bluuebunny/crossref_metadata_2025 huggingface dataset:
Edge modes of gravity. Part III. Corner simplicity constraints
Authors: Freidel Laurent , Geiller Marc , Pranzetti Daniele
Published: January 2021

Abstract

In the tetrad formulation of gravity, the so-called simplicity constraints play a central role. They appear in the Hamiltonian analysis of the theory, and in the Lagrangian path integral when constructing the gravity partition function from topological BF theory. We develop here a systematic analysis of the corner symplectic structure encoding the symmetry algebra of gravity, and perform a thorough analysis of the simplicity constraints. Starting from a precursor phase space with Poincaré and Heisenberg symmetry, we obtain the corner phase space of BF theory by imposing kinematical constraints. This amounts to fixing the Heisenberg frame with a choice of position and spin operators. The simplicity constraints then further reduce the Poincaré symmetry of the BF phase space to a Lorentz subalgebra. This picture provides a particle-like description of (quantum) geometry: the internal normal plays the role of the four-momentum, the Barbero-Immirzi parameter that of the mass, the flux that of a relativistic position, and the frame that of a spin harmonic oscillator. Moreover, we show that the corner area element corresponds to the Poincaré spin Casimir. We achieve this central result by properly splitting, in the continuum, the corner simplicity constraints into first and second class parts. We construct the complete set of Dirac observables, which includes the generators of the local $$ \mathfrak{sl}\left(2,\mathrm{\mathbb{C}}\right) $$
sl

2
ℂ

subalgebra of Poincaré, and the components of the tangential corner metric satisfying an $$ \mathfrak{sl}\left(2,\mathrm{\mathbb{R}}\right) $$
sl

2
ℝ

algebra. We then present a preliminary analysis of the covariant and continuous irreducible representations of the infinite-dimensional corner algebra. Moreover, as an alternative path to quantization, we also introduce a regularization of the corner algebra and interpret this discrete setting in terms of an extended notion of twisted geometries.
(Mis-)matching type-B anomalies on the Higgs branch
Authors: Niarchos V. , Papageorgakis C. , Pini A. , Pomoni E.
Published: January 2021

Abstract

Building on [1], we uncover new properties of type-B conformal anomalies for Coulomb-branch operators in continuous families of 4D $$ \mathcal{N} $$
N
= 2 SCFTs. We study a large class of such anomalies on the Higgs branch, where conformal symmetry is spontaneously broken, and compare them with their counterpart in the CFT phase. In Lagrangian the- ories, the non-perturbative matching of the anomalies can be determined with a weak coupling Feynman diagram computation involving massive multi-loop banana integrals. We extract the part corresponding to the anomalies of interest. Our calculations support the general conjecture that the Coulomb-branch type-B conformal anomalies always match on the Higgs branch when the IR Coulomb-branch chiral ring is empty. In the opposite case, there are anomalies that do not match. An intriguing implication of the mismatch is the existence of a second covariantly constant metric on the conformal manifold (other than the Zamolodchikov metric), which imposes previously unknown restrictions on its holonomy group.
MACC1 regulates clathrin-mediated endocytosis and receptor recycling of transferrin receptor and EGFR in colorectal cancer
Authors: Imbastari Francesca , Dahlmann Mathias , Sporbert Anje , Mattioli Camilla Ciolli , Mari Tommaso , Scholz Florian , Timm Lena , Twamley Shailey , Migotti Rebekka , Walther Wolfgang , Dittmar Gunnar , Rehm Armin , Stein Ulrike
Published: January 2021

Metastasis Associated in Colon Cancer 1 (MACC1) is a novel prognostic, predictive and causal biomarker for tumor progression and metastasis in many cancer types, including colorectal cancer. Besides its clinical value, little is known about its molecular function. Its similarity to SH3BP4, involved in regulating uptake and recycling of transmembrane receptors, suggests a role of MACC1 in endocytosis. By exploring the MACC1 interactome, we identified the clathrin-mediated endocytosis (CME)-associated proteins CLTC, DNM2 and AP-2 as MACC1 binding partners. We unveiled a MACC1-dependent routing of internalized transferrin receptor towards recycling. Elevated MACC1 expression caused also the activation and internalization of EGFR, a higher rate of receptor recycling, as well as earlier and stronger receptor activation and downstream signaling. These effects are limited by deletion of CME-related protein interaction sites in MACC1. Thus, MACC1 regulates CME and receptor recycling, causing increased growth factor-mediated downstream signaling and cell proliferation. This novel mechanism unveils potential therapeutic intervention points restricting MACC1-driven metastasis.
Risk of labour market marginalisation among young refugees and non-refugee migrants with common mental disorders
Authors: Di Thiene D. , Helgesson Magnus , Rahman S. , Alexanderson K. , Tiihonen J. , La Torre G. , Mittendorfer-Rutz E.
Published: January 2021

Purpose

Labour market marginalisation (LMM), i.e. long-term unemployment (LTU), long-term sickness absence (LTSA) and disability pension (DP), among young individuals with common mental disorders (CMDs) are a challenge for the welfare system, and refugees and non-refugee migrants seem particularly vulnerable. The aim was to investigate the risk of LMM in young adults with CMDs among refugees and non-refugee migrants compared to Swedish-born individuals and the role of country of birth, duration of residence and age at arrival.

Methods

A prospective cohort study was conducted including young adults (19–30 years) with inpatient or specialised outpatient healthcare due to CMDs and/or antidepressant prescriptions during 2009 (N = 69,515). Cox regression models were used to calculate hazard ratios (HRs) with 95% confidence intervals for the risk of LMM during 2010–2013.

Results

Both refugees and non-refugee migrants had a higher risk of LTU compared to Swedish-born individuals (HR refugees: Africa: 2.4; Asia: 2.2; Europe outside EU25: 1.6; South America: 1.4) with highest estimates in refugees from Afghanistan and Syria. Refugees from Africa and Asia had a lower risk of LTSA compared to Swedish-born individuals (HR: 0.6 and 0.7, respectively), particularly refugees from Afghanistan and Iraq. Especially among refugees, a longer duration of residence and a younger age at arrival were associated with a lower risk of LTU.

Conclusions

The risk of LTU among refugees and non-refugee migrants was higher and the risk of LTSA was lower, compared to Swedish-born individuals. Duration of residence and age at arrival had an influence on the risk of LTU, particularly among refugees.
Martelella alba sp. nov., isolated from mangrove rhizosphere soil within the Beibu Gulf
Authors: Li Mi , Gao Chenghai , Feng Yuyao , Liu Kai , Cao Pei , Liu Yonghong , Yi Xiangxi
Published: January 2021

Strain BGMRC 2036T was isolated from rhizosphere soil of Bruguiear gymnorrhiza collected from the Beibu Gulf of China. Optimum growth occurred at 28 °C, pH 7.0, and under the conditions of 3–5% (w/v) NaCl. The phylogenetic comparisons of 16S rRNA gene sequences displayed that strain BGMRC 2036T was closely related to Martelella limonii NBRC109441T (96.6% sequence similarity), M. mediterranea CGMCC 1.12224T (96.5%), M. lutilitoris GH2-6T (96.5%), M. radicis BM5-7T (96.2%), and M. mangrove BM9-1T (95.9%), M. suaedae NBRC109440T (95.8%). The phylogenomic tree based on the up-to-date bacterial core gene set indicated that the strain BGMRC 2036T form a clade formed with members of the genera Martelella. The major polar lipids include phosphatidylmethylethanolamine, phosphatidylglycerol, phosphatidylcholine, phosphotidylinositol, two unidentified phospholipids, and three unidentified ninhydrin positive phospholipids. The major respiratory quinone is Q-10, which is similar to those of genera Martelella. The main cellular fatty acids are C18:1ω7c, C16:0, and C12:0 aldehyde. Genome sequencing revealed a genome size of 4.99 Mbp and a G + C content of 62.3 mol%. Pairwise comparison of the genomes of the new strain BGMRC 2036T and the three reference strains M. endophytica YC 6887T, M. mediterranea CGMCC 1.12224T, and M. mangrovi USBA-857 indicated that gANI value was lower than 81% and a digital DNA–DNA hybridization value was lower than 27%. The strain BGMRC 2036T possessed genes putatively encoding riboflavin synthesis and flavodoxin A polyphasic taxonomic study suggested that strain BGMRC 2036T represented a novel species belonging to the genus Martelella, and it was named Martelella alba sp. nov. The type strain is BGMRC 2036T (=KCTC 52121T =NBRC 111908T).
I Like the Way You Eat It: Lemur (Indri indri) Gut Mycobiome and Geophagy
Authors: Borruso Luigimaria , Checcucci Alice , Torti Valeria , Correa Federico , Sandri Camillo , Luise Daine , Cavani Luciano , Modesto Monica , Spiezio Caterina , Mimmo Tanja , Cesco Stefano , Di Vito Maura , Bugli Francesca , Randrianarison Rose M. , Gamba Marco , Rarojoson Nianja J. , Zaborra Cesare Avesani , Mattarelli Paola , Trevisi Paolo , Giacoma Cristina
Published: January 2021

Here, we investigated the possible linkages among geophagy, soil characteristics, and gut mycobiome of indri (Indri indri), an endangered lemur species able to survive only in wild conditions. The soil eaten by indri resulted in enriched secondary oxide-hydroxides and clays, together with a high concentration of specific essential micronutrients. This could partially explain the role of the soil in detoxification and as a nutrient supply. Besides, we found that soil subject to geophagy and indris’ faeces shared about 8.9% of the fungal OTUs. Also, several genera (e.g. Fusarium, Aspergillus and Penicillium) commonly associated with soil and plant material were found in both geophagic soil and indri samples. On the contrary, some taxa with pathogenic potentials, such as Cryptococcus, were only found in indri samples. Further, many saprotrophs and plant-associated fungal taxa were detected in the indri faeces. These fungal species may be involved in the digestion processes of leaves and could have a beneficial role in their health. In conclusion, we found an intimate connection between gut mycobiome and soil, highlighting, once again, the potential consequent impacts on the wider habitat.
Spatiotemporal patterns of wolf, mesocarnivores and prey in a Mediterranean area
Authors: Rossa Mariana , Lovari Sandro , Ferretti Francesco
Published: January 2021

Spatial and temporal occurrence can mediate behavioural interactions between apex predators, mesocarnivores and herbivores. Predators should adapt their activity to that of prey, whereas predator avoidance would be expected to influence activity patterns and space use of prey and smaller competitors. We evaluated interspecific spatiotemporal relationships in a prey-rich community including an apex predator (the wolf), three wild ungulates and several smaller herbivores/mesocarnivores, through camera trapping. All considered species (i.e. wolves and potential prey/smaller competitors: wild boar, fallow deer, roe deer, crested porcupine, red fox and European badger) were active especially at night and/or twilight. Among wild ungulates, the wolf showed the greatest temporal overlap with the wild boar and the lowest one with the least abundant and used of them, i.e. the roe deer. The main prey (i.e. the fallow deer) showed more diurnal activity and a lower temporal overlap with the predator in sites with high wolf activity than in low-activity ones. Among mesocarnivores, the red fox showed extensive temporal overlap with the wolf: the overlap between the two canids was greater in sites intensively used by this apex predator than in sites with low wolf activity, supporting a concurrent study which suggested a potential for facilitative—rather than competitive—interactions. Spatiotemporal relationships suggest complex interactions between the apex predator, prey and smaller carnivores, for which a substantial temporal or spatial association was often supported.

Significance statement

There is a growing interest in the influence of apex predators on ecosystems through their effects on the behaviour of prey and smaller carnivores, especially in the light of the ongoing recovery of large carnivores in temperate areas. Predators should synchronise their activity to that of prey; conversely, prey and smaller carnivores would be expected to avoid predators. In a rich community including the wolf, three wild ungulates and several mesomammals, we detected (i) a substantial temporal overlap between wolves and wild boar, porcupines and mesocarnivores; (ii) a negative temporal association between the predator and its main prey (i.e. the fallow deer) and (iii) a great temporal overlap between the wolf and the red fox. We provide a baseline to evaluate temporal changes of predator-prey-mesocarnivore behavioural interactions along with variations of carnivore-prey densities.
Transplanting Organs from Donors with HIV or Hepatitis C: The Viral Frontier
Authors: Boyarsky Brian J. , Strauss Alexandra T. , Segev Dorry L.
Published: January 2021

A wide gap between the increasing demand for organs and the limited supply leads to immeasurable loss of life each year. The organ shortage could be attenuated by donors with human immunodeficiency virus (HIV) or hepatitis C virus (HCV). The transplantation of organs from HIV+ deceased donors into HIV+ individuals (HIV D+ /R+) was initiated in South Africa in 2010; however, this practice was forbidden in the USA until the HIV Organ Policy Equity (HOPE) Act in 2013. HIV D+/R+ transplantation is now practiced in the USA as part of ongoing research studies, helping to reduce waiting times for all patients on the waitlist. The introduction of direct acting antivirals for HCV has revolutionized the utilization of donors with HCV for HCV‐uninfected (HCV−) recipients. This is particularly relevant as the HCV donor pool has increased substantially in the context of the rise in deaths related to drug overdose from injection drug use. This article serves to review the current literature on using organs from donors with HIV or HCV.
Splenic Vein Diameter is a Risk Factor for the Portal Venous System Thrombosis After Partial Splenic Artery Embolization
Authors: Ogawa Satoyuki , Yamamoto Akira , Jogo Atsushi , Nakano Mariko M. , Kageyama Ken , Sohgawa Etsuji , Nishida Norifumi , Kaminou Toshio , Miki Yukio
Published: January 2021

Purpose

Portal venous system thrombosis is a complication of partial splenic artery embolization, and pre-treatment risk assessment is thus important. The purpose of this study was to identify the risk factors for portal venous system thrombosis after partial splenic artery embolization.

Materials and methods

We retrospectively analyzed 67 consecutive patients who underwent contrast-enhanced computed tomography before and after first partial splenic artery embolization between July 2007 and October 2018. As risk factors, we investigated age, sex, hematological data, liver function, steroid use, heparin use, and findings from pre- and post-treatment computed tomography. Uni- and multivariate analyses were performed to evaluate the relationship between thrombus appearance or growth and these factors. Values of p < 0.05 were considered significant.

Results

Partial splenic artery embolization was technically successful in all 67 patients. Nine patients showed appearance or growth of thrombus. Univariate analysis showed maximum diameter of the splenic vein before treatment (p = 0.0076), percentage of infarcted spleen (p = 0.017), and volume of infarcted spleen (p = 0.022) as significant risk factors. Multivariate analysis showed significant differences in maximum diameter of the splenic vein before treatment (p = 0.041) and percentage of infarcted spleen (p = 0.023). According to receiver operating characteristic analysis, cutoffs for maximum diameter of the splenic vein and percentage of infarcted spleen for distinguishing the appearance or growth of thrombus were 17 mm and 58.2%.

Conclusion

Large maximum diameter of the splenic vein before partial splenic artery embolization and high percentage of infarcted spleen after partial splenic artery embolization were identified as risk factors for portal venous system thrombosis.

Level of Evidence

Level 4, Case Series
Calcium scoring using virtual non-contrast images from a dual-layer spectral detector CT: comparison to true non-contrast data and evaluation of proportionality factor in a large patient collective
Authors: Gassert Felix G. , Schacky Claudio E. , Müller-Leisse Christina , Gassert Florian T. , Pahn Gregor , Laugwitz Karl-Ludwig , Makowski Marcus R. , Nadjiri Jonathan
Published: January 2021

Objective

Determination of coronary artery calcium scoring (CACS) in non-contrast computed tomography (CT) images has been shown to be an important prognostic factor in coronary artery disease (CAD). The objective of this study was to evaluate the accuracy of CACS from virtual non-contrast (VNC) imaging generated from spectral data in comparison to standard (true) non-contrast (TNC) imaging in a representative patient cohort with clinically approved software.

Methods

One hundred three patients referred to coronary CTA with suspicion of CAD were investigated on a dual-layer spectral detector CT (SDCT) scanner. CACS was calculated from both TNC and VNC images by software certified for medical use. Patients with a CACS of 0 were excluded from analysis.

Results

The mean age of the study population was 61 ± 11 years with 48 male patients (67%). Inter-quartile range of clinical CACS was 22–282. Correlation of measured CACS from true- and VNC images was high (0.95); p < 0.001. The slope was 3.83, indicating an underestimation of VNC CACS compared to TNC CACS by that factor. Visual analysis of the Bland-Altman plot of CACS showed good accordance with both methods after correction of VNC CACS by the abovementioned factor.

Conclusions

In clinical diagnostics of CAD, the determination of CACS is feasible using VNC images generated from spectral data obtained on a dual-layer spectral detector CT. When multiplied by a correction factor, results were in good agreement with the standard technique. This could enable radiation dose reductions by obviating the need for native scans typically used for CACS.

Key Points

• Calcium scoring is feasible from contrast-enhanced CT images using a dual-layer spectral detector CT scanner.

• When multiplied by a correction factor, calcium scoring from virtual non-contrast images shows good agreement with the standard technique.

• Omitting native scans for calcium scoring could enable radiation dose reduction.
The incidence of infantile hypertrophic pyloric stenosis nearly halved from 2005 to 2017: analysis of German administrative data
Authors: Oetzmann von Sochaczewski Christina , Muensterer Oliver J.
Published: January 2021

Purpose

Some paediatric surgical diseases showed a declining incidence in recent years, among which hypertrophic pyloric stenosis has been particularly striking shortly in the years after the millennium. We aimed to assess whether this development continued over the following decade, as it might offer the chance to better understand the underlying reasons.

Methods

We analysed data files obtained from the German federal statistics office for principal diagnosis of hypertrophic pyloric stenosis and pyloromyotomies from 2005 to 2017. Changes over time were assessed via linear regression for incidences per 1000 live births.

Results

In the respective time interval, there were a mean of 1009 pyloromyotomies (95% CI 906–1112) per year, of which a mean of 835 (95% CI 752–917) were performed in boys. The incidence of hypertrophic pyloric stenosis per 1000 live births almost halved between 2005 and 2017: it decreased by 0.12 pylorotomies annually (95% CI 0.09–0.14; P < 0.0001) in boys—from a maximum of 2.96 to a minimum of 1.63–and 0.03 pyloromyotomies annually (95% CI 0.02–0.04; P < 0.0001) in girls—from a maximum of 0.64 to a minimum of 0.28. There was considerable regional variation in incidences between the German länder.

Conclusion

The decreasing incidence of hypertrophic pyloric stenosis noted around the millenium continued into the following decades. The underlying reasons are unclear, which should prompt further research on the subject matter.
Implementation of the acutely presenting older patient (APOP) screening program in routine emergency department care
Authors: Blomaard Laura C. , de Groot Bas , Lucke Jacinta A. , de Gelder Jelle , Booijen Anja M. , Gussekloo Jacobijn , Mooijaart Simon P.
Published: January 2021

Objective

The aim of this study was to evaluate the effects of implementation of the acutely presenting older patient (APOP) screening program for older patients in routine emergency department (ED) care shortly after implementation.

Methods

We conducted an implementation study with before-after design, using the plan-do-study-act (PDSA) model for quality improvement, in the ED of a Dutch academic hospital. All consecutive patients ≥ 70 years during 2 months before and after implementation were included. The APOP program comprises screening for risk of functional decline, mortality and cognitive impairment, targeted interventions for high-risk patients and education of professionals. Outcome measures were compliance with interventions and impact on ED process, length of stay (LOS) and hospital admission rate.

Results

Two comparable groups of patients (median age 77 years) were included before (n = 920) and after (n = 953) implementation. After implementation 560 (59%) patients were screened of which 190 (34%) were high-risk patients. Some of the program interventions for high-risk patients in the ED were adhered to, some were not. More hospitalized patients received comprehensive geriatric assessment (CGA) after implementation (21% before vs. 31% after; p = 0.002). In 89% of high-risk patients who were discharged to home, telephone follow-up was initiated. Implementation did not influence median ED LOS (202 min before vs. 196 min after; p = 0.152) or hospital admission rate (40% before vs. 39% after; p = 0.410).

Conclusion

Implementation of the APOP screening program in routine ED care did not negatively impact the ED process and resulted in an increase of CGA and telephone follow-up in older patients. Future studies should investigate whether sustainable changes in management and patient outcomes occur after more PDSA cycles.
Intranasal sodium citrate in quantitative and qualitative olfactory dysfunction: results from a prospective, controlled trial of prolonged use in 60 patients
Authors: Whitcroft K. L. , Gunder N. , Cuevas M. , Andrews P. , Menzel S. , Haehner A. , Hummel T.
Published: January 2021

Objectives

We have previously shown that treatment with intranasal sodium citrate may be beneficial in post-infectious olfactory dysfunction. Sodium citrate reduces free intranasal calcium and is, therefore, thought to prevent calcium-mediated feedback inhibition at the level of the olfactory receptor. We aimed to determine whether treatment with a 2-week course of intranasal sodium citrate improves quantitative olfactory function in patients with post-infectious impairment. We also aimed to determine whether sodium citrate is beneficial in treating qualitative olfactory dysfunction.

Methods

We performed a prospective, controlled study. Patients applied intranasal sodium citrate solution to the right nasal cavity for 2 weeks. The left nasal cavity was untreated and, therefore, acted as an internal control. Monorhinal olfactory function was assessed using the “Sniffin’ Sticks” composite ‘TDI’ score, before and after treatment. The presence of parosmia and phantosmia was also assessed.

Results

Overall, there was a significant increase in TDI after treatment (using the best of right and left sides). Treatment with sodium citrate did not significantly improve quantitative olfactory function, compared to control. The proportion of patients reporting parosmia did not change significantly after treatment. However, there was a significant reduction in the proportion of patients reporting phantosmia, at the end of the study period.

Conclusions

Treatment with intranasal sodium citrate for a period of 2 weeks does not appear to improve quantitative olfactory function in patients with post-infectious impairment, compared to control. It may, however, be beneficial in treating phantosmia, which should be further addressed in future work.
Radiological and surgical aspects of round window visibility during cochlear implantation: a retrospective analysis
Authors: Jwair Saad , van Eijden Job J. M. , Blijleven Esther E. , Dankbaar Jan Willem , Thomeer Hans G. X. M.
Published: January 2021

Purpose

The round window approach has become the most preferred option for cochlear implant (CI) insertion, however, sometimes it may not be possible due to the (in)visibility of the round window membrane (RWM). We addressed the prevalence, consequences and indicators of difficult detection of the RWM in cochlear implant surgery.

Methods

This study retrospectively analysed the operative reports and preoperative high resolution axial-computed tomography (CT) scans of a consecutive cohort of patients who underwent a CI insertion. The main outcomes were surgical outcomes of the RW approach, and assessment of radiological
markers.

Results

The operative reports showed that RWM insertion was feasible in 151 out of 153 patients. In 18% of the patients the RWM was difficult to visualize. All these patients had at least one intraoperative event. The chorda tympani nerve (CTN) or posterior canal wall was affected in 8% of the 153 patients and the fallopian canal in 6%. These patients had a facial-chorda tympani nerve distance on the CT scan that was considerably smaller than normal patients (1.5 mm vs 2.3 mm). In addition, a prediction line towards the anterolateral side of the RWM was found to be more prevalent in these patients’ CT scans (sensitivity 81%, specificity 63%).

Conclusion

The RW approach is feasible in almost all patients undergoing CI surgery. Difficult visualisation of the RWM seems to lead to at least one intraoperative event. Radiological measures showed that these patients had a smaller facial recess and a more anteriorly placed facial nerve, which can be used to better plan a safe insertion approach.
Altered vitamin D3 metabolism in the ovary and periovarian adipose tissue of rats with letrozole-induced PCOS
Authors: Grzesiak Malgorzata , Burzawa Gabriela , Kurowska Patrycja , Blaszczyk Klaudia , Szlaga Agata , Blasiak Anna , Sechman Andrzej , Rak Agnieszka
Published: January 2021

Vitamin D3 (VD3) plays an important role in the ovary and its deficiency is associated with ovarian pathologies, including polycystic ovary syndrome (PCOS). However, there is no data related to VD3 metabolism in the ovary during PCOS. Herein, we investigated differences in the expression of VD3 receptor (VDR) and key VD3 metabolic enzymes, 1α-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24A1), in the ovary and periovarian adipose tissue (POAT) of control (proestrus and diestrus) and PCOS induced by letrozole rats. Vdr, Cyp27b1 and Cyp24a1 mRNA expression was determined, their protein abundance was examined and immunolocalized. Furthermore, VD3 metabolite concentrations in plasma (25OHD) and tissues (ovary and POAT; 1,25(OH)2D3), and plasma calcium level were determined. 25OHD concentration decreased markedly in letrozole-treated rats in comparison with controls, whereas calcium concentration did not vary among the examined groups. The amount of 1,25(OH)2D3 decreased in both ovary and POAT of PCOS rats. In the ovary, we found decreased Cyp27b1 and increased Vdr mRNA expression in letrozole-treated and diestrus control group. Corresponding protein abundances were down-regulated and up-regulated, respectively but only following letrozole treatment. In POAT, only Cyp27b1 transcript level and CYP27B1 protein abundance were decreased in letrozole-treated rats. VDR was immunolocalized in healthy and cystic follicles, while CYP27B1 and CYP24A1 were found exclusively in healthy ones. Concluding, our results provide the first evidence of disrupted VD3 metabolism in the ovary and POAT of PCOS rats. The reduced 1,25(OH)2D3 concentration in those tissues suggests their contribution to VD3 deficiency observed in PCOS and might implicate in PCOS pathogenesis.
Developmental exposure window influences silver toxicity but does not affect the susceptibility to subsequent exposures in zebrafish embryos
Authors: Robinson Paige C. , Littler Hannah R. , Lange Anke , Santos Eduarda M.
Published: January 2021

Silver is a non-essential, toxic metal widespread in freshwaters and capable of causing adverse effects to wildlife. Its toxic effects have been studied in detail but less is known about how sensitivity varies during development and whether pre-exposures affect tolerance upon re-exposure. We address these knowledge gaps using the zebrafish embryo (Danio rerio) model to investigate whether exposures encompassing stages of development prior to mid-blastula transition, when chorion hardening and epigenetic reprogramming occur, result in greater toxicity compared to those initiated after this period. We conducted exposures to silver initiated at 0.5 h post fertilisation (hpf) and 4 hpf to determine if toxicity differed. In parallel, we exposed embryos to the methylation inhibitor 5-azacytidine as a positive control. Toxicity increased when exposures started from 0.5 hpf compared to 4 hpf and LC50 were significantly lower by 1.2 and 7.6 times for silver and 5-azacyitidine, respectively. We then investigated whether pre-exposure to silver during early development (from 0.5 or 4 hpf) affected the outcome of subsequent exposures during the larvae stage, and found no alterations in toxicity compared to naïve larvae. Together, these data demonstrate that during early development zebrafish embryos are more sensitive to silver when experiments are initiated at the one-cell stage, but that pre-exposures do not influence the outcome of subsequent exposures, suggesting that no long-lasting memory capable of influencing future susceptibility was maintained under our experimental conditions. The finding that toxicity is greater for exposures initiated at the one-cell stage has implications for designing testing systems to assess chemical toxicity.
Mechanical ventilation-induced alterations of intracellular surfactant pool and blood–gas barrier in healthy and pre-injured lungs
Authors: Krischer Jeanne-Marie , Albert Karolin , Pfaffenroth Alexander , Lopez-Rodriguez Elena , Ruppert Clemens , Smith Bradford J. , Knudsen Lars
Published: January 2021

Mechanical ventilation triggers the manifestation of lung injury and pre-injured lungs are more susceptible. Ventilation-induced abnormalities of alveolar surfactant are involved in injury progression. The effects of mechanical ventilation on the surfactant system might be different in healthy compared to pre-injured lungs. In the present study, we investigated the effects of different positive end-expiratory pressure (PEEP) ventilations on the structure of the blood–gas barrier, the ultrastructure of alveolar epithelial type II (AE2) cells and the intracellular surfactant pool (= lamellar bodies, LB). Rats were randomized into bleomycin-pre-injured or healthy control groups. One day later, rats were either not ventilated, or ventilated with PEEP = 1 or 5 cmH2O and a tidal volume of 10 ml/kg bodyweight for 3 h. Left lungs were subjected to design-based stereology, right lungs to measurements of surfactant proteins (SP−) B and C expression. In pre-injured lungs without ventilation, the expression of SP-C was reduced by bleomycin; while, there were fewer and larger LB compared to healthy lungs. PEEP = 1 cmH2O ventilation of bleomycin-injured lungs was linked with the thickest blood–gas barrier due to increased septal interstitial volumes. In healthy lungs, increasing PEEP levels reduced mean AE2 cell size and volume of LB per AE2 cell; while in pre-injured lungs, volumes of AE2 cells and LB per cell remained stable across PEEPs. Instead, in pre-injured lungs, increasing PEEP levels increased the number and decreased the mean size of LB. In conclusion, mechanical ventilation-induced alterations in LB ultrastructure differ between healthy and pre-injured lungs. PEEP = 1 cmH2O but not PEEP = 5 cmH2O ventilation aggravated septal interstitial abnormalities after bleomycin challenge.
Characterization of epithelial cells, connective tissue cells and immune cells in human upper airway mucosa by immunofluorescence multichannel image cytometry: a pilot study
Authors: Giotakis Aris I. , Dudas Jozsef , Glueckert Rudolf , Dejaco Daniel , Ingruber Julia , Fleischer Felix , Innerhofer Veronika , Pinggera Leyla , Bektic-Tadic Ljilja , Gabriel Sarah A. M. , Riechelmann Herbert
Published: January 2021

Epithelial, connective tissue and immune cells contribute in various ways to the pathophysiology of chronic rhinosinusitis (CRS). However, data of their distribution in upper airway mucosa are sparse. We aimed to provide quantitative, purely informative data on the distribution of these cell lineages and their coexpression patterns, which might help identifying, e.g., cells in the epithelium undergoing through epithelial–mesenchymal transition (EMT). For this purpose, we used immunofluorescence multichannel image cytometry (IMIC). We examined fixed paraffin-embedded tissue samples (FFPE) of six patients with chronic rhinosinusitis (CRS) and of three patients without CRS (controls). The direct-conjugated antibodies pancytokeratin, vimentin and CD45/CD18 were used for coexpression analysis in epithelial layer and lamina propria. Image acquisition and analysis were performed with TissueFAXS and StrataQuest, respectively. To distinguish positive from negative expression, a ratio between cell-specific immunostaining intensity and background was developed. Isotype controls were used as negative controls. Per patient, a 4.5-mm2 tissue area was scanned and a median of 14,875 cells was recognized. The most common cell types were cytokeratin-single-positive (26%), vimentin-single-positive (13%) and CD45/CD18-single-positive with CD45/CD18–vimentin-double-positive cells (29%). In the patients with CRS, CD45/CD18-single-positive cells were 3–6 times higher compared to the control patients. In the epithelial layer, cytokeratin–vimentin-double-positive EMT cells were observed 3–5 times higher in the patients with CRS than in the control patients. This study provided quantitative data for the distribution of crucial cell types in CRS. Future studies may focus on the distribution and coexpression patterns of different immune cells in CRS or even cancer tissue.
Simple method of thawing cryo-stored samples preserves ultrastructural features in electron microscopy
Authors: Galhuber Markus , Kupper Nadja , Dohr Gottfried , Gauster Martin , Kwapiszewska Grazyna , Olschewski Andrea , Jandl Katharina , Gschwandtner Elisabeth , Schweiger Martina , Kratky Dagmar , Leitinger Gerd , Prokesch Andreas , Kolb Dagmar
Published: January 2021

Preservation of ultrastructural features in biological samples for electron microscopy (EM) is a challenging task that is routinely accomplished through chemical fixation or high-pressure freezing coupled to automated freeze substitution (AFS) using specialized devices. However, samples from clinical (e.g. “biobanking” of bulk biopsies) and preclinical (e.g. whole mouse tissues) specimens are often not specifically prepared for ultrastructural analyses but simply immersed in liquid nitrogen before long-term cryo-storage. We demonstrate that ultrastructural features of such samples are insufficiently conserved using AFS and developed a simple, rapid, and effective method for thawing that does not require specific instrumentation. This procedure consists of dry ice-cooled pre-trimming of frozen tissue and aldehyde fixation for 3 h at 37 °C followed by standard embedding steps. Herein investigated tissues comprised human term placentae, clinical lung samples, as well as mouse tissues of different composition (brown adipose tissue, white adipose tissue, cardiac muscle, skeletal muscle, liver). For all these tissues, we compared electron micrographs prepared from cryo-stored material with our method to images derived from directly prepared fresh tissues with standard chemical fixation. Our protocol yielded highly conserved ultrastructural features and tissue-specific details, largely matching the quality of fresh tissue samples. Furthermore, morphometric analysis of lipid droplets and mitochondria in livers of fasted mice demonstrated that statistically valid quantifications can be derived from samples prepared with our method. Overall, we provide a simple and effective protocol for accurate ultrastructural and morphometric analyses of cryo-stored bulk tissue samples.
Expression and enhancement of FABP4 in septoclasts of the growth plate in FABP5-deficient mouse tibiae
Authors: Bando Yasuhiko , Tokuda Nobuko , Ogasawara Yudai , Onozawa Go , Nagasaka Arata , Sakiyama Koji , Owada Yuji , Amano Osamu
Published: January 2021

In our previous study, fatty acid-binding protein 5 (FABP5) was expressed in septoclasts with long processes which are considered to resorb uncalcified matrix of the growth plate (GP) cartilage, and no apparent abnormalities were detected in the histo-architecture of the GP of FABP5-deficient (FABP5−/−) mice. Those finding lead us to hypothesize that another FABP can compensate the deletion of FABP5 in septoclasts of its gene-mutant mice. Based on the hypothesis, the present study examined the expression levels of several other FABPs in septoclasts and their morphology in FABP5−/− mouse tibiae. Processes of FABP5−/− septoclasts tend to be shorter than wild septoclasts. FABP4-positive septoclasts in FABP5−/− mice were more numerous than those cells in wild mice.

Peroxisome proliferator-activated receptor (PPAR) γ was expressed in FABP4-positive septoclasts of FABP5−/− mice as well as mice administered with GW1929, a PPARγ agonist, suggesting that the occurrence of PPARγ induces an increase of FABP4-positive septoclasts. The present finding suggests that the functional exertion of FABP5 in septoclasts is supplemented by FABP4 in normal and FABP5−/− mice, and that the expression of FABP4 is up-regulated in accompany with PPARγ in FABP5−/− for maintenance of resorptive activity in the GP.
Diverse functions of myosin VI in spermiogenesis
Authors: Zakrzewski Przemysław , Lenartowska Marta , Buss Folma
Published: January 2021

Spermiogenesis is the final stage of spermatogenesis, a differentiation process during which unpolarized spermatids undergo excessive remodeling that results in the formation of sperm. The actin cytoskeleton and associated actin-binding proteins play crucial roles during this process regulating organelle or vesicle delivery/segregation and forming unique testicular structures involved in spermatid remodeling. In addition, several myosin motor proteins including MYO6 generate force and movement during sperm differentiation. MYO6 is highly unusual as it moves towards the minus end of actin filaments in the opposite direction to other myosin motors. This specialized feature of MYO6 may explain the many proposed functions of this myosin in a wide array of cellular processes in animal cells, including endocytosis, secretion, stabilization of the Golgi complex, and regulation of actin dynamics. These diverse roles of MYO6 are mediated by a range of specialized cargo-adaptor proteins that link this myosin to distinct cellular compartments and processes. During sperm development in a number of different organisms, MYO6 carries out pivotal functions. In Drosophila, the MYO6 ortholog regulates actin reorganization during spermatid individualization and male KO flies are sterile. InC. elegans, the MYO6 ortholog mediates asymmetric segregation of cytosolic material and spermatid budding through cytokinesis, whereas in mice, this myosin regulates assembly of highly specialized actin-rich structures and formation of membrane compartments to allow the formation of fully differentiated sperm. In this review, we will present an overview and compare the diverse function of MYO6 in the specialized adaptations of spermiogenesis in flies, worms, and mammals.
Localisation and regulation of cholesterol transporters in the human hair follicle: mapping changes across the hair cycle
Authors: Palmer Megan A. , Smart Eleanor , Haslam Iain S.
Published: January 2021

Cholesterol has long been suspected of influencing hair biology, with dysregulated homeostasis implicated in several disorders of hair growth and cycling. Cholesterol transport proteins play a vital role in the control of cellular cholesterol levels and compartmentalisation. This research aimed to determine the cellular localisation, transport capability and regulatory control of cholesterol transport proteins across the hair cycle. Immunofluorescence microscopy in human hair follicle sections revealed differential expression of ATP-binding cassette (ABC) transporters across the hair cycle. Cholesterol transporter expression (ABCA1, ABCG1, ABCA5 and SCARB1) reduced as hair follicles transitioned from growth to regression. Staining for free cholesterol (filipin) revealed prominent cholesterol striations within the basement membrane of the hair bulb. Liver X receptor agonism demonstrated active regulation of ABCA1 and ABCG1, but not ABCA5 or SCARB1 in human hair follicles and primary keratinocytes. These results demonstrate the capacity of human hair follicles for cholesterol transport and trafficking. Future studies examining the role of cholesterol transport across the hair cycle may shed light on the role of lipid homeostasis in human hair disorders.
Autopsy findings after long-term treatment of COVID-19 patients with microbiological correlation
Authors: Evert Katja , Dienemann Thomas , Brochhausen Christoph , Lunz Dirk , Lubnow Matthias , Ritzka Markus , Keil Felix , Trummer Matthias , Scheiter Alexander , Salzberger Bernd , Reischl Udo , Boor Peter , Gessner André , Jantsch Jonathan , Calvisi Diego F. , Evert Matthias , Schmidt Barbara , Simon Michaela
Published: January 2021

Between April and June 2020, i.e., during the first wave of pandemic coronavirus disease 2019 (COVID-19), 55 patients underwent long-term treatment in the intensive care unit at the University Hospital of Regensburg. Most of them were transferred from smaller hospitals, often due to the need for an extracorporeal membrane oxygenation system. Autopsy was performed in 8/17 COVID-19-proven patients after long-term treatment (mean: 33.6 days). Autopsy revealed that the typical pathological changes occurring during the early stages of the disease (e.g., thrombosis, endothelitis, capillaritis) are less prevalent at this stage, while severe diffuse alveolar damage and especially coinfection with different fungal species were the most conspicuous finding. In addition, signs of macrophage activation syndrome was detected in 7 of 8 patients. Thus, fungal infections were a leading cause of death in our cohort of severely ill patients and may alter clinical management of patients, particularly in long-term periods of treatment.
Calendar age and puberty-related development of regional gray matter volume and white matter tracts during adolescence
Authors: Ando Ayaka , Parzer Peter , Kaess Michael , Schell Susanne , Henze Romy , Delorme Stefan , Stieltjes Bram , Resch Franz , Brunner Romuald , Koenig Julian
Published: January 2021

Background

Adolescence is a critical time for brain development. Findings from previous studies have been inconsistent, failing to distinguish the influence of pubertal status and aging on brain maturation. The current study sought to address these inconsistencies, addressing the trajectories of pubertal development and aging by longitudinally tracking structural brain development during adolescence.

Methods

Two cohorts of healthy children were recruited (cohort 1: 9–10 years old; cohort 2: 12–13 years old at baseline). MRI data were acquired for gray matter volume and white matter tract measures. To determine whether age, pubertal status, both or their interaction best modelled longitudinal data, we compared four multi-level linear regression models to the null model (general brain growth indexed by total segmented volume) using Bayesian model selection.

Results

Data were collected at baseline (n = 116), 12 months (n = 97) and 24 months (n = 84) after baseline. Findings demonstrated that the development of most regional gray matter volume, and white matter tract measures, were best modelled by age. Interestingly, precentral and paracentral regions of the cortex, as well as the accumbens demonstrated significant preference for the pubertal status model. None of the white matter tract measures were better modelled by pubertal status.

Limitations: The major limitation of this study is the two-cohort recruitment. Although this allowed a faster coverage of the age span, a complete per person trajectory over 6 years of development (9–15 years) could not be investigated.

Conclusions

Comparing the impact of age and pubertal status on regional gray matter volume and white matter tract measures, we found age to best predict longitudinal changes. Further longitudinal studies investigating the differential influence of puberty status and age on brain development in more diverse samples are needed to replicate the present results and address mechanisms underlying norm-variants in brain development.
Overview of CAPICE—Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe—an EU Marie Skłodowska-Curie International Training Network
Authors: Rajula Hema Sekhar Reddy , Manchia Mirko , Agarwal Kratika , Akingbuwa Wonuola A. , Allegrini Andrea G. , Diemer Elizabeth , Doering Sabrina , Haan Elis , Jami Eshim S. , Karhunen Ville , Leone Marica , Schellhas Laura , Thompson Ashley , van den Berg Stéphanie M. , Bergen Sarah E. , Kuja-Halkola Ralf , Hammerschlag Anke R. , Järvelin Marjo Riitta , Leval Amy , Lichtenstein Paul , Lundstrom Sebastian , Mauri Matteo , Munafò Marcus R. , Myers David , Plomin Robert , Rimfeld Kaili , Tiemeier Henning , Ystrom Eivind , Fanos Vassilios , Bartels Meike , Middeldorp Christel M.
Published: January 2021

The Roadmap for Mental Health and Wellbeing Research in Europe (ROAMER) identified child and adolescent mental illness as a priority area for research. CAPICE (Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe) is a European Union (EU) funded training network aimed at investigating the causes of individual differences in common childhood and adolescent psychopathology, especially depression, anxiety, and attention deficit hyperactivity disorder. CAPICE brings together eight birth and childhood cohorts as well as other cohorts from the EArly Genetics and Life course Epidemiology (EAGLE) consortium, including twin cohorts, with unique longitudinal data on environmental exposures and mental health problems, and genetic data on participants. Here we describe the objectives, summarize the methodological approaches and initial results, and present the dissemination strategy of the CAPICE network. Besides identifying genetic and epigenetic variants associated with these phenotypes, analyses have been performed to shed light on the role of genetic factors and the interplay with the environment in influencing the persistence of symptoms across the lifespan. Data harmonization and building an advanced data catalogue are also part of the work plan. Findings will be disseminated to non-academic parties, in close collaboration with the Global Alliance of Mental Illness Advocacy Networks-Europe (GAMIAN-Europe).