS balance and whether their activities change in chronic kidney disease (CKD) has not yet been elucidated. Objective: To examine whether NEP-mediated Ang (1–7) generation exceeds Ang II formation in the healthy kidney compared with diseased kidney. Methods and Results: In this exploratory study, we used liquid chromatography-tandem mass spectrometry to measure Ang II and Ang (1–7) synthesis rates of ACE, chymase and NEP, ACE2, PEP (prolyl-endopeptidase), PCP (prolyl-carboxypeptidase) in kidney biopsy homogenates in 11 healthy living kidney donors, and 12 patients with CKD. The spatial expression of RAS enzymes was determined by immunohistochemistry. Healthy kidneys showed higher NEP-mediated Ang (1–7) synthesis than Ang II formation, thus displaying a strong preference towards the reno-protective alternative RAS axis. In contrast, in CKD kidneys higher levels of Ang II were recorded, which originated from mast cell chymase activity. Conclusions: Ang (1–7) is the dominant RAS peptide in healthy human kidneys with NEP rather than ACE2 being essential for its generation. Severe RAS dysregulation is present in CKD dictated by high chymase-mediated Ang II formation. Kidney RAS enzyme analysis might lead to novel therapeutic approaches for CKD.