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1.
Curr Biol ; 34(12): R562-R563, 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38889674

ABSTRACT

Sauropterygians were the stratigraphically longest-ranging clade of Mesozoic marine reptiles with a global fossil record spanning ∼180 million years1. However, their early evolution has only been known from what is now the Northern Hemisphere, extending across the northern and trans-equatorial western margins of the Tethys paleo-ocean1 after the late-Early Triassic (late Olenekian, ∼248.8 million years [Ma] ago2), and via possible trans-Arctic migration1 to the Eastern Panthalassa super-ocean prior to the earliest Middle Triassic (Olenekian-earliest Anisian3,4, ∼247 Ma). Here, we describe the geologically oldest sea-going reptile from the Southern Hemisphere - a nothosaur (basal sauropterygian5) from the Middle Triassic (Anisian, after ∼246 Ma6) of New Zealand. Time-scaled ancestral range estimations thus reveal an unexpected circum-Gondwanan high-paleolatitude (>60° S7) dispersal from a northern Tethyan origination center. This coincides with the adaptive diversification of sauropterygians after the end-Permian mass extinction8 and suggests that rapid globalization accompanied their initial radiation in the earliest Mesozoic.


Subject(s)
Biological Evolution , Fossils , Reptiles , Animals , Fossils/anatomy & histology , Reptiles/anatomy & histology , Reptiles/classification , Reptiles/physiology , New Zealand , Animal Distribution , Aquatic Organisms , Internationality , Phylogeny
2.
Prim Health Care Res Dev ; 25: e4, 2024 Jan 08.
Article in English | MEDLINE | ID: mdl-38186355

ABSTRACT

AIMS: This study evaluates long-term changes in physical activity and its associations with various predictors after a behavior change program at the Norwegian Healthy Life Centers. BACKGROUND: Physical activity is recommended and is part of public health strategies to prevent noncommunicable diseases. METHODS: This longitudinal cohort, based on a controlled randomized trial, studies a population of 116 Healthy Life Center participants in South-Western Norway who wore SenseWear Armbands to measure time spent in moderate to vigorous physical activity and sedentary time based on metabolic equivalents. The measurements were obtained at baseline, immediately post-intervention, and 24 months after baseline. Linear mixed model analyses were performed to assess predictors for change in physical activity and sedentary time. FINDINGS: High physical activity levels at baseline were maintained during the 24-month study period. Young, male participants with good self-rated health, utilizing local PA facilities were most active, and young participants utilizing local facilities were also less sedentary. The participants with higher levels of education were less active initially but caught up with the difference during follow-up. A high degree of controlled regulation, characterized by bad conscience and external pressure, predicted more sedentary behavior and a trend toward being less physically active. Autonomous motivation was associated with less time spent on sedentary behaviors. People with high self-efficacy for physical activity were more sedentary initially but showed a reduction in their sedentary behavior.The study supports the importance of attending local training facilities and adopting motivation for behavioral change that is not based on guilt and external rewards. Interventions aimed at improving physical activity among people at risk for noncommunicable diseases benefit from habitual use of local training facilities, strengthening their self-perceived health and the development of internalized motivation. However, it has not been shown to mitigate social health disparities.


Subject(s)
Noncommunicable Diseases , Sedentary Behavior , Male , Humans , Life Style , Exercise , Norway
3.
J Chem Phys ; 159(11)2023 Sep 21.
Article in English | MEDLINE | ID: mdl-37712784

ABSTRACT

Interpreting high-dimensional data from molecular dynamics simulations is a persistent challenge. In this paper, we show that for a small peptide, deca-alanine, metastable states can be identified through a neural net based on structural information alone. While processing molecular dynamics data, dimensionality reduction is a necessary step that projects high-dimensional data onto a low-dimensional representation that, ideally, captures the conformational changes in the underlying data. Conventional methods make use of the temporal information contained in trajectories generated through integrating the equations of motion, which forgoes more efficient sampling schemes. We demonstrate that EncoderMap, an autoencoder architecture with an additional distance metric, can find a suitable low-dimensional representation to identify long-lived molecular conformations using exclusively structural information. For deca-alanine, which exhibits several helix-forming pathways, we show that this approach allows us to combine simulations with different biasing forces and yields representations comparable in quality to other established methods. Our results contribute to computational strategies for the rapid automatic exploration of the configuration space of peptides and proteins.

4.
Plant Cell Environ ; 46(11): 3337-3352, 2023 11.
Article in English | MEDLINE | ID: mdl-37249162

ABSTRACT

Conservative flowering behaviours, such as flowering during long days in summer or late flowering at a high leaf number, are often proposed to protect against variable winter and spring temperatures which lead to frost damage if premature flowering occurs. Yet, due the many factors in natural environments relative to the number of individuals compared, assessing which climate characteristics drive these flowering traits has been difficult. We applied a multidisciplinary approach to 10 winter-annual Arabidopsis thaliana populations from a wide climactic gradient in Norway. We used a variable reduction strategy to assess which of 100 climate descriptors from their home sites correlated most to their flowering behaviours when tested for responsiveness to photoperiod after saturation of vernalization; then, assessed sequence variation of 19 known environmental-response flowering genes. Photoperiod responsiveness inversely correlated with interannual variation in timing of growing season onset. Time to flowering appeared driven by growing season length, curtailed by cold fall temperatures. The distribution of FLM, TFL2 and HOS1 haplotypes, genes involved in ambient temperature response, correlated with growing-season climate. We show that long-day responsiveness and late flowering may be driven not by risk of spring frosts, but by growing season temperature and length, perhaps to opportunistically maximize growth.


Subject(s)
Arabidopsis Proteins , Arabidopsis , Humans , Arabidopsis/physiology , Temperature , Arabidopsis Proteins/genetics , Arabidopsis Proteins/metabolism , Seasons , Cold Temperature , Flowers/physiology , Photoperiod , Gene Expression Regulation, Plant , MADS Domain Proteins/genetics
5.
Eur Urol ; 84(5): 484-490, 2023 11.
Article in English | MEDLINE | ID: mdl-37117109

ABSTRACT

BACKGROUND: Little is known regarding functional outcomes after robot-assisted radical cystectomy (RARC) and intracorporeal neobladder (ICNB) reconstruction. OBJECTIVE: To report on urinary continence (UC) and erectile function (EF) at 12 mo after RARC and ICNB reconstruction and investigate predictors of these outcomes. DESIGN, SETTING, AND PARTICIPANTS: We used data from a multi-institutional database of patients who underwent RARC and ICNB reconstruction for bladder cancer. SURGICAL PROCEDURE: The cystoprostatectomy sensu stricto followed the conventional steps. ICNB reconstruction was performed at the physician's discretion according to the Studer/Wiklund, S pouch, Gaston, vescica ileale Padovana, or Hautmann technique. The techniques are detailed in the video accompanying the article. MEASUREMENTS: The outcomes measured were UC and EF at 12 mo. RESULTS AND LIMITATIONS: A total of 732 male patients were identified with a median age at diagnosis of 64 yr (interquartile range 58-70). The ICNB reconstruction technique was Studer/Wiklund in 74%, S pouch in 1.5%, Gaston in 19%, vescica ileale Padovana in 1.5%, and Hautmann in 4% of cases. The 12-mo UC rate was 86% for daytime and 66% for nighttime continence, including patients who reported the use of a safety pad (20% and 32%, respectively). The 12-mo EF rate was 55%, including men who reported potency with the aid of phosphodiesterase type 5 inhibitors (24%). After adjusting for potential confounders, neobladder type was not associated with UC. Unilateral nerve-sparing (odds ratio [OR] 3.85, 95% confidence interval [CI] 1.88-7.85; p < 0.001) and bilateral nerve-sparing (OR 6.25, 95% CI 3.55-11.0; p < 0.001), were positively associated with EF, whereas age (OR 0.93, 95% CI 0.91-0.95; p < 0.001) and an American Society of Anesthesiologists score of 3 (OR 0.46, 95% CI 0.25-0.89; p < 0.02) were inversely associated with EF. CONCLUSIONS: RARC and ICNB reconstruction are generally associated with good functional outcomes in terms of UC. EF is highly affected by the degree of nerve preservation, age, and comorbidities. PATIENT SUMMARY: We investigated functional outcomes after robot-assisted removal of the bladder in terms of urinary continence and erectile function. We found that, in general, patients have relatively good functional outcomes at 12 months after surgery.


Subject(s)
Erectile Dysfunction , Robotic Surgical Procedures , Robotics , Urinary Bladder Neoplasms , Urinary Diversion , Humans , Male , Urinary Bladder/surgery , Cystectomy/adverse effects , Cystectomy/methods , Erectile Dysfunction/etiology , Treatment Outcome , Urinary Bladder Neoplasms/surgery , Urinary Bladder Neoplasms/etiology , Robotic Surgical Procedures/adverse effects , Robotic Surgical Procedures/methods , Urinary Diversion/methods
6.
Eur Urol Focus ; 2023 Feb 28.
Article in English | MEDLINE | ID: mdl-36863963

ABSTRACT

BACKGROUND: As a local treatment for prostate cancer (PCa), robot-assisted radical prostatectomy (RARP) may have a quality of life (QoL) benefit over open surgery. Recent analyses revealed substantial between-country differences in the function and symptom scale scores for the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), which is typically used to assess patient-reported QoL. Such differences could have implications for multinational studies in PCa. OBJECTIVE: To examine whether nationality is significantly associated with patient-reported QoL. DESIGN, SETTING, AND PARTICIPANTS: The study cohort comprised Dutch and German patients with PCa treated with RARP in a single high-volume prostate center from 2006 to 2018. Analyses were restricted to patients who were preoperatively continent with at least one follow-up time point. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: QoL was measured in terms of the global Quality of Life (QL) scale score and the overall summary score for the EORTC QLQ-C30. Linear mixed models for repeated-measures multivariable analyses (MVAs) were used to examine the association between nationality and both the global QL score and the summary score. MVAs were further adjusted for QLQ-C30 baseline values, age, Charlson comorbidity index, preoperative prostate-specific antigen, surgical expertise, pathological tumor and nodal stage, Gleason grade, degree of nerve-sparing, surgical margin status, 30-d Clavien-Dindo grade complications, urinary continence recovery, and biochemical recurrence/postoperative radiotherapy. RESULTS AND LIMITATIONS: For Dutch (n = 1938) versus German (n = 6410) men, the mean baseline scores were 82.8 versus 71.9 for the global QL scale score and 93.4 versus 89.7 for the QLQ-C30 summary score. Urinary continence recovery (QL: +8.9, 95% confidence interval [CI] 8.1-9.8; p < 0001) and Dutch nationality (QL: +6.9, 95% CI 6.1-7.6; p < 0001) were the strongest positive contributors to the global QL and summary scores, respectively. The main limitation is the retrospective study design. In addition, our Dutch cohort may not be representative of the general Dutch population and reporting bias cannot be ruled out. CONCLUSIONS: Our findings provide observational evidence under specific conditions involving the same setting for patients of two different nationalities suggesting that cross-national patient-reported QoL differences appear to be real and may need to be taken into consideration in multinational studies. PATIENT SUMMARY: We observed differences in the quality-of-life scores reported by Dutch and German patients with prostate cancer after they underwent robot-assisted removal of the prostate. These findings should be taken into consideration in cross-national studies.

7.
Curr Biol ; 33(5): R178-R179, 2023 03 13.
Article in English | MEDLINE | ID: mdl-36917937

ABSTRACT

Reptiles first radiated into oceanic environments after the cataclysmic end-Permian mass extinction (EPME)1, 251.9 million years (Ma) ago. The geologically oldest fossils evincing this adaptive transition have been recovered from upper-Lower Triassic (lower Spathian) strata, ∼248.8 Ma2, and postdate a landmark turnover of amphibian-dominated to reptile-dominated marine ecosystems spanning the late Smithian crisis (LSC)3, ∼249.6 Ma4 -less than ∼2.3 Ma after the EPME. Here, we report ichthyopterygian (the group including 'fish-shaped' ichthyosaurians1) remains from the Arctic island of Spitsbergen that predate the LSC in later-middle to early-late Smithian5 deposits up to ∼250 Ma. Unexpectedly, however, their large size and spongy internal bone structure indicate a fully pelagic ichthyopterygian1,6. Given this unambiguous occurrence ∼2 Ma after the EPME, these pioneering seagoing tetrapods can now be feasibly recast as mass extinction survivors instead of ecological successors2,3 within the earliest Mesozoic marine predator communities.


Subject(s)
Biological Evolution , Fossils , Animals , Ecosystem , Reptiles/anatomy & histology , Oceans and Seas , Extinction, Biological , Phylogeny
9.
Small Bus Econ (Dordr) ; : 1-25, 2023 May 22.
Article in English | MEDLINE | ID: mdl-38625186

ABSTRACT

The remarkable ascent of entrepreneurship witnessed as a scientific field over the last 4 decades has been made possible by entrepreneurship's ability to absorb theories, paradigms, and methods from other fields such as economics, psychology, sociology, geography, and even biology. The respectability of entrepreneurship as an academic discipline is now evidenced by many other fields starting to borrow from the entrepreneurship view. In the present paper, seven examples are given from this "pay back" development. These examples were first presented during a seminar at the Erasmus Entrepreneurship Event called what has the entrepreneurship view to offer to other academic fields? This article elaborates on the core ideas of these presentations and focuses on the overarching question of how entrepreneurship research impacts the development of other academic fields. We found that entrepreneurship research questions the core assumptions of other academic fields and provides new insights into the antecedents, mechanisms, and consequences of their respective core phenomena. Moreover, entrepreneurship research helps to legitimize other academic fields both practically and academically.


Entrepreneurship research questions the core assumptions of other academic fields and legitimizes them both practically and academically. Since the 1980s, entrepreneurship research has seen tremendous growth and development, establishing itself as an academic field. Entrepreneurship is also taught extensively in leading business schools around the world. Indeed, few business schools do not address entrepreneurship in their curriculum. This represents a sea change: although entrepreneurs and new ventures had a remarkable impact on society, academia barely noticed it in the 1980s. Simply put: economics and business students rarely, if ever, encountered any mention of entrepreneurship during their studies. While entrepreneurship research has now developed its own methodological toolbox, it has extensively borrowed perspectives, theories, and methods from other fields. In the 2020s, we now find that entrepreneurship scholars are sharing its toolbox with other academic fields, questioning the core assumptions of other academic fields and providing new insights into the antecedents, mechanisms, and consequences of their respective core phenomena. Moreover, entrepreneurship research helps to legitimize other academic fields both practically and academically. Hence, entrepreneurship research now plays not just an important role in entrepreneurship education, practice, and policy but also throughout many other research fields.

10.
Eur Urol Open Sci ; 46: 82-87, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36506253

ABSTRACT

Background: Since the introduction of minimally invasive surgery, the number of simulation models available for teaching new surgeons has continued to increase. Objective: To evaluate and validate use of a model for teaching robot-assisted pyeloplasty. Design setting and participants: Twenty simulated robot-assisted pyeloplasty procedures were performed by experienced (n = 4) and novice (n = 16) surgeons using a chicken crop model at two different training centers using third- and fourth-generation robotic systems. Outcome measurements and statistical analysis: We evaluated the time needed to perform the procedure, and the sufficiency and patency of the anastomosis. Participants rated the efficiency, face validity, and possible acceptance of the model as part of a structured curriculum on a scale from 0 to10. Statistical significance for comparison of results was set at p < 0.05. Results and limitations: Robot-assisted pyeloplasty was successfully performed by 75% of the participants. The completion time was significantly higher in the novice group (p = 0.016). The model was deemed to be similar to the human ureteropelvic junction by the novice group. Both groups regarded the model as a useful simulation task as part of a standardized training curriculum, with mean scores of 6.5 versus 8.69 (p = 0.046) for face validity and 8 versus 9.25 for acceptance (p = 0.053) reported by the experienced versus novice group, respectively. Limitations of the study are the costs associated with the robotic system and the unequal number of participants in the groups. Conclusions: The chicken crop model is a low-cost and reproducible simulation model for accomplishing both the resection and reconstructive steps during the learning phase for robot-assisted pyeloplasty. Patient summary: We assessed the use of chickens as a model for practicing a robot-assisted operation called pyeloplasty to fix narrowing of the ureter (the tube that drains urine from the kidney to the bladder) where it attaches to the kidney. This model can be used for simulation of robot-assisted pyeloplasty when training new robotic surgeons.

11.
Eur Urol Open Sci ; 46: 45-52, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36506259

ABSTRACT

Background: Robot-assisted partial nephrectomy (RAPN) is a challenging procedure that is influenced by a multitude of factors. Objective: To assess the impact of prior surgical experience on perioperative outcomes in RAPN. Design setting and participants: In this retrospective multicenter study, results for 2548 RAPNs performed by 25 surgeons at eight robotic referral centers were analyzed. Perioperative data for all consecutive RAPNs from the start of each individual surgeon's experience were collected, as well as the number of prior open or laparoscopic kidney surgeries, pelvic surgeries (open, laparoscopic, robotic), and other robotic interventions. Intervention: Transperitoneal or retroperitoneal RAPN. Outcome measurements and statistical analysis: The impact of prior surgical experience on operative time, warm ischemia time (WIT), major complications, and margin, ischemia, complication (MIC) score (negative surgical margins, WIT ≤20 min, no major complications) was assessed via univariate and multivariable regression analyses accounting for age, gender, body mass index (BMI), American Society of Anesthesiologists score, PADUA score, and RAPN experience. Results and limitations: BMI, PADUA score, and surgical experience in RAPN had a strong impact on perioperative outcomes. A plateau effect for the learning curve was not observed. Prior laparoscopic kidney surgery significantly reduced the operative time (p < 0.001) and WIT (p < 0.001) and improved the MIC rate (p = 0.022). A greater number of prior robotic pelvic interventions decreased WIT (p = 0.011) and the rate of major complications (p < 0.001) and increased the MIC rate (p = 0.011), while prior experience in open kidney surgery did not. One limitation is the short-term follow-up. Conclusions: Mastering of RAPN is an ongoing learning process. However, prior experience in laparoscopic kidney and robot-assisted pelvic surgery seems to improve perioperative outcomes for surgeons when starting with RAPN, while experience in open surgery might not be crucial. Patient summary: In this multicenter analysis, we found that a high degree of experience in keyhole kidney surgery and robot-assisted pelvic surgery helps surgeons in achieving good initial outcomes when starting robot-assisted kidney surgery.

13.
World J Urol ; 40(12): 2955-2961, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36357604

ABSTRACT

OBJECTIVES: To assess if systematic (SBx) vs. transrectal or transperineal mpMRI-ultrasound targeted combined with systematic (TBx + SBx) biopsy confer different effects on treatment delay to radical prostatectomy measured as Gleason grade group (GGG) upgrade of prostate cancer (PCa). MATERIALS AND METHODS: We relied on a multi-institutional cohort of localized PCa patients who underwent RP in Martini-Klinik, Hamburg, or Prostate Center Northwest, Gronau, between 2014 and 2022. Analyses were restricted to PCa GGG 1-3 diagnosed at SBx (n = 4475) or TBx + SBx (n = 1282). Multivariable logistic regression modeling (MVA) predicting RP GGG upgrade of ≥ 1 was performed separately for SBx and TBx + SBx. RESULTS: Treatment delay to RP of < 90, 90-180 and 180-365 days was reported in 59%, 35% and 6.2% of SBx and in 60%, 34% and 5.9% of the TBx + SBx patients, respectively. Upgrade to GGG ≥ 4 at RP was detected in 15% of SBx patients and 0.86% of TBx patients. In MVA performed for SBx, treatment delay yielded independent predictor status (OR 1.17 95% CI 1.02-1.39, p = 0.028), whereas for TBx + SBx MVA, statistical significance was not achieved. CONCLUSION: Treatment delay remained independently associated with radical prostatectomy GGG upgrade after adjustment for clinical variables in the patients diagnosed with SBx alone, but not in those who received combined TBx + SBx. These findings can be explained through inherent misclassification rates of SBx, potentially obfuscating historical observations of natural PCa progression and potential dangers of treatment delay. Thus, mpMRI-guided combined TBx + SBx appears mandatory for prospective delay-based examinations of PCa.


Subject(s)
Prostate , Prostatic Neoplasms , Male , Humans , Prostate/diagnostic imaging , Prostate/surgery , Prostate/pathology , Prospective Studies , Time-to-Treatment , Image-Guided Biopsy , Prostatectomy , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/surgery , Magnetic Resonance Imaging
14.
J Urol ; 208(6): 1203-1213, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36001731

ABSTRACT

PURPOSE: We assessed the diagnostic yield of consecutive transperineal targeted biopsy of multiparametric magnetic resonance imaging index lesion and secondary lesion and additive systematic biopsy in patients who received combined targeted biopsy+systematic biopsy of prostate. MATERIALS AND METHODS: Of 1,467 patients with targeted biopsy+systematic biopsy, analyses were restricted to 571 patients with index lesion+secondary lesion, Prostate Imaging-Reporting and Data System score ≥3. Index lesion was defined as having the greatest Prostate Imaging-Reporting and Data System score and/or lesion volume as opposed to secondary lesion. We retrospectively compared clinically significant prostate cancer rates (ie, Gleason Grade Group ≥2) between index lesion+secondary lesion and index lesion+secondary lesion+systematic biopsy. Subgroup analyses in men with ipsilateral index lesion+secondary lesion focused on contralateral systematic biopsy. Multivariable logistic regression analyses to predict any clinically significant prostate cancer included age, previous biopsies, prostate specific antigen density, respective index lesion/secondary lesion volumes, side relation, Prostate Imaging-Reporting and Data System strata, and number of targeted biopsy and systematic biopsy cores. RESULTS: Clinically significant prostate cancer rates for index lesion+secondary lesion vs index lesion+secondary lesion+systematic biopsy were 38% vs 42% (P = .2) at expense of significantly higher median number of biopsy cores (9 vs 25, P < .001). In the subgroup with ipsilateral index lesion+secondary lesion (n = 236), contralateral systematic biopsy detected clinically significant prostate cancer in 17%. In the narrower subgroup with ipsilateral index lesion+secondary lesion (n = 131) without any clinically significant prostate cancer, contralateral systematic biopsy detected clinically significant prostate cancer in 3.8%. Multivariable logistic regression analyses confirmed contralateral systematic biopsy as independent predictor, but performed similarly without systematic biopsy information (area under the curve 87.1% vs 86.6%). CONCLUSIONS: Targeted biopsy of secondary lesion should be included in targeted biopsy protocols due to added diagnostic information. However, for targeted biopsy of index lesion+secondary lesion additional systematic biopsy is of limited informative value in terms of overall clinically significant prostate cancer detection. However, when index lesion+secondary lesion are ipsilateral, contralateral systematic biopsy should be recommended for purpose of prostate lobe information. Our results indicate great potential to reduce systematic biopsy cores and associated potential morbidity, and warrant prospective evaluation.


Subject(s)
Genital Neoplasms, Female , Multiparametric Magnetic Resonance Imaging , Prostatic Neoplasms , Male , Female , Humans , Image-Guided Biopsy/methods , Retrospective Studies , Ultrasonography, Interventional/methods , Prospective Studies , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/pathology , Magnetic Resonance Imaging/methods , Neoplasm Grading
15.
Org Biomol Chem ; 20(28): 5589-5601, 2022 07 20.
Article in English | MEDLINE | ID: mdl-35796650

ABSTRACT

The management of neurological disorders such as dementia associated with Alzheimer's or Parkinson's disease includes the use of cholinesterase inhibitors. These compounds can slow down the progression of these diseases and can also be used in the treatment of glaucoma and myasthenia gravis. The majority of the cholinesterase inhibitors used in the clinic are derived from natural products and our current paper describes the use of a small marine pharmacophore to develop potent and selective cholinesterase inhibitors. Fourteen small inhibitors were designed based on recent discoveries about the inhibitory potential of a range of related marine secondary metabolites. The compounds were evaluated, in kinetic enzymatic assays, for their ability to inhibit three different cholinesterase enzymes and it was shown that compounds with a high inhibitory activity towards electric eel and human recombinant acetylcholinesterase (IC50 between 20-70 µM) could be prepared. It was also shown that this compound class was particularly active against horse serum butyrylcholinesterase, with IC50 values between 0.8-16 µM, which is an order of magnitude more potent than the clinically used positive control neostigmine. The compounds were further tested for off-target toxicity against both human umbilical vein endothelial cells and bovine and human erythrocytes and were shown to display a low mammalian cellular toxicity. Overall, the study illustrates how the brominated dipeptide marine pharmacophore can be used as a versatile natural scaffold for the design of potent, and selective cholinesterase inhibitors.


Subject(s)
Alzheimer Disease , Cholinesterase Inhibitors , Acetylcholinesterase/metabolism , Alzheimer Disease/metabolism , Animals , Butyrylcholinesterase/metabolism , Cattle , Cholinesterase Inhibitors/chemistry , Electrophorus , Endothelial Cells/metabolism , Horses , Humans , Molecular Docking Simulation , Structure-Activity Relationship
16.
J Phys Chem B ; 126(27): 5007-5016, 2022 07 14.
Article in English | MEDLINE | ID: mdl-35792380

ABSTRACT

Capturing the autonomous self-assembly of molecular building blocks in computer simulations is a persistent challenge, requiring to model complex interactions and to access long time scales. Advanced sampling methods allow to bridge these time scales but typically need accurate low-dimensional representations of the transition pathways. In this work, we demonstrate for the self-assembly of two single-stranded DNA fragments into a ring-like structure how autoencoder neural networks can be employed to reliably provide a suitable low-dimensional representation and to expose transition pathways: The assembly proceeds through a two-step process with two distinct half-bound states, which are correctly identified by the neural net. We exploit this latent space representation to construct a Markov state model for predicting the four molecular conformations and their transition rates. We present a detailed comparison with two other low-dimensional representations based on empirically determined order parameters and a time-lagged independent component analysis (TICA). Our work opens up new avenues for the computational modeling of multistep and hierarchical self-assembly, which has proven challenging so far.


Subject(s)
Neural Networks, Computer , Computer Simulation , Molecular Conformation
17.
World J Urol ; 40(7): 1679-1688, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35670880

ABSTRACT

OBJECTIVE: To assess suitability of Comprehensive Complication Index (CCI®) vs. Clavien-Dindo classification (CDC) to capture 30-day morbidity after robot-assisted radical cystectomy (RARC). MATERIALS AND METHODS: A total of 128 patients with bladder cancer (BCa) undergoing intracorporeal RARC with pelvic lymph node dissection between 2015 and 2021 were included in a retrospective bi-institutional study, which adhered to standardized reporting criteria. Thirty-day complications were captured according to a procedure-specific catalog. Each complication was graded by the CDC and the CCI®. Multivariable linear regression (MVA) was used to identify predictors of higher morbidity. RESULTS: 381 complications were identified in 118 patients (92%). 55 (43%), 43 (34%), and 20 (16%) suffered from CDC grade I-II, IIIa, and ≥ IIIb complications, respectively. 16 (13%), 27 (21%), and 2 patients (1.6%) were reoperated, readmitted, and died within 30 days, respectively. 31 patients (24%) were upgraded to most severe complication (CCI® ≥ 33.7) when calculating morbidity burden compared to corresponding CDC grade accounting only for the highest complication. In MVA, only age was a positive estimate (0.44; 95% CI = 0.03-0.86; p = 0.04) for increased cumulative morbidity. CONCLUSION: The CCI® estimates of 30-day morbidity after RARC were substantially higher compared to CDC alone. These measurements are a prerequisite to tailor patient counseling regarding surgical approach, urinary diversion, and comparability of results between institutions.


Subject(s)
Robotic Surgical Procedures , Robotics , Urinary Bladder Neoplasms , Urinary Diversion , Cystectomy/adverse effects , Cystectomy/methods , Humans , Morbidity , Postoperative Complications/etiology , Retrospective Studies , Robotic Surgical Procedures/adverse effects , Treatment Outcome , Urinary Bladder Neoplasms/pathology , Urinary Diversion/methods
18.
PLoS One ; 17(6): e0269827, 2022.
Article in English | MEDLINE | ID: mdl-35700180

ABSTRACT

INTRODUCTION: Since the beginning of the pandemic in 2020, COVID-19 has changed the medical landscape. International recommendations for localized prostate cancer (PCa) include deferred treatment and adjusted therapeutic routines. MATERIALS AND METHODS: To longitudinally evaluate changes in PCa treatment strategies in urological and radiotherapy departments in Germany, a link to a survey was sent to 134 institutions covering two representative baseline weeks prior to the pandemic and 13 weeks from March 2020 to February 2021. The questionnaire captured the numbers of radical prostatectomies, prostate biopsies and case numbers for conventional and hypofractionation radiotherapy. The results were evaluated using descriptive analyses. RESULTS: A total of 35% of the questionnaires were completed. PCa therapy increased by 6% in 2020 compared to 2019. At baseline, a total of 69 radiotherapy series and 164 radical prostatectomies (RPs) were documented. The decrease to 60% during the first wave of COVID-19 particularly affected low-risk PCa. The recovery throughout the summer months was followed by a renewed reduction to 58% at the end of 2020. After a gradual decline to 61% until July 2020, the number of prostate biopsies remained stable (89% to 98%) during the second wave. The use of RP fluctuated after an initial decrease without apparent prioritization of risk groups. Conventional fractionation was used in 66% of patients, followed by moderate hypofractionation (30%) and ultrahypofractionation (4%). One limitation was a potential selection bias of the selected weeks and the low response rate. CONCLUSION: While the diagnosis and therapy of PCa were affected in both waves of the pandemic, the interim increase between the peaks led to a higher total number of patients in 2020 than in 2019. Recommendations regarding prioritization and fractionation routines were implemented heterogeneously, leaving unexplored potential for future pandemic challenges.


Subject(s)
COVID-19 , Prostatic Neoplasms , Humans , Male , Prostate/pathology , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/radiotherapy , Surveys and Questionnaires , Urologists
19.
J Urol ; 208(2): 333-340, 2022 08.
Article in English | MEDLINE | ID: mdl-35422136

ABSTRACT

PURPOSE: The purpose of this study was to investigate the effect of a surgically constructed bilateral peritoneal flap (PIF) as an adjunct to robot-assisted radical prostatectomy (RARP) and pelvic lymph node dissection (PLND) on the incidence of lymphoceles. MATERIALS AND METHODS: A total of 530 men with localized prostate cancer underwent a RARP with bilateral extended standardized PLND in a prospective randomized controlled trial. In group A, a PIF was created by suturing the margins of the bladder peritoneum to the ipsilateral endopelvic fascia at 2 points on each side. In group B, no PIF was created. The patients were followed 30 and 90 days after the surgery to assess the incidence, extent and treatment of lymphoceles. RESULTS: Lymphoceles occurred in 22% of group A patients and 33% of group B patients (p=0.008). Symptomatic lymphoceles were observed in 3.3% of group A patients and 8.1% of group B patients (p=0.027). Lymphoceles requiring intervention occurred significantly less frequently in group A patients (1.3%) than in group B patients (6.8%, p=0.002). The median lymphocele size was 4.3 cm in group A and 5.0 cm in group B (p=0.055). No statistically significant differences were observed in minor or major complications unrelated to lymphocele, blood loss, or surgical time between groups A and B. CONCLUSIONS: Bilateral PIFs in conjunction with RARP and PLND significantly reduce the total incidence of lymphoceles, the frequency of symptomatic lymphoceles and the rate of associated secondary interventions.


Subject(s)
Lymphocele , Prostatic Neoplasms , Robotic Surgical Procedures , Robotics , Humans , Incidence , Lymph Node Excision/adverse effects , Lymph Node Excision/methods , Lymphocele/epidemiology , Lymphocele/etiology , Lymphocele/prevention & control , Male , Pelvis , Peritoneum/surgery , Prospective Studies , Prostatectomy/adverse effects , Prostatectomy/methods , Prostatic Neoplasms/pathology , Robotic Surgical Procedures/adverse effects , Robotic Surgical Procedures/methods
20.
PeerJ ; 10: e13173, 2022.
Article in English | MEDLINE | ID: mdl-35415019

ABSTRACT

Ichthyosaurs from the Solnhofen Lagerstätte are among the only examples of soft tissue preservation in the major Middle Jurassic-middle Cretaceous family Ophthalmosauridae. However, few such specimens are currently described, and the taphonomical pathways for the preservation of soft tissue are not well understood. In order to answer this, two new ichthyosaur specimens, one nearly complete and one isolated tail, are described here. The nearly complete specimen is assigned to Aegirosaurus sp. It is accompanied by large amounts of incrustation pseudomorphs (epimorphs) of soft tissue preserved as apatite. It also preserves a nearly complete gastral basket, for the first time in ophthalmosaurids. Soft tissue samples were analyzed using X-ray diffraction (XRD) and scanning electron microscopy (SEM) coupled with energy dispersive spectroscopy (EDS) analysis. The analyses confirm the presence of apatite, with phosphate most likely derived from the body itself.


Subject(s)
Fossils , Phylogeny
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