bluuebunny/crossref_metadata_2025 huggingface dataset:
RETRACTED - Compact reduction in Lipschitz-free spaces
Authors: Aliaga Ramón J. , Noûs Camille , Petitjean Colin , Procházka Antonín
Published: December 2021

We prove a general principle satisfied by weakly precompact sets of Lipschitz-free spaces. By this principle, certain infinite dimensional phenomena in Lipschitz-free spaces over general metric spaces may be reduced to the same phenomena in free spaces over their compact subsets. As easy consequences we derive several new and some known results. The main new results are: $\mathcal {F}(X)$ is weakly sequentially complete for every superreflexive Banach space $X$, and $\mathcal {F}(M)$ has the Schur property and the approximation property for every scattered complete metric space $M$.
Characterization of simple sequence repeat loci for Peltigera membranacea (lichenized Ascomycota) and its Nostoc photobiont
Authors: Werth Silke , Pálsson Stefán Þór , Andrésson Ólafur S.
Published: December 2021

To facilitate population-genetic studies, we developed simple sequence repeat (SSR) markers and a molecular species identification assay for Peltigera membranacea (Ascomycota, Peltigerales), a common ground-dwelling lichen of forest and tundra ecosystems. Additional markers were developed for its Nostoc photobiont. Twenty-one fungal markers for P. membranacea were found to be polymorphic, with the number of alleles ranging from 3–21. Nei's unbiased gene diversity ranged from 0.588 to 0.640 in four significantly structured (FST = 0.059) mycobiont populations. For the Nostoc photobiont, 14 polymorphic SSR were developed, yielding 4–14 alleles each, with gene diversity ranging from 0.062 to 0.771 in four populations showing substantial population structure (FST = 0.278). The new markers developed are suitable for population genetic studies of Peltigera membranacea and of its cyanobiont, and at the same time allowed us to distinguish 98.5% of P. membranacea specimens from morphologically similar species of Peltigera.
A synopsis of the genusArthothelium(Arthoniales) in Tasmania
Authors: Kantvilas Gintaras
Published: December 2021

The genusArthotheliumA. Massal. in Tasmania comprises ten species. Five of these are described as new:A. bacidinumKantvilas, a saxicolous, littoral species with subglobose apothecia, non-macrocephalic ascospores, 25−40 × 11−19 μm, and containing the pigment Endoaurantiacum-gold which yields a K+ red reaction;A. insolitumKantvilas, lichenicolous in rainforest and characterized by subglobose apothecia, very large, non-macrocephalic ascospores, 50−80 × 22−40 μm, and containing the pigment Interveniens-brown which reacts K+ olive green;A. macounioidesKantvilas, corticolous in wet forest and characterized by sessile, convex apothecia, macrocephalic ascospores, 29−42 × 11−18 μm, and containing the pigment Endoaurantiacum-gold;A. magenteumKantvilas, a common wet forest epiphyte with applanate apothecia, non-macrocephalic ascospores, 25−55 × 11−22 μm, and containing a unique maroon-red, K+ pink pigment; andA. subtectumKantvilas, a saxicolous species with convex apothecia, macrocephalic ascospores, 22−36 × 9−14 μm, and containing Endoaurantiacum-gold. The New Zealand speciesA. endoaurantiacumMakhija & Patw. andA. suffusum(C. Knight) Müll. Arg., and the AustralianA. velatiumMüll. Arg. are recorded for Tasmania for the first time. The namesA. obtusulum(Nyl.) Müll. Arg.,A. pellucidum(C. Knight) Müll. Arg. andA. polycarpumMüll. Arg. are considered synonyms of the widespreadA. ampliatum(C. Knight & Mitten) Müll. Arg.Arthothelium feraxMüll. Arg. is a synonym ofA. interveniens(Nyl.) Zahlbr. andA. subspectabileVĕzda & Kantvilas is a synonym ofA. suffusum. The sole record ofA. macrothecum(Fée) A. Massal. from Tasmania is found to be based on a misidentification. A key to the species is provided. The importance of apothecial pigments, apothecial morphology and ascospore septation is discussed, and three pigments are characterized by their appearance in water and other standard media.
CME: Metformin – Dos und Don’ts CME-Fragen
Authors: Slahor Lea
Published: December 2021

Zusammenfassung. Obwohl sich die Diabetestherapie im Wandel befindet, stellt Metformin weiterhin die Standardtherapie bei Diabetes mellitus Typ 2 dar, fehlende Kontraindikationen vorausgesetzt. Metformin wird sowohl als Monotherapie als auch in Kombination mit allen anderen Präparaten in der Diabetestherapie eingesetzt. Als Biguanid wirkt Metformin über eine Hemmung der hepatischen Gluconeogenese und verbessert die Insulinsensitivät im peripheren Gewebe. Metformin führt zu einer moderaten Gewichtsabnahme und weist weitere Vorteile auf: Fehlendes Hypoglykämierisiko, gute Verträglichkeit, Langzeiterfahrungen in der Anwendung, geringe Therapiekosten. Die häufigsten gastrointestinalen Nebenwirkungen sind meist mild und passager, doch kann ein Vitamin-B12-Mangel auftreten. Auch wenn die Metformin-assoziierte Laktatazidose (MALA) selten auftritt, stellt diese eine relevante Komplikation dar, die mit einer hohen Mortalität assoziiert ist. Das Risiko steigt mit eingeschränkter Nierenfunktion, sodass die Metformindosis an die eGFR angepasst werden muss und Metformin bei einer eGFR <30 ml/min/1,73 m2 nicht eingesetzt werden darf. Als weitere Kontraindikationen gelten: aktive oder progrediente Lebererkrankung, Alkoholabusus, instabile oder akute Herzinsuffizienz, Situationen mit Hypoperfusion oder hämodynamische Instabilität, sowie eine Laktatazidose in der Vorgeschichte. Metformin bleibt eine moderne Therapie, deren Indikationen und Kontraindikationen es zu kennen gilt.
Microphysics of Summer Precipitation Over Yangtze‐Huai River Valley Region in China Revealed by GPM DPR Observation
Authors: Hu Xiong , Ai Weihua , Qiao Junqi , Hu Shensen , Han Ding , Yan Wei
Published: December 2021

Utilizing the measurements and retrievals from the Global Precipitation Measurement dual‐frequency precipitation radar data during the summer of 2014–2020, this study analyzes the precipitation microphysics for summer rainfall over the Yangtze‐Huai River Valley (YHRV) region in China with respect to the precipitation efficiency index (PEI). The results show that the mean near‐surface rain rate and PEI for convective precipitation are generally larger than that for stratiform precipitation. There are larger raindrops in near‐surface rainfall for convective precipitation than that for stratiform precipitation. The High PEI precipitation is characterized by the larger ratio of convective precipitation samples compared to that for the other two categories of precipitation. The mean mass‐weighted mean diameter (Dm) of the near‐surface raindrops increase along with the precipitation top height (PTH) in Moderate PEI precipitation for convective and stratiform precipitating clouds. The larger PEI indicates the larger occurrence of the heavy raindrops and strong radar echoes near the ground. The growth process of raindrops falling below the melting layer in the High PEI precipitation is dominated by collision‐coalescence while the collisional break up is the dominant process below the melting layer in Low PEI precipitation. It is further verified that the microphysical characteristics and mechanisms of summer rainfall over the YHRV region are similar to that of precipitation derived from tropical cyclones over the ocean during the monsoon period.
Evolution of Thermal Electron Distributions in the Magnetotail: Convective Heating and Scattering‐Induced Losses
Authors: Shustov P. I. , Lukin A. S. , Zhang X.‐J. , Artemyev A. V. , Petrukovich A. A. , Angelopoulos V.
Published: December 2021

Earth's magnetotail is filled with solar wind and ionospheric electrons, whose initial energies are significantly lower than the typical energies (temperatures) of plasmasheet electrons. One of the most common mechanisms responsible for heating of solar wind and ionospheric electrons in Earth's magnetotail is adiabatic heating caused by earthward convection of these electrons from the deep tail (i.e., from the region of a weak magnetic field) toward the region of stronger magnetic fields closer to Earth. This heating is moderated by electron losses into the ionosphere due to local wave scattering. In this study, we compare electron spectra from simultaneous observations of The Time History of Events and Macroscale Interactions during Substorms (THEMIS) spacecraft at different radial distances with spectra obtained from a simple model that includes adiabatic heating and losses. Our comparison shows that the model heating significantly overestimates the increase in energetic ( keV) electron fluxes, indicating that losses are essential for accurate modeling of the observed spectra. The required electron losses are similar to or even greater than the losses in the strong diffusion limit (when the loss cone is full). The latter can be interpreted as loss cone widening by field‐aligned electron acceleration.
Compositional Variation in the Crust of Peninsular Ranges and Surrounding Regions, Southern California, Revealed by Full‐Wave Seismic and Gravity Joint Inversion
Authors: Bao Xueyang , Guo Lianghui , Shen Yang
Published: December 2021

Detailed three‐dimensional models of crustal compositional variations are essential for better understanding crustal evolution and dynamics. High‐resolution wave speed and density models of the crust provide one of the most important constraints on crustal compositional variations, particularly at depths beyond direct rock sampling. Here we present a three‐dimensional density and wave speed model of Southern California obtained by jointly inverting gravity anomalies and seismic component‐differential phase delays with full‐wave sensitivity kernels, which provide a link between wave speed and density. Thus, unlike previous joint seismic and gravity inversions, the new model does not depend on an empirical relationship between wave speed and density. The resulting density and compressional‐to‐shear wave‐speed ratio (Vp/Vs) reveal detailed features of compositional variations in the upper and middle crust in the study area, such as the three‐dimensional geometry of the boundary between the western and eastern portions of the Peninsular Ranges batholith, the gabbro‐ and metavolcanics‐rich locations within the Western Peninsular Ranges batholith, the variation of sedimentary basin thickness beneath the Coachella Valley, and a likely intermediate‐to‐mafic batholith beneath the Coachella Valley and the Eastern Peninsular Ranges. The jointly inverted density and Vp/Vs values also suggest a lithological control on seismic activities off the major fault zones.
Seasonal Transformation and Spatial Variability of Water Masses Within MacKenzie Polynya, Prydz Bay
Authors: Portela Esther , Rintoul Stephen R. , Bestley Sophie , Herraiz‐Borreguero Laura , van Wijk Esmee , McMahon Clive R. , Roquet Fabien , Hindell Mark
Published: December 2021

We provide a detailed description of the spatial distribution, seasonality and transformation of the main water masses within MacKenzie Polynya (MP) in Prydz Bay, East Antarctica, using data from instrumented southern elephant seals. Dense Shelf Water (DSW) formation in MP shows large spatial variability that is related to the (a) local bathymetry, (b) water column preconditioning from the presence/absence of different water masses, and (c) proximity to the Amery Ice Shelf meltwater outflow. MP exhibits sustained sea ice production and brine rejection (thus, salinity increase) from April to October. However, new DSW is only formed from June onward, when the mixed layer deepens and convection is strong enough to break the stratification set by Antarctic Surface Water above and Ice Shelf Water below. We found no evidence of DSW export from MP to Darnley polynya, as previously suggested. Rather, our observations suggest some DSW formed in Darnley Polynya may drain toward the western Prydz Bay. Then, DSW is exported offshore from Prydz Bay through the Prydz Channel. The interplay between sea ice formation, meltwater input, and sea floor topography is likely to explain why some coastal polynyas form more DSW than others, as well as the temporal variability in DSW formation within a particular polynya.
Discovery of Quasi‐Stationary Equatorial Waves Trapped in Stratospheric QBO Westerly and Easterly Jets
Authors: Sakazaki Takatoshi , Hamilton Kevin
Published: December 2021

Quasi‐stationary planetary Rossby waves forced in the extratropical troposphere propagate upwards into the stratospheric vortex and can also be refracted toward the equator. To the extent that such waves penetrate the low latitudes they will be observable as quasi‐stationary zonal eddies in the equatorial middle stratosphere. These eddies should be strongly modulated by the phase of the Quasi‐Biennial Oscillation (QBO) of the mean zonal wind. In this project we used global reanalysis data to examine the quasi‐stationary waves in the monthly mean wind and geopotential fields near the equator and their relation to the QBO mean winds and the extratropical planetary waves. We discovered quasi‐stationary mid‐stratospheric eddy circulations near the equator that often take the form of equatorial planetary modes. Notably a quasi‐stationary equatorial Rossby mode structure can develop during westerly QBO phases, especially when the westerly mean jet is almost symmetric about the equator and deep in the vertical (often in November). More surprisingly, during the easterly QBO phase (EQBO), a modest amplitude quasi‐stationary equatorial Kelvin mode structure develops. Stationary equatorial waves forced in the troposphere will encounter critical surfaces at one or more levels below the mid‐stratosphere, and so presumably cannot account for our findings. A linear, steady model in an equatorial channel that was forced by observed fields specified at extratropical lateral boundaries also cannot fully reproduce the equatorial mode structures, especially for the Kelvin wave during EQBO. Other factors such as transient wave‐mean flow interaction or some dynamic instability might be responsible.
Identifying Global‐Scale Patterns of Vegetation Change During the Last Deglaciation From Paleoclimate Networks
Authors: Adam Moritz , Weitzel Nils , Rehfeld Kira
Published: December 2021

During the last deglaciation (∼19–11 ka before present), the global mean temperature increased by 3–8 K. The concurrent hydroclimate and land cover changes are not well constrained. Here, we use a pollen database to quantify global‐scale vegetation changes during this transitional period at orbital (∼104 years) and millennial timescales (∼103 years). We focus on the proportion of tree and shrub pollen, the arboreal pollen (AP) fraction. Temporal similarities over long distances are identified by a paleoclimate network approach. At the orbital scale, we find coherent AP variations in the low and mid‐latitudes which we attribute to the global climate forcing. While AP fractions predominantly increased through the deglaciation, we identify regions where AP fractions decreased. For millennial timescales, we do not observe spatially coherent similarity structures. We compare our results with networks computed from three deglacial climate simulations with the CCSM3, HadCM3, and LOVECLIM models. Networks based on simulated precipitation patterns reproduce the characteristics of the AP network. Sensitivity experiments with statistical emulators indicate that, indeed, precipitation variations explain the diagnosed patterns of vegetation change better than temperature and CO2 variations. Our findings support previous interpretations of deglacial forest evolution in the mid‐latitudes being the result of atmospheric circulation changes. The network analysis identifies differences in the vegetation‐climate‐CO2 relationship simulated by CCSM3 and HadCM3. We conclude that network analyses are a promising tool to benchmark transient climate simulations with dynamical vegetation changes. This may result in stronger constraints of future hydroclimate and land cover changes.
Improved Neutral Density Predictions Through Machine Learning Enabled Exospheric Temperature Model
Authors: Licata Richard J. , Mehta Piyush M. , Weimer Daniel R. , Tobiska W. Kent
Published: December 2021

The community has leveraged satellite accelerometer data sets in previous years to estimate neutral mass density and exospheric temperatures. We utilize derived temperature data and optimize a nonlinear machine‐learned (ML) regression model to improve upon the performance of the linear EXospheric TEMPeratures on a PoLyhedrAl gRid (EXTEMPLAR) model. The newly developed EXTEMPLAR‐ML model allows for exospheric temperature predictions at any location with one model and provides performance improvements over its predecessor. We achieve reductions in mean absolute error of 2 K on an independent test set while providing similar error standard deviation values. Comparing the performance of both EXTEMPLAR models and the Naval Research Laboratory Mass Spectrometer and Incoherent Scatter radar Extended model (NRLMSISE‐00) across different solar and geomagnetic activity levels shows that EXTEMPLAR‐ML has the lowest mean absolute error across 80% of conditions tested. A study for spatial errors demonstrated that at all grid locations, EXTEMPLAR‐ML has the lowest mean absolute error for over 60% of the polyhedral grid cells on the test set. Like EXTEMPLAR, our model's outputs can be utilized by NRLMSISE‐00 (exclusively) to more closely match satellite accelerometer‐derived densities. We conducted 10 case studies where we compare the accelerometer‐derived temperature and density estimates from four satellites to NRLMSISE‐00, EXTEMPLAR, and EXTEMPALR‐ML during major storm periods. These comparisons show that EXTEMPLAR‐ML generally has the best performance of the three models during storms. We use principal component analysis on EXTEMPLAR‐ML outputs to verify the physical response of the model to its drivers.
Erosion Mechanisms of Debris Flow on the Sediment Bed
Authors: Zheng Hongchao , Shi Zhenming , Yu Songbo , Fan Xuanmei , Hanley Kevin J. , Feng Shijin
Published: December 2021

Debris flows are common geological hazards in mountainous regions worldwide. The scale of debris flows can be significantly enhanced by basal erosion and bank collapse in the transportation process, resulting in an increase in casualties and property losses. However, the mechanisms of this growth are largely unclear. Here, we conduct a series of experiments to investigate the erosion of two different bed sediments (coarse‐grained and widely graded) by released flows with three different densities and two different volumes. The erosion mechanisms of bed sediments are revealed by comparing detailed sensor data for flow level, pore pressure and total normal stress. A flow nose develops on the coarse‐grained bed sediment, resulting in a high flow depth and low velocity, while a tabular flow develops on the widely graded bed sediment, leading to a low flow depth and high velocity. The mean erosion rates of the coarse‐grained bed sediment are generally higher than those of the widely graded bed sediment due to significant pore pressure developed in coarse‐grained bed sediment. The feedback effect of bed sediment on the erosion process strongly influences the flow depth and velocity, which in turn affects the mean erosion rate of bed sediment. The interaction between the overlying flow and sediment bed controls the erosion pattern: coarse‐grained bed sediment is eroded by a layer of mass movement whereas widely graded bed sediment is progressively scoured. The interaction between debris flow and bed sediment during erosion is principally attributed to pore‐pressure transmission.
Touchable cell biophysics property recognition platforms enable multifunctional blood smart health care
Authors: Chen Longfei , Liu Yantong , Xu Hongshan , Ma Linlu , Wang Yifan , Le Yu  , Wang Fang , Zhu Jiaomeng , Hu Xuejia , Yi Kezhen , Yang Yi , Shen Hui , Zhou Fuling , Gao Xiaoqi , Cheng Yanxiang , Bai Long , Duan Yongwei , Wang Fubing , Zhu Yimin
Published: December 2021

As a crucial biophysical property, red blood cell (RBC) deformability is pathologically altered in numerous disease states, and biochemical and structural changes occur over time in stored samples of otherwise normal RBCs. However, there is still a gap in applying it further to point-of-care blood devices due to the large external equipment (high-resolution microscope and microfluidic pump), associated operational difficulties, and professional analysis. Herein, we revolutionarily propose a smart optofluidic system to provide a differential diagnosis for blood testing via precise cell biophysics property recognition both mechanically and morphologically. Deformation of the RBC population is caused by pressing the hydrogel via an integrated mechanical transfer device. The biophysical properties of the cell population are obtained by the designed smartphone algorithm. Artificial intelligence-based modeling of cell biophysics properties related to blood diseases and quality was developed for online testing. We currently achieve 100% diagnostic accuracy for five typical clinical blood diseases (90 megaloblastic anemia, 78 myelofibrosis, 84 iron deficiency anemia, 48 thrombotic thrombocytopenic purpura, and 48 thalassemias) via real-world prospective implementation; furthermore, personalized blood quality (for transfusion in cardiac surgery) monitoring is achieved with an accuracy of 96.9%. This work suggests a potential basis for next-generation blood smart health care devices.
Pyroglutamate Aβ cascade as drug target in Alzheimer’s disease
Authors: Bayer Thomas A.
Published: December 2021

One of the central aims in Alzheimer’s disease (AD) research is the identification of clinically relevant drug targets. A plethora of potential molecular targets work very well in preclinical model systems both in vitro and in vivo in AD mouse models. However, the lack of translation into clinical settings in the AD field is a challenging endeavor. Although it is long known that N-terminally truncated and pyroglutamate-modified Abeta (AβpE3) peptides are abundantly present in the brain of AD patients, form stable and soluble low-molecular weight oligomers, and induce neurodegeneration in AD mouse models, their potential as drug target has not been generally accepted in the past. This situation has dramatically changed with the report that passive immunization with donanemab, an AβpE3-specific antibody, cleared aymloid plaques and stabilized cognitive deficits in a group of patients with mild AD in a phase II trial. This review summarizes the current knowledge on the molecular mechanisms of generation of AβpE, its biochemical properties, and the intervention points as a drug target in AD.
Role of the flagellar hook in the structural development and antibiotic tolerance of Pseudomonas aeruginosa biofilms
Authors: Valentin Jules D P , Straub Hervé , Pietsch Franziska , Lemare Marion , Ahrens Christian H , Schreiber Frank , Webb Jeremy S , van der Mei Henny C , Ren Qun
Published: December 2021

Pseudomonas aeruginosa biofilms exhibit an intrinsic resistance to antibiotics and constitute a considerable clinical threat. In cystic fibrosis, a common feature of biofilms formed by P. aeruginosa in the airway is the occurrence of mutants deficient in flagellar motility. This study investigates the impact of flagellum deletion on the structure and antibiotic tolerance of P. aeruginosa biofilms, and highlights a role for the flagellum in adaptation and cell survival during biofilm development. Mutations in the flagellar hook protein FlgE influence greatly P. aeruginosa biofilm structuring and antibiotic tolerance. Phenotypic analysis of the flgE knockout mutant compared to the wild type (WT) reveal increased fitness under planktonic conditions, reduced initial adhesion but enhanced formation of microcolony aggregates in a microfluidic environment, and decreased expression of genes involved in exopolysaccharide formation. Biofilm cells of the flgE knock-out mutant display enhanced tolerance towards multiple antibiotics, whereas its planktonic cells show similar resistance to the WT. Confocal microscopy of biofilms demonstrates that gentamicin does not affect the viability of cells located in the inner part of the flgE knock-out mutant biofilms due to reduced penetration. These findings suggest that deficiency in flagellar proteins like FlgE in biofilms and in cystic fibrosis infections represent phenotypic and evolutionary adaptations that alter the structure of P. aeruginosa biofilms conferring increased antibiotic tolerance.
Cerebrospinal fluid abnormalities in first- and multi-episode schizophrenia-spectrum disorders: impact of clinical and demographical variables
Authors: Oviedo-Salcedo Tatiana , Wagner Elias , Campana Mattia , Gagsteiger Anna , Strube Wolfgang , Eichhorn Peter , Louiset Marie-Luise , Luykx Jurjen , de Witte Lot D. , Kahn René S. , Benros Michael E. , Falkai Peter , Hasan Alkomiet
Published: December 2021

Multiple lines of evidence indicate that immunological and inflammatory alterations contribute at least in a subgroup to the pathophysiology of schizophrenia. In this retrospective chart review, we investigated whether clinical factors contribute to altered cerebrospinal fluid (CSF) findings in schizophrenia-spectrum disorders. Clinical data from electronic medical records of patients with psychotic disorders (ICD-10: F20-F29) who received routine CSF diagnostics at the Department of Psychiatry and Psychotherapy, LMU Munich, Germany, were included. Chi² tests for dichotomous outcomes and independent t tests for continuous outcomes were used to compare differences between groups. A total of 331 patients were included in the analyses (43.2% female and 56.8% male). The mean age was 37.67 years (±15.58). The mean duration of illness was 71.96 months (±102.59). In all, 40% (128/320) were first-episode psychosis (FEP) patients and 60% (192/320) were multi-episode psychosis (MEP) patients. Elevated CSF protein levels were found in 19.8% and elevated CSF/serum albumin ratios (QAlb) in 29.4% of the cases. Pleocytosis was found in 6.1% of patients. MEP patients showed significantly higher mean QAlb compared with FEP patients (t(304.57) = −2.75, p = 0.006), which did not remain significant after correcting for age. QAlb elevation occurred more frequently in men (X2(1) = 14.76, p = <0.001). For treatment resistance, family history, and cMRI alterations, no significant differences in CSF-related outcomes were detected. Our work extends other retrospective cohorts confirming a relevant degree of CSF alterations in schizophrenia-spectrum disorders and shows the difficulty to relate these alterations to clinical and disease course trajectories. More research is needed to develop treatment response predictors from CSF analyses.
Oncogenic microRNA-181d binding to OGT contributes to resistance of ovarian cancer cells to cisplatin
Authors: Huang Wei , Chen Ling , Zhu Kean , Wang Donglian
Published: December 2021

Ovarian cancer (OC), a common gynecological cancer, is characterized by a high malignant potential. MicroRNAs (miRNAs or miRs) have been associated with the chemo- or radiotherapeutic resistance of human malignancies. Herein, the current study set out to explore the regulatory mechanism of miR-181d involved in the cisplatin (DDP) resistance of OC cells. Firstly, in-situ hybridization method was performed to identify miR-181d expression in ovarian tissues of DDP-resistant or DDP-sensitive patients. In addition, miR-181d expression in A2780 cells and A2780/DDP cell lines was determined by RT-qPCR. Gain- and loss-of-function experiments were then performed to characterize the effect of miR-181d on OC cell behaviors. We probed the miR-181d affinity to OGT, as well as the downstream glycosylation of KEAP1 and ubiquitination of NRF2. Further, in vivo experiments were performed to define the role of miR-181d in tumor resistance to DDP. miR-181d was highly expressed in the ovarian tissues of DDP-resistant patients and the A2780/DDP cell line. Ectopic expression of miR-181d augmented DDP resistance in OC cells. In addition, miR-181d was found to target the 3′UTR of OGT mRNA, and negatively regulate the OGT expression. Mechanistic results indicated that OGT repressed NRF2 expression through glycosylation of KEAP1, thereby inhibiting the DDP resistance of OC cells. Furthermore, miR-181d negatively orchestrated the OGT/KEAP1/NRF2 axis to enhance the OC resistance to DDP in vivo. Overall, these findings suggest that miR-181d-mediated OGT inhibition restricts the glycosylation of KEAP1, and then reduces the ubiquitination and degradation of NRF2, leading to DDP resistance of OC. This study provides new insights for prevention and control of OC.
Design of a methotrexate-controlled chemical dimerization system and its use in bio-electronic devices
Authors: Guo Zhong , Smutok Oleh , Johnston Wayne A. , Walden Patricia , Ungerer Jacobus P. J. , Peat Thomas S. , Newman Janet , Parker Jake , Nebl Tom , Hepburn Caryn , Melman Artem , Suderman Richard J. , Katz Evgeny , Alexandrov Kirill
Published: December 2021

Natural evolution produced polypeptides that selectively recognize chemical entities and their polymers, ranging from ions to proteins and nucleic acids. Such selective interactions serve as entry points to biological signaling and metabolic pathways. The ability to engineer artificial versions of such entry points is a key goal of synthetic biology, bioengineering and bioelectronics. We set out to map the optimal strategy for developing artificial small molecule:protein complexes that function as chemically induced dimerization (CID) systems. Using several starting points, we evolved CID systems controlled by a therapeutic drug methotrexate. Biophysical and structural analysis of methotrexate-controlled CID system reveals the critical role played by drug-induced conformational change in ligand-controlled protein complex assembly. We demonstrate utility of the developed CID by constructing electrochemical biosensors of methotrexate that enable quantification of methotrexate in human serum. Furthermore, using the methotrexate and functionally related biosensor of rapamycin we developed a multiplexed bioelectronic system that can perform repeated measurements of multiple analytes. The presented results open the door for construction of genetically encoded signaling systems for use in bioelectronics and diagnostics, as well as metabolic and signaling network engineering.
Human miRNA miR-675 inhibits DUX4 expression and may be exploited as a potential treatment for Facioscapulohumeral muscular dystrophy
Authors: Saad Nizar Y. , Al-Kharsan Mustafa , Garwick-Coppens Sara E. , Chermahini Gholamhossein Amini , Harper Madison A. , Palo Andrew , Boudreau Ryan L. , Harper Scott Q.
Published: December 2021

Facioscapulohumeral muscular dystrophy (FSHD) is a potentially devastating myopathy caused by de-repression of the DUX4 gene in skeletal muscles. Effective therapies will likely involve DUX4 inhibition. RNA interference (RNAi) is one powerful approach to inhibit DUX4, and we previously described a RNAi gene therapy to achieve DUX4 silencing in FSHD cells and mice using engineered microRNAs. Here we report a strategy to direct RNAi against DUX4 using the natural microRNA miR-675, which is derived from the lncRNA H19. Human miR-675 inhibits DUX4 expression and associated outcomes in FSHD cell models. In addition, miR-675 delivery using gene therapy protects muscles from DUX4-associated death in mice. Finally, we show that three known miR-675-upregulating small molecules inhibit DUX4 and DUX4-activated FSHD biomarkers in FSHD patient-derived myotubes. To our knowledge, this is the first study demonstrating the use of small molecules to suppress a dominant disease gene using an RNAi mechanism.
Plasticity within the barrel domain of BamA mediates a hybrid-barrel mechanism by BAM
Authors: Wu Runrun , Bakelar Jeremy W. , Lundquist Karl , Zhang Zijian , Kuo Katie M. , Ryoo David , Pang Yui Tik , Sun Chen , White Tommi , Klose Thomas , Jiang Wen , Gumbart James C. , Noinaj Nicholas
Published: December 2021

In Gram-negative bacteria, the biogenesis of β-barrel outer membrane proteins is mediated by the β-barrel assembly machinery (BAM). The mechanism employed by BAM is complex and so far- incompletely understood. Here, we report the structures of BAM in nanodiscs, prepared using polar lipids and native membranes, where we observe an outward-open state. Mutations in the barrel domain of BamA reveal that plasticity in BAM is essential, particularly along the lateral seam of the barrel domain, which is further supported by molecular dynamics simulations that show conformational dynamics in BAM are modulated by the accessory proteins. We also report the structure of BAM in complex with EspP, which reveals an early folding intermediate where EspP threads from the underside of BAM and incorporates into the barrel domain of BamA, supporting a hybrid-barrel budding mechanism in which the substrate is folded into the membrane sequentially rather than as a single unit.
Engineering Bacillus subtilis for the formation of a durable living biocomposite material
Authors: Kang Sun-Young , Pokhrel Anaya , Bratsch Sara , Benson Joey J. , Seo Seung-Oh , Quin Maureen B. , Aksan Alptekin , Schmidt-Dannert Claudia
Published: December 2021

Engineered living materials (ELMs) are a fast-growing area of research that combine approaches in synthetic biology and material science. Here, we engineer B. subtilis to become a living component of a silica material composed of self-assembling protein scaffolds for functionalization and cross-linking of cells. B. subtilis is engineered to display SpyTags on polar flagella for cell attachment to SpyCatcher modified secreted scaffolds. We engineer endospore limited B. subtilis cells to become a structural component of the material with spores for long-term storage of genetic programming. Silica biomineralization peptides are screened and scaffolds designed for silica polymerization to fabricate biocomposite materials with enhanced mechanical properties. We show that the resulting ELM can be regenerated from a piece of cell containing silica material and that new functions can be incorporated by co-cultivation of engineered B. subtilis strains. We believe that this work will serve as a framework for the future design of resilient ELMs.
Carbohydrates from Pseudomonas aeruginosa biofilms interact with immune C-type lectins and interfere with their receptor function
Authors: Singh Sonali , Almuhanna Yasir , Alshahrani Mohammad Y. , Lowman Douglas W. , Rice Peter J. , Gell Chris , Ma Zuchao , Graves Bridget , Jackson Darryl , Lee Kelly , Juarez Rucha , Koranteng Janice , Muntaka Sirina , Daniel A. Mitchell  , da Silva Ana C. , Hussain Farah , Yilmaz Gokhan , Mastrotto Francesca , Irie Yasuhiko , Williams Paul , Williams David L. , Cámara Miguel , Martinez-Pomares Luisa
Published: December 2021

Bacterial biofilms represent a challenge to the healthcare system because of their resilience against antimicrobials and immune attack. Biofilms consist of bacterial aggregates embedded in an extracellular polymeric substance (EPS) composed of polysaccharides, nucleic acids and proteins. We hypothesised that carbohydrates could contribute to immune recognition ofPseudomonas aeruginosabiofilms by engaging C-type lectins. Here we show binding of Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN, CD209), mannose receptor (MR, CD206) and Dectin-2 toP. aeruginosabiofilms. We also demonstrate that DC-SIGN, unlike MR and Dectin-2, recognises planktonicP. aeruginosacultures and this interaction depends on the presence of the common polysaccharide antigen. Within biofilms DC-SIGN, Dectin-2 and MR ligands appear as discrete clusters with dispersed DC-SIGN ligands also found among bacterial aggregates. DC-SIGN, MR and Dectin-2 bind to carbohydrates purified fromP. aeruginosabiofilms, particularly the high molecular weight fraction (HMW; >132,000 Da), with KDs in the nM range. These HMW carbohydrates contain 74.9–80.9% mannose, display α-mannan segments, interfere with the endocytic activity of cell-associated DC-SIGN and MR and inhibit Dectin-2-mediated cellular activation. In addition, biofilm carbohydrates reduce the association of the DC-SIGN ligand Lewisx, but not fucose, to human monocyte-derived dendritic cells (moDCs), and alter moDC morphology without affecting early cytokine production in response to lipopolysaccharide orP. aeruginosacultures. This work identifies the presence of ligands for three important C-type lectins withinP. aeruginosabiofilm structures and purified biofilm carbohydrates and highlights the potential for these receptors to impact immunity toP. aeruginosainfection.
Incidence and characteristics of death from peptic ulcer among cancer patients in the United States
Authors: Yang Pengcheng , Zheng Yongqiang , Zhang Lei , Hou Xiaohua
Published: December 2021

Most cancer patients die of non-cancer causes, and peptic ulcer is one cause that deserves attention. To characterize the incidence and risk factors of death from peptic ulcer among cancer patients, we extracted the data of cancer patients registered in the Surveillance Epidemiology and End Results (SEER) program from 1975 to 2016. Out of the 8,471,051 patients extracted from SEER, 4,698 died from peptic ulcer, with a mortality rate of 9.08/100,000 person-years. Meanwhile, the mortality rate in the general population was 5.09/100,000 person-years, giving a standardized mortality ratio (SMR) of 1.78 (95% confidence interval, 1.73–1.84). Patients who are female, of other race, unmarried, and with distant tumor stage have greater SMRs. A higher SMR was associated with a younger age at diagnosis. Among those aged < 40 years at diagnosis, the plurality of fatal peptic ulcers occurred in patients with leukemia and lymphoma, while in patients aged > 40 years, the majority occurred in those with prostate, breast, colorectum, and lung cancer. Patients with upper digestive system malignancies had the highest SMRs and hazard ratios (HRs), which could be ascribed to radiotherapy-induced damage to the gastroduodenum. The risk declined rapidly one year after diagnosis. However, the SMRs in the upper digestive system cancer survivors increased significantly over ten years after diagnosis. Upper digestive system cancers adjacent to the gastroduodenum were associated with higher SMRs and HRs compared with other types of cancer, possibly contributing partially to the damage caused by radiotherapy on the radiosensitive gastroduodenum.
Observation of a giant nonlinear wave-packet on the surface of the ocean
Authors: Onorato Miguel , Cavaleri Luigi , Randoux Stephane , Suret Pierre , Ruiz Maria Isabel , de Alfonso Marta , Benetazzo Alvise
Published: December 2021

In many physical systems such as ocean waves, nonlinear optics, plasma physics etc., extreme events and rare fluctuations of a wave field have been widely observed and discussed. In the field of oceanography and naval architecture, their understanding is fundamental for a correct design of platforms and ships, and for performing safe operations at sea. Here, we report a measurement of an impressive and unique wave packet recorded in the Bay of Biscay in the North-East of the Atlantic Ocean. An analysis of the spatial extension of the packet that includes three large waves reveals that it extents for more than 1 km, with individual crests moving faster than 100 km/h. The central and largest wave in the packet was 27.8 m high in a sea with significant wave height of 11 m. A detailed analysis of the data using the nonlinear Fourier analysis reveals that the wave packet is characterized by a non trivial nonlinear content. This observation opens a new paradigm which requires new understanding of the dynamics of ocean waves and, more in general, of nonlinear and dispersive waves.
Evaluation of a 5-HT2B receptor agonist in a murine model of amyotrophic lateral sclerosis
Authors: Arnoux Alizée , Ayme-Dietrich Estelle , Dieterle Stéphane , Goy Marc-Antoine , Schann Stephan , Frauli Mélanie , Monassier Laurent , Dupuis Luc
Published: December 2021

Degeneration of brainstem serotonin neurons has been demonstrated in ALS patients and mouse models and was found responsible for the development of spasticity. Consistent with involvement of central serotonin pathways, 5-HT2B receptor (5-HT2BR) was upregulated in microglia of ALS mice. Its deletion worsened disease outcome in the Sod1G86R mouse model and led to microglial degeneration. In ALS patients, a polymorphism in HTR2B gene leading to higher receptor expression in CNS, was associated with increased survival in patients as well as prevention of microglial degeneration. Thus, the aim of our study was to determine the effect of a 5-HT2BR agonist : BW723C86 (BW), in the Sod1G86R mouse model. Despite good pharmacokinetic and pharmacological profiles, BW did not ameliorate disease outcome or motor neuron degeneration in a fast progressing mouse model of ALS despite evidence of modulation of microglial gene expression.
Tailoring interfacial effect in multilayers with Dzyaloshinskii–Moriya interaction by helium ion irradiation
Authors: Sud A. , Tacchi S. , Sagkovits D. , Barton C. , Sall M. , Diez L. H. , Stylianidis E. , Smith N. , Wright L. , Zhang S. , Zhang X. , Ravelosona D. , Carlotti G. , Kurebayashi H. , Kazakova O. , Cubukcu M.
Published: December 2021

We show a method to control magnetic interfacial effects in multilayers with Dzyaloshinskii–Moriya interaction (DMI) using helium (He$$^{+}$$

+

) ion irradiation. We report results from SQUID magnetometry, ferromagnetic resonance as well as Brillouin light scattering results on multilayers with DMI as a function of irradiation fluence to study the effect of irradiation on the magnetic properties of the multilayers. Our results show clear evidence of the He$$^{+}$$

+

irradiation effects on the magnetic properties which is consistent with interface modification due to the effects of the He$$^{+}$$

+

irradiation. This external degree of freedom offers promising perspectives to further improve the control of magnetic skyrmions in multilayers, that could push them towards integration in future technologies.
Development of a sticker sealed microfluidic device for in situ analytical measurements using synchrotron radiation
Authors: Neckel Itamar T. , de Castro Lucas F. , Callefo Flavia , Teixeira Verônica C. , Gobbi Angelo L. , Piazzetta Maria H. , de Oliveira Ricardo A. G. , Lima Renato S. , Vicente Rafael A. , Galante Douglas , Tolentino Helio C. N.
Published: December 2021

Shedding synchrotron light on microfluidic systems, exploring several contrasts in situ/operando at the nanoscale, like X-ray fluorescence, diffraction, luminescence, and absorption, has the potential to reveal new properties and functionalities of materials across diverse areas, such as green energy, photonics, and nanomedicine. In this work, we present the micro-fabrication and characterization of a multifunctional polyester/glass sealed microfluidic device well-suited to combine with analytical X-ray techniques. The device consists of smooth microchannels patterned on glass, where three gold electrodes are deposited into the channels to serve in situ electrochemistry analysis or standard electrical measurements. It has been efficiently sealed through an ultraviolet-sensitive sticker-like layer based on a polyester film, and The burst pressure determined by pumping water through the microchannel(up to 0.22 MPa). Overall, the device has demonstrated exquisite chemical resistance to organic solvents, and its efficiency in the presence of biological samples (proteins) is remarkable. The device potentialities, and its high transparency to X-rays, have been demonstrated by taking advantage of the X-ray nanoprobe Carnaúba/Sirius/LNLS, by obtaining 2D X-ray nanofluorescence maps on the microchannel filled with water and after an electrochemical nucleation reaction. To wrap up, the microfluidic device characterized here has the potential to be employed in standard laboratory experiments as well as in in situ and in vivo analytical experiments using a wide electromagnetic window, from infrared to X-rays, which could serve experiments in many branches of science.
All-fiber ultrafast amplifier at 1.9 μm based on thulium-doped normal dispersion fiber and LMA fiber compressor
Authors: Voropaev Vasilii , Batov Daniil , Voronets Andrey , Vlasov Dmitrii , Jafari Rana , Donodin Aleksandr , Tarabrin Mikhail , Trebino Rick , Lazarev Vladimir
Published: December 2021

The duration reduction and the peak power increase of ultrashort pulses generated by all-fiber sources at a wavelength of $$1.9\,\upmu \hbox {m}$$

1.9

μ
m

are urgent tasks. Finding an effective and easy way to improve these characteristics of ultrafast lasers can allow a broad implementation of wideband coherent supercontinuum sources in the mid-IR range required for various applications. As an alternative approach to sub-100 fs pulse generation, we present an ultrafast all-fiber amplifier based on a normal-dispersion germanosilicate thulium-doped active fiber and a large-mode-area silica-fiber compressor. The output pulses have the following characteristics: the central wavelength of $$1.9\,\upmu \hbox {m}$$

1.9

μ
m

, the repetition rate of 23.8 MHz, the energy per pulse period of 25 nJ, the average power of 600 mW, and a random output polarization. The pulse intensity and phase profiles were measured via the second-harmonic-generation frequency-resolved optical gating technique for a linearly polarized pulse. The linearly polarized pulse has a duration of 71 fs and a peak power of 128.7 kW. The maximum estimated peak power for all polarizations is 220 kW. The dynamics of ultrashort-pulse propagation in the amplifier were analyzed using numerical simulations.
Decoding accelerometry for classification and prediction of critically ill patients with severe brain injury
Authors: Bhattacharyay Shubhayu , Rattray John , Wang Matthew , Dziedzic Peter H. , Calvillo Eusebia , Kim Han B. , Joshi Eshan , Kudela Pawel , Etienne-Cummings Ralph , Stevens Robert D.
Published: December 2021

Our goal is to explore quantitative motor features in critically ill patients with severe brain injury (SBI). We hypothesized that computational decoding of these features would yield information on underlying neurological states and outcomes. Using wearable microsensors placed on all extremities, we recorded a median 24.1 (IQR: 22.8–25.1) hours of high-frequency accelerometry data per patient from a prospective cohort (n = 69) admitted to the ICU with SBI. Models were trained using time-, frequency-, and wavelet-domain features and levels of responsiveness and outcome as labels. The two primary tasks were detection of levels of responsiveness, assessed by motor sub-score of the Glasgow Coma Scale (GCSm), and prediction of functional outcome at discharge, measured with the Glasgow Outcome Scale–Extended (GOSE). Detection models achieved significant (AUC: 0.70 [95% CI: 0.53–0.85]) and consistent (observation windows: 12 min–9 h) discrimination of SBI patients capable of purposeful movement (GCSm > 4). Prediction models accurately discriminated patients of upper moderate disability or better (GOSE > 5) with 2–6 h of observation (AUC: 0.82 [95% CI: 0.75–0.90]). Results suggest that time series analysis of motor activity yields clinically relevant insights on underlying functional states and short-term outcomes in patients with SBI.