bluuebunny/crossref_metadata_2025_split huggingface dataset:
HCV infection in hemophilia A patients is associated with altered cytokines and chemokines profile and might modulate the levels of FVIII inhibitor
Authors: Bolina‐Santos Eduarda , Chaves Daniel G. , da Silva‐Malta Maria C. F. , Carmo Ricardo A. , Barbosa‐Stancioli Edel F. , Lobato Martins Marina 
Published: November 2021

AbstractPrevalence of hepatitis C virus (HCV) is high in hemophilia A patients and the development of FVIII inhibitor is another challenge in the management of these individuals. The influence of HCV infection in the occurrence of inhibitors was investigated by the comparison of clinical and laboratory data from noninfected (NI, n = 96) and chronically HCV‐infected (HCV, n = 58) hemophilia A patients. Concentrations of plasmatic cytokines (IL‐2, IL‐4, IL‐6, IL‐10, TNF, IFN‐γ, and IL‐17A) and chemokines (CCL2, CCL5, CXCL8, CXCL9, and CXCL10) were quantified from patients' samples. The results showed that older age, use of cryoprecipitate and fresh frozen plasma, and severe hemophilia were associated with HCV infection, whereas exclusive use of virus inactivated clotting factors was a protector factor to acquiring HCV infection. HCV infection was strongly associated with low levels of inhibitor (OR = 20.53, p < 0.001). Patients with a history of inhibitor (INB+) presented a mixed immune profile characterized by higher levels of pro‐and anti‐inflammatory cytokines than those without a history of inhibitor (INB−). The highest levels of CCL2 and CXCL8 were seen in HCVINB−, whereas CXCL9 and CXCL10 in HCVINB+. Heatmap analysis of the set of cytokines and chemokines concentration distributed HCV patients into two distinct clusters, HCVINB+ and HCVINB‐, both characterized by low concentrations of IL‐4, while noninfected patients were grouped in a single block regardless of inhibitor development history (NIINB−/INB+). This finding suggests that the strong association between HCV infection and low levels of factor VIII inhibitors might be due to the modulation of the cytokine and chemokine network established by the antiviral response.
Astragalus polysaccharide regulates brown adipocytes differentiation by miR‐6911 targeting Prdm16
Authors: Zhang Shihe , Song Pengkang , Chen Xiaoyou , Wang Yu , Gao Xuyang , Liang Lin , Zhao Junxing 
Published: November 2021

AbstractBrown adipose tissue (BAT) is a specialized tissue in mammals related to thermogenesis. The Astragalus polysaccharide (APS) is the major natural active component of Astragalus membranaceus, which has been recognized as one of the most popular herbal medicines worldwide. The role and possible mechanisms of APS on brown adipocytes differentiation is not well defined. Here, we explored the effect of APS on the differentiation of brown adipocytes in C3H10T 1/2 cells. The results showed that APS promoted the differentiation of brown adipocytes and improved insulin sensitivity along with significant increases in the expression of brown adipogenic marker proteins (C/EBPα, C/EBPβ, and PPARγ), thermogenesis marker proteins (UCP1, PRDM16, and PGC‐1α), and insulin sensitivity marker protein (GLUT4). Meanwhile, the results showed that the amount of the phosphorylation of insulin receptor substrate 1 (p‐IRS1) and phospho‐AKT (p‐AKT) which are critical factors in the insulin signaling pathway was increased without changing the total amount of IRS and AKT. Furthermore, the results of RNA‐seq showed that APS altered the expression profiles of various miRNAs, and among which the expression of miR‐6911 as a universal regulatory factor was significantly decreased. Importantly, we found that miR‐6911 regulated the differentiation of brown adipocytes by targeting PR domain‐containing 16 (Prdm16). In addition, after transfection of miR‐6911 mimics, compared with the control and inhibitor group, PRDM16 protein expression significantly decreased, which was accompanied by the decrease of PPARγ, UCP1, and PGC‐1α. Collectively, our results indicated that APS regulated brown adipocytes differentiation in C3H10T 1/2 cells via miRNA‐6911 targeting Prdm16.
Topographic Cues Guiding Cell Polarization via Distinct Cellular Mechanosensing Pathways
Authors: Liu Wei , Sun Qian , Zheng Zi‐Li , Gao Ya‐Ting , Zhu Guan‐Yin , Wei Qiang , Xu Jia‐Zhuang , Li Zhong‐Ming , Zhao Chang‐Sheng 
Published: November 2021

AbstractCell polarization exists in a variety of tissues to regulate cell behaviors and functions. Space constraint (spatially limiting cell extension) and adhesion induction (guiding adhesome growth) are two main ways to induce cell polarization according to the microenvironment topographies. However, the mechanism of cell polarization induced by these two ways and the downstream effects on cell functions are yet to be understood. Here, space constraint and adhesion induction guiding cell polarization are achieved by substrate groove arrays in micro and nano size, respectively. Although the morphology of polarized cells is similar on both structures, the signaling pathways to induce the cell polarization and the downstream functions are distinctly different. The adhesion induction (nano‐groove) leads to the formation of focal adhesions and activates the RhoA/ROCK pathway to enhance the myosin‐based intracellular force, while the space constraint (micro‐groove) only activates the formation of pseudopodia. The enhanced intracellular force caused by adhesion induction inhibits the chromatin condensation, which promotes the osteogenic differentiation of stem cells. This study presents an overview of cell polarization and mechanosensing at biointerface to aid in the design of novel biomaterials.
Precisely Defining Local Gradients of Stimuli‐Responsive Hydrogels for Complex 2D‐to‐4D Shape Evolutions
Authors: Yin Jincai , Fan Wenxin , Xu Zihan , Duan Jinghua , Xia Yanzhi , Nie Zhihong , Sui Kunyan 
Published: November 2021

AbstractThe intellectualization and complication of existing self‐shaping materials are limited by the inseparable monotonic relationship between their deformation rate and deformation degree (i.e., a higher deformation rate is accompanied by a high deformation degree). This causes that they can only deform from 2D to 3D states. Here, a simple yet versatile strategy to decouple the monotonic correlation between the deformation rate and deformation degree of self‐shaping hydrogels is presented for achieving complex deformations from 2D to temporary 3D to 3D (2D‐to‐4D). It is demonstrated that when the gradient hydrogels prepared by photopolymerization possess dense polymer networks, the local regions with a high deformation rate can exhibit a low deformation degree. The resulting hydrogels can thus deform in a novel 2D‐to‐4D mode under external stimuli. During the deformation, they first transform into the temporary shapes induced by the local deformation rate difference, and then transform into the final shapes determined by the local deformation degree difference. Through controlling the ultraviolet irradiation direction and time to precisely program the local gradients of self‐shaping hydrogels, they can be designed to produce various unprecedented yet controllable 2D‐to‐4D shape evolutions on demand, such as transformable origami, sequential gesture actions in finger‐guessing games, mobile octopuses, time switch, etc.
Emissions- und staufreier alpenquerender Güterverkehr: Wachstumspotenziale und -hürden für den Verkehrsträger Schiene am Beispiel „Brenner-Pass“
Authors: Weidemann Hans-Jürgen 
Published: November 2021

ZusammenfassungDie Staaten Europas laufen Gefahr, ihre ambitionierten verkehrs- und klimapolitischen Ziele für den Güterverkehr zu verfehlen. Zugleich sind wesentliche Kernstrecken in Europa durch den massiven Lkw-Verkehr überlastet. Dem nur langsamen Ausbau der Fernstraßen steht eine signifikante Zunahme der Transportleistung durch schwere Lkw gegenüber. Europas Straßenverkehr drohen Fahrermangel, Dauerstau und Kostensteigerung. Bereits seit 2010 übersteigt die Transportleistung im Straßengüterverkehr mit über 400 Mrd. Tonnen- Kilometer die Kapazität der Autobahnen. Grafik 1 zeigt die tatsächliche Verkehrsleistung in Mrd. Tonnenkilometern (rote Kurve), welche die nominale Kapazität der Bundesautobahnen in Deutschland seit etwa 2010 übersteigt (schwarze Kurve) – und die Anzahl der Staus in Deutschland, die sich seit der Überlastung der Autobahnen in nur sechs Jahren vervierfacht hat.
Herausforderungen im internationalen Schienenfernverkehr in Europa
Authors: Kampp Marco 
Published: November 2021

ZusammenfassungEin wichtiger Bestandteil der grenzüberschreitenden Mobilität in Europa ist der internationalen Schienenfernverkehr. Dieser Beitrag gibt einen kurzen Überblick über die Entwicklung des internationalen Schienenfernverkehrs und möchte auf bestehende Herausforderungen in einem europäischen Kontext hinweisen.
Europäische Verkehrspolitik
Authors: Dorfmann Herbert 
Published: November 2021

ZusammenfassungBereits im Vertrag von Rom, unterzeichnet im Jahre 1957, hoben die Mitgliedstaaten der Europäischen Wirtschaftsgemeinschaft die Bedeutung einer gemeinsamen Verkehrspolitik (Art 74–Art 84) die neben der Agrar- und Handelspolitik zu den ersten gemeinsamen Politikbereichen der Gemeinschaft gehörte, hervor. Die Einführung einer gemeinsamen Verkehrspolitik erfolgte jedoch erst nach einer Untätigkeitsklage des Europäischen Parlaments und dem Urteil des Europäischen Gerichtshofs vom 22. Mai 1985. Der Rat wurde darin aufgefordert tätig zu werden und die Entwicklung einer gemeinsamen Verkehrspolitik in die Wege zu leiten.
Praktische Herausforderungen und Zukunftsvisionen im internationalen Personen- und Güterverkehr – Eine Podiumsdiskussion
Authors: Huber Eva Maria 
Published: November 2021

ZusammenfassungAm 1. Februar 2019 fand an der Universität Innsbruck eine moderierte Podiumsdiskussion statt, im Rahmen derer Expertinnen und Experten aus der Transportwirtschaft zum gedanklichen Austausch über den Personen- und Güterverkehr in Europa zusammenkamen. Die Veranstaltung diente nicht nur der Bestandsaufnahme, auch Zukunftsvisionen für den Personen- und Güterverkehr wurden ausgiebig diskutiert. Dazu zeigten die Teilnehmenden auf, in welchen Bereichen aus praktischer Sicht derzeit akuter Regelungsbedarf besteht. Daneben sorgte auch die Mobilität in der Europaregion Tirol-Südtirol-Trentino bei allen Teilnehmenden für Diskussionsstoff. Insgesamt konnten viele wertvolle Erkenntnisse gesammelt werden, die hier dokumentiert und im Anschluss aus rechtswissenschaftlicher Sicht bewertet werden sollen. Zunächst werden die einzelnen Diskussionsbeiträge kurz dargestellt.
Il trasporto multimodale nel diritto dell’Unione Europea: un fenomeno trasportistico emergente privo di un’adeguata regolamentazione
Authors: Perathoner Christoph 
Published: November 2021

ZusammenfassungA settant’anni dalla lungimirante dichiarazione dell’allora Ministro degli Esteri francese Robert Schuman (1886–1963) il 9 maggio 1950 a Parigi, è possibile constatare come il lungo e sempre fragile processo di integrazione europea, finalizzato a realizzare “un’unione sempre più stretta tra i popoli dell’Europa”, abbia permesso il raggiungimento di obiettivi che hanno fondamentalmente migliorato la convivenza e la cooperazione sul nostro continente. In tal senso, un traguardo essenziale per gli Stati membri dell’UE è rappresentato dalla creazione di un mercato interno che assicura “la libera circolazione delle merci, delle persone, dei servizi e dei capitali”. Invero, l’istaurazione del mercato interno – al pari dell’integrazione europea – è un processo in continua evoluzione. La ratio istitutiva di un mercato unico sul continente europeo è quella di creare i presupposti per una crescita economica equilibrata, per ottenere la stabilità dei prezzi, per poter costruire un’economia sociale di mercato fortemente competitiva, che miri alla piena occupazione e al progresso sociale, e tutto questo con l’impegno di raggiungere un elevato livello di tutela e di miglioramento della qualità dell’ambiente e della vita delle persone.
Die Querbezüge zwischen UN-Kaufrecht (CISG) und COTIF-Eisenbahngüterbeförderungsrecht (CIM)
Authors: Koller Thomas 
Published: November 2021

ZusammenfassungEin beachtlicher Teil des grenzüberschreitenden Warenhandels erfolgt per Eisenbahntransport. Zwischen dem internationalen Kaufrecht und dem Eisenbahngüterbeförderungsrecht bestehen daher zahlreiche Berührungspunkte. Viele dieser Gütertransaktionen unterliegen kaufrechtlich dem CISG und transportrechtlich den Einheitlichen Rechtsvorschriften für den Vertrag über die internationale Eisenbahnbeförderung von Gütern (CIM). Der folgende Beitrag analysiert verschiedene Probleme an den Schnittstellen zwischen dem UN-Kaufrecht und den CIM.
La smart mobility nell’ordinamento giuridico dell’UE e le potenzialità di sviluppo nelle città europee
Authors: Perathoner Christoph 
Published: November 2021

ZusammenfassungL’emergenza epidemiologica da COVID-19, che, partendo dalla Cina, in poche settimane si è propagata in tutti i continenti di questo pianeta, mettendone in ginocchio la popolazione, ha legittimato i governi di molti Paesi ad emanare provvedimenti restrittivi, conferendo di fatto agli Stati il potere di comprimere le libertà e i diritti fondamentali dei singoli in maniera del tutto inedita per le nostre generazioni.
Wartezeiten auf einen Psychotherapieplatz vor und nach der Psychotherapiestrukturreform
Authors: Singer Susanne , Maier Lena , Paserat Anke , Lang Klaus , Wirp Bernhild , Kobes Jörg , Porsch Udo , Mittag Martina , Toenges Gerrit , Engesser Deborah 
Published: November 2021

Zusammenfassung
Hintergrund und Fragestellung
Die Psychotherapiestrukturreform im Jahr 2017 verfolgte u. a. das Ziel, die Wartezeiten auf Psychotherapien zu verringern. Diese Studie ging der Frage nach, ob dieses Ziel erreicht wurde.

Methoden
Psychotherapiepraxen aus 7 Bundesländern entnahmen ihren Akten die Daten für Erstkontakt, Erstgespräch und Behandlungsbeginn. Der Vergleich der Wartezeiten auf ein Erstgespräch und auf den Beginn der Behandlung vor vs. nach der Reform erfolgte mithilfe von Kaplan-Meier-Kurven und stratifizierten Log-Rank-Tests.

Ergebnis
Akten von 1548 Patienten aus 9 Praxen wurden ausgewertet. Die durchschnittliche Wartezeit auf ein Erstgespräch lag sowohl vor als auch nach der Reform bei 3 Wochen (p = 0,20). Die Zeit zwischen der Anmeldung und dem Behandlungsbeginn erhöhte sich von durchschnittlich 18 auf 20 Wochen, wobei nach der Reform v. a. die sehr kurzen Wartezeiten (<10 Wochen) abnahmen (p = 0,0004).

Diskussion
Die in den Praxen dokumentierten Daten liefern keine Anhaltspunkte dafür, dass sich die Wartezeit auf Erstgespräche bei Psychotherapeuten verkürzt hat. Das Warten auf einen Psychotherapieplatz scheint insgesamt etwas länger geworden zu sein, sodass in dieser Hinsicht keine Verbesserung der Versorgung durch die Reform festgestellt werden konnte.
Integrated exposure–response analysis of efficacy and safety of lurbinectedin to support the dose regimen in small-cell lung cancer
Authors: Fernández-Teruel Carlos , Fudio Salvador , Lubomirov Rubin 
Published: November 2021

Abstract
Purpose
These exposure–response (E–R) analyses integrated lurbinectedin effects on key efficacy and safety variables in relapsed SCLC to determine the adequacy of the dose regimen of 3.2 mg/m2 1-h intravenous infusion every 3 weeks (q3wk).

Methods
Logistic models and Cox regression analyses were applied to correlate lurbinectedin exposure metrics (AUCtot and AUCu) with efficacy and safety endpoints: objective response rate (ORR) and overall survival (OS) in SCLC patients (n = 99) treated in study B-005 with 3.2 mg/m2 q3wk, and incidence of grade 4 (G4) neutropenia and grade 3–4 (G ≥ 3) thrombocytopenia in a pool of cancer patients from single-agent phase I to III studies (n = 692) treated at a wide range of doses. A clinical utility index was used to assess the appropriateness of the selected dose.

Results
Effect of lurbinectedin AUCu on ORR best fitted to a sigmoid-maximal response (Emax) logistic model, where Emax was dependent on chemotherapy-free interval (CTFI). Cox regression analysis with OS found relationships with both CTFI and AUCu. An Emax logistic model for G4 neutropenia and a linear logistic model for G ≥ 3 thrombocytopenia, which retained platelets and albumin at baseline and body surface area, best fitted to AUCtot and AUCu. AUCu between approximately 1000 and 1700 ng·h/L provided the best benefit/risk ratio, and the dose of 3.2 mg/m2 provided median AUCu of 1400 ng·h/L, thus maximizing the proportion of patients within that lurbinectedin target exposure range.

Conclusions
The relationships evidenced in this integrated E–R analysis support a favorable benefit-risk profile for lurbinectedin 3.2 mg/m2 q3wk.

Trial registration
Clinicaltrials.gov: NCT02454972; registered May 27, 2015.
An ALNS algorithm for the static dial-a-ride problem with ride and waiting time minimization
Authors: Pfeiffer Christian , Schulz Arne 
Published: November 2021

AbstractThe paper investigates the static dial-a-ride problem with ride and waiting time minimization. This is a new problem setting of significant practical relevance because several ride-sharing providers launched in recent years in large European cities. In contrast to the standard dial-a-ride problem, these providers focus on the general public. Therefore, they are amongst others in competition with taxis and private cars, which makes a more customer-oriented objective necessary. We present an adaptive large neighbourhood search (ALNS) as well as a dynamic programming algorithm (DP), which are tested in comprehensive computational studies. Although the DP can only be used for a single tour and, due to the computational effort, as a restricted version or for small instances, the ALNS also works efficiently for larger instances. The results indicate that ride-sharing proposals may help to solve the trade-off between individual transport, profitability of the provider, and reduction of traffic and pollution.
The Rat Genome Database (RGD) facilitates genomic and phenotypic data integration across multiple species for biomedical research
Authors: Kaldunski M. L. , Smith J. R. , Hayman G. T. , Brodie K. , De Pons J. L. , Demos W. M. , Gibson A. C. , Hill M. L. , Hoffman M. J. , Lamers L. , Laulederkind S. J. F. , Nalabolu H. S. , Thorat K. , Thota J. , Tutaj M. , Tutaj M. A. , Vedi M. , Wang S. J. , Zacher S. , Dwinell M. R. , Kwitek A. E. 
Published: November 2021

AbstractModel organism research is essential for discovering the mechanisms of human diseases by defining biologically meaningful gene to disease relationships. The Rat Genome Database (RGD, (https://rgd.mcw.edu)) is a cross-species knowledgebase and the premier online resource for rat genetic and physiologic data. This rich resource is enhanced by the inclusion and integration of comparative data for human and mouse, as well as other human disease models including chinchilla, dog, bonobo, pig, 13-lined ground squirrel, green monkey, and naked mole-rat. Functional information has been added to records via the assignment of annotations based on sequence similarity to human, rat, and mouse genes. RGD has also imported well-supported cross-species data from external resources. To enable use of these data, RGD has developed a robust infrastructure of standardized ontologies, data formats, and disease- and species-centric portals, complemented with a suite of innovative tools for discovery and analysis. Using examples of single-gene and polygenic human diseases, we illustrate how data from multiple species can help to identify or confirm a gene as involved in a disease and to identify model organisms that can be studied to understand the pathophysiology of a gene or pathway. The ultimate aim of this report is to demonstrate the utility of RGD not only as the core resource for the rat research community but also as a source of bioinformatic tools to support a wider audience, empowering the search for appropriate models for human afflictions.
Hydrogen Sulfide Inhibits Cadmium-Induced Cell Death of Cucumber Seedling Root Tips by Protecting Mitochondrial Physiological Function
Authors: Luo Shilei , Tang Zhongqi , Yu Jihua , Liao Weibiao , Xie Jianming , Lv Jian , Liu Zeci , Calderón-Urrea Alejandro 
Published: November 2021

AbstractHydrogen sulfide (H2S) can alleviate Cd-induced cell death, but the molecular mechanisms are not clear. To shed light on these mechanisms, cell death induced by 200 μM cadmium chloride in cucumber seedlings root tips was used as a model system. Here, we report that the negative effect of Cd stress in mitochondrial physiological functions include changes in cytochrome c/a, mitochondrial membrane permeability transition pores, and adenosine triphosphatase (ATPase). Moreover, Cd stress led to the release of mitochondrial Ca2+into the cytosol. Exogenous application of sodium hydrosulfide (NaHS, a donor of H2S) inhibited cell death and maintains mitochondrial function by reducing mitochondrial hydrogen peroxide accumulation, increasing ATPase activity and down-regulatingCsVDACandCsANTexpression. In summary, H2S suppressed Cd-induced cell death by improving mitochondrial physiological properties.
Dorsal instrumentation with and without vertebral body replacement in patients with thoracolumbar osteoporotic fractures shows comparable outcome measures
Authors: Schwendner Maximilian , Motov Stefan , Ryang Yu-Mi , Meyer Bernhard , Krieg Sandro M. 
Published: November 2021

Abstract
Purpose
In the surgical treatment of osteoporotic spine fractures, there is no clear recommendation, which treatment is best for the individual patient with vertebra plana and/or neurological deficit requiring instrumentation. The aim of this study was to evaluate clinical and radiological outcomes after dorsal or 360° instrumentation of osteoporotic fractures of the thoracolumbar spine in a cohort of patients representing clinical reality.

Methods
A total of 116 consecutive patients were operated on between 2008 and 2020. Inclusion criteria were osteoporotic fracture, thoracolumbar location, and dorsal instrumentation. In 79 cases, vertebral body replacement (VBR) was performed additionally. Patient outcomes including complications, EQ-5D at follow-up, and sagittal correction were analyzed.

Results
Medical and surgical complications occurred in 59.5% of patients with 360° instrumentation compared to 64.9% of patients with dorsal instrumentation only (p = 0.684). Dorsal instrumentation plus VBR resulted in a sagittal correction of 9.3 ± 7.4° (0.1–31.6°) compared to 6.0 ± 5.6° (0.2–22.8°) after dorsal instrumentation only, respectively (p = 0.0065). EQ-5D was completed by 79 patients after 4.00 ± 2.88 years (0.1–11.8 years) and was 0.56 ± 0.32 (− 0.21–1.00) for VBR compared to 0.56 ± 0.34 (− 0.08–1.00) without VBR after dorsal instrumentation (p = 0.994).

Conclusion
360° instrumentation represents a legitimate surgical technique with no additional morbidity even for the elderly and multimorbid osteoporotic population. Particularly, if sufficient long-term construct stability is in doubt or ventral stenosis is present, there is no need to abstain from additional ventral reinforcement and decompression.
Tumefactive demyelinating CNS lesion in a 60-year-old woman with familial Mediterranean fever
Authors: Trostel Constanze , Laichinger Kornelia , Hauser Till-Karsten , Saur Sebastian , Krumbholz Markus , Henes Jörg , Ziemann Ulf , Kowarik Markus C. 
Published: November 2021

SummaryWe here report on a 60-year-old woman with familial Mediterranean fever (FMF) who developed cognitive impairment 16 years after initial diagnosis. On MRI, a new extensive white matter lesion in the right frontal lobe with mild local mass effect but without contrast enhancement was detectable and classified as a tumefactive lesion. Additional MR spectroscopy showed markedly increased choline levels accompanied by a significant lactate peak, highly suggestive of a low-florid demyelinating process. Although diffuse central nervous system (CNS) lesions have been described in single FMF cases, tumefactive lesions have not been observed in FMF patients without concomitant multiple sclerosis. In summary, this case highlights rare differential diagnoses of atypical, inflammatory CNS lesions and the clinical utility of MR spectroscopy.