bluuebunny/crossref_metadata_2025 huggingface dataset:
Vom Schilddrüsenknoten zum Schilddrüsenkarzinom
Authors: Kaderli Reto Martin , Trepp Roman
Published: November 2020

Zusammenfassung. Schilddrüsenknoten finden sich mit einer Prävalenz von etwa 1 % pro Lebensjahr, wobei etwa 5 % der Knoten maligne sind. Die primäre Diagnostik besteht aus einer Bestimmung des TSH-Wertes und einer Halssonographie. Je nach Befund ist eine zusätzliche labormässige, szintigraphische oder bioptische Abklärung indiziert. Bei Schilddrüsenkarzinomen gilt es primär die chirurgische Therapie zu evaluieren. Es gibt weltweit zumindest neun verschiedene klinische Guidelines, um ein standardisiertes perioperatives Management zu ermöglichen, wobei im deutschsprachigen Raum am häufigsten die Guidelines der Chirurgischen Arbeitsgemeinschaft für Endokrinologie (CAEK) und der American Thyroid Association (ATA) verwendet werden. Individuelle Therapiekonzepte werden am interdisziplinären endokrinologischen Tumorboard festgelegt. Die Indikation für eine allfällige postoperative Radiojodtherapie oder Schilddrüsenhormonsubstitution in TSH-Suppressionsdosis wird bei Diagnose eines differenzierten (papillären oder follikulären) Schilddrüsenkarzinoms entsprechend der American Thyroid Association (ATA) Risikostratifizierung gestellt.
Primärer Hyperparathyreoidismus
Authors: Köberle Roswitha , Bendik Claudine Falconnier
Published: November 2020

Zusammenfassung. Der primäre Hyperparathyreoidismus ist eine häufige endokrinologische Erkrankung mit Einfluss auf die Kalziumhomöostase und damit mannigfaltigen Symptomen unterschiedlicher Ausprägung. Diese werden häufig übersehen, da sich manche Patienten mit unspezifischen Symptomen präsentieren oder gar asymptomatisch sind. Die Diagnose wird durch die Bestimmung der Kalzium- und Parathormonwerte, sowie die Messung der Kalziumausscheidung im 24-Stunden-Urin gestellt. Eine Operation ist die einzige Therapie, die Heilung verspricht. Sobald die Operationsindikation gegeben ist, wird eine bildgebende Lokalisationsdiagnostik durchgeführt, um eine fokussierte Parathyreoidektomie zu ermöglichen. Dies verspricht eine geringe Komplikations- und hohe Erfolgsrate. Zur Kontrolle wird intraoperativ der Parathormonspiegel monitorisiert. Als Erweiterung der Technik gilt die bilaterale Halsexploration, die in speziellen Fällen angewendet werden muss. Eine endokrine chirurgische Expertise ist vor allem bei der Reoperation, beim hereditären primären Hyperparathyreoidismus und bei Karzinomen von Bedeutung. Wird aus verschiedenen Gründen beschlossen nicht zu operieren, steht eine medikamentöse Behandlung zur Verfügung, welche jedoch einer kontinuierlichen Verlaufskontrolle bedarf. Es hat sich gezeigt, dass interdisziplinäres Management die Voraussetzung ist, für die Patienten ein bestmögliches Ergebnis zu erzielen.
No significant effect of caffeine on five kilometer running performance after muscle damage
Authors: Al-Nawaiseh Ali M. , Pritchett Robert C. , Pritchett Kelly Kerr , Bataineh Mo’ath F. , Taifour Akef M. , Bellar David , Schoeff Makenzie A. , Fox Brian , Judge Amy , Judge Lawrence W.
Published: November 2020

Abstract. Caffeine has documented hypoalgesic effects during exercise. However, there is a lack of research focusing on caffeine’s potential analgesic effects to ameliorate delayed onset muscle soreness. A placebo controlled randomized cross-over trial was carried out to determine if 5 mg/kg of body weight (mg/kgBW) of caffeine attenuates muscle pain and improves 5 k running performance following delayed onset muscle soreness. Prior to participating, eleven runners (9 male; 2 female; age, 24.5 ± 6.3 years; height, 173.6 ± 7.8 cm; body mass, 66.3 ± 7.5 kg; BMI, 23.18 kg/m2 ± 1.6; VO2max61.0 ± 6.1 ml/kg/min−1), were asked to discontinue supplement use for 72 hours and abstain from caffeine consumption for 48 hours. Participants performed a 30-minute downhill run on a treadmill set at −10% grade at 70% VO2maxto induce delayed onset of muscle soreness. Participants then returned 48 hours after to complete a 5 k time trial run where they consumed either 5 mg/kgBW of caffeine or a placebo. Rate of perceived exertion and heart rate were taken every two minutes during the trial. There was no detectable statistical difference between 5 k performance between caffeine (1074.9 ± 119.7 sec) or placebo (1053.8 ± 86.8 sec) ( p = .41). Algometer readings were similar between both treatments for muscle soreness in the rectus femoris ( p = .791) and the vastus medialis oblique ( p = .371). Muscle soreness ratings were found to be greater in the caffeine condition compared to the placebo condition ( p = .030). There was no effect of treatment on rating of perceived exertion between conditions ( p = .574). The present study suggests that caffeine is not effective at reducing muscle soreness, rating of perceived exertion, or improving running performance in a time trial in the presence of muscle soreness.
Employee Strengths Use and Thriving at Work
Authors: Ding He , Chu Xixi
Published: November 2020

Abstract. This study aimed to investigate the relationship of employee strengths use with thriving at work by proposing a moderated mediation model. Data were collected at two time points, spaced by a 2-week interval. A total of 260 medical staff completed strengths use, perceived humble leadership, self-efficacy, and thriving scales. The results of path analysis showed that strengths use is positively related to thriving, and self-efficacy mediates the relationship of strengths use with thriving. In addition, this study also found perceived humble leadership to positively moderate the direct relationship of strengths use with self-efficacy and the indirect relationship of strengths use with thriving via self-efficacy. This study contributes to a better understanding of how and when strengths use affects thriving.
Seasonal and Interannual Variability of the Currents off the New Guinea Coast From Mooring Measurements
Authors: Zhang Linlin , Wu Jie , Wang Fujun , Hu Shijian , Wang Qingye , Jia Fan , Wang Fan , Hu Dunxin
Published: November 2020

Seasonal and interannual variability of the New Guinea Coastal Current (NGCC) and New Guinea Coastal Undercurrent (NGCUC) were investigated with 3 years of mooring measurements off the northern coast of New Guinea and outputs from the Ocean General Circulation Model for the Earth Simulator during 1980–2018. Acoustic Doppler Current Profilers mounted on the two moorings captured variations of the currents in the upper 800 m off the New Guinea coast during 2015–2018. NGCC is a seasonally reversing current in the upper 100 m, which flows southeastward in boreal winter with maximum velocity of 63 cm/s near the surface, and flows northwestward in boreal summer with maximum velocity of −55 cm/s at 80 m. NGCUC flows northwestward all year round between 100 and 400 m, and its temporal mean velocity reaches −40 cm/s at 200 m. A seasonally reversing current named New Guinea Coastal Intermediate Current with speed of 10 cm/s is detected below the NGCUC, which is in phase with the NGCC on seasonal time scale. Seasonal variation of the NGCUC is also in phase with that of the NGCC, and it is strong in boreal summer and weak in winter. Such seasonal signal reaches down to the depth of 800 m. Both mooring measurements and model outputs indicate that NGCUC demonstrates significant interannual variations associated with El Nino‐Southern Oscillation (ENSO), with its velocity core shoaling during El Nino and deepening during La Nina, but the net transport of NGCUC exhibits no significant relationship with ENSO.
Advanced View at the Ocean Surface
Authors: Panfilova M. , Karaev V. , Mitnik L. , Titchenko Y. , Ryabkova M. , Meshkov E.
Published: November 2020

Improvement of methods for satellite monitoring of the world ocean state is one of the most important areas of the remote sensing because of the influence the oceans have on the Earth's climate. Currently, only one parameter is measured on a regular basis on a global scale: the significant wave height which is obtained from spaceborne radar altimeter data. It is known that at small incidence angles within the framework of Kirchhoff approximation, the backscattering radar cross section depends mainly on the mean square slope (mss) of the sea surface; therefore, this parameter can be measured. The performed studies lead to the improvement of the methods for processing the data from a precipitation radar. We demonstrate that the mss of the large‐scale (compared to the radar wavelength) sea waves can be restored within the swath, that is, about 115 km wide. The aim of this work is to communicate these new possibilities to the broad research community involved in the studies of the oceans. In this paper, a review of the results is performed and the prospects for global monitoring are first shown. On the basis of the precipitation radar data, it becomes possible to measure global fields of sea wave slopes, which in turn will help scientists to analyze the processes of air‐sea interaction. Availability of this new mss parameter essentially doubles the amount of available descriptors of sea waves, which will advance the understanding of the processes occurring in the oceans.
Correction: Imatinib mesylate inhibits STAT5 phosphorylation in response to IL-7 and promotes T cell lymphopenia in chronic myelogenous leukemia patients
Authors: Thiant S. , Moutuou M. M. , Laflamme P. , Boumedine R. Sidi , Leboeuf D. M. , Busque L. , Roy J. , Guimond M.
Published: November 2020

A correction to this paper has been published and can be accessed via a link at the top of the paper.
Polyandry blocks gene drive in a wild house mouse population
Authors: Manser Andri , König Barbara , Lindholm Anna K.
Published: November 2020

Gene drives are genetic elements that manipulate Mendelian inheritance ratios in their favour. Understanding the forces that explain drive frequency in natural populations is a long-standing focus of evolutionary research. Recently, the possibility to create artificial drive constructs to modify pest populations has exacerbated our need to understand how drive spreads in natural populations. Here, we study the impact of polyandry on a well-known gene drive, called t haplotype, in an intensively monitored population of wild house mice. First, we show that house mice are highly polyandrous: 47% of 682 litters were sired by more than one male. Second, we find that drive-carrying males are particularly compromised in sperm competition, resulting in reduced reproductive success. As a result, drive frequency decreased during the 4.5 year observation period. Overall, we provide the first direct evidence that the spread of a gene drive is hampered by reproductive behaviour in a natural population.
Selection, biophysical and structural analysis of synthetic nanobodies that effectively neutralize SARS-CoV-2
Authors: Custódio Tânia F. , Das Hrishikesh , Sheward Daniel J. , Hanke Leo , Pazicky Samuel , Pieprzyk Joanna , Sorgenfrei Michèle , Schroer Martin A. , Gruzinov Andrey Yu. , Jeffries Cy M. , Graewert Melissa A. , Svergun Dmitri I. , Dobrev Nikolay , Remans Kim , Seeger Markus A. , McInerney Gerald M. , Murrell Ben , Hällberg B. Martin , Löw Christian
Published: November 2020

The coronavirus SARS-CoV-2 is the cause of the ongoing COVID-19 pandemic. Therapeutic neutralizing antibodies constitute a key short-to-medium term approach to tackle COVID-19. However, traditional antibody production is hampered by long development times and costly production. Here, we report the rapid isolation and characterization of nanobodies from a synthetic library, known as sybodies (Sb), that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Several binders with low nanomolar affinities and efficient neutralization activity were identified of which Sb23 displayed high affinity and neutralized pseudovirus with an IC50 of 0.6 µg/ml. A cryo-EM structure of the spike bound to Sb23 showed that Sb23 binds competitively in the ACE2 binding site. Furthermore, the cryo-EM reconstruction revealed an unusual conformation of the spike where two RBDs are in the ‘up’ ACE2-binding conformation. The combined approach represents an alternative, fast workflow to select binders with neutralizing activity against newly emerging viruses.
Small molecules as potent biphasic modulators of protein liquid-liquid phase separation
Authors: Babinchak W. Michael , Dumm Benjamin K. , Venus Sarah , Boyko Solomiia , Putnam Andrea A. , Jankowsky Eckhard , Surewicz Witold K.
Published: November 2020

Liquid-liquid phase separation (LLPS) of proteins that leads to formation of membrane-less organelles is critical to many biochemical processes in the cell. However, dysregulated LLPS can also facilitate aberrant phase transitions and lead to protein aggregation and disease. Accordingly, there is great interest in identifying small molecules that modulate LLPS. Here, we demonstrate that 4,4’-dianilino-1,1’-binaphthyl-5,5’-disulfonic acid (bis-ANS) and similar compounds are potent biphasic modulators of protein LLPS. Depending on context, bis-ANS can both induce LLPS de novo as well as prevent formation of homotypic liquid droplets. Our study also reveals the mechanisms by which bis-ANS and related compounds modulate LLPS and identify key chemical features of small molecules required for this activity. These findings may provide a foundation for the rational design of small molecule modulators of LLPS with therapeutic value.
Discovery of driver non-coding splice-site-creating mutations in cancer
Authors: Cao Song , Zhou Daniel Cui , Oh Clara , Jayasinghe Reyka G. , Zhao Yanyan , Yoon Christopher J. , Wyczalkowski Matthew A. , Bailey Matthew H. , Tsou Terrence , Gao Qingsong , Malone Andrew , Reynolds Sheila , Shmulevich Ilya , Wendl Michael C. , Chen Feng , Ding Li
Published: November 2020

Non-coding mutations can create splice sites, however the true extent of how such somatic non-coding mutations affect RNA splicing are largely unexplored. Here we use the MiSplice pipeline to analyze 783 cancer cases with WGS data and 9494 cases with WES data, discovering 562 non-coding mutations that lead to splicing alterations. Notably, most of these mutations create new exons. Introns associated with new exon creation are significantly larger than the genome-wide average intron size. We find that some mutation-induced splicing alterations are located in genes important in tumorigenesis (ATRX, BCOR, CDKN2B, MAP3K1, MAP3K4, MDM2, SMAD4, STK11, TP53 etc.), often leading to truncated proteins and affecting gene expression. The pattern emerging from these exon-creating mutations suggests that splice sites created by non-coding mutations interact with pre-existing potential splice sites that originally lacked a suitable splicing pair to induce new exon formation. Our study suggests the importance of investigating biological and clinical consequences of noncoding splice-inducing mutations that were previously neglected by conventional annotation pipelines. MiSplice will be useful for automatically annotating the splicing impact of coding and non-coding mutations in future large-scale analyses.
Cysteine oxidation and disulfide formation in the ribosomal exit tunnel
Authors: Schulte Linda , Mao Jiafei , Reitz Julian , Sreeramulu Sridhar , Kudlinzki Denis , Hodirnau Victor-Valentin , Meier-Credo Jakob , Saxena Krishna , Buhr Florian , Langer Julian D. , Blackledge Martin , Frangakis Achilleas S. , Glaubitz Clemens , Schwalbe Harald
Published: November 2020

Understanding the conformational sampling of translation-arrested ribosome nascent chain complexes is key to understand co-translational folding. Up to now, coupling of cysteine oxidation, disulfide bond formation and structure formation in nascent chains has remained elusive. Here, we investigate the eye-lens protein γB-crystallin in the ribosomal exit tunnel. Using mass spectrometry, theoretical simulations, dynamic nuclear polarization-enhanced solid-state nuclear magnetic resonance and cryo-electron microscopy, we show that thiol groups of cysteine residues undergo S-glutathionylation and S-nitrosylation and form non-native disulfide bonds. Thus, covalent modification chemistry occurs already prior to nascent chain release as the ribosome exit tunnel provides sufficient space even for disulfide bond formation which can guide protein folding.
R-spondins are BMP receptor antagonists in Xenopus early embryonic development
Authors: Lee Hyeyoon , Seidl Carina , Sun Rui , Glinka Andrey , Niehrs Christof
Published: November 2020

BMP signaling plays key roles in development, stem cells, adult tissue homeostasis, and disease. How BMP receptors are extracellularly modulated and in which physiological context, is therefore of prime importance. R-spondins (RSPOs) are a small family of secreted proteins that co-activate WNT signaling and function as potent stem cell effectors and oncogenes. Evidence is mounting that RSPOs act WNT-independently but how and in which physiological processes remains enigmatic. Here we show that RSPO2 and RSPO3 also act as BMP antagonists. RSPO2 is a high affinity ligand for the type I BMP receptor BMPR1A/ALK3, and it engages ZNRF3 to trigger internalization and degradation of BMPR1A. In early Xenopus embryos, Rspo2 is a negative feedback inhibitor in the BMP4 synexpression group and regulates dorsoventral axis formation. We conclude that R-spondins are bifunctional ligands, which activate WNT- and inhibit BMP signaling via ZNRF3, with implications for development and cancer.
Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer
Authors: Desbois Mélanie , Udyavar Akshata R. , Ryner Lisa , Kozlowski Cleopatra , Guan Yinghui , Dürrbaum Milena , Lu Shan , Fortin Jean-Philippe , Koeppen Hartmut , Ziai James , Chang Ching-Wei , Keerthivasan Shilpa , Plante Marie , Bourgon Richard , Bais Carlos , Hegde Priti , Daemen Anneleen , Turley Shannon , Wang Yulei
Published: November 2020

Close proximity between cytotoxic T lymphocytes and tumour cells is required for effective immunotherapy. However, what controls the spatial distribution of T cells in the tumour microenvironment is not well understood. Here we couple digital pathology and transcriptome analysis on a large ovarian tumour cohort and develop a machine learning approach to molecularly classify and characterize tumour-immune phenotypes. Our study identifies two important hallmarks characterizing T cell excluded tumours: 1) loss of antigen presentation on tumour cells and 2) upregulation of TGFβ and activated stroma. Furthermore, we identify TGFβ as an important mediator of T cell exclusion. TGFβ reduces MHC-I expression in ovarian cancer cells in vitro. TGFβ also activates fibroblasts and induces extracellular matrix production as a potential physical barrier to hinder T cell infiltration. Our findings indicate that targeting TGFβ might be a promising strategy to overcome T cell exclusion and improve clinical benefits of cancer immunotherapy.
Universal and versatile morphology engineering via hot fluorous solvent soaking for organic bulk heterojunction
Authors: Shan Tong , Zhang Yi , Wang Yan , Xie Ziyi , Wei Qingyun , Xu Jinqiu , Zhang Ming , Wang Cheng , Bao Qinye , Wang Xin , Chen Chun-Chao , Huang Jingsong , Chen Qi , Liu Feng , Chen Liwei , Zhong Hongliang
Published: November 2020

After explosive growth of efficiency in organic solar cells (OSCs), achieving ideal morphology of bulk heterojunction remains crucial and challenging for advancing OSCs into consumer market. Herein, by utilizing the amphiphobic nature and temperature-dependent miscibility of fluorous solvent, hot fluorous solvent soaking method is developed to optimize the morphology with various donor/acceptor combinations including polymer/small-molecule, all-polymer and all-small-molecule systems. By immersing blend film into hot fluorous solvent which is utilized as liquid medium with better thermal conductivity, the molecular reorganization is accelerated. Furthermore, fluorous solvent can be miscible with the residue of chloroform and chloronaphthalene above upper critical solution temperature. This mixed solvent diffuses around inside the active layer and selectively promotes molecular reorganization, leading to optimized morphology. Compared to widely-used thermal annealing, this approach processed under mild conditions achieves superior photovoltaic performance, indicating the practicality and universality for morphological optimization in OSCs as well as other optoelectronic devices.
Charge-generating mid-gap trap states define the thermodynamic limit of organic photovoltaic devices
Authors: Zarrabi Nasim , Sandberg Oskar J. , Zeiske Stefan , Li Wei , Riley Drew B. , Meredith Paul , Armin Ardalan
Published: November 2020

Detailed balance is a cornerstone of our understanding of artificial light-harvesting systems. For next generation organic solar cells, this involves intermolecular charge-transfer (CT) states whose energies set the maximum open circuit voltage VOC. We have directly observed sub-gap states significantly lower in energy than the CT states in the external quantum efficiency spectra of a significant number of organic semiconductor blends. Taking these states into account and using the principle of reciprocity between emission and absorption results in non-physical radiative limits for the VOC. We propose and provide compelling evidence for these states being non-equilibrium mid-gap traps which contribute to photocurrent by a non-linear process of optical release, upconverting them to the CT state. This motivates the implementation of a two-diode model which is often used in emissive inorganic semiconductors. The model accurately describes the dark current, VOC and the long-debated ideality factor in organic solar cells. Additionally, the charge-generating mid-gap traps have important consequences for our current understanding of both solar cells and photodiodes – in the latter case defining a detectivity limit several orders of magnitude lower than previously thought.
Photoinduced Dirac semimetal in ZrTe5
Authors: Konstantinova T. , Wu L. , Yin W.-G. , Tao J. , Gu G. D. , Wang X. J. , Yang Jie , Zaliznyak I. A. , Zhu Y.
Published: November 2020

Novel phases of matter with unique properties that emerge from quantum and topological protection present an important thrust of modern research. Of particular interest is to engineer these phases on demand using ultrafast external stimuli, such as photoexcitation, which offers prospects of their integration into future devices compatible with optical communication and information technology. Here, we use MeV Ultrafast Electron Diffraction (UED) to show how a transient three-dimensional (3D) Dirac semimetal state can be induced by a femtosecond laser pulse in a topological insulator ZrTe5. We observe marked changes in Bragg diffraction, which are characteristic of bond distortions in the photoinduced state. Using the atomic positions refined from the UED, we perform density functional theory (DFT) analysis of the electronic band structure. Our results reveal that the equilibrium state of ZrTe5 is a topological insulator with a small band gap of ~ 25 meV, consistent with angle-resolved photoemission (ARPES) experiments. However, the gap is closed in the presence of strong spin-orbit coupling (SOC) in the photoinduced transient state, where massless Dirac fermions emerge in the chiral band structure. The time scale of the relaxation dynamics to the transient Dirac semimetal state is remarkably long, τ ~ 160 ps, which is two orders of magnitude longer than the conventional phonon-driven structural relaxation. The long relaxation is consistent with the vanishing density of states in Dirac spectrum and slow spin-repolarization of the SOC-controlled band structure accompanying the emergence of Dirac fermions.
Robust, universal, and persistent bud secretion adhesion in horse-chestnut trees
Authors: Voigt Dagmar , Kim Jaekang , Jantschke Anne , Varenberg Michael
Published: November 2020

Buds of horse-chestnut trees are covered with a viscous fluid, which remains sticky after long-term exposure to heat, frost, radiation, precipitation, deposition of aerosols and particles, attacks by microbes and arthropods. The present study demonstrates that the secretion does not dry out under arid conditions, not melt at 50 °C, and not change significantly under UV radiation or frost at a microscopic level. It is slightly swellable under wet conditions; and, it universally wets and adheres to substrates having different polarities. Measured pull-off forces do not differ between hydrophilic and lipophilic surfaces, ranging between 58 and 186 mN, and resulting in an adhesive strength up to 204 kPa. The mechanical and chemical properties of secretion resemble those of pressure-sensitive adhesives. The Raman, infrared, and nuclear magnetic resonance spectra show the clear presence of saturated aliphatic hydrocarbons, esters, free carboxylic acids, as well as minor amounts of amides and aromatic compounds. We suggest a multi-component material (aliphatic hydrocarbon resin), including alkanes, fatty acids, amides, and tackifying terpenoids embedded in a fluid matrix (fatty acids) comprising nonpolar and polar portions serving the universal and robust adhesive properties. These characteristics matter for ecological-evolutionary aspects and can inspire innovative designs of multifunctional, biomimetic pressure-sensitive adhesives and varnishes.
Assessing ecological uncertainty and simulation model sensitivity to evaluate an invasive plant species’ potential impacts to the landscape
Authors: Jarnevich Catherine S. , Young Nicholas E. , Cullinane Thomas Catherine , Grissom Perry , Backer Dana , Frid Leonardo
Published: November 2020

Ecological forecasts of the extent and impacts of invasive species can inform conservation management decisions. Such forecasts are hampered by ecological uncertainties associated with non-analog conditions resulting from the introduction of an invader to an ecosystem. We developed a state-and-transition simulation model tied to a fire behavior model to simulate the spread of buffelgrass (Cenchrus ciliaris) in Saguaro National Park, AZ, USA over a 30-year period. The simulation models forecast the potential extent and impact of a buffelgrass invasion including size and frequency of fire events and displacement of saguaro cacti and other native species. Using simulation models allowed us to evaluate how model uncertainties affected forecasted landscape outcomes. We compared scenarios covering a range of parameter uncertainties including model initialization (landscape susceptibility to invasion) and expert-identified ecological uncertainties (buffelgrass patch infill rates and precipitation). Our simulations showed substantial differences in the amount of buffelgrass on the landscape and the size and frequency of fires for dry years with slow patch infill scenarios compared to wet years with fast patch infill scenarios. We identified uncertainty in buffelgrass patch infill rates as a key area for research to improve forecasts. Our approach could be used to investigate novel processes in other invaded systems.
Characterisation of the main PSA glycoforms in aggressive prostate cancer
Authors: Gratacós-Mulleras Anna , Duran Adrià , Asadi Shehni Akram , Ferrer-Batallé Montserrat , Ramírez Manel , Comet Josep , de Llorens Rafael , Saldova Radka , Llop Esther , Peracaula Rosa
Published: November 2020

Serum levels of prostate specific antigen (PSA) are commonly used for prostate cancer (PCa) detection. However, their lack of specificity to distinguish benign prostate pathologies from PCa, or indolent from aggressive PCa have prompted the study of new non-invasive PCa biomarkers. Aberrant glycosylation is involved in neoplastic progression and specific changes in PSA glycosylation pattern, as the reduction in the percentage of α2,6-sialic acid (SA) are associated with PCa aggressiveness. In this study, we have characterised the main sialylated PSA glycoforms from blood serum of aggressive PCa patients and have compared with those of standard PSA from healthy individuals’ seminal plasma. PSA was immunoprecipitated and α2,6-SA were separated from α2,3-SA glycoforms using SNA affinity chromatography. PSA N-glycans were released, labelled and analysed by hydrophilic interaction liquid chromatography combined with exoglycosidase digestions. The results showed that blood serum PSA sialylated glycoforms containing GalNAc residues were largely increased in aggressive PCa patients, whereas the disialylated core fucosylated biantennary structures with α2,6-SA, which are the major PSA glycoforms in standard PSA from healthy individuals, were markedly reduced in aggressive PCa. The identification of these main PSA glycoforms altered in aggressive PCa opens the way to design specific strategies to target them, which will be useful to improve PCa risk stratification.
Author Correction: Boundary effects of expectation in human pain perception
Authors: Hird E. J. , Charalambous C. , El-Deredy W. , Jones A. K. P. , Talmi D.
Published: November 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Effect of anthelmintic treatment on serum free IGF-1 and IGFBP-3: a cluster-randomized-controlled trial in Indonesia
Authors: Kurniawan Farid , Tahapary Dicky L. , de Ruiter Karin , Yunir Em , Biermasz Nienke R. , Smit Johannes W. A. , Supali Taniawati , Sartono Erliyani , Yazdanbakhsh Maria , Soewondo Pradana
Published: November 2020

In children, soil-transmitted helminth infections have been linked to poor nutritional status and growth retardation in association with lower levels of IGF-1. In adults, IGF-1 has an anabolic and metabolic function and is related to nutritional status. Here, we assessed the impact of helminth infection on free IGF-1 and its major binding protein, IGFBP-3, in adults. The levels of IGF-1 and IGFBP3 were measured in 1669 subjects aged ≥ 16 years, before and after receiving four rounds of albendazole 400 mg/day or matching placebo for three consecutive days. Helminth infection status was assessed by microscopy (Kato-Katz) and PCR. Serum free IGF-1 level was significantly lower in helminth-infected subjects [mean difference and 95% CI − 0.068 (− 0.103; − 0.033), P < 0.001 after adjustment for age, sex, body mass index, and fasting insulin level]. There was no difference in IGFBP-3 level between helminth infected versus non-infected subjects. In the whole study population, albendazole treatment significantly increased serum free IGF-1 level [estimate and 95% CI 0.031 (0.004; − 0.057), P = 0.024] whereas no effect was found on the IGFBP-3 level. Our study showed that helminth infection in adults is associated with lower free IGF-1 levels but not with IGFBP-3 and albendazole treatment significantly increases free IGF-1 levels in the study population.

Clinical Trial Registration: https://www.isrctn.com/ISRCTN75636394.
Reconstitution of rat fetal testis during the masculinisation programming window induces focal dysgenesis consistent with testicular dysgenesis syndrome
Authors: Smart Ellie , Macdonald Joni , Smith Lee B. , Mitchell Rod T.
Published: November 2020

Focal dysgenesis is a consistent feature of testicular dysgenesis syndrome (TDS) in humans. Rodent studies show that perturbation of androgens (e.g. following phthalate exposure) during a fetal masculinisation programming window (MPW) predisposes to a TDS phenotype. This study aimed to determine whether dissociation and reconstitution of rat fetal testis tissue during the MPW can be used to model and manipulate seminiferous cord development, including induction of focal dysgenesis, as described in TDS. Dissociated fetal rat testes were xenotransplanted subcutaneously into recipient mice for 4 weeks. Transplanted mice were treated with vehicle or di-n-butyl-phthalate (DBP, a plasticising chemical known to induce testicular dysgenesis in vivo in rats). Testosterone production by the transplants was measured in recipient mice and immunofluorescence was performed on the retrieved transplants to identify features consistent with focal testicular dysgenesis. Re-aggregation of rat fetal testis tissue xenotransplants during the MPW results in reconstitution of seminiferous cords. Features of focal testicular dysgenesis were present in re-aggregated testis, including ectopic Sertoli cells and intratubular Leydig cells (ITLCs). DBP exposure of recipient mice reduced androgen-dependent seminal vesicle weight (8.3 vs 26.7 mg; p < 0.05), but did not enhance features of focal dysgenesis including number of ITLCs (0.07 vs 0.10 cells/mm2; p > 0.05). We conclude that seminiferous cord reformation during the MPW results in development of focal dysgenesis. The system may be used to separate specific effects (e.g. androgen suppression) of individual chemical exposures from other mechanisms that may be conserved in TDS.
Preconditioning the immature lung with enhanced Nrf2 activity protects against oxidant-induced hypoalveolarization in mice
Authors: Tamatam Chandra M. , Reddy Narsa M. , Potteti Haranatha R. , Ankireddy Aparna , Noone Patrick M. , Yamamoto Masayuki , Kensler Thomas W. , Reddy Sekhar P.
Published: November 2020

Bronchopulmonary dysplasia (BPD) is a chronic disease of preterm babies with poor clinical outcomes. Nrf2 transcription factor is crucial for cytoprotective response, whereas Keap1—an endogenous inhibitor of Nrf2 signaling—dampens these protective responses. Nrf2-sufficient (wild type) newborn mice exposed to hyperoxia develop hypoalveolarization, which phenocopies human BPD, and Nrf2 deficiency worsens it. In this study, we used PND1 pups bearing bearing hypomorphic Keap1 floxed alleles (Keap1f/f) with increased levels of Nrf2 to test the hypothesis that constitutive levels of Nrf2 in the premature lung are insufficient to mitigate hyperoxia-induced hypoalveolarization. Both wildtype and Keap1f/f pups at PND1 were exposed to hyperoxia for 72 h and then allowed to recover at room air for two weeks (at PND18), sacrificed, and lung hypoalveolarization and inflammation assessed. Hyperoxia-induced lung hypoalveolarization was remarkably lower in Keap1f/f pups than in wildtype counterparts (28.9% vs 2.4%, wildtype vs Keap1f/f). Likewise, Keap1f/f pups were protected against prolonged (96 h) hyperoxia-induced hypoalveolarization. However, there were no differences in hyperoxia-induced lung inflammatory response immediately after exposure or at PND18. Lack of hypoalveolarization in Keap1f/f pups was accompanied by increased levels of expression of antioxidant genes and GSH as assessed immediately following hyperoxia. Keap1 knockdown resulted in upregulation of lung cell proliferation postnatally but had opposing effects following hyperoxia. Collectively, our study demonstrates that augmenting endogenous Nrf2 activation by targeting Keap1 may provide a physiological way to prevent hypoalveolarization associated with prematurity.
Risk factors for respiratory Aspergillus fumigatus in German Cystic Fibrosis patients and impact on lung function
Authors: Düesberg Uta , Wosniok Julia , Naehrlich Lutz , Eschenhagen Patience , Schwarz Carsten
Published: November 2020

Airway inflammation and chronic lung infections in cystic fibrosis (CF) patients are mostly caused by bacteria, e.g. Pseudomonas aeruginosa (PA). The role of fungi in the CF lung is still not well elucidated, but evidence for a harmful and complex role is getting stronger. The most common filamentous fungus in CF is Aspergillus fumigatus (AF). Age and continuous antibiotic treatment have been discussed as risk factors for AF colonisation but did not differentiate between transient and persistent AF colonisation. Also, the impact of co-colonisation of PA and AF on lung function is still under investigation. Data from patients with CF registered in the German Cystic Fibrosis Registry database in 2016 and 2017 were retrospectively analysed, involving descriptive and multivariate analysis to assess risk factors for transient or persistent AF colonisation. Age represented an independent risk factor for persistent AF colonisation. Prevalence was low in children less than ten years, highest in the middle age and getting lower in higher age (≥ 50 years). Continuous antibiotic lung treatment was significantly associated with AF prevalence in all age groups. CF patients with chronic PA infection had a lower lung function (FEV1%predicted), which was not influenced by an additional AF colonisation. AF colonisation without chronic PA infection, however, was significantly associated with a lower function, too. Older age up to 49 years and continuous antibiotic use were found to be the main risk factors for AF permanent colonisation. AF might be associated with decrease of lung function if not disguised by chronic PA infection.
Validation of a wearable cuff-less wristwatch-type blood pressure monitoring device
Authors: Moon Joon Ho , Kang Myung-Kyun , Choi Chang-Eun , Min Jeonghee , Lee Hae-Young , Lim Soo
Published: November 2020

Ambulatory blood pressure (BP) monitoring is recommended to improve the management of hypertension. Here, we investigated the accuracy of BP estimated using a wearable cuff-less device, InBodyWATCH, compared with BP measured using a manual sphygmomanometer. Thirty-five adults were enrolled (age 57.1 ± 17.9 years). The BP was estimated using InBodyWATCH with an individualized estimation based on a neural network model. Three paired sets of BPs from the two devices were compared using correlation analysis and Bland–Altman plots (n = 105 paired BP readings). The correlations for both systolic and diastolic BP (SBP and DBP) between the two devices were high (r = 0.964 and 0.939, both P < 0.001). The mean difference was 2.2 ± 6.1 mmHg for SBP and −0.2 ± 4.2 mmHg for DBP; these were not significant (P = 0.472 for SBP and P = 0.880 for DBP). The proportions of estimated SBP/DBP obtained from the InBodyWATCH within ± 5 mmHg of manual SBP/DBP were 71.4%/83.8%; within ± 10 mmHg they were 86.7%/98.1%; and within ± 15 mmHg they were 97.1%/99.0%. The estimated BP from this wearable cuff-less device correlated highly with the manual BP and showed good accuracy, suggesting its potential to be used in ambulatory BP monitoring.
Reusable magnetite nanoparticles–biochar composites for the efficient removal of chromate from water
Authors: Alam Md. Samrat , Bishop Brendan , Chen Ning , Safari Salman , Warter Viola , Byrne James M. , Warchola Tyler , Kappler Andreas , Konhauser Kurt O. , Alessi Daniel S.
Published: November 2020

Biochar (BC) and magnetite (Fe3O4) nanoparticles (MNP) have both received considerable recent attention in part due to their potential use in water treatment. While both are effective independently in the removal of a range of anionic metals from aqueous solution, the efficacy of these materials is reduced considerably at neutral pH due to decreased metal adsorption and MNP aggregation. In addition to synthetic metal oxide–biochar composites for use in treatment and remediation technologies, aggregates may also occur in nature when pyrolytic carbon is deposited in soils. In this study, we tested whether magnetite synthesized in the presence of biochar leads to increased removal efficiency of hexavalent chromium, Cr(VI), at the mildly acidic to neutral pH values characteristic of most natural and contaminated aqueous environments. To do so, magnetite nanoparticles and biochar produced from ground willow were synthesized to form composites (MNP–BC). Batch studies showed that MNP–BC markedly enhanced both adsorption and reduction of Cr(VI) from aqueous solution at acidic to neutral pH as compared to MNP and BC separately, suggesting a strong synergetic effect of hybridizing Fe3O4 with BC. Mechanistically, the Cr(VI) removal processes occurred through both adsorption and intraparticle diffusion followed by reduction to Cr(III). Synchrotron-based X-ray absorption spectroscopy analyses confirmed that Cr(VI) was reduced at the surface of MNP–BC, with electrons derived directly from both biochar and magnetite at low pH, while at near-neutral pH, biochar increased Cr(VI) reduction by inhibiting MNP aggregation. Extended X-ray absorption fine structure fitting results confirmed that the Cr(III) precipitates consist of Cr(OH)3 and chromite (Cr2FeO4) nanoparticles. Our results demonstrate that MNP–BC composites have great potential as a material for the treatment of chromate-containing aqueous solutions across a wide range of pH values, and provide information valuable broadly relevant to soils and sediments that contain biochar.
Engineering cofactor supply and NADH-dependent d-galacturonic acid reductases for redox-balanced production of l-galactonate in Saccharomyces cerevisiae
Authors: Harth Simon , Wagner Jacqueline , Sens Tamina , Choe Jun-yong , Benz J. Philipp , Weuster-Botz Dirk , Oreb Mislav
Published: November 2020

d-Galacturonic acid (GalA) is the major constituent of pectin-rich biomass, an abundant and underutilized agricultural byproduct. By one reductive step catalyzed by GalA reductases, GalA is converted to the polyhydroxy acid l-galactonate (GalOA), the first intermediate of the fungal GalA catabolic pathway, which also has interesting properties for potential applications as an additive to nutrients and cosmetics. Previous attempts to establish the production of GalOA or the full GalA catabolic pathway in Saccharomyces cerevisiae proved challenging, presumably due to the inefficient supply of NADPH, the preferred cofactor of GalA reductases. Here, we tested this hypothesis by coupling the reduction of GalA to the oxidation of the sugar alcohol sorbitol that has a higher reduction state compared to glucose and thereby yields the necessary redox cofactors. By choosing a suitable sorbitol dehydrogenase, we designed yeast strains in which the sorbitol metabolism yields a “surplus” of either NADPH or NADH. By biotransformation experiments in controlled bioreactors, we demonstrate a nearly complete conversion of consumed GalA into GalOA and a highly efficient utilization of the co-substrate sorbitol in providing NADPH. Furthermore, we performed structure-guided mutagenesis of GalA reductases to change their cofactor preference from NADPH towards NADH and demonstrated their functionality by the production of GalOA in combination with the NADH-yielding sorbitol metabolism. Moreover, the engineered enzymes enabled a doubling of GalOA yields when glucose was used as a co-substrate. This significantly expands the possibilities for metabolic engineering of GalOA production and valorization of pectin-rich biomass in general.
Abdominal subcutaneous fat quantification in obese patients from limited field-of-view MRI data
Authors: Michel Sophia , Linder Nicolas , Eggebrecht Tobias , Schaudinn Alexander , Blüher Matthias , Dietrich Arne , Denecke Timm , Busse Harald
Published: November 2020

Different types of adipose tissue can be accurately localized and quantified by tomographic imaging techniques (MRI or CT). One common shortcoming for the abdominal subcutaneous adipose tissue (ASAT) of obese subjects is the technically restricted imaging field of view (FOV). This work derives equations for the conversion between six surrogate measures and fully segmented ASAT volume and discusses the predictive power of these image-based quantities. Clinical (gender, age, anthropometry) and MRI data (1.5 T, two-point Dixon sequence) of 193 overweight and obese patients (116 female, 77 male) from a single research center for obesity were analyzed retrospectively. Six surrogate measures of fully segmented ASAT volume (VASAT) were considered: two simple ASAT lengths, two partial areas (Ap-FH, Ap-ASIS) and two partial volumes (Vp-FH, Vp-ASIS) limited by either the femoral heads (FH) or the anterior superior iliac spine (ASIS). Least-squares regression between each measure and VASAT provided slope and intercept for the computation of estimated ASAT volumes (V~ASAT). Goodness of fit was evaluated by coefficient of determination (R2) and standard deviation of percent differences (sd%) between V~ASAT and VASAT. Best agreement was observed for partial volume Vp-FH (sd% = 14.4% and R2 = 0.78), followed by Vp-ASIS (sd% = 18.1% and R2 = 0.69) and AWFASIS (sd% = 23.9% and R2 = 0.54), with minor gender differences only. Other estimates from simple lengths and partial areas were moderate only (sd% > 23.0% and R2 < 0.50). Gender differences in R2 generally ranged between 0.02 (dven) and 0.29 (Ap-FH). The common FOV restriction for MRI volumetry of ASAT in obese subjects can best be overcome by estimating VASAT from Vp-FH using the equation derived here. The very simple AWFASIS can be used with reservation.
Identification and characterization of the proteolytic flagellin from the common freshwater bacterium Hylemonella gracilis
Authors: Eckhard Ulrich , Blöchl Constantin , Jenkins Benjamin G. L. , Mansfield Michael J. , Huber Christian G. , Doxey Andrew C. , Brandstetter Hans
Published: November 2020

Flagellins are the protein components of bacterial flagella and assemble in up to 20,000 copies to form extracellular flagellar filaments. An unusual family of flagellins was recently discovered that contains a unique metalloprotease domain within its surface-exposed hypervariable region. To date, these proteolytic flagellins (also termed flagellinolysins) have only been characterized in the Gram-positive organism Clostridium haemolyticum, where flagellinolysin was shown to be proteolytically active and capable of cleaving extracellular protein substrates. The biological function of flagellinolysin and its activity in other organisms, however, remain unclear. Here, using molecular biochemistry and proteomics, we have performed an initial characterization of a novel flagellinolysin identified from Hylemonella gracilis, a Gram-negative organism originally isolated from pond water. We demonstrate that H. gracilis flagellinolysin (HgrFlaMP) is an active calcium-dependent zinc metallopeptidase and characterize its cleavage specificity profile using both trypsin and GluC-derived peptide libraries and protein substrates. Based on high-throughput degradomic assays, HgrFlaMP cleaved 784 unique peptides and displayed a cleavage site specificity similar to flagellinolysin from C. haemolyticum. Additionally, by using a set of six protein substrates, we identified 206 protein-embedded cleavage sites, further refining the substrate preference of HgrFlaMP, which is dominated by large hydrophobic amino acids in P1′, and small hydrophobic or medium-sized polar residues on the amino-terminal side of the scissile bond. Intriguingly, recombinant HgrFlaMP was also capable of cleaving full-length flagellins from another species, suggesting its potential involvement in interbacterial interactions. Our study reports the first experimentally characterized proteolytic flagellin in a Gram-negative organism, and provides new insights into flagellum-mediated enzymatic activity.