bluuebunny/crossref_metadata_2025 huggingface dataset:
An evidence‐based, risk‐adapted algorithm for antifungal prophylaxis reduces risk for invasive mold infections in children with hematologic malignancies
Authors: Dutta Ankhi , Ikwuezunma Ashley , Castellanos Maria I. , Brackett Julienne , Reddy Kiranmye , Mahajan Priya , Marshburn Ann M. , Kamdar Kala , Paek Hana , Palazzi Debra L. , Rabin Karen R. , Scheurer Michael E. , Gramatges Maria M.
Published: July 2021

Background

Children with hematologic malignancies, especially those who receive intensive chemotherapy, are at high risk for invasive mold infections (IMI) that confer substantial mortality. Randomized controlled trials support the use of antifungal prophylaxis with antimold activity as an optimal strategy for risk reduction in this population, but studies outlining the practical application of evidence‐based recommendations are lacking.

Procedure

We conducted a 15‐year, single‐institution retrospective review in a diverse cohort of children with hematologic malignancies treated with chemotherapy to determine the incidence of proven or probable IMI diagnosed between 2006 and 2020. Multivariable logistic regression was used to identify host and disease factors associated with IMI risk. We then compared the incidence and type of IMI and related factors before and after 2016 implementation of an evidence‐based, risk‐adapted antifungal prophylaxis algorithm that broadened coverage to include molds in patients at highest risk for IMI.

Results

We identified 61 cases of proven or probable IMI in 1456 patients diagnosed with hematologic malignancies during the study period (4.2%). Implementation of an antifungal prophylaxis algorithm reduced the IMI incidence in this population from 4.8% to 2.9%. Both Hispanic ethnicity and cancer diagnosis prior to 2016 were associated with risk for IMI.

Conclusion

An evidence‐based, risk‐adapted approach to antifungal prophylaxis for children with hematologic malignancies is an effective strategy to reduce incidence of IMI.
Novel G‐CSF conjugated anionic globular dendrimer: Preparation and biological activity assessment
Authors: Mousavi Motlagh Seyed Shahaboddin , Seyedhamzeh Mohammad , Ahangari Cohan Reza , Shafiee Ardestani Mehdi , Vaziri Behrouz , Azadmanesh Kayhan , Saberi Sahar , Masoumi Vahideh
Published: July 2021

The most crucial role of granulocyte colony‐stimulating factor (G‐CSF) in the body is to increase the strength of immune system. In recent years, research on the use of nanoparticles in pharmaceuticals has been considered, most of which have been for drug‐loading purposes. In this study, a novel G‐CSF conjugated dendrimer was synthesized and characterized using different techniques. In vitro cytotoxicity was assessed on A549 and L929 cells, while abnormal toxicity was studied in mice. In vitro and in vivo biological activities were assessed in NFS60 cells and rats, respectively. In addition, in vivo distribution, plasma half‐life, and histopathological effect were studied in rat. The characterization tests confirmed the successful conjugation. There was no difference between G‐CSF cytotoxicity before and after conjugation, and no difference with the control group. No mice showed abnormal toxicity. Although in vitro biological activity revealed both conjugated and free G‐CSF promote proliferation cells, biological activity decreased significantly after conjugation about one‐third of the unconjugated form. Nonetheless, in vivo biological activity of conjugated G‐CSF increased by more than 2.5‐fold relative to the unconjugated form, totally. Fortunately, no histopathologic adverse effect was observed in vital rat tissues. Also, in vivo distribution of the conjugate was similar to the native protein with an enhanced terminal half‐life. Our data revealed that G‐CSF conjugated dendrimer could be considered as a candidate to improve the in vivo biological activity of G‐CSF. Moreover, multivalent capability of the dendrimer may be used for other new potentials of G‐CSF in future perspectives.
Pharmacological hypotheses: Is acetaminophen selective in its cyclooxygenase inhibition?
Authors: Esh Christopher J. , Chrismas Bryna C. R. , Mauger Alexis R. , Taylor Lee
Published: July 2021

The precise mechanistic action of acetaminophen (ACT; paracetamol) remains debated. ACT’s analgesic and antipyretic actions are attributed to cyclooxygenase (COX) inhibition preventing prostaglandin (PG) synthesis. Two COX isoforms (COX1/2) share 60% sequence structure, yet their functions vary. COX variants have been sequenced among various mammalian species including humans. A COX1 splice variant (often termed COX3) is purported by some as the elusive target of ACT’s mechanism of action. Yet a physiologically functional COX3 isoform has not been sequenced in humans, refuting these claims. ACT may selectively inhibit COX2, with evidence of a 4.4‐fold greater COX2 inhibition than COX1. However, this is markedly lower than other available selective COX2 inhibitors (up to 433‐fold) and tempered by proof of potent COX1 inhibition within intact cells when peroxide tone is low. COX isoform inhibition by ACT may depend on subtle in vivo physiological variations specific to ACT. In vivo ACT efficacy is reliant on intact cells and low peroxide tone while the arachidonic acid concentration state can dictate the COX isoform preferred for PG synthesis. ACT is an effective antipyretic (COX2 preference for PG synthesis) and can reduce afebrile core temperature (likely COX1 preference for PG synthesis). Thus, we suggest with specificity to human in vivo physiology that ACT: (i) does not act on a third COX isoform; (ii) is not selective in its COX inhibition; and (iii) inhibition of COX isoforms are determined by subtle and nuanced physiological variations. Robust research designs are required in humans to objectively confirm these hypotheses.
Polyphenols as anticancer agents: Toxicological concern to healthy cells
Authors: Islam Badar ul , Suhail Mohd , Khan Mohammed Kaleem , Zughaibi Torki A. , Alserihi Raed F , Zaidi Syed Kashif , Tabrez Shams
Published: July 2021

Polyphenols are a group of diverse chemical compounds present in a wide range of plants. Various biological properties such as antiallergic, antiviral, antibacterial, anticarcinogenic, antiinflammatory, antithrombotic, vasodilatory, and hepatoprotective effect of different polyphenols have been reported in the scientific literature. The major classes of polyphenols are flavonoids, stilbenoids, lignans, and polyphenolic acids. Flavonoids are a large class of food constituents comprising flavones, isoflavanones, flavanones, flavonols, catechins, and anthocyanins sub‐classes. Even with seemingly broad biological activities, their use is minimal clinically. Among the other concurrent problems such as limited bioavailability, rapid metabolism, untargeted delivery, the toxicity associated with these polyphenols has been a topic of concern lately. These polyphenols have been reported to result in different forms of toxicity that include organ toxicity, genotoxicity, mutagenicity, cytotoxicity, etc. In the present article, we have tried to unravel the toxicological aspect of these polyphenols to healthy cells. Further high‐quality studies are needed to establish the clinical efficacy and toxicology concern leading to further exploration of these polyphenols.
Predictive monitoring using machine learning algorithms and a real‐life example on schizophrenia
Authors: Huberts Leo C. E. , Does Ronald J. M. M. , Ravesteijn Bastian , Lokkerbol Joran
Published: July 2021

Predictive process monitoring aims to produce early warnings of unwanted events. We consider the use of the machine learning method extreme gradient boosting as the forecasting model in predictive monitoring. A tuning algorithm is proposed as the signaling method to produce a required false alarm rate. We demonstrate the procedure using a unique data set on mental health in the Netherlands. The goal of this application is to support healthcare workers in identifying the risk of a mental health crisis in people diagnosed with schizophrenia. The procedure we outline offers promising results and a novel approach to predictive monitoring.
Inflammation protein quantification by multiple reaction monitoring mass spectrometry in lipopolysaccharide‐stimulated THP‐1 cells
Authors: Illiano Anna , Pinto Gabriella , Gaglione Rosa , Arciello Angela , Amoresano Angela
Published: July 2021

Rationale

Inflammation is a cascade of events mediated by a cytokine network triggering the cellular response. In order to monitor the modulation of the crucial inflammatory proteins, e.g., Tumour Necrosis Factor‐α (TNF‐α), Interferon‐γ (INF‐γ), Interleukin‐8 (IL‐8) and Interleukin‐10 (IL‐10), upon stimulation with endotoxins, differentiated and undifferentiated THP‐1 cells were treated with lipopolysaccharides (LPSs) from E. coli, key cell wall components of Gram‐negative bacteria.

Methods

The multiple reaction monitoring mass spectrometry (MRM‐MS) method was optimized by using the standard proteins to be quantified, in order to construct external calibration curves and define the analytical parameters. The developed method was used to quantify the above‐mentioned inflammatory proteins in THP‐1 differentiated cells upon stimulation with LPSs with high accuracy, sensitivity, and robustness.

Results

The analysis of such proteins in MRM mode allowed the kinetics of stimulation along the time up to 24 h to be followed and the MS results were found to be comparable with those obtained by Western‐blotting. A significant increase in TNF‐α release triggered a cascade mechanism leading to the production of INF‐γ and IL‐8. IL‐10, instead, was found to be constant throughout the process.

Conclusions

The developed MRM‐MS method allowed the quantification of TNF‐α, INF‐γ, IL‐8 and IL‐10 along a time‐course from 2 to 24 h. Hence, a trace of the kinetics of the inflammatory response in THP‐1 cells upon stimulation with E. coli LPSs was obtained. Finally, the extensibility of the developed MRM method to serum samples and other matrices demonstrated the versatility of the approach and the possibility to quantify multiple target proteins in different biological samples by using a few microliters in a single analysis.
Controlled CRISPR‐Cas9 Ribonucleoprotein Delivery for Sensitized Photothermal Therapy
Authors: Chen Chao , Ma Yupei , Du Shiyu , Wu Yueyao , Shen Peiliang , Yan Tao , Li Xueqing , Song Yujun , Zha Zhengbao , Han Xin
Published: July 2021

Manipulation of CRISPR delivery for stimuli‐responsive gene editing is crucial for cancer therapeutics through maximizing efficacy and minimizing side‐effects. However, realizing controlled gene editing for synergistic combination therapy remains a key challenge. Here, a near‐infrared (NIR) light‐triggered thermo‐responsive copper sulfide (CuS) multifunctional nanotherapeutic platform is constructed to achieve controlled release of CRISPR‐Cas9 ribonucleoprotein (RNP) and doxorubicin for tumor synergistic combination therapy involving in gene therapy, mild‐photothermal therapy (PTT), and chemotherapy. The semiconductor CuS serves as a “photothermal converter” and can stably convert NIR light (808 nm) into local thermal effect to provide photothermal stimulation. The double‐strand formed between CuS nanoparticle‐linked DNA fragments and single‐guide RNA is employed as a controlled element in response to photothermal stimulation for controlled gene editing and drug release. Hsp90α, one subunit of heat shock protein 90 (Hsp90), is targeted by Cas9 RNP to reduce tumor heat tolerance for enhanced mild‐PTT effects (≈43 °C). Significant synergistic therapy efficacy can be observed by twice NIR light irradiation both in vitro and in vivo, compared to PTT alone. Overall, this exogenously controlled method provides a versatile strategy for controlled gene editing and drug release with potentially synergistic combination therapy.
Long‐Residence Pneumonia Vaccine Developed Using PEG‐Grafted Hybrid Nanovesicles from Cell Membrane Fusion of Mycoplasma and IFN‐γ‐Primed Macrophages
Authors: Zhang Zhenzhen , Wang Haiyan , Xie Xing , Chen Rong , Li Jun , Ni Bo , Yu Pei , Liu Zunfeng , Shao Guoqing , Xiong Qiyan , Wei Yanna , Liu Beibei , Feng Zhixin , Zhou Xiang , Zhang Chao
Published: July 2021

CD8+ T cell responses play a critical regulatory role in protection against mycoplasma infection‐related respiratory diseases. Nanovesicles derived from cell membranes have been shown to induce CD8+ T cell responses. Moreover, the short residence time of mycoplasma membrane‐related vaccines in local lymph nodes limits the efficacy of current mycoplasma vaccines. Here, a long‐residence pneumonia vaccine is developed using nanovesicles prepared by cell membrane fusion of Mycoplasma hyopneumoniae and interferon‐γ (IFN‐γ   )‐primed macrophages, which are grafted with polyethylene glycol to increase residence time in the lymph nodes. Upregulation of intercellular adhesion molecule‐1 (ICAM‐1) on the membrane of IFN‐γ‐primed macrophages increases the targeting of the hybrid nanovesicle vaccine to the local lymph nodes, with increased CD8+ T cell activation. A mechanistic study reveals that CD8+ T cell activation is achieved via a pathway involving upregulation of C‐C motif chemokine ligand 2/3 expression by E26 transformation‐specific sequences, followed by increased immune‐stimulatory activity of dendritic cells. In vivo, prophylactic testing reveals that the hybrid nanovesicle vaccine triggers a long‐term immune response, as evidenced by a memory CD8+ T cell response against mycoplasma infection. The current study provides a new design strategy for mycoplasma vaccines that involves a hybrid method using biological sources and artificial modification.
Electric Field Induced Biomimetic Transmembrane Electron Transport Using Carbon Nanotube Porins
Authors: Hicks Jacqueline M. , Yao Yun‐Chiao , Barber Sydney , Neate Nigel , Watts Julie A. , Noy Aleksandr , Rawson Frankie J.
Published: July 2021

Cells modulate their homeostasis through the control of redox reactions via transmembrane electron transport systems. These are largely mediated via oxidoreductase enzymes. Their use in biology has been linked to a host of systems including reprogramming for energy requirements in cancer. Consequently, the ability to modulate membrane redox systems may give rise to opportunities to modulate underlying biology. The current work aims to develop a wireless bipolar electrochemical approach to form on‐demand electron transfer across biological membranes. To achieve this goal, it is shown that by using membrane inserted carbon nanotube porins (CNTPs) that can act as bipolar nanoelectrodes, one can control electron flow with externally applied electric fields across membranes. Before this work, bipolar electrochemistry has been thought to require high applied voltages not compatible with biological systems. It is shown that bipolar electrochemical reaction via gold reduction at the nanotubes can be modulated at low cell‐friendly voltages, providing an opportunity to use bipolar electrodes to control electron flux across membranes. The authors provide new mechanistic insight into this newly describe phenomena at the nanoscale. The results presented give rise to a new method using CNTPs to modulate cell behavior via wireless control of membrane electron transfer.
Diseases and histopathological findings from lesional pinnae of 10 bats
Authors: Boone Johann M. , Fountain Kay , Williams Jonathan , Lloyd David H. , Killick Rowena , Rodriguez Barbón Alberto , Stidworthy Mark F. , Loeffler Anette
Published: July 2021

Pinnae are vital structures for echolocation and survival in many species of bats. Pinnal lesions have been described as common in captive bats, but information on specific diseases affecting the pinnae is scarce. A collection of histological sections of lesional pinnae from 10 bats, archived by bat conservation centers worldwide, was examined to identify potential aetiologies of disease. No neoplastic changes were seen but all pinnae showed inflammation, most commonly intraepidermal pustular dermatitis, deep perivascular dermatitis, nodular and/or diffuse dermatitis, and panniculitis. All bats with deep inflammation had concurrent pinnal perichondritis and cartilage necrosis. Microbial overgrowth was frequent, and pyoderma was confirmed in two bats based on histopathological and culture findings. Although no single aetiological agent was identified, deep inflammation was common and severe, highlighting the potential detriment to affected bats and the need for future study of these delicate structures.
New Aspects of Uranium Ore Concentration by using Acidic Media Solutions
Authors: Aly Hanan A. S. , El‐Taher Atef , Tork Hossam S. , Abdel‐Rahman Mohamed A. E.
Published: July 2021

The present investigation aims to compare the leaching characteristics of uranium isotopes in acidic and alkaline dissolving solutions with different concentrations. The leachate of uranium is prepared from sedimentary rocks collected from SW Sinai, Egypt. The uranium isotope activity concentration was measured using gamma counting recorded by the HPGe detector. Additionally, activity ratios as well as the leaching efficiency of different uranium isotopes were calculated. Results have shown that sulfuric acid at 40 % has been able to outpace other concentrations in dissolving a higher ratio of uranium isotopes with a 1 : 4 solid to acid ratio and 2 days as soaking time.234Th contributes to the 234U activity causes a significant efficiency difference as opposed to 235U & 238U in prepared bearing solutions. The recorded pH values in a bearing solution of different samples at investigated leaching conditions were oscillated from −1.2 to 4 due to lead impurities diffusion to bearing solutions.
EFT compatible PBHs: effective spawning of the seeds for primordial black holes during inflation
Authors: Ashoorioon Amjad , Rostami Abasalt , Firouzjaee Javad T.
Published: July 2021

Abstract

Most of the inflationary scenarios that try to explain the origin of Primordial Black Holes (PBHs) from the enhancements of the power spectrum to values of order one, at the relevant scales, run into clashes with the Effective Field Theory (EFT) criteria or fail to enhance the power spectrum to such large amplitudes. In this paper, we unravel a mechanism for enhancing the power spectrum during inflation that does not use the flattening of the potential or reduction of the sound speed of scalar perturbations. The mechanism is based on this observation in the formalism of Extended EFT of inflation (EEFToI) with the sixth order polynomial dispersion relation for scalar perturbations that if the quartic coefficient in the dispersion relation is negative and smaller than a certain threshold, the amplitude of the power spectrum is enhanced substantially. The instability mechanism must arrange to kick in at the scales of interest related to the mass of the PBHs one would like to produce, which can be ten(s) of solar mass PBHs, suitable for LIGO events, or 10−17− 10−13 solar mass PBHs, which can comprise the whole dark matter energy density. We argue that the strong coupling is avoided for the range of parameters that the mechanisms enhance the power spectrum to the required amount.
Sharp boundaries for the swampland
Authors: Caron-Huot Simon , Mazáč Dalimil , Rastelli Leonardo , Simmons-Duffin David
Published: July 2021

Abstract

We reconsider the problem of bounding higher derivative couplings in consistent weakly coupled gravitational theories, starting from general assumptions about analyticity and Regge growth of the S-matrix. Higher derivative couplings are expected to be of order one in the units of the UV cutoff. Our approach justifies this expectation and allows to prove precise bounds on the order one coefficients. Our main tool are dispersive sum rules for the S-matrix. We overcome the difficulties presented by the graviton pole by measuring couplings at small impact parameter, rather than in the forward limit. We illustrate the method in theories containing a massless scalar coupled to gravity, and in theories with maximal supersymmetry.
Interior product, Lie derivative and Wilson line in the KBc subsector of open string field theory
Authors: Hata Hiroyuki , Takeda Daichi
Published: July 2021

Abstract

The open string field theory of Witten (SFT) has a close formal similarity with Chern-Simons theory in three dimensions. This similarity is due to the fact that the former theory has concepts corresponding to forms, exterior derivative, wedge product and integration over the manifold. In this paper, we introduce the interior product and the Lie derivative in the KBc subsector of SFT. The interior product in SFT is specified by a two-component “tangent vector” and lowers the ghost number by one (like the ordinary interior product maps a p-form to (p − 1)-form). The Lie derivative in SFT is defined as the anti-commutator of the interior product and the BRST operator. The important property of these two operations is that they respect the KBc algebra.

Deforming the original (K, B, c) by using the Lie derivative, we can consider an infinite copies of the KBc algebra, which we call the KBc manifold. As an application, we construct the Wilson line on the manifold, which could play a role in reproducing degenerate fluctuation modes around a multi-brane solution.
Some New Rational Gushel Fourfolds
Authors: Staglianò Giovanni
Published: July 2021

We provide explicit equations and parameterizations of some new rational Gushel–Mukai fourfolds of special type.
Primary metabolic processes as drivers of leaf ageing
Authors: Kanojia Aakansha , Shrestha Deny K. , Dijkwel Paul P.
Published: July 2021

Ageing in plants is a highly coordinated and complex process that starts with the birth of the plant or plant organ and ends with its death. A vivid manifestation of the final stage of leaf ageing is exemplified by the autumn colours of deciduous trees. Over the past decades, technological advances have allowed plant ageing to be studied on a systems biology level, by means of multi-omics approaches. Here, we review some of these studies and argue that these provide strong support for basic metabolic processes as drivers for ageing. In particular, core cellular processes that control the metabolism of chlorophyll, amino acids, sugars, DNA and reactive oxygen species correlate with leaf ageing. However, while multi-omics studies excel at identifying correlative processes and pathways, molecular genetic approaches can provide proof that such processes and pathways control ageing, by means of knock-out and ectopic expression of predicted regulatory genes. Therefore, we also review historic and current molecular evidence to directly test the hypotheses unveiled by the systems biology approaches. We found that the molecular genetic approaches, by and large, confirm the multi-omics-derived hypotheses with notable exceptions, where there is scant evidence that chlorophyll and DNA metabolism are important drivers of leaf ageing. We present a model that summarises the core cellular processes that drive leaf ageing and propose that developmental processes are tightly linked to primary metabolism to inevitably lead to ageing and death.
Total body irradiation as part of conditioning regimens in childhood leukemia—long-term outcome, toxicity, and secondary malignancies
Authors: Gruen Arne , Exner Sebastian , Kühl Jörn-Sven , von Stackelberg Arend , Budach Volker , Stromberger Carmen , Boehmer Dirk
Published: July 2021

Background

Total body irradiation (TBI) is an established part of conditioning regimens prior to stem cell transplantation in childhood leukemia but is associated with long-term toxicity. We retrospectively analyzed survival, long-term toxicity, and secondary malignancies in a pooled cohort of pediatric patients (pts.) treated with the same TBI regimen.

Methods

Analyzed were 109 pts. treated between September 1996 and November 2015. Conditioning treatment according to EBMT guidelines and the ALL SCTped 2012 FORUM trial consisted of chemotherapy (CT) and TBI with 2 Gy b.i.d. on 3 consecutive days to a total dose of 12 Gy. Median follow-up was 97.9 months (2–228 months).

Results

Overall survival (OS) in our cohort at 2, 5, and 10 years was 86.1, 75.5, and 63.0%, respectively. Median survival was not reached. Long-term toxicity developed in 47 pts. After chronically abnormal liver and kidney parameters in 31 and 7 pts., respectively, growth retardation was the most frequent finding as seen in 13 pts. Secondary malignancies were rare (n = 3).

Conclusion

TBI-containing conditioning regimens in pediatric stem cell transplantation (SCT) are highly effective. Efforts to replace TBI- with CT-containing regimens have only been successful in subgroups of pts. Although we could show long-term toxicity in 43% of pts., overall survival was 63% at 10 years. Still, long-term effects such as growth retardation can permanently impact the pts.’ quality of life and functioning. Along with new substances, efforts should be undertaken to optimize TBI techniques and accompany the treatment by systematic follow-up programs beyond 5 years to improve detection of rare events.
Development of B. carinata with super-high erucic acid content through interspecific hybridization
Authors: Roslinsky Vicky , Falk Kevin C. , Gaebelein Roman , Mason Annaliese S. , Eynck Christina
Published: July 2021

Key message

Disomic alien chromosome addition Brassica carinata lines with super-high erucic acid content were developed through interspecific hybridization with B. juncea and characterized using molecular, cytological and biochemical techniques.

Brassica carinata [A.] Braun (BBCC, 2n = 34) is a climate-resilient oilseed. Its seed oil is high in erucic acid (> 40%), rendering it well suited for the production of biofuel and other bio-based applications. To enhance the competitiveness of B. carinata with high erucic B. napus (HEAR), lines with super-high erucic acid content were developed through interspecific hybridization. To this end, a fad2B null allele from Brassica juncea (AABB, 2n = 36) was introgressed into B. carinata, resulting in a B. carinata fad2B mutant with erucic acid levels of over 50%. Subsequently, the FAE allele from B. rapa spp. yellow sarson (AA, 2n = 20) was transferred to the fad2B B. carinata line, yielding lines with erucic acid contents of up to 57.9%. Molecular analysis using the Brassica 90 K Illumina Infinium™ SNP genotyping array identified these lines as disomic alien chromosome addition lines, with two extra A08 chromosomes containing the BrFAE gene. The alien chromosomes from B. rapa were clearly distinguished by molecular cytogenetics in one of the addition lines. Analysis of microspore-derived offspring and hybrids from crosses with a CMS B. carinata line showed that the transfer rate of the A08 chromosome into male gametes was over 98%, resulting in almost completely stable transmission of an A08 chromosome copy into the progeny. The increase in erucic acid levels was accompanied by changes in the proportions of other fatty acids depending on the genetic changes that were introduced in the interspecific hybrids, providing valuable insights into erucic acid metabolism in Brassica.
DR15-DQ6 remains dominantly protective against type 1 diabetes throughout the first five decades of life
Authors: Thomas Nicholas J. , Dennis John M. , Sharp Seth A. , Kaur Akaal , Misra Shivani , Walkey Helen C. , Johnston Desmond G. , Oliver Nick S. , Hagopian William A. , Weedon Michael N. , Patel Kashyap A. , Oram Richard A.
Published: July 2021

Aims/hypothesis

Among white European children developing type 1 diabetes, the otherwise common HLA haplotype DR15-DQ6 is rare, and highly protective. Adult-onset type 1 diabetes is now known to represent more overall cases than childhood onset, but it is not known whether DR15-DQ6 is protective in older-adult-onset type 1 diabetes. We sought to quantify DR15-DQ6 protection against type 1 diabetes as age of onset increased.

Methods

In two independent cohorts we assessed the proportion of type 1 diabetes cases presenting through the first 50 years of life with DR15-DQ6, compared with population controls. In the After Diabetes Diagnosis Research Support System-2 (ADDRESS-2) cohort (n = 1458) clinician-diagnosed type 1 diabetes was confirmed by positivity for one or more islet-specific autoantibodies. In UK Biobank (n = 2502), we estimated type 1 diabetes incidence rates relative to baseline HLA risk for each HLA group using Poisson regression. Analyses were restricted to white Europeans and were performed in three groups according to age at type 1 diabetes onset: 0–18 years, 19–30 years and 31–50 years.

Results

DR15-DQ6 was protective against type 1 diabetes through to age 50 years (OR < 1 for each age group, allp < 0.001). The following ORs for type 1 diabetes, relative to a neutral HLA genotype, were observed in ADDRESS-2: age 5–18 years OR 0.16 (95% CI 0.08, 0.31); age 19–30 years OR 0.10 (0.04, 0.23); and age 31–50 years OR 0.37 (0.21, 0.68). DR15-DQ6 also remained highly protective at all ages in UK Biobank. Without DR15-DQ6, the presence of major type 1 diabetes high-risk haplotype (either DR3-DQ2 or DR4-DQ8) was associated with increased risk of type 1 diabetes.

Conclusions/interpretation

HLA DR15-DQ6 confers dominant protection from type 1 diabetes across the first five decades of life.

Graphical abstract
A continuum theory for mineral solid solutions undergoing chemo-mechanical processes
Authors: Clavijo Santiago P. , Espath Luis , Sarmiento Adel , Calo Victor M.
Published: July 2021

Recent studies on metamorphic petrology as well as microstructural observations suggest the influence of mechanical effects upon chemically active metamorphic minerals. Thus, the understanding of such a coupling is crucial to describe the dynamics of geomaterials. In this effort, we derive a thermodynamically consistent framework to characterize the evolution of chemically active minerals. We model the metamorphic mineral assemblages as a solid-species solution where the species mass transport and chemical reaction drive the stress generation process. The theoretical foundations of the framework rely on modern continuum mechanics, thermodynamics far from equilibrium, and the phase-field model. We treat the mineral solid solution as a continuum body, and following the Larché and Cahn network model, we define displacement and strain fields. Consequently, we obtain a set of coupled chemo-mechanical equations. We use the aforementioned framework to study single minerals as solid solutions during metamorphism. Furthermore, we emphasise the use of the phase-field framework as a promising tool to model complex multi-physics processes in geoscience. Without loss of generality, we use common physical and chemical parameters found in the geoscience literature to portrait a comprehensive view of the underlying physics. Thereby, we carry out 2D and 3D numerical simulations using material parameters for mineral solid solutions to showcase and verify the chemo-mechanical interactions of mineral solid solutions that undergo spinodal decomposition, chemical reactions, and deformation.
Analysis of dimensional accuracy for micro-milled areal material measures with kinematic simulation
Authors: Klauer Katja , Eifler Matthias , Kirsch Benjamin , Böß Volker , Seewig Jörg , Aurich Jan C.
Published: July 2021

The calibration of areal surface topography measuring instruments is of high relevance to estimate the measurement uncertainty and to guarantee the traceability of the measurement results. Calibration structures for optical measuring instruments must be sufficiently small to determine the limits of the instruments.

Besides other methods, micro-milling is a suitable process for manufacturing areal material measures. For the manufacturing by micro-milling with ball end mills, the tool radius (effective cutter radius) is the corresponding limiting factor: if the tool radius is too large to penetrate the concave profile details without removing the surrounding material, deviations from the target geometry will occur. These deviations can be detected and excluded before experimental manufacturing with the aid of a kinematic simulation.

In this study, a kinematic simulation model for the prediction of the dimensional accuracy of micro-milled areal material measures is developed and validated. Subsequently, a radius study is conducted to determine how the tool radius r of the tool influences the dimensional accuracy of an areal crossed sinusoidal (ACS) geometry according to ISO 25178-70 [1] with a defined amplitude d and period length p. The resulting theoretical surface texture parameters are evaluated and compared to the target values. It was shown that the surface texture parameters deviate from the nominal values depending on the effective cutter radius used. Based on the results of the study, it can be determined with which effective tool radius the measurands Sa and Sq of the material measures are best met. The ideal effective radius for the application considered is between 50 and 75 μm.
Operational complexity and right linear grammars
Authors: Dassow Jürgen
Published: July 2021

For a regular language L, let $${{\,\mathrm{Var}\,}}(L)$$

Var

(
L
)

be the minimal number of nonterminals necessary to generate L by right linear grammars. Moreover, for natural numbers $$k_1,k_2,\ldots ,k_n$$

k
1

,

k
2

,
…
,

k
n

and an n-ary regularity preserving operation f, let $$g_f^{{{\,\mathrm{Var}\,}}}(k_1,k_2,\ldots ,k_n)$$

g
f

Var

(

k
1

,

k
2

,
…
,

k
n

)

be the set of all numbers k such that there are regular languages $$L_1,L_2,\ldots , L_n$$

L
1

,

L
2

,
…
,

L
n

such that $${{\,\mathrm{Var}\,}}(L_i)=k_i$$

Var

(

L
i

)

=

k
i

for $$1\le i\le n$$

1
≤
i
≤
n

and $${{\,\mathrm{Var}\,}}(f(L_1,L_2,\ldots , L_n))=k$$

Var

(
f

(

L
1

,

L
2

,
…
,

L
n

)

)
=
k

. We completely determine the sets $$g_f^{{{\,\mathrm{Var}\,}}}$$

g
f

Var

for the operations reversal, Kleene-closures $$+$$
+
and $$*$$

∗

, and union; and we give partial results for product and intersection.
Heat capacity, entropy, configurational entropy, and viscosity of magnesium silicate glasses and liquids
Authors: Majzlan Juraj , Tangeman Jean A. , Dachs Edgar
Published: July 2021

In this work, five Mg-silicate glasses with compositions between MgSiO$$_3$$

3

and Mg$$_2$$

2

SiO$$_4$$

4

were synthesized by aerodynamic levitation combined with laser melting. Low-temperature heat capacity ($$C_p$$

C
p

) was measured (by relaxation calorimetry in the range 2–310 K) for all of them, with the resulting vibrational entropies at T = 298.15 K: sample MG50 with composition Mg$$_{0.996}$$

0.996

SiO$$_{2.996}$$

2.996

and entropy 72.88 J mol$$^{-1}$$

-
1

K$$^{-1}$$

-
1

; MG54 Mg$$_{1.174}$$

1.174

SiO$$_{3.174}$$

3.174

78.54; MG58 Mg$$_{1.364}$$

1.364

SiO$$_{3.364}$$

3.364

85.05; MG62 Mg$$_{1.611}$$

1.611

SiO$$_{3.611}$$

3.611

91.40; and MG67 Mg$$_{1.907}$$

1.907

SiO$$_{3.907}$$

3.907

102.75. Heat capacity of the glasses is higher than that of the corresponding crystal mixtures below 200 K but plunges below the C$$_{p,\mathrm{crystal}}$$

p
,
crystal

at higher temperatures. High-temperature $$C_p$$

C
p

was measured (by differential scanning calorimetry in the range 300–970 K) for MG50 and MG67 up to $$\approx $$
≈
1000 K. Using our $$C_p$$

C
p

data, selected data for entropies of fusion, $$C_p$$

C
p

of crystals, and fictive temperatures, the configurational entropy ($$S_\mathrm{conf}$$

S
conf

) at glass transition temperature ($$T_\mathrm{g}$$

T
g

) were calculated. For the near-forsterite glass MG67, the $$S_\mathrm{conf}$$

S
conf

is 1.9 J mol$$^{-1}$$

-
1

K$$^{-1}$$

-
1

at $$T_\mathrm{g}$$

T
g

= 1040 K. As this small value is a difference of several large numbers, its uncertainty is relatively high; we consider a conservative estimate of 15 J mol$$^{-1}$$

-
1

K$$^{-1}$$

-
1

. Using the expression $$\log \eta = A + B/[T S_\mathrm{conf}(T)]$$

log
η
=
A
+
B
/
[
T

S
conf

(
T
)

]

, the available experimental viscosities ($$\eta $$
η
) and the temperature-dependent configurational entropy from our work, we refined the parameters $$A = -2.34$$

A
=
-
2.34

and $$B = 76,500$$

B
=
76
,
500

for this equation, with $$S_\mathrm{conf} (T) = 1.90+(83.7 \ln (T/1040))$$

S
conf

(
T
)

=
1.90
+

(
83.7
ln

(
T
/
1040
)

)

. The configurational entropy for the enstatitic MG50 glass is 16.8 J mol$$^{-1}$$

-
1

K$$^{-1}$$

-
1

at $$T_\mathrm{g}$$

T
g

= 1063 K. The presented data can be combined with enthalpies of formation and thermophysical properties of Mg-silicate glasses for models that could elucidate geological and geophysical observations in the crust and mantle of the Earth.
Management of cell death in parasitic infections
Authors: Bosurgi Lidia , Rothlin Carla V.
Published: July 2021

For a long time, host cell death during parasitic infection has been considered a reflection of tissue damage, and often associated with disease pathogenesis. However, during their evolution, protozoan and helminth parasites have developed strategies to interfere with cell death so as to spread and survive in the infected host, thereby ascribing a more intriguing role to infection-associated cell death. In this review, we examine the mechanisms used by intracellular and extracellular parasites to respectively inhibit or trigger programmed cell death. We further dissect the role of the prototypical “eat-me signal” phosphatidylserine (PtdSer) which, by being exposed on the cell surface of damaged host cells as well as on some viable parasites via a process of apoptotic mimicry, leads to their recognition and up-take by the neighboring phagocytes. Although barely dissected so far, the engagement of different PtdSer receptors on macrophages, by shaping the host immune response, affects the overall infection outcome in models of both protozoan and helminth infections. In this scenario, further understanding of the molecular and cellular regulation of the PtdSer exposing cell-macrophage interaction might allow the identification of new therapeutic targets for the management of parasitic infection.
Correction to: Injuries of the isolated larynx-hyoid complex in post-mortem computed tomography (PMCT) and post-mortem fine preparation (PMFP) - a comparison of 54 forensic cases
Authors: Treitl Karla Maria , Aigner Laura Isabel , Gazov Evgenij , Fischer Florian , Schinner Regina , Schmid-Tannwald Christine , Kirchhoff Sonja , Scherr Michael Karl
Published: July 2021

A Correction to this paper has been published: 10.1007/s00330-021-08135-x
Experimental evaluation of methodologies for single transient cavitation bubble generation in liquids
Authors: Podbevšek Darjan , Lokar Žiga , Podobnikar Jure , Petkovšek Rok , Dular Matevž
Published: July 2021

Single bubble dynamics are of fundamental importance for understanding the underlying mechanisms in liquid–vapor transition phenomenon known as cavitation. In the past years, numerous studies were published and results were extrapolated from one technique to another and further on to “real-world” cavitation. In the present paper, we highlight the issues of using various experimental approaches to study the cavitation bubble phenomenon and its effects. We scrutinize the transients bubble generation mechanisms behind tension-based and energy deposition-based techniques and overview the physics behind the bubble production. Four vapor bubble generation methods, which are most commonly used in single bubble research, are directly compared in this study: the pulsed laser technique, a high- and low-voltage spark discharge and the tube arrest method. Important modifications to the experimental techniques are implemented, demonstrating improvement of the bubble production range, control and repeatability. Results are compared to other similar techniques from the literature, and an extensive report on the topic is given in the scope of this work. Simple-to-implement techniques are presented and categorized herein, in order to help with future experimental design. Repeatability and sphericity of the produced bubbles are examined, as well as a comprehensive overview on the subject, listing the bubble production range and highlighting the attributes and limitation for the transient cavitation bubble techniques.

Graphic abstract
Correction to: Surgical management of peripheral nerve sheath tumours in children, with special consideration of neurofibromatoses
Authors: Zipfel Julian , Al-Hariri Meizer , Gugel Isabel , Haas-Lude Karin , Grimm Alexander , Warmann Steven , Krimmel Michael , Mautner Victor-Felix , Tatagiba Marcos , Schuhmann Martin U.
Published: July 2021

A correction to this paper has been published: https://doi.org/10.1007/s00381-021-05228-2
Diastolic dysfunction in individuals with and without heart failure with preserved ejection fraction
Authors: Wenzel Jan-Per , Kellen Ramona Bei der , Magnussen Christina , Blankenberg Stefan , Schrage Benedikt , Schnabel Renate , Nikorowitsch Julius
Published: July 2021

Aim

Left ventricular diastolic dysfunction (DD), a common finding in the general population, is considered to be associated with heart failure with preserved ejection faction (HFpEF). Here we evaluate the prevalence and correlates of DD in subjects with and without HFpEF in a middle-aged sample of the general population.

Methods and results

From the first 10,000 participants of the population-based Hamburg City Health Study (HCHS), 5913 subjects (mean age 64.4 ± 8.3 years, 51.3% females), qualified for the current analysis. Diastolic dysfunction (DD) was identified in 753 (12.7%) participants. Of those, 11.2% showed DD without HFpEF (ALVDD) while 1.3% suffered from DD with HFpEF (DDwHFpEF). In multivariable regression analysis adjusted for major cardiovascular risk factors, ALVDD was associated with arterial hypertension (OR 2.0, p < 0.001) and HbA1c (OR 1.2, p = 0.007). Associations of both ALVDD and DDwHFpEF were: age (OR 1.7, p < 0.001; OR 2.7, p < 0.001), BMI (OR 1.2, p < 0.001; OR 1.6, p = 0.001), and left ventricular mass index (LVMI). In contrast, female sex (OR 2.5, p = 0.006), atrial fibrillation (OR 2.6, p = 0.024), CAD (OR 7.2, p < 0.001) COPD (OR 3.9, p < 0.001), and QRS duration (OR 1.4, p = 0.005) were strongly associated with DDwHFpEF but not with ALVDD.

Conclusion

The prevalence of DD in a sample from the first 10,000 participants of the population-based HCHS was 12.7% of whom 1.3% suffered from HFpEF. DD with and without HFpEF showed significant associations with different major cardiovascular risk factors and comorbidities warranting further research for their possible role in the formation of both ALVDD and DDwHFpEF.
Analysis of tribological behaviour of titanium nitride-coated stainless steel with the use of wavelet-based methods
Authors: Łępicka Magdalena , Górski Grzegorz , Grądzka-Dahlke Małgorzata , Litak Grzegorz , Ambrożkiewicz Bartłomiej
Published: July 2021

Tribological behaviour is characterized by the strong nonlinear effects in its response, which are hardly identified with standard signal processing methods. One of the challenges in the analysis of wear phenomena is identification of its propagation and potential quantification. In our study, we propose application of wavelet-based methods, i.e. continuous wavelet transform and scale index for analysis of the dynamical response in the tribological pair. The analysed parameter will be the coefficient of friction, which is slightly changing with wear of the tribological pair. The performed analysis shows the variable response of the system in each considered state. Moreover, results obtained with wavelets are useful for its determination. The proposed methods can be particularly useful in the transportation applications, where the quantification of the friction force between the sliding counterparts is a crucial parameter, responsible for the power losses. Early and efficient identification of wear allows to predict damage and avoid undesirable downtime or time-consuming exchange of a worn out part.
Soil Denitrification, the Missing Piece in the Puzzle of Nitrogen Budget in Lowland Agricultural Basins
Authors: Soana Elisa , Vincenzi Fabio , Colombani Nicolò , Mastrocicco Micòl , Fano Elisa Anna , Castaldelli Giuseppe
Published: July 2021

Denitrification is a key process buffering the environmental impacts of agricultural nitrate loads but, at present, remains the least understood and poorly quantified sink in nitrogen budgets at the watershed scale. The present work deals with a comprehensive and detailed analysis of nitrogen sources and sinks in the Burana–Volano–Navigabile basin, the southernmost portion of the Po River valley (Northern Italy), an intensively cultivated (> 85% of basin surface) low-lying landscape. Agricultural census data, extensive monitoring of surface–groundwater interactions, and laboratory experiments targeting N fluxes and pools were combined to provide reliable estimates of soil denitrification at the basin scale. In the agricultural soils of the basin, nitrogen inputs exceeded outputs by nearly 40% (~ 80 kg N ha−1year−1), but this condition of potential N excess did not translate into widespread nitrate pollution. The general scarcity of inorganic nitrogen species in groundwater and soils indicated limited leakage and storage. Multiple pieces of evidence supported that soil denitrification was the process that needed to be introduced in the budget to explain the fate of the missing nitrogen. Denitrification was likely boosted in the soils of the studied basin, prone to waterlogged conditions and consequently oxygen-limited, owing to peculiar features such as fine texture, low hydraulic conductivity, and shallow water table. The present study highlighted the substantial contribution of soil denitrification to balancing nitrogen inputs and outputs in agricultural lowland basins, a paramount ecosystem function preventing eutrophication phenomena.
Sex-specific growth of nestlings of the Whiskered Tern Chlidonias hybrida, a species with sexual size dimorphism and female brood desertion
Authors: Banach Agata , Neubauer Grzegorz , Flis Adam , Ledwoń Mateusz
Published: July 2021

The growth of a nestling during the first few weeks after hatching is crucial for its further life and is sensitive to the conditions experienced during this period. Among species exhibiting Sexual Size Dimorphism (SSD), one of the most important factors influencing growth parameters is the sex of the hatchlings. In this study, we tested whether sex and other factors (hatching date, egg volume, brood size and sex ratio in the brood) were related to sex on growth parameters in Whiskered Tern(Chlidonias hybrida) chicks. In this species, males are 3%–10% larger than females when adult. At hatching, only the total head length was greater in males than females, but values close to fledging were greater for most of the measured parameters (3%—tarsus, 4%—total head length, 13%—body mass). Moreover, the maximum body mass growth rate was higher in males but females entered the rapid growth phase somewhat earlier and achieved the final total head length sooner. Nestling growth was also significantly correlated with brood size and hatching date, though mostly negatively (e.g. lower tarsus and total head length asymptote, lower maximum growth rate and growth rate constant of total head length in bigger and later clutches). The occurrence of SSD during the nestling period and higher maximum growth rate of body mass in males indicates that the costs of raising sons may be higher than of raising daughters. However, we did not find evidence of either sex-biased nestling mortality or skewed sex ratio.
Immundefiziente Labortiere im System des Tierschutzrechts
Authors: Iglauer Franz , Martínez José , Schenkel Johannes
Published: July 2021

Zucht und Haltung immundefizienter Labortiere wurden bislang nicht als Tierversuch gewertet, soweit
die Tiere mit an Sicherheit grenzender Wahrscheinlichkeit nicht aufgrund des Immundefekts leiden müssen.
Das aufgrund des Wahrscheinlichkeitsmaßstabs hinzunehmende Restrisiko, insbesondere durch äußere
Ereignisse hat sich in der versuchstierkundlichen Praxis nicht realisiert. Trotzdem wertet die EU-Kommission
nunmehr Zucht und Haltung immundefizienter Labortiere grundsätzlich als Tierversuch – mit erheblichem
administrativem Mehraufwand in den mit Tieren forschenden Wissenschaften und der behördlichen Praxis.
Im Folgenden wird aus versuchstierkundlicher und rechtlicher Perspektive festgestellt, dass diese Neubewertung
der Kommission weder sachgemäß noch verhältnismäßig ist.