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Abstract IONIS‐FXIRX (BAY2306001) is an antisense oligonucleotide that inhibits the synthesis of coagulation factor XI (FXI) and has been investigated in healthy volunteers and patients with end‐stage renal disease (ESRD). FXI‐LICA (BAY2976217) shares the same RNA sequence as IONIS‐FXIRX but contains a GalNAc‐conjugation that facilitates asialoglycoprotein receptor (ASGPR)‐mediated uptake into hepatocytes. FXI‐LICA has been studied in healthy volunteers and is currently investigated in patients with ESRD on hemodialysis. We present a model‐informed bridging approach that facilitates the extrapolation of the dose‐exposure‐FXI relationship from IONIS‐FXIRX to FXI‐LICA in patients with ESRD and, thus, supports the selection of FX‐LICA doses being investigated in patients with ESRD. A two‐compartment pharmacokinetic (PK) model, with mixed first‐ and zero‐order subcutaneous absorption and first‐order elimination, was combined with an indirect response model for the inhibitory effect on the FXI synthesis rate via an effect compartment. This PK/pharmacodynamic model adequately described the median trends, as well as the interindividual variabilities for plasma drug concentration and FXI activity in healthy volunteers of IONIS‐FXIRX and FXI‐LICA, and in patients with ESRD of IONIS‐FXIRX. The model was then used to predict dose‐dependent steady‐state FXI activity following repeat once‐monthly doses of FXI‐LICA in a virtual ESRD patient population. Under the assumption of similar ASGPR expression in patients with ESRD and healthy volunteers, doses of 40 mg, 80 mg, and 120 mg FXI‐LICA are expected to cover the target range of clinical interest for steady‐state FXI activity in the phase IIb study of FXI‐LICA in patients with ESRD undergoing hemodialysis.

Cell-free secretomes represent a promising new therapeutic avenue in regenerative medicine, and γ-irradiation of human peripheral blood mononuclear cells (PBMCs) has been shown to promote the release of paracrine factors with high regenerative potential. Recently, the use of alternative irradiation sources, such as artificially generated β- or electron-irradiation, is encouraged by authorities. Since the effect of the less hazardous electron-radiation on the production and functions of paracrine factors has not been tested so far, we compared the effects of γ- and electron-irradiation on PBMCs and determined the efficacy of both radiation sources for producing regenerative secretomes. Exposure to 60 Gy γ-rays from a radioactive nuclide and 60 Gy electron-irradiation provided by a linear accelerator comparably induced cell death and DNA damage. The transcriptional landscapes of PBMCs exposed to either radiation source shared a high degree of similarity. Secretion patterns of proteins, lipids, and extracellular vesicles displayed similar profiles after γ- and electron-irradiation. Lastly, we detected comparable biological activities in functional assays reflecting the regenerative potential of the secretomes. Taken together, we were able to demonstrate that electron-irradiation is an effective, alternative radiation source for producing therapeutic, cell-free secretomes. Our study paves the way for future clinical trials employing secretomes generated with electron-irradiation in tissue-regenerative medicine.

A genetic algorithm (GA) was used in this study to develop a standard penetration test (SPT)-based design method for the axial capacity of driven piles. A total of 72 pile load tests was collected from literature and divided into two groups based on their measurements. The first group had the load-transfer distribution measurements for extracting both the unit side and tip resistances. These unit resistances were correlated by the GA with soil measurements and pile properties to develop the design method. The second group, where only the total capacity measurements were available, were used to validate the new design method and compare its performance with three existing SPT-based design methods. The new GA-derived design method considers nonlinear relationships with the effective stress and pile length and provides an unbiased prediction with a low coefficient of variation (COV) of 40.0 %, while the three existing methods overestimate the capacity by a factor of 1.62 to 1.65 with a high COV of 40.3 % to 52.8 %, which could result in an under design of pile foundations. This study shows that the GA was able to obtain complex relationships with great accuracy and the new design method can be applied to new cases reasonably well.

The lack of scalable, high-quality insulators is a major problem hindering the progress on electronic devices built from 2D materials. Here, the authors review the current state-of-the-art and the future prospects of suitable insulators for 2D technologies.

Current methods to generate sequence-function data at large scale are either technically complex or limited to specific applications. Here the authors introduce DNA-based phenotypic recording to overcome these limitations and enable deep learning for accurate prediction of function from sequence.

Developing information systems and collaboration support in the field of intensive home care is faced with challenging conditions of empirical work for requirements elicitation. On the one hand, the huge variety of aspects and situation-related characteristics require a deliberate analysis and close interaction with caregivers and relatives to identify the needs and constraints of technical support. On the other hand, the relevant places are hardly accessible. To be able to visit and observe the clients in situ, consent is needed by the caregiver, the client, and the relatives living with them, and a high level of privacy and confidentiality has to be maintained. Based on an ethnographical data gathering and analysis, this article provides a comprehensive categorization that characterizes the work of caregivers in intensive home, to make the work of information system designers in this field more efficient: activities, interpersonal interaction, documentation, qualification, interaction with technology, client autonomy, history of medical records, and feedback on intensive home care. Finally, these categories are compared with related work of socio-technical design of health care information systems.

The main problem in the realization of the rights to a favorable environment, including in the Arctic regions, is the difficulty of establishing and proving the causal link between economic activity and damage to health. Modern scientific achievements make it possible to establish the connection between the micro-environment and health and, therefore, to provide indemnification of damage. But the causal link between degradation of macro environment and human health is less studied, which leads to complications in judicial practice.

NeuroLF is a dedicated brain PET system with an octagonal prism shape housed in a scanner head that can be positioned around a patient’s head. Because it does not have MR or CT capabilities, attenuation correction based on an estimation of the attenuation map is a crucial feature. In this article, we demonstrate this method on [18F]FDG PET brain scans performed with a low-resolution proof of concept prototype of NeuroLF called BPET. We perform an affine registration of a template PET scan to the uncorrected emission image, and then apply the resulting transform to the corresponding template attenuation map. Using a whole-body PET/CT system as reference, we quantitively show that this method yields comparable image quality (0.893 average correlation to reference scan) to using the reference µ-map as obtained from the CT scan of the imaged patient (0.908 average correlation). We conclude from this initial study that attenuation correction using template registration instead of a patient CT delivers similar results and is an option for patients undergoing brain PET.

Previous studies have demonstrated an involvement of chromatin-remodelling SWI/SNF complexes in the development of prostate cancer, suggesting both tumor suppressor and oncogenic activities. SMARCD1/BAF60A, SMARCD2/BAF60B, and SMARCD3/BAF60C are mutually exclusive accessory subunits that confer functional specificity and are components of all known SWI/SNF subtypes. To assess the role of SWI/SNF in prostate tumorigenesis, we studied the functions and functional relations of the SMARCD family members. Performing RNA-seq in LnCAP cells grown in the presence or absence of dihydrotestosterone, we found that the SMARCD proteins are involved in the regulation of numerous hormone-dependent AR-driven genes. Moreover, we demonstrated that all SMARCD proteins can regulate AR-downstream targets in androgen-depleted cells, suggesting an involvement in the progression to castration-resistance. However, our approach also revealed a regulatory role for SMARCD proteins through antagonization of AR-signalling. We further demonstrated that the SMARCD proteins are involved in several important cellular processes such as the maintenance of cellular morphology and cytokinesis. Taken together, our findings suggest that the SMARCD proteins play an important, yet paradoxical, role in prostate carcinogenesis. Our approach also unmasked the complex interplay of paralogue SWI/SNF proteins that must be considered for the development of safe and efficient therapies targeting SWI/SNF.

Cycloalkenes are bulk petrochemicals that are currently obtained from fossil fuels. Here, the authors developed multi enzyme pathways in combination with a Ru-catalyzed metathesis reaction for the one-pot production of cyclopentene, cyclohexene, and cycloheptene from olive oil-derived intermediates.

Abstract Background Cathepsin K is an attractive therapeutic target for diseases in which bone resorption is excessive such as osteoporosis and osteoarthritis (OA). The current paper characterized the pharmacological profile of the potent and selective cathepsin K inhibitor, MIV-711, in vitro and in cynomolgus monkeys, and assessed translation to human based on a single dose clinical study in man. Methods The potency and selectivity of MIV-711 were assessed in vitro using recombinant enzyme assays and differentiated human osteoclasts. MIV-711 was administered to healthy cynomolgus monkeys (3–30 µmol/kg, p.o.). Plasma levels of MIV-711 and the bone resorption biomarker CTX-I were measured after single dose experiments, and urine levels of CTX-I, NTX-I and CTX-II biomarkers were measured after repeat dose experiments. The safety, pharmacokinetics and pharmacodynamics (serum CTX-I) of MIV-711 were assessed in human healthy subjects after single ascending doses from 20 to 600 mg. Results MIV-711 was a potent inhibitor of human cathepsin K (Ki: 0.98 nmol/L) with > 1300-fold selectivity towards other human cathepsins. MIV-711 inhibited human osteoclast-mediated bone resorption with an IC50 value of 43 nmol/L. Single oral doses of MIV-711 to monkeys reduced plasma levels of CTX-I in a dose-dependent fashion by up to 57% at trough. The effect on CTX-I was linearly correlated to the plasma exposure of MIV-711, while the efficacy duration outlasted plasma exposure. Repeat oral dosing with MIV-711 also reduced urinary levels of the bone resorption biomarkers CTX-I (by 93%) and NTX-I (by 71%) and the cartilage degradation biomarker CTX-II (by 71%). MIV-711 was safe and well-tolerated when given as single ascending doses to healthy subjects. MIV-711 reduced serum CTX-I levels in a dose-dependent manner by up to 79% at trough. The relationship between MIV-711 exposure and effects on these biomarkers in humans was virtually identical when compared to the corresponding monkey data. Conclusions MIV-711 is a potent and selective cathepsin K inhibitor with dose-dependent effects on biomarkers of bone and cartilage degradation in monkey and human. Taken together, MIV-711 shows promise for the treatment of bone and cartilage related disorders in humans, such as OA. Trial Registration EudraCT number 2011-003024-12, registered on June 22nd 2011

This study aims to identify the histological basis for the extraordinary, fast movement of the style in Marantaceae. Although this explosive pollination mechanism was subject of many studies, quantitative measurements to document volumetric changes have never been conducted. Based on physical parameters and limitations (poroelastic time), the movement itself is by far too fast to be explained by turgor changes solely. Therefore, we address the hypothesis that the style contains elastic structures to store energy allowing the fast movement. We provide an experimental approach in Goeppertia bachemiana to identify histological differences of styles in various states, i.e., steady, unreleased, and released state. Cross and longitudinal sections were used to reconstruct the cell volume in different sectors of the style. Histological data were discussed with respect to a putative water shift (turgor movement) and elastic instabilities that were proposed to explain the style movement of Marantaceae. Current data show, that the upper epidermis is under tensile stress in the unreleased state. After style release, the lower side of the style revealed an enormous water up-take. According to our results, we hypothesize that the fast style movement of G. bachemiana is likely based on an elastically stretched upper epidermis, whereas a “soaking tissue” at the lower side presumably mediates the up curling of the style. The experimental data show that at least for G. bachemiana, physical limitations such as the poroelastic time are suitable parameters to predict movements that are based on elastic instabilities.

Tests of the Bell-Kochen-Specker theorem aim at showing that the measurement statistics of a single qutrit are incompatible with noncontextual realism. Here, the authors use a superconducting qutrit with deterministic readouts to violate a noncontextuality inequality, ruling out several loopholes.

Rational design in metabolic engineering is often difficult and limited to small screens, favouring construction of compressed smart libraries. Here the authors introduce RedLibs, an algorithm to design combinatorial RBS libraries to allow pathway optimization with minimal experimental resources.

The paper contains an overview of the development and erection of the Viennese town fortifications during the reign of Ferdinand I, its medieval requirements, difficult financing and contemporary influences on the construction work. Furthermore, a brief comparison with other residences, namely Graz, Wiener Neustadt and Prague, is made.

The explosive pollination mechanism of the prayer plants (Marantaceae) is unique among plants. After a tactile stimulus by a pollinator, the style curls up rapidly and mediates pollen exchange. It is still under discussion whether this explosive movement is released electrophysiologically, i.e. by a change in the membrane potential (as in Venus flytrap), or purely mechanically. In the present study, electrophysiological experiments are conducted to clarify the mechanism. Artificial release experiments (chemical and electrical) and electrophysiological measurements were conducted with two phylogenetically distant species, Goeppertia bachemiana (E. Morren) Borchs. & S. Suárez and Donax canniformis (G. Forst.) K. Schum. Electric responses recorded after style release by extracellular measurements are characterised as variation potentials due to their long repolarization phase and lack of self-perpetuation. In both species, chemical and electric stimulations do not release the style movement. It is concluded that the style movement in Marantaceae is released mechanically by relieving the tissue pressure. Accordingly, the variation potential is an effect of the movement and not its cause. The study exemplarily shows that fast movements in plants are not necessarily initiated by electric changes of the membrane as known from the Venus flytrap.

Carbon monoxide (CO) dampens pro-inflammatory responses in a peroxisome proliferator-activated receptor-γ (PPARγ) and p38 mitogen-activated protein kinase (MAPK) dependent manner. Previously, we demonstrated that CO inhibits lipopolysaccharide (LPS)-induced expression of the proinflammatory early growth response-1 (Egr-1) transcription factor in macrophages via activation of PPARγ. Here, we further characterize the molecular mechanisms by which CO modulates the activity of PPARγ and Egr-1 repression. We demonstrate that CO enhances SUMOylation of PPARγ which we find was attributed to mitochondrial ROS generation. Ectopic expression of a SUMOylation-defective PPARγ-K365R mutant partially abolished CO-mediated suppression of LPS-induced Egr-1 promoter activity. Expression of a PPARγ-K77R mutant did not impair the effect of CO. In addition to PPARγ SUMOylation, CO-activated p38 MAPK was responsible for Egr-1 repression. Blocking both CO-induced PPARγ SUMOylation and p38 activation, completely reversed the effects of CO on inflammatory gene expression. In primary macrophages isolated form C57/BL6 male mice, we identify mitochondrial ROS formation by CO as the upstream trigger for the observed effects on Egr-1 in part through uncoupling protein 2 (UCP2). Macrophages derived from bone marrow isolated from Ucp2 gene Knock-Out C57/BL6 mice (Ucp2(-/-)), produced significantly less ROS with CO exposure versus wild-type macrophages. Moreover, absence of UCP2 resulted in a complete loss of CO mediated Egr-1 repression. Collectively, these results indentify p38 activation, PPARγ-SUMOylation and ROS formation via UCP2 as a cooperative system by which CO impacts the inflammatory response.

Objective. Image quality in whole-body MRI (WB-MRI) may be degraded by faulty radiofrequency (RF) coil elements or mispositioning of the coil arrays. Phantom-based quality control (QC) is used to identify broken RF coil elements but the frequency of these acquisitions is limited by scanner and staff availability. This work aimed to develop a scan-specific QC acquisition and processing pipeline to detect broken RF coil elements, which is sufficiently rapid to be added to the clinical WB-MRI protocol. The purpose of this is to improve the quality of WB-MRI by reducing the number of patient examinations conducted with suboptimal equipment. Approach. A rapid acquisition (14 s additional acquisition time per imaging station) was developed that identifies broken RF coil elements by acquiring images from each individual coil element and using the integral body coil. This acquisition was added to one centre's clinical WB-MRI protocol for one year (892 examinations) to evaluate the effect of this scan-specific QC. To demonstrate applicability in multi-centre imaging trials, the technique was also implemented on scanners from three manufacturers. Main results . Over the course of the study RF coil elements were flagged as potentially broken on five occasions, with the faults confirmed in four of those cases. The method had a precision of 80% and a recall of 100% for detecting faulty RF coil elements. The coil array positioning measurements were consistent across scanners and have been used to define the expected variation in signal. Significance . The technique demonstrated here can identify faulty RF coil elements and positioning errors and is a practical addition to the clinical WB-MRI protocol. This approach was fully implemented on systems from two manufacturers and partially implemented on a third. It has potential to reduce the number of clinical examinations conducted with suboptimal hardware and improve image quality across multi-centre studies., (Creative Commons Attribution license.)

The British and Irish Chapter of the International Society for Magnetic Resonance in Medicine (BIC-ISMRM) held a workshop entitled "Steps on the path to clinical translation" in Cardiff, UK, on 7th September 2022. The aim of the workshop was to promote discussion within the MR community about the problems and potential solutions for translating quantitative MR (qMR) imaging and spectroscopic biomarkers into clinical application and drug studies. Invited speakers presented the perspectives of radiologists, radiographers, clinical physicists, vendors, imaging Contract/Clinical Research Organizations (CROs), open science networks, metrologists, imaging networks, and those developing consensus methods. A round-table discussion was held in which workshop participants discussed a range of questions pertinent to clinical translation of qMR imaging and spectroscopic biomarkers. Each group summarized their findings via three main conclusions and three further questions. These questions were used as the basis of an online survey of the broader UK MR community., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Primary central nervous system lymphoma (PCNSL) has variable imaging appearances, which overlap with those of glioblastoma (GBM), thereby necessitating invasive tissue diagnosis. We aimed to investigate whether a rapid filtration histogram analysis of clinical MRI data supports the distinction of PCNSL from GBM. Ninety tumours (PCNSL n = 48, GBM n = 42) were analysed using pre-treatment MRI sequences (T 1 -weighted contrast-enhanced (T 1 CE), T 2 -weighted (T 2 ), and apparent diffusion coefficient maps (ADC)). The segmentations were completed with proprietary texture analysis software (TexRAD version 3.3). Filtered (five filter sizes SSF = 2-6 mm) and unfiltered (SSF = 0) histogram parameters were compared using Mann-Whitney U non-parametric testing, with receiver operating characteristic (ROC) derived area under the curve (AUC) analysis for significant results. Across all ( n = 90) tumours, the optimal algorithm performance was achieved using an unfiltered ADC mean and the mean of positive pixels (MPP), with a sensitivity of 83.8%, specificity of 8.9%, and AUC of 0.88. For subgroup analysis with >1/3 necrosis masses, ADC permitted the identification of PCNSL with a sensitivity of 96.9% and specificity of 100%. For T 1 CE-derived regions, the distinction was less accurate, with a sensitivity of 71.4%, specificity of 77.1%, and AUC of 0.779. A role may exist for cross-sectional texture analysis without complex machine learning models to differentiate PCNSL from GBM. ADC appears the most suitable sequence, especially for necrotic lesion distinction.

BackgroundStenosis of the internal carotid artery has a higher risk for stroke. Many investigations have focused on structure and plaque composition as signs of plaque vulnerability, but few studies have analyzed hemodynamic changes in the brain as a risk factor.PurposeTo use 3-T MRI methods including contrast material-enhanced MR angiography, carotid plaque imaging, and arterial spin labeling (ASL) to identify imaging parameters that best help distinguish between asymptomatic and symptomatic participants with carotid stenosis.Materials and MethodsParticipants with carotid stenosis from two ongoing prospective studies who underwent ASL and carotid plaque imaging with use of 3-T MRI in the same setting from 2014 to 2018 were studied. Participants were assessed clinically for recent symptoms (transient ischemic attack or stroke) and divided equally into symptomatic and nonsymptomatic groups. Reviewers were blinded to the symptomatic status and MRI scans were analyzed for the degree of stenosis, plaque surface structure, presence of intraplaque hemorrhage (IPH), circle of Willis collaterals, and the presence and severity of arterial transit artifacts (ATAs) at ASL imaging. MRI findings were correlated with symptomatic status by using t tests and the Fisher exact test.ResultsA total of 44 participants (mean age, 71 years ± 10 [standard deviation]; 31 men) were evaluated. ATAs were seen only in participants with greater than 70% stenosis (16 of 28 patients; P < .001) and were associated with absence of anterior communicating artery (13 of 16 patients; P = .003). There was no association between history of symptoms and degree of stenosis (27 patients with ≥70% stenosis and 17 patients with <70%; P = .54), IPH (12 patients with IPH and 32 patients without IPH; P = .31), and plaque surface structure (17 patients with irregular or ulcerated plaque and 27 with smooth plaque; P = .54). Participants with ATAs ( n = 16) were more likely to be symptomatic than were those without ATAs ( n = 28) ( P = .004). Symptomatic status also was associated with the severity of ATAs ( P = .002).ConclusionArterial transit artifacts were the only factor associated with recent ischemic symptoms in participants with carotid stenosis. The degree of stenosis, plaque ulceration, and intraplaque hemorrhage were not associated with symptomatic status.© RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Zaharchuk in this issue.