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Attachment of human noroviruses to histo blood group antigens (HBGAs) is essential for infection, but how this binding event promotes the infection of host cells is unknown. Here, we employ protein NMR experiments supported by mass spectrometry and crystallography to study HBGA binding to the P-domain of a prevalent virus strain (GII.4). We report a highly selective transformation of asparagine 373, located in an antigenic loop adjoining the HBGA binding site, into an iso-aspartate residue. This spontaneous post-translational modification (PTM) proceeds with an estimated half-life of a few days at physiological temperatures, independent of the presence of HBGAs but dramatically affecting HBGA recognition. Sequence conservation and the surface-exposed position of this PTM suggest an important role in infection and immune recognition for many norovirus strains. Attachment of human noroviruses to histo blood group antigens (HBGAs) is essential for infection. Here the authors report that an asparagine residue located near the HBGA-attachment site can convert into an iso-aspartate residue through spontaneous deamidation and influence HBGA recognition.

Despite the improvement of therapeutic options, melanoma patients with advanced metastatic disease are still in high need of durable treatments. Analysis of clinical data from patients receiving targeted and/or immunotherapy, along with genetic and functional studies in preclinical melanoma models, demonstrates the key role of the microphthalmia-associated transcription factor (MITF) throughout disease progression, and provides a solid rationale for its therapeutic inhibition. However, direct targeting of MITF or other basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factors is unprecedented. Here, we report on the discovery of ligands for the DNA binding domain of MITF, using fragment-based screening (FBS) by nuclear magnetic resonance (NMR). Initial fragments, binding the kink pocket of MITF very weakly, are optimized to sub-micromolar affinities by structure-based design enabled by X-ray crystallography and biophysics. Furthermore, NMR experiments and molecular dynamics simulations reveal a dynamic conformational exchange between helices in the asymmetric homodimer, a phenomenon that is perturbed by ligand binding. This work advances our knowledge on direct targeting of bHLH-LZ DNA binding domains and sets the basis to further explore pharmacological inhibition of MITF. In this work, fragments identified by 19F-NMR are optimized into submicromolar binders of the MITF transcription factor. These results support direct targeting of bHLH-LZ DNA binding domains and provide a foundation for the development of new melanoma therapies.

Crystal structures of enzymes are indispensable to understanding their mechanisms on a molecular level. It, however, remains challenging to determine which structures are adopted in solution, especially for dynamic complexes. Here, we study the bilobed decapping enzyme Dcp2 that removes the 5′ cap structure from eukaryotic mRNA and thereby efficiently terminates gene expression. The numerous Dcp2 structures can be grouped into six states where the domain orientation between the catalytic and regulatory domains significantly differs. Despite this wealth of structural information it is not possible to correlate these states with the catalytic cycle or the activity of the enzyme. Using methyl transverse relaxation-optimized NMR spectroscopy, we demonstrate that only three of the six domain orientations are present in solution, where Dcp2 adopts an open, a closed, or a catalytically active state. We show how mRNA substrate and the activator proteins Dcp1 and Edc1 influence the dynamic equilibria between these states and how this modulates catalytic activity. Importantly, the active state of the complex is only stably formed in the presence of both activators and the mRNA substrate or the m7GDP decapping product, which we rationalize based on a crystal structure of the Dcp1:Dcp2:Edc1:m7GDP complex. Interestingly, we find that the activating mechanisms in Dcp2 also result in a shift of the substrate specificity from bacterial to eukaryotic mRNA.

Research during the last decade has led to several competing concepts of bioavailability and to many more methods to measure bioavailability. One reason for disagreement is the confusion of two fundamentally different parameters, accessible quantity and chemical activity. The accessible quantity describes a mass of contaminants, which can become available to, for example, biodegradation and biouptake. It can be determined with mild extraction schemes or depletive sampling techniques. The chemical activity, on the other hand, quantifies the potential for spontaneous physicochemical processes, such as diffusion, sorption, and partitioning. For instance, the chemical activity of a sediment contaminant determines its equilibrium partitioning concentration in sediment‐dwelling organisms, and differences in chemical activity determine the direction and extent of diffusion between environmental compartments. Chemical activity can be measured with equilibrium sampling devices and, theoretically, is closely linked to fugacity and freely dissolved concentration. The distinction between accessibility and chemical activity is outlined, and the benefits and limitation of both endpoints are provided. Finally, examples of how to measure and apply them are presented.

Since computed tomography (CT) is a part of standard diagnostic protocol in pancreatic ductal adenocarcinoma (PDAC), we have evaluated the value of CT for sarcopenia screening in patients with PDAC, intending to expand the diagnostic value of tomographic studies. In our study, we included 177 patients with available CT images. Two groups were formed: Group 1 consisted of 117 patients with PDAC in various locations and stages and Group 2, or the control group, consisted of 60 \"nominally healthy\" patients with other somatic non-oncological diseases. The body mass index (BMI) was defined as a ratio of patient’s weight to the square of their height (kg/m 2 ). CT-based body composition analysis was performed using commercially available software with evaluation of sarcopenia using skeletal muscle index (SMI, cm 2 /m 2 ). Based on the SMI values, sarcopenia was found in 67.5% of patients (79 out of 117) in the first patient group. It was found more frequently in males (42 out of 56; 75%) than in females (37 out of 61; 60.6%). Additionally, we observed a decrease in muscle mass (hidden sarcopenia) in 79.7% in patients with a normal BMI. Even in overweight patients, sarcopenia was found in 50% (sarcopenic obesity). In patients with reduced BMI sarcopenia was found in all cases (100%). Statistically significant difference of SMI between two groups was revealed for both sexes (p = 0,0001), with no significant difference between groups in BMI. BMI is an inaccurate value for the assessment of body composition as it does not reflect in the details the human body structure. As SMI may correlate with the prognosis, decreased muscle mass- especially \"hidden\" sarcopenia or sarcopenic obesity- should be reported. The use of CT-based evaluation of sarcopenia and sarcopenic obesity will allow for a better treatment response assessment in patients with cancer cachexia.

Purpose To determine incidence and risk factors for traumatic graft rupture following primary and revision anterior cruciate ligament (ACL) reconstruction. Methods All cases of isolated ACL reconstructions (primary or revision) performed at our institution between January 2007 and December 2010 were included. From this group of 2467 primary reconstructions (32.4 ± 12.2 years) and 448 revision reconstructions (33.0 ± 10.4 years), we identified all patients who underwent revision ACL reconstruction following traumatic graft rupture in further course and all patients who underwent contralateral primary ACL reconstruction until January 2014. Age, gender, time from index procedure and graft diameter (for hamstring autografts) were analysed in terms of being a potential risk factor for graft rupture. Results Within a follow-up period of 5.0 ± 1.1 years (3.0–7.0), a total of 82 traumatic graft ruptures were identified, resulting in an incidence of 2.8 %. Seventy-three cases were seen following primary reconstructions (3.0 %), and nine cases following revision reconstructions (2.0 %), respectively (n.s.). Age younger than 25 years was identified as a risk factor for both groups ( p  = 0.001 and p  = 0.008; odds ratio 6.0 and 6.4, respectively). In primary reconstruction, male patients had a higher risk of graft rupture compared with females (3.7 vs. 1.6 %; p  = 0.005), and the first year after index procedure was associated with a higher risk of graft rupture compared with the following ( p  < 0.001). Graft diameter did not influence the risk of graft rupture. Incidence of contralateral ACL rupture was 3.1 %, which was not different to the incidence of graft rupture ipsilaterally (n.s.). Conclusion No statistically significant differences were seen between graft rupture incidence of primary and revision ACL reconstructions. Young age (<25 years) and short time to the index procedure (especially within the first year) were confirmed as risk factors for graft rupture in both groups. Male gender was a risk factor for primary reconstructions. Graft diameter had no influence on graft rupture rates. No difference in incidence of graft rupture compared to ACL rupture on the contralateral side was apparent. Level of evidence Retrospective case series, Level IV.

Low-power energy harvesting has been demonstrated as a feasible alternative for the power supply of next-generation smart sensors and IoT end devices. In many cases, the output of kinetic energy harvesters is an alternating current (AC) requiring rectification in order to supply the electronic load. The rectifier design and selection can have a considerable influence on the energy harvesting system performance in terms of extracted output power and conversion losses. This paper presents a quantitative comparison of three passive rectifiers in a low-power, low-voltage electromagnetic energy harvesting sub-system, namely the full-wave bridge rectifier (FWR), the voltage doubler (VD), and the negative voltage converter rectifier (NVC). Based on a variable reluctance energy harvesting system, we investigate each of the rectifiers with respect to their performance and their effect on the overall energy extraction. We conduct experiments under the conditions of a low-speed rotational energy harvesting application with rotational speeds of 5 rpm to 20 rpm, and verify the experiments in an end-to-end energy harvesting evaluation. Two performance metrics—power conversion efficiency (PCE) and power extraction efficiency (PEE)—are obtained from the measurements to evaluate the performance of the system implementation adopting each of the rectifiers. The results show that the FWR with PEEs of 20% at 5 rpm to 40% at 20 rpm has a low performance in comparison to the VD (40–60%) and NVC (20–70%) rectifiers. The VD-based interface circuit demonstrates the best performance under low rotational speeds, whereas the NVC outperforms the VD at higher speeds (>18 rpm). Finally, the end-to-end system evaluation is conducted with a self-powered rpm sensing system, which demonstrates an improved performance with the VD rectifier implementation reaching the system’s maximum sampling rate (40 Hz) at a rotational speed of approximately 15.5 rpm.

A model based noise correction algorithm was developed to improve the accuracy of CT perfusion (CTp) blood flow (BF) measurements affected by image noise. The algorithm used tissue attenuation curves (TACs), generated by convolving an impulse response function (IRF) with an arterial input function (AIF) averaged from 59 patient datasets. Gaussian noise was introduced to simulate noise, and BF was measured using deconvolution. The algorithm iteratively compared BF without added noise against noise-impacted BF to estimate ground-truth BF (GTBF). Performance was evaluated with digital perfusion phantoms (DPPs) for GTBF values of 5–420 ml/100 ml/min and added noise (standard deviation 25 HU), measuring absolute difference from GTBF and contrast-to-noise ratio (CNR). For clinical evaluation, CTp data from 14 pancreatic ductal adenocarcinoma (PDAC) patients was used. For DPPs, noise-impacted and noise-corrected BF were 140 ± 111 ml/100 ml/min and 131 ± 125 ml/100 ml/min, compared to GTBF of 131 ± 127 ml/100 ml/min. Post-correction, the absolute difference reduced from 18.8 to 3.6 ml/100 ml/min, with CNR improving from 2.52 to 2.66. In clinical datasets, BF for parenchyma shifted from 148 ± 50.8 to 84.1 ± 96.9 ml/100 ml/min, and for PDAC, from 45.8 ± 20.3 to 13.3 ± 18.7 ml/100 ml/min. The algorithm reduced noise impact, improving BF accuracy and CNR, with potential for lower-dose CT without compromising diagnostic quality.

For a period exceeding five decades, industrial and scientific communities, in conjunction with regulators, have utilized a complexified, standardized system (e.g., OECD, Organisation for Economic Co-operation and Development; ISO, International Organization for Standardization; ASTM, American Society for Testing and Materials; CEN, Comité Européen de Normalisation) for the estimation of biodegradability of organic compounds. This system has been adopted in numerous countries worldwide and has also been integrated into European legislation (REACH, registration, authorisation, and restriction of chemicals). In recent years, a number of deficiencies have been identified in the standardized biodegradation test systems. This comprehensive review sets out the fields in which improvements are necessary to set up the next generation of reliable, standardized biodegradation tests. The main focus of the review is the challenges and modifications needed to test difficult-to-test compounds such as volatile, hydrophobic compounds, UVCBs (unknown or variable composition, complex reaction products or biological materials), water-soluble polymers, and plastics. Recent advances in the characterization of inocula for biodegradation tests are also addressed, which offer a valuable opportunity to enhance the reliability and reproducibility of biodegradation assays. Moreover, the potential for predicting biodegradation in the environment is a subject that is discussed in this text. Key points • It is essential that the OECD system of biodegradability tests be subjected to a thorough re-examination and further technical development. • It is evident that UVCBs, hydrophobic compounds, and polymers present particular challenges in the context of OECD/ISO biodegradation tests. • It is necessary that inocula for OECD/ISO-based biodegradation tests are characterized in a much more comprehensive manner.