Quantification of short‐term transformations of proglacial landforms in a temperate, debris‐charged glacial landsystem, Kvíárjökull, Iceland

Proglacial areas are dynamic landscapes and important indicators of geomorphic changes related to climate warming. Systematic and repeat surveys of landforms presently evolving on glacier forelands facilitate the quantification of rates of change and an improved understanding of the processes generating those changes. We report short-term (2014–2022) transformations of the proglacial landscape in front of Kvíárjökull, SE Iceland, and place them in a longer-term context of glacial landsystem evolution using aerial image archives since 1945. Short-term quantification uses a time series of uncrewed aerial vehicle (UAV) surveys, processed utilizing a structure-from-motion (SfM) workflow, to produce digital elevation models (DEMs) and orthophoto mosaics. The land elements surveyed include a kame terrace staircase, an outwash plain, an ice-cored hummocky moraine complex and ice-cored hummocky terrain with discontinuous sinuous ridges, for which elevation and volumetric changes are quantified. The kame terraces between 2014 and 2022 and the outwash plain between 2016 and 2022 were mainly stable with, respectively, 87% and 85% of their surfaces showing no change. The ice-cored hummocky terrain with discontinuous sinuous ridges underwent a volume loss of 64,632 m3 in 2016–2022, with a maximum surface lowering of ≤9 m. The most dynamic land element was the ice-cored hummocky moraine complex, with transformations recorded for more than 87% of its area in 2014–2022; the surface was lowered by ≤23 m in some places, with a total volume loss of 365,773 m3. Our results confirm the ongoing degradation of ice-cored moraine and outwash complexes at variable rates related to buried ice volume and age of deglaciation. The evolution of chaotic hummocky terrain from debris-covered glacier ice, glacitectonic thrust masses, outwash fans/heads and complex englacial esker networks is an important modern analogue for informing palaeoglaciological reconstructions

Serendipitous alkylation of a Plk1 ligand uncovers a new binding channel

We obtained unanticipated synthetic byproducts from alkylation of the δ[superscript 1] nitrogen (N3) of the histidine imidazole ring of the polo-like kinase-1 (Plk1) polo-box domain (PBD)-binding peptide PLHSpT. For the highest-affinity byproduct, bearing a C[subscript 6]H[subscript 5](CH[subscript 2])[subscript 8]– group, a Plk1 PBD cocrystal structure revealed a new binding channel that had previously been occluded. An N-terminal PEGylated version of this peptide containing a hydrolytically stable phosphothreonyl residue (pT) bound the Plk1 PBD with affinity equal to that of the non-PEGylated parent but showed markedly less interaction with the PBDs of the two closely related proteins Plk2 and Plk3. Treatment of cultured cells with this PEGylated peptide resulted in delocalization of Plk1 from centrosomes and kinetochores and in chromosome misalignment that effectively induced mitotic block and apoptotic cell death. This work provides insights that might advance efforts to develop Plk1 PBD-binding inhibitors as potential Plk1-specific anticancer agents.National Institutes of Health (U.S.) (Grant GM60594)National Institutes of Health (U.S.) (Grant GM68762)National Institutes of Health (U.S.) (Grant CA112967

Evaluation of the Influence of Processing Parameters in Structure-from-Motion Software on the Quality of Digital Elevation Models and Orthomosaics in the Context of Studies on Earth Surface Dynamics

The fully automated Structure-from-Motion approach for developing digital elevation models and orthomosaics has been known and used in photogrammetry for at least 15 years. Years of practice and experience have allowed researchers to provide a solid description of the applicability and limitations of this method. That being said, the impact of input processing parameters in software on the quality of photogrammetric products has yet to be fully ascertained empirically. This study is aimed at identifying the most advantageous processing workflow to fill this research gap by testing 375 different setup variations in the Agisoft Metashape software for the same set of images acquired using an unmanned aerial vehicle in a proglacial area. The purpose of the experiment was to determine three workflows: (1) the fastest, which has the shortest calculation time; (2) the best quality, which is as accurate as possible, regardless of the time taken for the calculations; and (3) the optimal, which is a compromise between accuracy and calculation time. Each of the 375 processing setup variations was assessed based on final product accuracy, i.e., orthomosaics and digital elevation models. The three workflows were selected based on calculating the height differences between the digital elevation models and the control points that did not participate in their georeferencing. The analyses of the root mean square errors (RMSE) and standard deviations indicate that excluding some of the optimization parameters during the camera optimization stage results in high RMSE and an increase in the values of standard deviation errors. Furthermore, it was shown that increasing the detail of individual processing steps in software does not always positively affect the accuracy of the resulting models. The experiment resulted in the development of three different workflows in the form of Python scripts for Agisoft Metashape software, which will help users to process image sets efficiently in the context of earth surface dynamics studies

Dynamic and Multi-Pharmacophore Modeling for Designing Polo-Box Domain Inhibitors

The polo-like kinase 1 (Plk1) is a critical regulator of cell division that is overexpressed in many types of tumors. Thus, a strategy in the treatment of cancer has been to target the kinase activity (ATPase domain) or substrate-binding domain (Polo-box Domain, PBD) of Plk1. However, only few synthetic small molecules have been identified that target the Plk1-PBD. Here, we have applied an integrative approach that combines pharmacophore modeling, molecular docking, virtual screening, and in vitro testing to discover novel Plk1-PBD inhibitors. Nine Plk1-PBD crystal structures were used to generate structure-based hypotheses. A common pharmacophore model (Hypo1) composed of five chemical features was selected from the 9 structure-based hypotheses and used for virtual screening of a drug-like database consisting of 159,757 compounds to identify novel Plk1-PBD inhibitors. The virtual screening technique revealed 9,327 compounds with a maximum fit value of 3 or greater, which were selected and subjected to molecular docking analyses. This approach yielded 93 compounds that made good interactions with critical residues within the Plk1-PBD active site. The testing of these 93 compounds in vitro for their ability to inhibit the Plk1-PBD, showed that many of these compounds had Plk1-PBD inhibitory activity and that compound Chemistry_28272 was the most potent Plk1-PBD inhibitor. Thus Chemistry_28272 and the other top compounds are novel Plk1-PBD inhibitors and could be used for the development of cancer therapeutics

Preliminary outcomes of the European multicentre experience with the ZSI 375 artificial urinary sphincter for treatment of stress urinary incontinence in men

Introduction The ZSI 375 is a new artificial urinary sphincter utilised in men suffering from stress urinary incontinence (SUI). We present the first European multicentre study on the effectiveness of ZSI 375. Material and methods This study was conducted in a retrospective, non-randomized format in centres across Europe. Between May 2009 and December 2014, ZSI 375 was fitted in 109 SUI patients following radical prostatectomy, transurethral resection of prostate (TURP), rectal surgery and high intensity focused ultrasound (HIFU). Patients with history of pelvic radiotherapy or previous surgical treatment for incontinence or stricture were excluded from the series. Follow-up was completed by December 2016. The key outcome measures included overall improvement and complication rates. Results A total of 109 patients in 10 European centres were recruited and had the ZSI 375 device implanted. The average patient age was 72 years old. The indication for the majority of patients was incontinence following radical prostatectomy (100/109 patients, 91.74%). On average, patients were incontinent for 48.6 months prior to treatment. All patients used ≥4 pads daily at baseline and thus were classified as suffering from ‘severe incontinence’. The average follow-up until the final visit was 43 months. The pad usage decreased to 0.84 on average by the last visit. There were no reported cases of device infection. A total of 9 patients had urethral cuff erosion (8.25%),which was the most common complication in this series. A further 3 men (2.75%) experienced mechanical failure requiring subsequent device reimplantation. The implantation of the ZSI 375 device was considered successful in 92.66% of patients. Conclusions The ZSI 375 is an effective surgical treatment option in men with severe stress urinary incontinence

Identification of High Affinity Polo-like Kinase 1 (Plk1) Polo-box Domain Binding Peptides Using Oxime-Based Diversification

In an effort to develop improved binding antagonists of the polo-like kinase 1 (Plk1) polo-box domain (PBD), we optimized interactions of the known high affinity 5-mer peptide PLHSpT using oxime-based post solid-phase peptide diversification of the N-terminal Pro residue. This allowed us to achieve up to two orders of magnitude potency enhancement. An X-ray crystal structure of the highest affinity analogue in complex with Plk1 PBD revealed new binding interactions in a hydrophobic channel that had been occluded in X-ray structures of the unliganded protein. This study represents an important example where amino acid modification by post solid-phase oxime ligation can facilitate the development of protein–protein interaction inhibitors by identifying new binding pockets that would not otherwise be accessible to coded amino acid residues.National Institutes of Health (U.S.) (Grant R01 GM60594)National Institutes of Health (U.S.) (Grant ES015339