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Abstract Lipoprotein (a) [Lp(a)] is suspected to have antifibrinolytic effects, however, its relevance for the severity of venous thromboembolic events remains unclear. We studied the association of Lp(a) levels with thrombus load in pulmonary embolism (PE). 90 patients (40% female, median age 70 [56–79] years) at our tertiary care hospital with a diagnosis of acute PE, available Lp(a) levels and CT pulmonary angiography (CT-PA) performed between April 2017 and December 2019 were included. All CT-PA scans were reanalyzed and thrombus load was determined via Qanadli CT obstruction index (CTOI) and most proximal thrombus location. Median Lp(a) levels were 11.4 [9.3–29.1] mg/dL, median D-dimer levels were 4.6 [2.1–9.8] mg/L, median CTOI was 23 [8–50], central PE was present in 27 (30%) patients. Lp(a) did not correlate with CTOI (r = 0.02, p = 0.922) and was not associated with thrombus location (p = 0.369). CTOI significantly correlated with D-dimer (r = 0.43, p

Abstract PCR is tolerant to single nucleotide mismatches. Therefore, genotyping of point mutations by PCR requires special conditions for the amplification of allele-specific PCR fragments. MS-PCR (mutagenically separated PCR) is an improved version of ARMS (amplification refractory mutation system) in which additional nucleotide mismatches near the mutation site are used to separate the wt fragments from the mutant fragments in a single-tube PCR. In the originally described procedure, the resulting fragments are resolved on agarose gels according to differences in size introduced by different lengths of the allele-specific primers. In order to evaluate the PCR fragments by melting curve analysis, we enlarged the difference in the melting temperatures of the fragments of the two alleles by increasing the GC content of the longer allele-specific primer resulting in a higher melting temperature of the corresponding fragment. Using the murine retinal degeneration mutations rd1 and rd8 as an example, we show that such primers result in an easy to handle genotyping procedure: qPCR followed by melting curve analysis. In summary, MS-PCR is a simple and easy-to-use method for detecting single nucleotide variants.

Abstract Recent studies show declining trends in hysterectomy rates in several countries. The objective of this study was to analyse hysterectomy time trends in Germany over a fifteen-year period using an age-period-cohort approach. Using an ecological study design, inpatient data from Diagnoses Related Group on hysterectomies by subtype performed in Germany from 2005 to 2019 were retrieved from the German Statistical Office. Descriptive time trends and age-period-cohort analyses were then performed. A total of 1,974,836 hysterectomies were performed over the study period. The absolute number of hysterectomies reduced progressively from 155,680 (365 procedures/100,000 women) in 2005 to 101,046 (257 procedures/100,000 women) in 2019. Total and radical hysterectomy decreased by 49.7% and 44.2%, respectively, whilst subtotal hysterectomy increased five-fold. The age-period-cohort analysis revealed highest hysterectomy rates in women aged 45–49 for total and subtotal hysterectomy with 608.63 procedures/100,000 women (95% CI 565.70, 654.82) and 151.30 procedures/100,000 women (95% CI 138.38, 165.44) respectively. Radical hysterectomy peaked later at 65–69 years with a rate of 40.63 procedures/100,000 women (95% CI 38.84, 42.52). The risk of undergoing total or radical hysterectomy decreased over the study period but increased for subtotal hysterectomy. Although, overall hysterectomy rates have declined, subtotal hysterectomy rates have increased; reflecting changes in clinical practice largely influenced by the availability of uterus-sparing options, evolving guidelines and introduction of newer surgical approaches.

Abstract Alterations in the structure and composition of Bruch’s membrane (BrM) and loss of retinal pigment epithelial (RPE) cells are associated with various ocular diseases, notably age-related macular degeneration (AMD) as well as several inherited retinal diseases (IRDs). We explored the influence of stiffness as a major BrM characteristic on the RPE transcriptome and morphology. ARPE-19 cells were plated on soft ( $$E={30}\,\hbox {kPa}$$ E = 30 kPa ) or stiff ( $$E={80}\,\hbox {kPa}$$ E = 80 kPa ) polyacrylamide gels (PA gels) or standard tissue culture plastic (TCP). Next-generation sequencing (NGS) data on differentially expressed small RNAs (sRNAs) and messenger RNAs (mRNAs) were validated by qPCR, immunofluorescence or western blotting. The microRNA (miRNA) fraction of sRNAs grew with substrate stiffness and distinct miRNAs such as miR-204 or miR-222 were differentially expressed. mRNA targets of differentially expressed miRNAs were stably expressed, suggesting a homeostatic effect of miRNAs. mRNA transcription patterns were substrate stiffness-dependent, including components of Wnt/beta-catenin signaling, Microphthalmia-Associated Transcription Factor (MITF) and Dicer. These findings highlight the relevance of mechanical properties of the extracellular matrix (ECM) in cell culture experiments, especially those focusing on ECM-related diseases, such as AMD.

Abstract The interplay between spin-orbit interaction and magnetic order is one of the most active research fields in condensed matter physics and drives the search for materials with novel, and tunable, magnetic and spin properties. Here we report on a variety of unique and unexpected observations in thin multiferroic Ge1−x Mn x Te films. The ferrimagnetic order parameter in this ferroelectric semiconductor is found to switch direction under magnetostochastic resonance with current pulses many orders of magnitude lower as for typical spin-orbit torque systems. Upon a switching event, the magnetic order spreads coherently and collectively over macroscopic distances through a correlated spin-glass state. Utilizing these observations, we apply a novel methodology to controllably harness this stochastic magnetization dynamics.

Abstract Two-dimensional (2D) materials are a key target for many applications in the modern day. Self-assembly is one approach that can bring us closer to this goal, which usually relies upon strong, directional interactions instead of covalent bonds. Control over less directional forces is more challenging and usually does not result in as well-defined materials. Explicitly incorporating topography into the design as a guiding effect to enhance the interacting forces can help to form highly ordered structures. Herein, we show the process of shape-assisted self-assembly to be consistent across a range of derivatives that highlights the restriction of rotational motion and is verified using a diverse combination of solid state analyses. A molecular curvature governed angle distribution nurtures monomers into loose columns that then arrange to form 2D structures with long-range order observed in both crystalline and soft materials. These features strengthen the idea that shape becomes an important design principle leading towards precise molecular self-assembly and the inception of new materials.

BackgroundMultiple risk factors contribute jointly to the development and progression of cardiometabolic diseases. Therefore, joint longitudinal trajectories of multiple risk factors might represent different degrees of cardiometabolic risk.MethodsWe analyzed population-based data comprising three examinations (Exam 1: 1999-2001, Exam 2: 2006-2008, Exam 3: 2013-2014) of 976 male and 1004 female participants of the KORA cohort (Southern Germany). Participants were followed up for cardiometabolic diseases, including cardiovascular mortality, myocardial infarction and stroke, or a diagnosis of type 2 diabetes, until 2016. Longitudinal multivariate k-means clustering identified sex-specific trajectory clusters based on nine cardiometabolic risk factors (age, systolic and diastolic blood pressure, body-mass-index, waist circumference, Hemoglobin-A1c, total cholesterol, high- and low-density lipoprotein cholesterol). Associations between clusters and cardiometabolic events were assessed by logistic regression models.ResultsWe identified three trajectory clusters for men and women, respectively. Trajectory clusters reflected a distinct distribution of cardiometabolic risk burden and were associated with prevalent cardiometabolic disease at Exam 3 (men: odds ratio (OR)ClusterII = 2.0, 95% confidence interval: (0.9-4.5); ORClusterIII = 10.5 (4.8-22.9); women: ORClusterII = 1.7 (0.6-4.7); ORClusterIII = 5.8 (2.6-12.9)). Trajectory clusters were furthermore associated with incident cardiometabolic cases after Exam 3 (men: ORClusterII = 3.5 (1.1-15.6); ORClusterIII = 7.5 (2.4-32.7); women: ORClusterII = 5.0 (1.1-34.1); ORClusterIII = 8.0 (2.2-51.7)). Associations remained significant after adjusting for a single time point cardiovascular risk score (Framingham).ConclusionsOn a population-based level, distinct longitudinal risk profiles over a 14-year time period are differentially associated with cardiometabolic events. Our results suggest that longitudinal data may provide additional information beyond single time-point measures. Their inclusion in cardiometabolic risk assessment might improve early identification of individuals at risk.

The ferroelectric material α-GeTe(111) is an excellent playground for spin-to charge conversion due to its strong Rashba coupling. Here, the authors reveal an ultrafast modulation of its Rashba coupling on the femtosecond timescale.

In this work, we present the preliminary results of radar observations of Near-Earth Objects (NEOs) carried out by European radio telescopes in the framework of the European Space Agency (ESA) project “NEO observation concepts for radar systems”, aimed at deriving the functional requirements of a planetary radar system, evaluating the available European assets to perform NEO radar observations, and carrying out test radar campaigns. In the first part of the project, we executed the performance analysis of a possible European planetary radar system. Instrumental features, as much as issues like the impact of weather conditions on signal propagation at different radio frequencies, were considered. This paper focused on the test campaigns, performed in the years 2021–2022 in collaboration with the Jet Propulsion Laboratory (JPL), which led to the observation of several asteroids including 2021 AF8, (4660) Nereus, and 2005 LW3, which allowed us to derive astrometric measurements, as well as to measure physical properties, such as rotation periods, and observe how one of the targets is actually a binary asteroid. The obtained results demonstrated that European radio astronomical dishes, although employed only as receivers (in bistatic or multistatic configurations) and for a limited amount of time, are able to provide a significant contribution to the constitution of a European network to increase the opportunities for NEO monitoring and studies, if a transmitting antenna—equipped with a suitable high-power transmitter—were made available.

The snow surrounding research facilities and shore tourist-landing sites in Antarctica was found to be darker than elsewhere in the continent, which suggests that local emissions of black carbon are accelerating seasonal snowmelt in impacted regions.

Abstract Attributable to the Montreal Protocol, the most successful environmental treaty ever, human-made ozone-depleting substances are declining and the stratospheric Antarctic ozone layer is recovering. However, the Antarctic ozone hole continues to occur every year, with the severity of ozone loss strongly modulated by meteorological conditions. In late November and early December 2020, we measured at the northern tip of the Antarctic Peninsula the highest ultraviolet (UV) irradiances recorded in the Antarctic continent in more than two decades. On Dec. 2nd, the noon-time UV index on King George Island peaked at 14.3, very close to the largest UV index ever recorded in the continent. On Dec. 3rd, the erythemal daily dose at the same site was among the highest on Earth, only comparable to those recorded at high altitude sites in the Atacama Desert, near the Tropic of Capricorn. Here we show that, despite the Antarctic ozone recovery observed in early spring, the conditions that favor these extreme surface UV events persist in late spring, when the biologically effective UV radiation is more consequential. These conditions include long-lasting ozone holes (attributable to the polar vortex dynamics) that often bring ozone-depleted air over the Antarctic Peninsula in late spring. The fact that these conditions have been occurring at about the same frequency during the last two decades explains the persistence of extreme surface UV events in Antarctica.

With the advances in technology and data science, machine learning (ML) is being rapidly adopted by the health care sector. However, there is a lack of literature addressing the health conditions targeted by the ML prediction models within primary health care (PHC) to date. To fill this gap in knowledge, we conducted a systematic review following the PRISMA guidelines to identify health conditions targeted by ML in PHC. We searched the Cochrane Library, Web of Science, PubMed, Elsevier, BioRxiv, Association of Computing Machinery (ACM), and IEEE Xplore databases for studies published from January 1990 to January 2022. We included primary studies addressing ML diagnostic or prognostic predictive models that were supplied completely or partially by real-world PHC data. Studies selection, data extraction, and risk of bias assessment using the prediction model study risk of bias assessment tool were performed by two investigators. Health conditions were categorized according to international classification of diseases (ICD-10). Extracted data were analyzed quantitatively. We identified 106 studies investigating 42 health conditions. These studies included 207 ML prediction models supplied by the PHC data of 24.2 million participants from 19 countries. We found that 92.4% of the studies were retrospective and 77.3% of the studies reported diagnostic predictive ML models. A majority (76.4%) of all the studies were for models' development without conducting external validation. Risk of bias assessment revealed that 90.8% of the studies were of high or unclear risk of bias. The most frequently reported health conditions were diabetes mellitus (19.8%) and Alzheimer's disease (11.3%). Our study provides a summary on the presently available ML prediction models within PHC. We draw the attention of digital health policy makers, ML models developer, and health care professionals for more future interdisciplinary research collaboration in this regard.

The angular distribution of the sky radiance determines the energy generation of solar power technologies as well as the ultraviolet (UV) doses delivered to the biosphere. The sky-diffuse radiance distribution depends on the wavelength, the solar elevation, and the atmospheric conditions. Here, we report on ground-based measurements of the all-sky radiance at three sites in the Southern Hemisphere across a transect of about 5,000 km: Santiago (33°S, a mid-latitude city of 6 million inhabitants with endemic poor air quality), King George Island (62°S, at the northern tip of the Antarctic Peninsula, one of the cloudiest regions on Earth), and Union Glacier (79°S, a snow-covered glacier in the vast interior of Western Antarctica). The sites were strategically selected for studying the influence of urban aerosols, frequent and thick clouds, and extremely high albedo on the sky-diffuse radiance distribution. Our results show that, due to changing site-specific atmospheric conditions, the characterization of the weather-driven sky radiance distribution may require ground-based measurements.

Abstract Light pollution is an environmental stressor of global extent that is growing exponentially in area and intensity. Artificial skyglow, a form of light pollution with large range, is hypothesized to have environmental impact at ecosystem level. However, testing the impact of skyglow at large scales and in a controlled fashion under in situ conditions has remained elusive so far. Here we present the first experimental setup to mimic skyglow at ecosystem level outdoors in an aquatic environment. Spatially diffuse and homogeneous surface illumination that is adjustable between 0.01 and 10 lx, resembling rural to urban skyglow levels, was achieved with white light-emitting diodes at a large-scale lake enclosure facility. The illumination system was enabled by optical modeling with Monte-Carlo raytracing and validated by measurements. Our method can be adapted to other outdoor and indoor skyglow experiments, urgently needed to understand the impact of skyglow on ecosystems.

Abstract Surface albedo is an important forcing parameter that drives the radiative energy budget as it determines the fraction of the downwelling solar irradiance that the surface reflects. Here we report on ground-based measurements of the spectral albedo (350–2200 nm) carried out at 20 sites across a North–South transect of approximately 1300 km in the Atacama Desert, from latitude 18° S to latitude 30° S. These spectral measurements were used to evaluate remote sensing estimates of the albedo derived from the Moderate Resolution Imaging Spectroradiometer (MODIS). We found that the relative mean bias error (RMBE) of MODIS-derived estimates was within ± 5% of ground-based measurements in most of the Atacama Desert (18–27° S). Although the correlation between MODIS-derived estimates and ground-based measurements remained relatively high (R= 0.94), RMBE values were slightly larger in the southernmost part of the desert (27–30° S). Both MODIS-derived data and ground-based measurements show that the albedo at some bright spots in the Atacama Desert may be high enough (up to 0.25 in visible range) for considerably boosting the performance of bifacial photovoltaic technologies (6–12%).

Abstract Summer temperatures are often above freezing along the Antarctic coastline, which makes ice shelves and coastal snowpacks vulnerable to warming events (understood as periods of consecutive days with warmer than usual conditions). Here, we project changes in the frequency, duration and amplitude of summertime warming events expected until end of century according to two emission scenarios. By using both global and regional climate models, we found that these events are expected to be more frequent and last longer, continent-wide. By end of century, the number of warming events is projected to double in most of West Antarctica and to triple in the vast interior of East Antarctica, even under a moderate-emission scenario. We also found that the expected rise of warming events in coastal areas surrounding the continent will likely lead to enhanced surface melt, which may pose a risk for the future stability of several Antarctic ice shelves.

Abstract Quantum well (QW) heterostructures have been extensively used for the realization of a wide range of optical and electronic devices. Exploiting their potential for further improvement and development requires a fundamental understanding of their electronic structure. So far, the most commonly used experimental techniques for this purpose have been all-optical spectroscopy methods that, however, are generally averaging in momentum space. Additional information can be gained by angle-resolved photoelectron spectroscopy (ARPES), which measures the electronic structure with momentum resolution. Here we report on the use of extremely low-energy ARPES (photon energy ~ 7 eV) to increase depth sensitivity and access buried QW states, located at 3 nm and 6 nm below the surface of cubic-GaN/AlN and GaAs/AlGaAs heterostructures, respectively. We find that the QW states in cubic-GaN/AlN can indeed be observed, but not their energy dispersion, because of the high surface roughness. The GaAs/AlGaAs QW states, on the other hand, are buried too deep to be detected by extremely low-energy ARPES. Since the sample surface is much flatter, the ARPES spectra of the GaAs/AlGaAs show distinct features in momentum space, which can be reconducted to the band structure of the topmost surface layer of the QW structure. Our results provide important information about the samples’ properties required to perform extremely low-energy ARPES experiments on electronic states buried in semiconductor heterostructures.

Abstract Despite the reported low expression of the primary SARS-CoV-2 receptor ACE2 in distinct ocular tissues, some clinical evidence suggests that SARS-CoV-2 can infect the eye. In this study, we explored potential entry sites for SARS-CoV-2 by viral S protein histochemistry on various ocular tissues and compared the staining patterns with RNA and protein expression of TMPRSS2 and ACE2. Potential viral entry sites were investigated by histochemistry using tagged recombinant viral S protein on 52 ocular tissue samples including specimens of the cornea, conjunctiva, lid margin, lacrimal gland tissue, retina, choroid, and RPE. In addition, ACE2 and TMPRSS2 immunohistochemistry were performed on the same ocular tissue, each with distinct antibodies binding to different epitopes. Lung tissue samples were used as positive controls. Finally, bulk RNA sequencing (RNA-Seq) was used to determine the expression of ACE2 and its auxiliary factors in the tissues mentioned above. S protein histochemistry revealed a positive staining in lung tissue but absent staining in the cornea, the conjunctiva, eye lid samples, the lacrimal glands, the retina and the optic nerve which was supported by hardly any immunoreactivity for ACE2 and TMPRSS2 and scarce ACE2 and TMPRSS2 RNA expression. Negligible staining with antibodies targeting ACE2 or TMPRSS2 was seen in the main and accessory lacrimal glands. In contrast, ocular staining (S protein, ACE2, TMPRSS2) was distinctly present in pigmented cells of the RPE and choroid, as well as in the ciliary body and the iris stroma. S protein histochemistry revealed hardly any SARS-CoV-2 entry sites in all ocular tissues examined. Similarly, no significant ACE2 or TMPRSS2 expression was found in extra- and intraocular tissue. While this study suggest a rather low risk of ocular infection with SARS-CoV-2, it should be noted, that potential viral entry sites may increase in response to inflammation or in certain disease states.

Our understanding on the humoral immunity induced by SARS-CoV-2 is still lacking. Here the authors analyze B cell responses at the single cell level to find that, in severe COVID-19 patients, plasmablasts shift from IFN to TGFβ instruction to produce IgA antibodies that are not specific to dominant SARS-CoV-2 antigens.

Abstract Allogenic transplants of the cornea are prone to rejection, especially in repetitive transplantation and in scarred or highly vascularized recipient sites. Patients with these ailments would particularly benefit from the possibility to use non-immunogenic decellularized tissue scaffolds for transplantation, which may be repopulated by host cells in situ or in vitro. So, the aim of this study was to develop a fast and efficient decellularization method for creating a human corneal extracellular matrix scaffold suitable for repopulation with human cells from the corneal limbus. To decellularize human donor corneas, sodium deoxycholate, deoxyribonuclease I, and dextran were assessed to remove cells and nuclei and to control tissue swelling, respectively. We evaluated the decellularization effects on the ultrastructure, optical, mechanical, and biological properties of the human cornea. Scaffold recellularization was studied using primary human limbal epithelial cells, stromal cells, and melanocytes in vitro and a lamellar transplantation approach ex vivo. Our data strongly suggest that this approach allowed the effective removal of cellular and nuclear material in a very short period of time while preserving extracellular matrix proteins, glycosaminoglycans, tissue structure, and optical transmission properties. In vitro recellularization demonstrated good biocompatibility of the decellularized human cornea and ex vivo transplantation revealed complete epithelialization and stromal repopulation from the host tissue. Thus, the generated decellularized human corneal scaffold could be a promising biological material for anterior corneal reconstruction in the treatment of corneal defects.

Abstract Predicting radiative forcing due to Antarctic stratospheric ozone recovery requires detecting changes in the ozone vertical distribution. In this endeavor, the Limb Profiler of the Ozone Mapping and Profiler Suite (OMPS-LP), aboard the Suomi NPP satellite, has played a key role providing ozone profiles over Antarctica since 2011. Here, we compare ozone profiles derived from OMPS-LP data (version 2.5 algorithm) with balloon-borne ozonesondes launched from 8 Antarctic stations over the period 2012–2020. Comparisons focus on the layer from 12.5 to 27.5 km and include ozone profiles retrieved during the Sudden Stratospheric Warming (SSW) event registered in Spring 2019. We found that, over the period December-January–February-March, the root mean square error (RMSE) tends to be larger (about 20%) in the lower stratosphere (12.5–17.5 km) and smaller (about 10%) within higher layers (17.5–27.5 km). During the ozone hole season (September–October–November), RMSE values rise up to 40% within the layer from 12.5 to 22 km. Nevertheless, relative to balloon-borne measurements, the mean bias error of OMPS-derived Antarctic ozone profiles is generally lower than 0.3 ppmv, regardless of the season.

Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

BackgroundWe investigated the uptake of opportunistic cervical cancer screening (CCS) and other risk factors and their association with cervical cancer in Germany in a case-control study.Methods and findingsWe recruited incident cases of cervical cancer (ICD-10 C53) diagnosed between 2012 and 2016 and matched with three population-based controls, based on age and region of residence. Cases and controls reported their CCS participation during the past ten years (frequent: every three years; no or infrequent: less than every three years) and other relevant variables. We fitted conditional logistic regression models, reporting odds ratios (OR) and 95% confidence intervals (95% CI). We report overall and stratified analyses by histologic group (squamous cell-SCC, and adenocarcinoma-AC), T category (T1 and T2+), and age (ConclusionAlthough women who frequently attended CCS were less likely to develop cervical cancer, especially larger tumours, the high proportion of cases who had been frequently screened prior to diagnosis underscores the need to investigate the quality of cytology and treatment of precancerous lesions in Germany.

The Andean snowpack is an important source of water for many communities. As other snow-covered regions around the world, the Andes are sensitive to black carbon (BC) deposition from fossil fuel and biomass combustion. BC darkens the snow surface, reduces the albedo, and accelerates melting. Here, we report on measurements of the BC content conducted by using the meltwater filtration (MF) technique in snow samples collected across a transect of more than 2500 km from the mid-latitude Andes to the southern tip of South America. Addressing some of the key knowledge gaps regarding the effects of the BC deposition on the Andean snow, we identified BC-impacted areas, assessed the BC-related albedo reduction, and estimated the resulting snow losses. We found that BC concentrations in our samples generally ranged from 2 to 15 ng g ^−1 , except for the nearly BC-free Patagonian Icefields and for the BC-impacted sites nearby Santiago (a metropolis of 6 million inhabitants). We estimate that the seasonal snowpack shrinking attributable to the BC deposition ranges from 4 mm water equivalent (w.e.) at relatively clean sites in Patagonia to 241 mm w.e. at heavily impacted sites close to Santiago.

Two subclasses of ligand-gated ion channels (ASIC3 and P2X3) are both present at sensory neurons and might be therefore subject to receptor crosstalk. Here authors use electrophysiology, biochemistry and co-immunoprecipitation to show that the two ion channels interact and affect P2X3 currents.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21276-3

Transitions between topological phases of matter protected by different symmetries remain rare. Here, Mandal et al. report a quantum phase transition from a topological crystalline insulator to a Z2 topological insulator by doping Bi into Pb1-x Sn x Se (111) thin films.

Abstract Although intraocular pressure is the main the risk factor for the development of glaucoma, other risk factors such as vascular dysfunction might play an additional pathogenic role. Hypertriglyceridemia, which may lead to vascular dysfunction, has been implicated in the development of glaucoma. The objective of this meta-analysis was to investigate the association of triglyceride levels with the risk of glaucoma in case-control studies. Seventeen case-control studies were included investigating the difference in triglyceride levels in patients with glaucoma (N = 1 391) compared to subjects without glaucoma (N = 25 575). In random effects meta-analysis, the pooled mean triglyceride level across all studies and patients with and without glaucoma was 132.9 mg/dL (95%CI: 124.0–141.7). Patients with glaucoma had significantly higher mean triglyceride levels than patients without glaucoma (absolute difference = 14.2 mg/dL, 95%CI: 5.8–22.5, p

Abstract Cardiovascular risk assessment in patients with diabetes relies on traditional risk factors. However, numerous novel biomarkers have been found to be independent predictors of cardiovascular disease, which might significantly improve risk prediction in diabetic patients. We aimed to improve prediction of cardiovascular risk in diabetic patients by investigating 135 evolving biomarkers. Based on selected biomarkers a clinically applicable prediction algorithm for long-term cardiovascular mortality was designed. We prospectively enrolled 864 diabetic patients of the LUdwigshafen RIsk and Cardiovascular health (LURIC) study with a median follow-up of 9.6 years. Independent risk factors were selected using bootstrapping based on a Cox regression analysis. The following seven variables were selected for the final multivariate model: NT-proBNP, age, male sex, renin, diabetes duration, Lp-PLA2 and 25-OH vitamin D3. The risk score based on the aforementioned variables demonstrated an excellent discriminatory power for 10-year cardiovascular survival with a C-statistic of 0.76 (P

Genome-wide association studies (GWAS) have become a key tool to discover genetic markers for complex traits; however, environmental factors that interact with genes are rarely considered. Here, the authors conduct a GWAS of obesity traits, and find that smoking may alter genetic susceptibilities.

Heat-assisted magnetic recording (HAMR) is often considered the next major step in the storage industry: it is predicted to increase the storage capacity, the read/write speed and the data lifetime of future hard disk drives. However, despite more than a decade of development work, the reliability is still a prime concern. Featuring an inherently fragile surface-plasmon resonator as a highly localized heat source, as part of a near-field transducer (NFT), the current industry concepts still fail to deliver drives with sufficient lifetime. This study presents a method to aid conventional NFT-designs by additional grazing-incidence laser illumination, which may open an alternative route to high-durability HAMR. Magnetic switching is demonstrated on consumer-grade CoCrPt perpendicular magnetic recording media using a green and a near-infrared diode laser. Sub-500 nm magnetic features are written in the absence of a NFT in a moderate bias field of only μ0H = 0.3 T with individual laser pulses of 40 mW power and 50 ns duration with a laser spot size of 3 μm (short axis) at the sample surface – six times larger than the magnetic features. Herein, the presence of a nanoscopic object, i.e., the tip of an atomic force microscope in the focus of the laser at the sample surface, has no impact on the recorded magnetic features – thus suggesting full compatibility with NFT-HAMR.

T cells are crucial players in obesity-mediated adipose tissue inflammation. We hypothesized that osteopontin (OPN), an inflammatory protein with enhanced activity when proteolytically cleaved, affects the number of viable T cells in adipose tissue and assessed inhibition of the interaction between T cells and thrombin and matrix metalloproteinases-cleaved OPN using antibodies and postimmune sera. Gene expression of T cell markers in adipose tissue from wild-type (wt) and Spp1-/- (OPN deficient) mice was analyzed after 16 weeks of high fat diet (HFD) or low fat diet (LFD) feeding. CD3, CD8 and OPN gene expression in omental adipose tissue from individuals with obesity was measured. OPN-T cell interactions were assessed with a fluorescence-based adhesion assay and blocked with antibodies targeting OPN. Comparison of T cell gene expression in adipose tissue from wt and Spp1-/- mice showed that OPN affected the number of T cells while in humans, levels of OPN correlated with T cell markers in omental adipose tissue. The interaction between T cells and cleaved OPN was blocked by postimmune sera following OPN peptide vaccinations and with monoclonal antibodies. In conclusion, levels of OPN affected the number of T cells in obesity and antibodies against cleaved OPN antagonize OPN-T cell interactions.

Chikungunya virus is a mosquito transmitted untreatable emergent pathogen that causes joint pain and fever. Here the authors perform a host genome-wide loss-of-function screen to identify targets for chikungunya antiviral drugs and validate hits using a mouse model of chikungunya infection.

Due to the considerable impact of clouds on the energy balance in the atmosphere and on the earth surface, they are of great importance for various applications in meteorology or remote sensing. An important aspect of the cloud research studies is the detection of cloudy pixels from the processing of satellite images. In this research, we investigated a stereographic method on a new set of Meteosat images, namely the combination of the high resolution visible (HRV) channel of the Meteosat-8 Indian Ocean Data Coverage (IODC) as a stereo pair with the HRV channel of the Meteosat Second Generation (MSG) Meteosat-10 image at 0° E. In addition, an approach based on the outputs from stereo analysis was proposed to detect cloudy pixels. This approach is introduced with a 2D-scatterplot based on the parallax value and the minimum intersection distance. The mentioned scatterplot was applied to determine/detect cloudy pixels in various image subsets with different amounts of cloud cover. Apart from the general advantage of the applied stereography method, which only depends on geometric relationships, the cloud detection results are also improved because: (1) The stereo pair is the HRV bands of the Spinning Enhanced Visible and InfraRed Imager (SEVIRI) sensor, with the highest spatial resolution available from the Meteosat geostationary platform; and (2) the time difference between the image pairs is nearly 5 s, which improves the matching results and also decreases the effect of cloud movements. In order to prove this improvement, the results of this stereo-based approach were compared with three different reflectance-based target detection techniques, including the adaptive coherent estimator (ACE), constrained energy minimization (CEM), and matched filter (MF). The comparison of the receiver operating characteristics (ROC) detection curves and the area under these curves (AUC) showed better detection results with the proposed method. The AUC value was 0.79, 0.90, 0.90, and 0.93 respectively for ACE, CEM, MF, and the proposed stereo-based detection approach. The results of this research shall enable a more realistic modelling of down-welling solar irradiance in the future.

Cocaine- and amphetamine-regulated transcript (CART) is widely expressed in the hypothalamus and an important regulator of energy homeostasis; however, the specific contributions of different CART neuronal populations to this process are not known. Here, we show that depolarization of mouse arcuate nucleus (Arc) CART neurons via DREADD technology decreases energy expenditure and physical activity, while it exerts the opposite effects in CART neurons in the lateral hypothalamus (LHA). Importantly, when stimulating these neuronal populations in the absence of CART, the effects were attenuated. In contrast, while activation of CART neurons in the LHA stimulated feeding in the presence of CART, endogenous CART inhibited food intake in response to Arc CART neuron activation. Taken together, these results demonstrate anorexigenic but anabolic effects of CART upon Arc neuron activation, and orexigenic but catabolic effects upon LHA-neuron activation, highlighting the complex and nuclei-specific functions of CART in controlling feeding and energy homeostasis.

Retinal vein occlusion (RVO) has been investigated in several laser-induced animal models using pigs, rabbits and rats. However, laser-induced RVO has been rarely reported in mice, despite the impressive number of available mutants, ease of handling and cost effectiveness. The aim of this study was to further assess the feasibility of a RVO mouse model for gene expression analysis and its possible use to investigate effects of hypoxia.C57Bl/6J mice were injected with eosin Y for photo-sensitization. Subsequently, large retinal veins were laser-treated in one eye to induce vascular occlusion. Contralateral control eyes received non-occlusive retinal laser treatment sparing large vessels. The animals were followed for up to eight days and assessed by funduscopy, angiography, hypoxyprobe staining, histopathology and gene expression analysis by qPCR and RNA sequencing (RNAseq). Another group of mice was left untreated and studied at a single time point to determine baseline characteristics.Laser-induced RVO persisted in half of the treated veins for three days, and in a third of the veins for the whole observation period of 8 days. Funduscopy revealed large areas of retinal swelling in all laser-treated eyes, irrespective of vascular targeting or occlusion status. Damage of the outer retina, retinal pigment epithelium (RPE), and even choroid and sclera at the laser site was observed in histological sections. Genes associated with inflammation or cell damage were highly up-regulated in all laser-treated eyes as detected by RNAseq and qPCR. Retinal hypoxia was observed by hypoxyprobe staining in all RVO eyes for up to 5 days with a maximal extension at days 2 and 3, but no significant RVO-dependent changes in gene expression were detected for angiogenesis- or hypoxia-related genes.The laser-induced RVO mouse model is characterized by a predominant general inflammatory and tissue damage response, which may obscure distinct hypoxia- and angiogenesis-related effects. A non-occlusive laser treatment control is essential to allow for proper data interpretation and should be mandatory in animal studies of laser-induced RVO to dissect laser-induced tissue damage from vascular occlusion effects.

To study distinct aspects of human monocyte-derived macrophage (MDM) activation by human corneal tissue as a possible initial stage in human corneal allograft rejection.Human monocytes were isolated from peripheral blood mononuclear cells (PBMC) and differentiated into MDM. Human corneas with or without endothelium were fragmented using a standardized protocol. MDM were stimulated with human corneal fragments, corneal fragment supernatant, lipopolysaccharide (LPS) or interferon-gamma (IFNγ), and expression profiles for 34 cytokines were determined in MDM-conditioned media using a Luminex bead-based multiplex assay. Data from clinical aqueous humour samples served for comparison and validation. To assess cell recruitment, immunogenicity of corneal endothelial cells (CEC), monocyte survival and differentiation, we applied transwell migration assays, cell viability assays and fluorescence-activated cell sorting, respectively.Corneal fragments induced MDM to release distinct cytokines into the medium. Media thus conditioned in vitro by stimulated MDM shared cytokine patterns, namely MCP-1, MIP-1α and MIP-1β, with human aqueous humor samples obtained in human corneal allograft rejection. The presence of CEC in tissue fragments used for MDM stimulation attenuated the upregulation of distinct pro-inflammatory chemokines, like MCP-3 and IL-8, reduced the monocyte survival time, and diminished monocyte-to-macrophage differentiation induced by conditioned media. Distinct anti-inflammatory cytokines, like IL-4 and IL-13, were upregulated in the presence of corneal endothelium. Cornea fragment-stimulated MDMs induced recruitment of monocytes from a PBMC pool in a transwell migration model, modulated immune cell viability and promoted further immune cell recruitment and differentiation.Human macrophages respond to allogenic corneal tissue and generate an inflammatory milieu. This can drive further recruitment of immunocompetent cells and modulate cell survival and differentiation of the cells recruited. These observations are consistent with the hypothesis that macrophages play a significant role in the initiation of corneal transplant rejection. Our data also indicate that distinct aspects of early human corneal transplant rejection can be modelled in vitro.

Osteopontin (OPN), a secreted protein involved in inflammatory processes and cancer, induces cell adhesion, migration, and activation of inflammatory pathways in various cell types. Cells bind OPN via integrins at a canonical RGD region in the full length form as well as to a contiguous cryptic site that some have shown is unmasked upon thrombin or matrix metalloproteinase cleavage. Thus, the adhesive capacity of osteopontin is enhanced by proteolytic cleavage that may occur in inflammatory conditions such as obesity, atherosclerosis, rheumatoid arthritis, tumor growth and metastasis. Our aim was to inhibit cellular adhesion to recombinant truncated proteins that correspond to the N-terminal cleavage products of thrombin- or matrix metalloproteinase-cleaved OPN in vitro. We specifically targeted the cryptic integrin binding site with monoclonal antibodies and antisera induced by peptide immunization of mice. HEK 293 cells adhered markedly stronger to truncated OPN proteins than to full length OPN. Without affecting cell binding to the full length form, the raised monoclonal antibodies specifically impeded cellular adhesion to the OPN fragments. Moreover, we show that the peptides used for immunization were able to induce antisera, which impeded adhesion either to all OPN forms, including the full-length form, or selectively to the corresponding truncated recombinant proteins. In conclusion, we developed immunological tools to selectively target functional properties of protease-cleaved OPN forms, which could find applications in treatment and prevention of various inflammatory diseases and cancers.

The European black fly Simulium (Simulium) colombaschense (Scopoli), once responsible for as many as 22,000 livestock deaths per year, is chromosomally mapped, permitting its evolutionary relationships and pest drivers to be inferred. The species is 12 fixed inversions removed from the standard sequence of the subgenus Simulium. Three of these fixed inversions, 38 autosomal polymorphisms, and a complex set of 12 X and 6 Y chromosomes in 29 zygotic combinations uniquely characterize S. colombaschense and reveal 5 cytoforms: 'A' in the Danube watershed, 'B' in Italy's Adige River, 'C' in the Aliakmonas River of Greece, 'D' in the Aoös drainage in Greece, and 'E' in the Belá River of Slovakia. 'C' and 'D' are reproductively isolated from one another, and 'B' is considered a cytotype of 'A,' the probable name bearer of colombaschense. The species status of 'E' cannot be determined without additional collections. Three derived polytene sequences, based on outgroup comparisons, place S. colombaschense in a clade of species composed of the S. jenningsi, S. malyschevi, and S. reptans species groups. Only cytoforms 'A' and 'B' are pests. Within the Simuliidae, pest status is reached through one of two principal pathways, both of which promote the production of large populations of blood-seeking flies: (1) colonization of the world's largest rivers (habitat specialization) or (2) colonization of multiple habitat types (habitat generalization). Evolutionary acquisition of the ability to colonize large rivers by an ancestor of the S. jenningsi-malyschevi-reptans clade set the scene for the pest status of S. colombaschense and other big-river members of the clade. In an ironic twist, the macrogenome of S. colombaschense reveals that the name associated with history's worst simuliid pest represents a complex of species, two or more of which are nonpests potentially vulnerable to loss of their limited habitat.

BACKGROUND:Impaired renal function causes dyslipidemia that contributes to elevated cardiovascular risk in patients with chronic kidney disease (CKD). The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a regulator of the LDL receptor and plasma cholesterol concentrations. Its relationship to kidney function and cardiovascular events in patients with reduced glomerular filtration rate (GFR) has not been explored. METHODS:Lipid parameters including PCSK9 were measured in two independent cohorts. CARE FOR HOMe (Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Forth Homburg evaluation) enrolled 443 patients with reduced GFR (between 90 and 15 ml/min/1.73 m2) referred for nephrological care that were prospectively followed for the occurrence of a composite cardiovascular endpoint. As a replication cohort, PCSK9 was quantitated in 1450 patients with GFR between 90 and 15 ml/min/1.73 m2 enrolled in the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) that were prospectively followed for cardiovascular deaths. RESULTS:PCSK9 concentrations did not correlate with baseline GFR (CARE FOR HOMe: r = -0.034; p = 0.479; LURIC: r = -0.017; p = 0.512). 91 patients in CARE FOR HOMe and 335 patients in LURIC reached an endpoint during a median follow-up of 3.0 [1.8-4.1] years and 10.0 [7.3-10.6] years, respectively. Kaplan-Meier analyses showed that PCSK9 concentrations did not predict cardiovascular events in either cohort [CARE FOR HOMe (p = 0.622); LURIC (p = 0.729)]. Sensitivity analyses according to statin intake yielded similar results. CONCLUSION:In two well characterized independent cohort studies, PCSK9 plasma levels did not correlate with kidney function. Furthermore, PCSK9 plasma concentrations were not associated with cardiovascular events in patients with reduced renal function.

Contemporaneous plant communities may retain a mark of past disturbances in their ecological patterns. However, unraveling the history of disturbance on natural systems at a large scale is often unfeasible, due to the complexity of the factors involved and lack of historical data. Here we aim at demonstrating how comparing observed spatial structure of tree assemblages with that expected in a hypothetical, undisturbed scenario can shed light on how natural European forests are. Borrowing an analytical approach developed in the field of network analysis, we assessed how much the observed ecological patterns of nestedness (i.e. positive co-occurrence), segregation (i.e. negative co-occurrence), and modularity in tree assemblages deviate from randomness, and from those projected by Potential Natural Vegetation (PNV) geobotanical expert assessments. We found clear evidence that European forests are far from a natural condition, showing only moderate signals (especially at higher latitudes) of the ecological spatial structure typical of undisturbed vegetation (i.e. nestedness). Our results highlight how taking into account spatial structure along with diversity can be a fundamental tool to address this problem and assess the degree of naturalness in species assemblages.

A family of putative PECTIN ESTERASE INHIBITOR (PEI) genes, which were detected in the genomic region co-segregating with the resistance gene Rrs2 against scald caused by Rhynchosporium commune in barley, were characterized and tested for their possible involvement in mediating resistance to the pathogen by complementation and overexpression analysis. The sequences of the respective genes were derived from two BAC contigs originating from the susceptible cultivar 'Morex'. For the genes HvPEI2, HvPEI3, HvPEI4 and HvPEI6, specific haplotypes for 18 resistant and 23 susceptible cultivars were detected after PCR-amplification and haplotype-specific CAPS-markers were developed. None of the tested candidate genes HvPEI2, HvPEI3 and HvPEI4 alone conferred a high resistance level in transgenic over-expression plants, though an improvement of the resistance level was observed especially with OE-lines for gene HvPEI4. These results do not confirm but also do not exclude an involvement of the PEI gene family in the response to the pathogen. A candidate for the resistance gene Rrs2 could not be identified yet. It is possible that Rrs2 is a PEI gene or another type of gene which has not been detected in the susceptible cultivar 'Morex' or the full resistance reaction requires the presence of several PEI genes.

The originally published version of this article contained an error in the name of the author Flóra Gölöncsér, which was incorrectly given as Flóra Göröncsér. This has now been corrected in both the PDF and HTML versions of the article.

The regional assessment of global change effects on plant phenology usually relies on local observations that need to be up-scaled. Therefore, methodological difficulties mostly related to data spatial resolution and congruency arise while performing broader-scale evaluations. Geostatiscs could be a useful tool to solve this type of problem, provided that a database with adequate spatial and temporal resolution is available. An assessment of variations in air temperature and plant phenology was carried out at the country level by using two German datasets regarding spring phenological phases of 15 plant species and air temperature. The data were collected from 1961–2002 at 1,279 and 675 sites, respectively. The annual mean air temperature in Germany was found to rise from 8.3°C in the 1961–1990 period to 9.1°C in the 1991–2002 term. The overall 15-species mean for the start of spring was found to be 6 days earlier in the latter period. The geostatistical analysis of the data revealed the suitability of Syringa vulgaris to be used as an indicator species to detect phenological changes in German forests. Moreover, their spatial patterns were found to be related to altitude and latitude. Therefore, geostatistics proved to be a useful tool to overcome some of the methodological problems related to the regional assessments of global change impacts on terrestrial ecosystems.