bluuebunny/crossref_metadata_2025 huggingface dataset:
Spherical contours, IR divergences and the geometry of Feynman parameter integrands at one loop
Authors: Srikant Akshay Yelleshpur
Published: July 2020

Abstract

Spherical contours introduced in [1] translate the concept of “discontinuity across a branch cut” to Feynman parameter space. In this paper, we further explore spherical contours and connect them to the computation of leading IR divergences of 1 loop graphs directly in Feynman parameter space. These spherical contours can be used to develop a Feynman parameter space analog of “Leading Singularities” of loop integrands which allows us to develop a method of determining Feynman parameter integrands without the need to sum over Feynman diagrams in momentum space. Finally, we explore some interesting features of Feynman parameter integrands in $$ \mathcal{N} $$
N
= 4 SYM.
A personalised screening strategy for diabetic retinopathy: a cost-effectiveness perspective
Authors: Emamipour Sajad , van der Heijden Amber A. W. A. , Nijpels Giel , Elders Petra , Beulens Joline W. J. , Postma Maarten J. , van Boven Job F. M. , Feenstra Talitha L.
Published: July 2020

Aims/hypothesis

In this study we examined the cost-effectiveness of three different screening strategies for diabetic retinopathy: using a personalised adaptive model, annual screening (fixed intervals), and the current Dutch guideline (stratified based on previous retinopathy grade).

Methods

For each individual, optimal diabetic retinopathy screening intervals were determined, using a validated risk prediction model. Observational data (1998–2017) from the Hoorn Diabetes Care System cohort of people with type 2 diabetes were used (n = 5514). The missing values of retinopathy grades were imputed using two scenarios of slow and fast sight-threatening retinopathy (STR) progression. By comparing the model-based screening intervals to observed time to develop STR, the number of delayed STR diagnoses was determined. Costs were calculated using the healthcare perspective and the societal perspective. Finally, outcomes and costs were compared for the different screening strategies.

Results

For the fast STR progression scenario, personalised screening resulted in 11.6% more delayed STR diagnoses and €11.4 less costs per patient compared to annual screening from a healthcare perspective. The personalised screening model performed better in terms of timely diagnosis of STR (8.8% less delayed STR diagnosis) but it was slightly more expensive (€1.8 per patient from a healthcare perspective) than the Dutch guideline strategy.

Conclusions/interpretation

The personalised diabetic retinopathy screening model is more cost-effective than the Dutch guideline screening strategy. Although the personalised screening strategy was less effective, in terms of timely diagnosis of STR patients, than annual screening, the number of delayed STR diagnoses is low and the cost saving is considerable. With around one million people with type 2 diabetes in the Netherlands, implementing this personalised model could save €11.4 million per year compared with annual screening, at the cost of 658 delayed STR diagnoses with a maximum delayed time to diagnosis of 48 months.

Graphical abstract
Coverage of the requirements of first and second level stroke unit in Italy
Authors: Bandettini di Poggio Monica , Toni Danilo , Gandolfo Carlo , Paolicelli Damiano , Zini Andrea , Agostoni Elio , Bandini Fabio , Ragno Michele , Altavista Maria Concetta , Bertolotto Antonio , Siciliano Gabriele , Vecchio Michele , Tambasco Nicola , Gambardella Antonio , Manganotti Paolo , Melis Maurizio , Onofrj Marco , De Michele Giuseppe , Reale Nicoletta , Tedeschi Gioacchino , Mancardi GianLuigi
Published: July 2020

Background and aim

In the scientific literature, there is unanimous consensus that hospitalization in stroke unit (SU) is the most important treatment for stroke patients. In this regard, the Act number 70/2015 by the Italian government identified specific skills that contribute to a classification of SU and outlined a “hub and spoke” stroke network. The aim of our study was to check the coverage of requirements of first and second level SU in the national territory and to shed light on any deficit or misdistribution of resources.

Material and methods

In 2019, a survey on the current situation related to stroke care in Italy was carried out by the Italian Society of Neurology (SIN), The Italian Stroke Organization (ISO), and the Association for the Fight against Stroke (A.L.I.Ce).

Results

First level SU was found to be 58 against a requirement, according to the Act 70/2015, of 240. Second level SU was found to be 52 compared with an expected requirement of 60. Neurointerventionists were 280 nationally, with a requirement of 240. A misdistribution of resources within individual regions was often seen.

Conclusions

The survey demonstrated a severe shortage of beds dedicated to cerebrovascular diseases, mainly because of lack of first level SU, especially in central and southern Italy. It also suggests that the current hub and spoke system is not yet fully implemented across the country and that resources should be better distributed in order to ensure uniform and fair care for all stroke patients on the whole territory.
Economic feasibility analysis and optimization of hybrid renewable energy systems for rural electrification in Peru
Authors: Rinaldi Fabio , Moghaddampoor Farzad , Najafi Behzad , Marchesi Renzo
Published: July 2020

The majority of rural communities in developing countries (such as Peru) are not connected to the electrical grid. Hybrid energy production from available renewable resources (e.g., wind and solar) and diesel engines is considered as an economically viable and environmentally friendly alternative for electrification in these areas. Motivated by the lack of a comprehensive investigation dedicated to the techno-economic analysis of hybrid systems (PV–wind–diesel) for off-grid electrification in Peru, the present work is focused on determining the optimal configuration of these systems for remote Peruvian villages. Three small communities without access to the grid (Campo serio, El potrero, and Silicucho), which are located in different climatic zones of Peru, have been accordingly selected as case studies. Seven different configurations including single component systems (solar, wind, and diesel) and hybrid ones are considered. While taking into account the meteorological data and load characteristics of the communities along with the diesel fuel’s price and the cost of components, HOMER software is utilized to determine the optimal sizing of the system [resulting in the lowest net present cost (NPC)] considering different scenarios. The obtained configurations are then compared considering other state-of-the-art economic indices [initial capital cost, total annual operating cost, and the cost of energy (COE)], the generation fractions, and the resulting CO2 emissions. The obtained results have revealed that, for all of the investigated communities, the hybrid solar–wind–diesel system is the most economically viable scenario. Considering the latter scenario, the obtained optimal configuration leads to an NPC of USD 227,335 (COE: 0.478 USD/kWh) for Campo serio, USD 183,851 (COE: 0.460 USD/kWh) for El potrero, and USD 146,583 (COE: 0.504 USD/kWh) for Silicucho. Furthermore, employing the optimal configurations a renewable fraction (with respect to the total generation) of 94% is obtained for Campo serio and Silicucho, while the achieved renewable fraction for El potrero is 97%. Moreover, for the case of Campo serio, the resulting CO2 emission of the obtained optimal system is determined to be 6.1% of that of a diesel-only unit, while the latter ratio is determined to be 2.7% for El potrero and 9.9% for that of Silicucho. The optimal configurations that are obtained and presented in the present paper can be utilized as guideline for designing electrification systems (with a minimized cost) for the considered communities and other villages with similar characteristics (population and climatic conditions).

Graphic abstract
Active tyrosine phenol-lyase aggregates induced by terminally attached functional peptides in Escherichia coli
Authors: Han Hongmei , Zeng Weizhu , Zhang Guoqiang , Zhou Jingwen
Published: July 2020

The formation of inclusion bodies (IBs) without enzyme activity in bacterial research is generally undesirable. Researchers have attempted to recovery the enzyme activities of IBs, which are commonly known as active IBs. Tyrosine phenol-lyase (TPL) is an important enzyme that can convert pyruvate and phenol into 3,4-dihydroxyphenyl-l-alanine (L-DOPA) and IBs of TPL can commonly occur. To induce the correct folding and recover the enzyme activity of the IBs, peptides, such as ELK16, DKL6, L6KD, ELP10, ELP20, L6K2, EAK16, 18A, and GFIL16, were fused to the carboxyl terminus of TPL. The results showed that aggregate particles of TPL-DKL6, TPL-ELP10, TPL-EAK16, TPL-18A, and TPL-GFIL16 improved the enzyme activity by 40.9%, 50.7%, 48.9%, 86.6%, and 97.9%, respectively. The peptides TPL-DKL6, TPL-EAK16, TPL-18A, and TPL-GFIL16 displayed significantly improved thermostability compared with TPL. L-DOPA titer of TPL-ELP10, TPL-EAK16, TPL-18A, and TPL-GFIL16, with cells reaching 37.8 g/L, 53.8 g/L, 37.5 g/L, and 29.1 g/L, had an improvement of 111%, 201%, 109%, and 63%, respectively. A higher activity and L-DOPA titer of the TPL-EAK16 could be valuable for its industrial application to biosynthesize L-DOPA.
How is COVID-19 Affecting the Mental Health of Children with Special Educational Needs and Disabilities and Their Families?
Authors: Asbury Kathryn , Fox Laura , Deniz Emre , Code Aimee , Toseeb Umar
Published: July 2020

Parents of children with Special Educational Needs and Disabilities in the UK (n = 241) were asked to describe the impact of COVID-19 on their own mental health and that of their child. An inductive content analysis of the data was undertaken. Both parents and children appear to be experiencing loss, worry and changes in mood and behaviour as a result of the rapid social changes that have occurred. Some parents reported feeling overwhelmed and described the impact of child understanding and awareness. Finally, a minority of parents reported that COVID-19 has had little impact on mental health in their family, or has even led to improvements. Implications for how to support these families in the immediate future are discussed.
Predicting site-specific storm wave run-up
Authors: Fiedler Julia W. , Young Adam P. , Ludka Bonnie C. , O’Reilly William C. , Henderson Cassandra , Merrifield Mark A. , Guza R. T.
Published: July 2020

Storm wave run-up causes beach erosion, wave overtopping, and street flooding. Extreme runup estimates may be improved, relative to predictions from general empirical formulae with default parameter values, by using historical storm waves and eroded profiles in numerical runup simulations. A climatology of storm wave run-up at Imperial Beach, California is developed using the numerical model SWASH, and over a decade of hindcast spectral waves and observed depth profiles. For use in a local flood warning system, the relationship between incident wave energy spectra E(f) and SWASH-modeled shoreline water levels is approximated with the numerically simple integrated power law approximation (IPA). Broad and multi-peaked E(f) are accommodated by characterizing wave forcing with frequency-weighted integrals of E(f). This integral approach improves runup estimates compared to the more commonly used bulk parameterization using deep water wave height $$H_0$$

H
0

and deep water wavelength $$L_0$$

L
0

Hunt (Trans Am Soc Civ Eng 126(4):542–570, 1961) and Stockdon et al. (Coast Eng 53(7):573–588, 2006. 10.1016/j.coastaleng.2005.12.005). Scaling of energy and frequency contributions in IPA, determined by searching parameter space for the best fit to SWASH, show an $$H_0L_0$$

H
0

L
0

scaling is near optimal. IPA performance is tested with LiDAR observations of storm run-up, which reached 2.5 m above the offshore water level, overtopped backshore riprap, and eroded the foreshore beach slope. Driven with estimates from a regional wave model and observed $$\beta _f$$

β
f

, the IPA reproduced observed run-up with $$<30\%$$

<
30
%

error. However, errors in model physics, depth profile, and incoming wave predictions partially cancelled. IPA (or alternative empirical forms) can be calibrated (using SWASH or similar) for sites where historical waves and eroded bathymetry are available.
Quality evaluation of Angelicae acutilobae radix: individual differences and localization of (Z)-ligustilide in Angelica acutiloba root
Authors: Kudo Yoshitomi , Ando Hirokazu , Sasaki Yohei
Published: July 2020

It has been difficult to evaluate the quality of Angelicae acutilobae Radix (Toki) because of large differences in the contents of its chemical constituents. In this research, we revealed individual differences and localization of (Z)-ligustilide in Toki cultivated and processed under the same conditions. Thirteen Toki samples (dry weight: 68.2 g–132.3 g) were divided and categorized into 13 parts and the (Z)-ligustilide content of each part was quantified. Total (Z)-ligustilide content ranged from 0.08% to 0.22% and the maximum difference between samples was approximately 2.8-fold. In addition, the localization of (Z)-ligustilide was examined. (Z)-Ligustilide content was the highest in lateral root at 0.19%, followed by main root at 0.13%, and the lowest in root head at 0.09%. Furthermore, the content tended to increase as the root became thinner. In particular, the difference in content between the inner side of upper root head (removed 5 mm from the epidermis 0.06%) and the 1.1–3.0 mm in diameter lateral root (0.24%) was largest at approximately 4.1-fold. We revealed that not only differences among individuals but also localization is a factor affecting the quality of Toki. In contrast, individuals with higher root part (main root + lateral root) weight ratio in whole root dry weight had higher (Z)-ligustilide content. The difference in (Z)-ligustilide content among individuals is due to the balance between root head part and root other than head part. It is possible to predict (Z)-ligustilide content from weight ratio of root part to whole root.
Evaluation of Volumetric Change of Intracerebral Hemorrhage in Patients Treated with Thrombolysis for Intraventricular Hemorrhage
Authors: Staub-Bartelt Franziska , van Lieshout Jasper Hans , Beez Thomas , Kram Rainer , Hänggi Daniel , Beseoglu Kerim
Published: July 2020

Background

Intraventricular hemorrhage (IVH) is often caused by irruption of intracerebral hemorrhage (ICH) of basal ganglia or thalamus into the ventricular system. Instillation of recombinant tissue plasminogen activator (rtPA) via an external ventricular drainage (EVD) has been shown to effectively decrease IVH volumes while the impact of rtPA instillation on ICH volumes remains unclear. In this series, we analyzed volumetric changes of ICH in patients with and without intrathecal lysis therapy.

Methods

Between 01/2013 and 01/2019, 36 patients with IVH caused by hemorrhage of basal ganglia, thalamus or brain stem were treated with rtPA via an EVD (Group A). Initial volumes were determined in the first available computed tomography (CT) scan, final volumes in the last CT scan before discharge. During the same period, 41 patients with ICH without relevant IVH were treated without intrathecal lysis therapy at our neurocritical care unit (Group B). Serial CT scans were evaluated separately for changes in ICH volumes for both cohorts using OsiriX DICOM viewer. The Wilcoxon signed-rank test was performed for statistical analysis in not normally distributed variables.

Results

Median initial volume of ICH for treatment Group A was 6.5 ml and was reduced to 5.0 ml after first instillation of rtPA (p < 0.01). Twenty-six patients received a second treatment with rtPA (ICH volume reduction 4.5 to 3.3 ml, p < 0.01) and of this cohort further 16 patients underwent a third treatment (ICH volume reduction 3.0 ml to 1.5 ml, p < 0.01). Comparison of first and last CT scan in Group A confirmed an overall median percentage reduction of 91.7% (n = 36, p < 0.01) of ICH volumes and hematoma resolution in Group A was significantly more effective compared to non-rtPA group, Group B (percentage reduction = 68%) independent of initial hematoma volume in the regression analysis (p = 0.07, mean 11.1, 95%CI 7.7–14.5). There were no adverse events in Group A related to rtPA instillation.

Conclusion

Intrathecal lysis therapy leads to a significant reduction in the intraparenchymal hematoma volume with faster clot resolution compared to the spontaneous hematoma resorption. Furthermore, intrathecal rtPA application had no adverse effect on ICH volume.
Selection of Histological Parameters for the Development of an Analytical Method for Discriminating Fresh and Frozen/Thawed Common Octopus (Octopus vulgaris) and Preventing Frauds along the Seafood Chain
Authors: Tinacci L. , Armani A. , Scardino G. , Guidi A. , Nucera D. , Miragliotta V. , Abramo F.
Published: July 2020

This study aimed at selecting effective histological indicators of the freezing process, for the discrimination of fresh and frozen common octopus Octopus vulgaris. Histological indices of freezing process were selected in mantle and arm muscle and axial nerve tissues. Seven histological parameters were chosen: overall muscle tissue structural organization (a); gaping among muscle bundles (b); presence of optically empty spaces between and within muscle bundles (c); white spaces percentage between and within muscle bundles (d); overall nerve structural organization (e); presence of linear fissures and/or empty spaces within neuropil and axonal tract (f); presence of empty spaces within connective tissue matrix surrounding the nerve (g); empty space percentage within arm axial nerve region (h). The parameters were assessed on 150 mantle muscle sections (a, b, c, d), 150 arm muscle (b, c) and nervous (e, f, g, h) tissue sections belonging to 20 fresh exemplars further subdued to conventional freezing procedure at − 20 °C, 25 fresh curled exemplars, 25 exemplars industrially frozen at − 80 °C, and 20 thawed, curled, and individually quick frozen exemplars. Overall structural organization (a, e), gaping (b), and presence of optically empty spaces (c, f) confirmed significant morphological freezing indices in mantle and arm sections. In mantle, two d values (d < 25% and 25% < d < 33%) were proposed as complementary thresholds to be applied in association with b and c indices for freezing discrimination. These parameters appear eligible to set a method for discriminating fresh/thawed octopus products to be applied both in official control and self-check activities.
Peripheral blood lymphocyte proviral DNA predicts neurocognitive impairment in clade C HIV
Authors: Ruhanya Vurayai , Jacobs Graeme Brendon , Nyandoro George , Paul Robert H. , Joska John A. , Seedat Soraya , Glashoff Richard Helmuth , Engelbrecht Susan
Published: July 2020

It is not known if proviral DNA in the periphery corresponds to cognitive status in clade C as it does in clade B and recombinant forms. A cross-sectional study was conducted on participants investigated for HIV-associated neurocognitive impairment in South Africa. HIV-1 proviral DNA was quantified using a PCR assay targeting a highly conserved HIV-1 LTR-gag region. Fifty-four (36.7%) participants were cognitively impaired and 93 (63.3%) were not impaired. Forty-three (79.6%) of the cognitively impaired participants were female and 11 (20.4%) were male. There was no significant age difference between cognitively impaired and unimpaired participants (p = 0.42). HIV-1 DNA in cognitively impaired PLWH was significantly higher than in cognitively normal individuals (p = .016). Considering impaired participants, lymphocyte HIV-1 DNA was significantly higher in males than females (p = 0.02). There was a modest positive correlation between lymphocyte HIV-1 DNA and global deficit scores (GDS) r = 0.176; p = 0.03). The two measures of viral load, lymphocyte HIV-1 DNA copies/million and plasma RNA copies/ml, were positively correlated (r = 0.39; p < .001). After adjusting for other covariates, age, sex, treatment status, and the interactions between impairment and treatment, the multivariate regression showed association between proviral load and neurocognitive impairment; omega effect size was 0.04, p value = 0.010. The burden of HIV-1 peripheral blood lymphocyte proviral DNA corresponds to neurocognitive impairment among individuals infected with clade C disease. Therefore, therapeutic strategies to reduce the HIV-1 proviral DNA reservoir in lymphocytes may improve neurocognitive outcomes in PLWH.
Similarities and Differences in Cellular Processing of Biologically Relevant Nanoparticles
Authors: Kepsutlu Burcu , McNally James
Published: July 2020

Nanoparticles are endocytosed and trafficked within cells by selecting one or more of the cell's intrinsic processing pathways. However, general rules which drive this selection have not yet been defined. Therefore, each nanoparticle has to be investigated separately to determine its endocytosis and intracellular trafficking pathways. By using cryo SXT to investigate the cellular interaction of two different nanoparticles, we have uncovered some general rules about nanoparticle interactions with cells. Our results highlight not only the importance of cryo-SXT for nanoparticle investigation in the medical field, but also demonstrate that a well-controlled analysis makes it possible to discern general rules about cell-nanoparticle interactions.
Förderung sozial-kognitiver Problemlösestrategien von Vorschulkindern
Authors: Mackowiak Katja , Kula Antje , Brunemund Laura , Walter Ulla
Published: July 2020

Zusammenfassung. Die Fähigkeit, Herausforderungen und Probleme im Alltag erfolgreich zu bewältigen, gilt als wesentliche Lebenskompetenz bzw. Resilienzfacette und schützt Kinder in ihrer gesamten Entwicklung. Entsprechend ist die Förderung der Problemlösefähigkeiten ein wichtiger Aspekt der Prävention und Gesundheitsförderung (PGF) bereits im Vorschulalter. Das Verbundprojekt „Alltagsintegrierte Unterstützung kindlicher Bildungsprozesse in inklusiven Kindertageseinrichtungen (KoAkiK)“1möchte Kinder durch eine anregende Lernumgebung im Kita-Alltag in ihren Problemlösekompetenzen stärken. Im Beitrag wird untersucht, wie sich die sozial-kognitiven Problemlösestrategien einer Teilstichprobe von 115 Kindern (Interventionsgruppe: n = 82; Kontrollgruppe: n = 33) innerhalb eines Jahres entwickeln. Die Ergebnisse zeigen eine große Varianz und entwicklungsbedingte Veränderungen in den Problemlösestrategien der Kinder. Dabei überwiegen sozial angemessene Strategien. Effekte der Intervention lassen sich (noch) nicht nachweisen. Dies wird vor dem Hintergrund der aktuellen Forschungslage diskutiert.
Kindspezifische Prozessqualität
Authors: Linberg Anja , Kluczniok Katharina
Published: July 2020

Zusammenfassung. Pädagogische Prozesse als zentrales Merkmal der Qualität frühkindlicher Betreuung stehen mit der Entwicklung kindlicher Fähigkeiten wie Sprache oder Mathematik in Verbindung und sind gleichzeitig von strukturellen Merkmalen abhängig. Bislang wurden diese Prozesse vor allem gruppenbezogen erfasst. Damit bleibt jedoch unklar, welche Qualität ein einzelnes Kind in einer Gruppe erfährt. Daher wird in diesem Beitrag eine kindspezifische Sichtweise eingenommen und Niveau, Bedingungen und Effekte dieser kindspezifischen Prozessqualität anhand von Daten der Studie Bildungsprozesse, Kompetenzentwicklung und Selektionsentscheidungen im Vorschul- und Schulalter (BiKS; n = 94 Kinder) untersucht. Ergebnisse zeigen, dass sich die kindspezifische Prozessqualität in Hinblick auf mathematische und sprachliche Anregung auf einem niedrigen bis mittleren Niveau bewegt, diese neben klassischen Strukturmerkmalen von individuellen Merkmalen des Kindes abhängt und sich Tendenzen erkennen lassen, dass diese mit mathematischen und sprachlichen Fähigkeiten des Kindes am Ende der Kindergartenzeit in Beziehung steht.
Multifocal photoacoustic microscopy using a single-element ultrasonic transducer through an ergodic relay
Authors: Li Yang , Wong Terence T. W. , Shi Junhui , Hsu Hsun-Chia , Wang Lihong V.
Published: July 2020

Optical-resolution photoacoustic microscopy (OR-PAM) has demonstrated high-spatial-resolution imaging of optical absorption in biological tissue. To date, most OR-PAM systems rely on mechanical scanning with confocally aligned optical excitation and ultrasonic detection, limiting the wide-field imaging speed of these systems. Although several multifocal OR-PA (MFOR-PA) systems have attempted to address this limitation, they are hindered by the complex design in a constrained physical space. Here, we present a two-dimensional (2D) MFOR-PAM system that utilizes a 2D microlens array and an acoustic ergodic relay. Using a single-element ultrasonic transducer, this system can detect PA signals generated from 400 optical foci in parallel and then raster scan the optical foci patterns to form an MFOR-PAM image. This system improves the imaging resolution of an acoustic ergodic relay system from 220 to 13 μm and enables 400-folds shorter scanning time than that of a conventional OR-PAM system at the same resolution and laser repetition rate. We demonstrated the imaging ability of the system with both in vitro and in vivo experiments.
Post-transplant multimorbidity index and quality of life in patients with chronic graft-versus-host disease—results from a joint evaluation of a prospective German multicenter validation trial and a cohort from the National Institutes of Health
Authors: Wolff Daniel , Herzberg Philipp Y. , Herrmann Anne , Pavletic Steven Z. , Heussner Pia , Mumm Friederike , Höfer Christina , Hilgendorf Inken , Hemmati Philipp G. , Holler Ernst , Greinix Hildegard , Mitchell Sandra A.
Published: July 2020

Comorbidity after allogeneic hematopoietic stem cell transplantation (alloHSCT) impairs quality of life (QoL), physical functioning, and survival. We developed a new standardized measure to capture comorbidity after transplantation, the Post-transplant Multimorbidity Index (PTMI) in a cohort of 50 long term survivors. We subsequently evaluated the content validity and impact on survival and QoL within a multicenter trial, including 208 patients (pts) after alloHSCT, who were prospectively evaluated applying the FACT-BMT, the Human Activity Profile (HAP), the SF-36 v.2, PTMI and the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI). The most prevalent comorbidities were compensated arterial hypertension (28.4%), ambulatory infections (25.5%), iron overload (23%), mild renal function impairment (20%), and osteoporosis (13%). Applying the PTMI 13% of patients had no comorbidity, while 37.1% had 1–3 comorbidities, 27.4% had 4–6 comorbidities, and 13.5% had > 6 comorbidities. Chronic graft-versus-host disease (cGvHD) was significantly associated with the PTMI, while age and prior acute GvHD were not. In contrast, the HCT-CI was not associated with the presence of cGvHD. cGvHD was significantly associated with depression (r = 0.16), neurological disease (r = 0.21), osteoporosis (r = 0.18) and nonmelanoma skin cancer (r = 0.26). The PTMI demonstrated strong measurement properties and compared to the HCT-CI captured a wider range of comorbidities associated with cGvHD.
RIP3-mediated necroptosis is regulated by inter-filament assembly of RIP homotypic interaction motif
Authors: Hu Hong , Wu Xialian , Wu Guoxiang , Nan Ning , Zhang Jing , Zhu Xinxin , Zhang Yu , Shu Zhaoqian , Liu Jia , Liu Xiaoyan , Lu Junxia , Wang Huayi
Published: July 2020

Necroptosis is mediated by signaling complexes called necrosomes, which contain receptor-interacting protein 3 (RIP3) and upstream effectors, such as RIP1. In necrosomes, the RIP homotypic interaction motif (RHIM) of RIP3 and RIP1 forms amyloidal complex. But how the amyloidal necrosomes control RIP3 activation and cell necroptosis has not been determined. Here, we showed that RIP3 amyloid fibrils could further assemble into large fibrillar networks which presents as cellular puncta during necroptosis. A viral RHIM-containing necroptosis inhibitor M45 could form heteroamyloid with RIP3 in cells and prevent RIP3 puncta formation and cell necroptosis. We characterized mutual antagonism between RIP3–RHIM and M45–RHIM in necroptosis regulation, which was caused by distinct inter-filament interactions in RIP3, M45 amyloids revealed with atomic force microscopy. Moreover, double mutations Asn464 and Met468 in RIP3–RHIM to Asp disrupted RIP3 kinase-dependent necroptosis. While the mutant RIP3(N464D/M468D) could form amyloid as wild type upon necroptosis induction. Based on these results, we propose that RIP3 amyloid formation is required but not sufficient in necroptosis signaling, the ordered inter-filament assembly of RIP3 is critical in RIP3 amyloid mediated kinase activation and cell necroptosis.
Correction: The integrated stress response induces R-loops and hinders replication fork progression
Authors: Choo Josephine Ann Mun Yee , Schlösser Denise , Manzini Valentina , Magerhans Anna , Dobbelstein Matthias
Published: July 2020

In the original version of this Article, the figures were not in the correct sequence, and the references and legends did not match with the figures. This has now been corrected in the PDF and HTML versions of the Article.
Pyroptotic cell death in the R6/2 mouse model of Huntington’s disease: new insight on the inflammasome
Authors: Paldino Emanuela , D’Angelo Vincenza , Sancesario Giuseppe , Fusco Francesca R.
Published: July 2020

Mechanisms of tissue damage in Huntington’s disease involve excitotoxicity, mitochondrial damage, and neuroinflammation, including microglia activation. In the present study, we investigate the role of pyroptosis process in the striatal neurons of the R6/2 mouse model of Huntington’s disease. Transgenic mice were sacrificed at 4 and 13 weeks of age. After sacrifice, histological and immunohistochemical studies were performed. We found that NLRP3 and Caspase-1 were intensely expressed in 13-week-old R6/2 mice. Moreover, NLRP3 expression levels were higher in striatal spiny projection neurons and in parvalbumin interneurons, which are prone to degenerate in HD.
Demographic and prosocial intrapersonal characteristics of biobank participants and refusers: the findings of a survey in the Netherlands
Authors: Broekstra Reinder , Aris-Meijer Judith , Maeckelberghe Els , Stolk Ronald , Otten Sabine
Published: July 2020

Research in genetics relies heavily on voluntary contributions of personal data. We aimed to acquire insights into the differences between participants and refusers of participation in a Dutch population-based biobank. Accordingly, we assessed the demographic and prosocial intrapersonal characteristics of respondents who participated (n = 2615) or refused to participate (n = 404) in the Lifelines biobank and databank. Our results indicated that health-related values critically influence participation decisions. The participation threshold for Lifelines was determined by an absence of health-related values and of trust in government. Therefore, considering these factors in communication and recruitment strategies could enhance participation in biomedical research. No indications were found of a stronger general prosociality of participants or their trust in researchers beyond the context of biobanking. This emphasizes the contextual understanding of the decision of participation in biobanking. Our findings may contribute to improving recruitment strategies by incorporating relevant values and/or highlighting prosocial benefits. Moreover, they foreground the need to address trust issues in collaborations between data repositories and commercial companies. Future research should explore how prosocial intrapersonal characteristics drive participation and withdrawal decisions and relate to contextual attributes.
Retromer stabilization results in neuroprotection in a model of Amyotrophic Lateral Sclerosis
Authors: Muzio Luca , Sirtori Riccardo , Gornati Davide , Eleuteri Simona , Fossaghi Andrea , Brancaccio Diego , Manzoni Leonardo , Ottoboni Linda , Feo Luca De , Quattrini Angelo , Mastrangelo Eloise , Sorrentino Luca , Scalone Emanuele , Comi Giancarlo , Marinelli Luciana , Riva Nilo , Milani Mario , Seneci Pierfausto , Martino Gianvito
Published: July 2020

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the degeneration of upper and lower motor neurons (MNs). We find a significant reduction of the retromer complex subunit VPS35 in iPSCs-derived MNs from ALS patients, in MNs from ALS post mortem explants and in MNs from SOD1G93A mice. Being the retromer involved in trafficking of hydrolases, a pathological hallmark in ALS, we design, synthesize and characterize an array of retromer stabilizers based on bis-guanylhydrazones connected by a 1,3-phenyl ring linker. We select compound 2a as a potent and bioavailable interactor of VPS35-VPS29. Indeed, while increasing retromer stability in ALS mice, compound 2a attenuates locomotion impairment and increases MNs survival. Moreover, compound 2a increases VPS35 in iPSCs-derived MNs and shows brain bioavailability. Our results clearly suggest the retromer as a valuable druggable target in ALS.
Néel-type skyrmion in WTe2/Fe3GeTe2 van der Waals heterostructure
Authors: Wu Yingying , Zhang Senfu , Zhang Junwei , Wang Wei , Zhu Yang Lin , Hu Jin , Yin Gen , Wong Kin , Fang Chi , Wan Caihua , Han Xiufeng , Shao Qiming , Taniguchi Takashi , Watanabe Kenji , Zang Jiadong , Mao Zhiqiang , Zhang Xixiang , Wang Kang L.
Published: July 2020

The promise of high-density and low-energy-consumption devices motivates the search for layered structures that stabilize chiral spin textures such as topologically protected skyrmions. At the same time, recently discovered long-range intrinsic magnetic orders in the two-dimensional van der Waals materials provide a new platform for the discovery of novel physics and effects. Here we demonstrate the Dzyaloshinskii–Moriya interaction and Néel-type skyrmions are induced at the WTe2/Fe3GeTe2 interface. Transport measurements show the topological Hall effect in this heterostructure for temperatures below 100 K. Furthermore, Lorentz transmission electron microscopy is used to directly image Néel-type skyrmion lattice and the stripe-like magnetic domain structures as well. The interfacial coupling induced Dzyaloshinskii–Moriya interaction is estimated to have a large energy of 1.0 mJ m−2. This work paves a path towards the skyrmionic devices based on van der Waals layered heterostructures.
Ceramic resonators for targeted clinical magnetic resonance imaging of the breast
Authors: Shchelokova Alena , Ivanov Viacheslav , Mikhailovskaya Anna , Kretov Egor , Sushkov Ivan , Serebryakova Svetlana , Nenasheva Elizaveta , Melchakova Irina , Belov Pavel , Slobozhanyuk Alexey , Andreychenko Anna
Published: July 2020

Currently, human magnetic resonance (MR) examinations are becoming highly specialized with a pre-defined and often relatively small target in the body. Conventionally, clinical MR equipment is designed to be universal that compromises its efficiency for small targets. Here, we present a concept for targeted clinical magnetic resonance imaging (MRI), which can be directly integrated into the existing clinical MR systems, and demonstrate its feasibility for breast imaging. The concept comprises spatial redistribution and passive focusing of the radiofrequency magnetic flux with the aid of an artificial resonator to maximize the efficiency of a conventional MR system for the area of interest. The approach offers the prospect of a targeted MRI and brings novel opportunities for high quality specialized MR examinations within any existing MR system.
Mapping allosteric communications within individual proteins
Authors: Wang Jian , Jain Abha , McDonald Leanna R. , Gambogi Craig , Lee Andrew L. , Dokholyan Nikolay V.
Published: July 2020

Allostery in proteins influences various biological processes such as regulation of gene transcription and activities of enzymes and cell signaling. Computational approaches for analysis of allosteric coupling provide inexpensive opportunities to predict mutations and to design small-molecule agents to control protein function and cellular activity. We develop a computationally efficient network-based method, Ohm, to identify and characterize allosteric communication networks within proteins. Unlike previously developed simulation-based approaches, Ohm relies solely on the structure of the protein of interest. We use Ohm to map allosteric networks in a dataset composed of 20 proteins experimentally identified to be allosterically regulated. Further, the Ohm allostery prediction for the protein CheY correlates well with NMR CHESCA studies. Our webserver, Ohm.dokhlab.org, automatically determines allosteric network architecture and identifies critical coupled residues within this network.
The suboptimality of perceptual decision making with multiple alternatives
Authors: Yeon Jiwon , Rahnev Dobromir
Published: July 2020

It is becoming widely appreciated that human perceptual decision making is suboptimal but the nature and origins of this suboptimality remain poorly understood. Most past research has employed tasks with two stimulus categories, but such designs cannot fully capture the limitations inherent in naturalistic perceptual decisions where choices are rarely between only two alternatives. We conduct four experiments with tasks involving multiple alternatives and use computational modeling to determine the decision-level representation on which the perceptual decisions are based. The results from all four experiments point to the existence of robust suboptimality such that most of the information in the sensory representation is lost during the transformation to a decision-level representation. These results reveal severe limits in the quality of decision-level representations for multiple alternatives and have strong implications about perceptual decision making in naturalistic settings.
Exploiting natural chemical photosensitivity of anhydrotetracycline and tetracycline for dynamic and setpoint chemo-optogenetic control
Authors: Baumschlager Armin , Rullan Marc , Khammash Mustafa
Published: July 2020

The transcriptional inducer anhydrotetracycline (aTc) and the bacteriostatic antibiotic tetracycline (Tc) are commonly used in all fields of biology for control of transcription or translation. A drawback of these and other small molecule inducers is the difficulty of their removal from cell cultures, limiting their application for dynamic control. Here, we describe a simple method to overcome this limitation, and show that the natural photosensitivity of aTc/Tc can be exploited to turn them into highly predictable optogenetic transcriptional- and growth-regulators. This new optogenetic class uniquely features both dynamic and setpoint control which act via population-memory adjustable through opto-chemical modulation. We demonstrate this method by applying it for dynamic gene expression control and for enhancing the performance of an existing optogenetic system. We then expand the utility of the aTc system by constructing a new chemical bandpass filter that increases its aTc response range. The simplicity of our method enables scientists and biotechnologists to use their existing systems employing aTc/Tc for dynamic optogenetic experiments without genetic modification.
Stable high-capacity and high-rate silicon-based lithium battery anodes upon two-dimensional covalent encapsulation
Authors: Zhang Xinghao , Wang Denghui , Qiu Xiongying , Ma Yingjie , Kong Debin , Müllen Klaus , Li Xianglong , Zhi Linjie
Published: July 2020

Silicon is a promising anode material for lithium-ion and post lithium-ion batteries but suffers from a large volume change upon lithiation and delithiation. The resulting instabilities of bulk and interfacial structures severely hamper performance and obstruct practical use. Stability improvements have been achieved, although at the expense of rate capability. Herein, a protocol is developed which we describe as two-dimensional covalent encapsulation. Two-dimensional, covalently bound silicon-carbon hybrids serve as proof-of-concept of a new material design. Their high reversibility, capacity and rate capability furnish a remarkable level of integrated performances when referred to weight, volume and area. Different from existing strategies, the two-dimensional covalent binding creates a robust and efficient contact between the silicon and electrically conductive media, enabling stable and fast electron, as well as ion, transport from and to silicon. As evidenced by interfacial morphology and chemical composition, this design profoundly changes the interface between silicon and the electrolyte, securing the as-created contact to persist upon cycling. Combined with a simple, facile and scalable manufacturing process, this study opens a new avenue to stabilize silicon without sacrificing other device parameters. The results hold great promise for both further rational improvement and mass production of advanced energy storage materials.
Distinct genetic architectures and environmental factors associate with host response to the γ2-herpesvirus infections
Authors: Sallah Neneh , Miley Wendell , Labo Nazzarena , Carstensen Tommy , Fatumo Segun , Gurdasani Deepti , Pollard Martin O. , Dilthey Alexander T. , Mentzer Alexander J. , Marshall Vickie , Cornejo Castro Elena M. , Pomilla Cristina , Young Elizabeth H. , Asiki Gershim , Hibberd Martin L. , Sandhu Manjinder , Kellam Paul , Newton Robert , Whitby Denise , Barroso Inês
Published: July 2020

Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr Virus (EBV) establish life-long infections and are associated with malignancies. Striking geographic variation in incidence and the fact that virus alone is insufficient to cause disease, suggests other co-factors are involved. Here we present epidemiological analysis and genome-wide association study (GWAS) in 4365 individuals from an African population cohort, to assess the influence of host genetic and non-genetic factors on virus antibody responses. EBV/KSHV co-infection (OR = 5.71(1.58–7.12)), HIV positivity (OR = 2.22(1.32–3.73)) and living in a more rural area (OR = 1.38(1.01–1.89)) are strongly associated with immunogenicity. GWAS reveals associations with KSHV antibody response in the HLA-B/C region (p = 6.64 × 10−09). For EBV, associations are identified for VCA (rs71542439, p = 1.15 × 10−12). Human leucocyte antigen (HLA) and trans-ancestry fine-mapping substantiate that distinct variants in HLA-DQA1 (p = 5.24 × 10−44) are driving associations for EBNA-1 in Africa. This study highlights complex interactions between KSHV and EBV, in addition to distinct genetic architectures resulting in important differences in pathogenesis and transmission.
A neurovascular high-frequency optical coherence tomography system enables in situ cerebrovascular volumetric microscopy
Authors: Ughi Giovanni J. , Marosfoi Miklos G. , King Robert M. , Caroff Jildaz , Peterson Lindsy M. , Duncan Benjamin H. , Langan Erin T. , Collins Amanda , Leporati Anita , Rousselle Serge , Lopes Demetrius K. , Gounis Matthew J. , Puri Ajit S.
Published: July 2020

Intravascular imaging has emerged as a valuable tool for the treatment of coronary and peripheral artery disease; however, no solution is available for safe and reliable use in the tortuous vascular anatomy of the brain. Endovascular treatment of stroke is delivered under image guidance with insufficient resolution to adequately assess underlying arterial pathology and therapeutic devices. High-resolution imaging, enabling surgeons to visualize cerebral arteries' microstructure and micron-level features of neurovascular devices, would have a profound impact in the research, diagnosis, and treatment of cerebrovascular diseases. Here, we present a neurovascular high-frequency optical coherence tomography (HF-OCT) system, including an imaging console and an endoscopic probe designed to rapidly acquire volumetric microscopy data at a resolution approaching 10 microns in tortuous cerebrovascular anatomies. Using a combination of in vitro, ex vivo, and in vivo models, the feasibility of HF-OCT for cerebrovascular imaging was demonstrated.
Theoretical and empirical quantification of the accuracy of polygenic scores in ancestry divergent populations
Authors: Wang Ying , Guo Jing , Ni Guiyan , Yang Jian , Visscher Peter M. , Yengo Loic
Published: July 2020

Polygenic scores (PGS) have been widely used to predict disease risk using variants identified from genome-wide association studies (GWAS). To date, most GWAS have been conducted in populations of European ancestry, which limits the use of GWAS-derived PGS in non-European ancestry populations. Here, we derive a theoretical model of the relative accuracy (RA) of PGS across ancestries. We show through extensive simulations that the RA of PGS based on genome-wide significant SNPs can be predicted accurately from modelling linkage disequilibrium (LD), minor allele frequencies (MAF), cross-population correlations of causal SNP effects and heritability. We find that LD and MAF differences between ancestries can explain between 70 and 80% of the loss of RA of European-based PGS in African ancestry for traits like body mass index and type 2 diabetes. Our results suggest that causal variants underlying common genetic variation identified in European ancestry GWAS are mostly shared across continents.
Author Correction: Jawsamycin exhibits in vivo antifungal properties by inhibiting Spt14/Gpi3-mediated biosynthesis of glycosylphosphatidylinositol
Authors: Fu Yue , Estoppey David , Roggo Silvio , Pistorius Dominik , Fuchs Florian , Studer Christian , Ibrahim Ashraf S. , Aust Thomas , Grandjean Frederic , Mihalic Manuel , Memmert Klaus , Prindle Vivian , Richard Etienne , Riedl Ralph , Schuierer Sven , Weber Eric , Hunziker Jürg , Petersen Frank , Tao Jianshi , Hoepfner Dominic
Published: July 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Temperature-regulated heterogeneous extracellular matrix gene expression defines biofilm morphology in Clostridium perfringens
Authors: Obana Nozomu , Nakamura Kouji , Nomura Nobuhiko
Published: July 2020

Cells in biofilms dynamically adapt to surrounding environmental conditions, which alters biofilm architecture. The obligate anaerobic pathogen Clostridium perfringens shows different biofilm structures in different temperatures. Here we find that the temperature-regulated production of extracellular polymeric substance (EPS) is necessary for morphological changes in biofilms. We identify BsaA proteins as an EPS matrix necessary for pellicle biofilm formation at lower temperature and find that extracellularly secreted BsaA protein forms filamentous polymers. We show that sipW-bsaA operon expression is bimodal, and the EPS-producing population size is increased at a lower temperature. This heterogeneous expression of the EPS gene requires a two-component system. We find that EPS-producing cells cover EPS-nonproducing cells attaching to the bottom surface. In the deletion mutant of pilA2, encoding a type IV pilin, the EPS gene expression is ON in the whole population. This heterogeneity is further regulated by the cleavage of the pilA2 mRNA by RNase Y, causing temperature-responsive EPS expression in biofilms. As temperature is an environmental cue, C. perfringens may modulate EPS expression to induce morphological changes in biofilm structure as a strategy for adapting to interhost and external environments.