bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I dose-finding, pharmacokinetics and genotyping study of olaparib and lurbinectedin in patients with advanced solid tumors
Authors: Poveda Andres , Oaknin Ana , Romero Ignacio , Guerrero-Zotano Angel , Fariñas-Madrid Lorena , Rodriguez-Freixinos Victor , Mallol Pedro , Lopez-Reig Raquel , Lopez-Guerrero Jose Antonio 
Published: February 2021

AbstractThe poly (ADP-Ribose) polymerase (PARP) inhibitor olaparib has shown antitumor activity in patients with ovarian or breast cancer with or without BRCA1/2 mutations. Lurbinectedin is an ecteinascidin that generates DNA double-strand breaks. We hypothesized that the combination of olaparib and lurbinectedin maximizes the DNA damage increasing the efficacy. A 3 + 3 dose-escalation study examined olaparib tablets with lurbinectedin every 21 days. The purpose of this phase I study is to determine the dose-limiting toxicities (DLTs) of the combination, to investigate the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), efficacy, pharmacokinetics, in addition to genotyping and translational studies. In total, 20 patients with ovarian and endometrial cancers were included. The most common adverse events were asthenia, nausea, vomiting, constipation, abdominal pain, neutropenia, anemia. DLT grade 4 neutropenia was observed in two patients in dose level (DL) 5, DL4 was defined as the MTD, and the RP2D was lurbinectedin 1.5 mg/m2 + olaparib 250 mg twice a day (BID). Mutational analysis revealed a median of 2 mutations/case, 53% of patients with mutations in the homologous recombination (HR) pathway. None of the patients reached a complete or partial response; however, 60% of stable disease was achieved. In conclusion, olaparib in combination with lurbinectedin was well tolerated with a disease control rate of 60%. These results deserve further evaluation of the combination in a phase II trial.
Three-dimensional tonotopic mapping of the human cochlea based on synchrotron radiation phase-contrast imaging
Authors: Li Hao , Helpard Luke , Ekeroot Jonas , Rohani Seyed Alireza , Zhu Ning , Rask-Andersen Helge , Ladak Hanif M. , Agrawal Sumit 
Published: February 2021

AbstractThe human cochlea transforms sound waves into electrical signals in the acoustic nerve fibers with high acuity. This transformation occurs via vibrating anisotropic membranes (basilar and tectorial membranes) and frequency-specific hair cell receptors. Frequency-positions can be mapped within the cochlea to create a tonotopic chart which fits an almost-exponential function with lowest frequencies positioned apically and highest frequencies positioned at the cochlear base (Bekesy 1960, Greenwood 1961). To date, models of frequency positions have been based on a two-dimensional analysis with inaccurate representations of the cochlear hook region. In the present study, the first three-dimensional frequency analysis of the cochlea using dendritic mapping to obtain accurate tonotopic maps of the human basilar membrane/organ of Corti and the spiral ganglion was performed. A novel imaging technique, synchrotron radiation phase-contrast imaging, was used and a spiral ganglion frequency function was estimated by nonlinear least squares fitting a Greenwood-like function (F = A (10ax − K)) to the data. The three-dimensional tonotopic data presented herein has large implications for validating electrode position and creating customized frequency maps for cochlear implant recipients.
Quantitative phase microscopy for non-invasive live cell population monitoring
Authors: Aknoun Sherazade , Yonnet Manuel , Djabari Zied , Graslin Fanny , Taylor Mark , Pourcher Thierry , Wattellier Benoit , Pognonec Philippe 
Published: February 2021

AbstractWe present here a label-free development based on preexisting Quantitative Phase Imaging (QPI) that allows non-invasive live monitoring of both individual cells and cell populations. Growth, death, effect of toxic compounds are quantified under visible light with a standard inverted microscope. We show that considering the global biomass of a cell population is a more robust and accurate method to assess its growth parameters in comparison to compiling individually segmented cells. This is especially true for confluent conditions. This method expands the use of light microscopy in answering biological questions concerning live cell populations even at high density. In contrast to labeling or lysis of cells this method does not alter the cells and could be useful in high-throughput screening and toxicity studies.
Changes in the human footprint in and around Indonesia’s terrestrial national parks between 2012 and 2017
Authors: Dwiyahreni Asri A. , Fuad Habiburrachman A. H. , Muhtar Sunaryo , Soesilo T. E. Budhi , Margules Chris , Supriatna Jatna 
Published: February 2021

AbstractThe human footprint (HF) was developed to measure of the impact of human activities on the environment. The human footprint has been found to be closely related to the vulnerability of protected areas around the world. In Indonesia, as nature conservation is still seen as hindering economic development, it is especially important to assess the human footprint in order to comprehend the overall pressures resulting from the various human activities on Indonesia’s national parks. This study measured the change in the human footprint in and around 43 terrestrial national parks over 5 years, between 2012 and 2017. As many as 37 out of 43 NPs experienced an increase in the HF, ranging from 0.4 to 77.3%. Tanjung Puting in Kalimantan experienced the greatest increase (77.3%), while Ujung Kulon in Jawa Bali bioregion had the greatest decrease (10.5%). An increase in human population density and improved access to parks from roads, rivers and coastlines are the main drivers of increasing impacts on national parks.
Occurrences of non-linear phenomena and vocal harshness in dog whines as indicators of stress and ageing
Authors: Marx András , Lenkei Rita , Pérez Fraga Paula , Bakos Viktória , Kubinyi Enikő , Faragó Tamás 
Published: February 2021

AbstractDuring social interactions, acoustic parameters of tetrapods’ vocalisations reflect the emotional state of the caller. Higher levels of spectral noise and the occurrence of irregularities (non-linear phenomena NLP) might be negative arousal indicators in alarm calls, although less is known about other distress vocalisations. Family dogs experience different levels of stress during separation from their owner and may vocalise extensively. Analysing their whines can provide evidence for the relationship between arousal and NLP. We recorded 167 family dogs’ separation behaviour including vocalisations, assessed their stress level based on behaviour and tested how these, their individual features, and owner reported separation-related problems (SRP) relate to their whines’ (N = 4086) spectral noise and NLP. Dogs with SRP produced NLP whines more likely. More active dogs and dogs that tried to escape produced noisier whines. Older dogs’ whines were more harmonic than younger ones’, but they also showed a higher NLP ratio. Our results show that vocal harshness and NLP are associated with arousal in contact calls, and thus might function as stress indicators. The higher occurrence of NLP in older dogs irrespective to separation stress suggests loss in precise neural control of the larynx, and hence can be a potential ageing indicator.
Development of water-soluble prodrugs of the bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 as potential cardioprotective agents against anthracycline cardiotoxicity
Authors: Bavlovič Piskáčková Hana , Jansová Hana , Kubeš Jan , Karabanovich Galina , Váňová Nela , Kollárová-Brázdová Petra , Melnikova Iuliia , Jirkovská Anna , Lenčová-Popelová Olga , Chládek Jaroslav , Roh Jaroslav , Šimůnek Tomáš , Štěrba Martin , Štěrbová-Kovaříková Petra 
Published: February 2021

AbstractThe bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 has been previously identified as a more potent analog of dexrazoxane (ICRF-187), a drug used in clinical practice against anthracycline cardiotoxicity. However, the poor aqueous solubility of ICRF-193 has precluded its further in vivo development as a cardioprotective agent. To overcome this issue, water-soluble prodrugs of ICRF-193 were prepared, their abilities to release ICRF-193 were investigated using a novel UHPLC-MS/MS assay, and their cytoprotective effects against anthracycline cardiotoxicity were tested in vitro in neonatal ventricular cardiomyocytes (NVCMs). Based on the obtained results, the bis(2-aminoacetoxymethyl)-type prodrug GK-667 was selected for advanced investigations due to its straightforward synthesis, sufficient solubility, low cytotoxicity and favorable ICRF-193 release. Upon administration of GK-667 to NVCMs, the released ICRF-193 penetrated well into the cells, reached sufficient intracellular concentrations and provided effective cytoprotection against anthracycline toxicity. The pharmacokinetics of the prodrug, ICRF-193 and its rings-opened metabolite was estimated in vivo after administration of GK-667 to rabbits. The plasma concentrations of ICRF-193 reached were found to be adequate to achieve cardioprotective effects in vivo. Hence, GK-667 was demonstrated to be a pharmaceutically acceptable prodrug of ICRF-193 and a promising drug candidate for further evaluation as a potential cardioprotectant against chronic anthracycline toxicity.
Experimentally constrained early reproduction shapes life history trajectories and behaviour
Authors: Canal David , Garcia-Gonzalez Francisco , Garamszegi László Zsolt 
Published: February 2021

AbstractThe trade-off between current and future reproduction is a cornerstone of life history theory, but the role of within-individual plasticity on life history decisions and its connections with overall fitness and behaviour remains largely unknown. By manipulating available resources for oviposition at the beginning of the reproductive period, we experimentally constrained individual life history trajectories to take different routes in a laboratory study system, the beetle Callosobruchus maculatus, and investigated its causal effects on fecundity, survival and behaviour. Compared to females without resource limitations, females experiencing restricted conditions for oviposition had reduced fecundity early in life but increased fecundity when resources became plentiful (relative to both the previous phase and the control group) at the expense of longevity. Constrained reproduction in early life also affected behaviour, as movement activity changed differently in the two experimental groups. Experiencing reproductive constraints has, therefore, consequences for future reproduction investments and behaviour, which may lead individuals to follow different life history strategies.
Design and optimisation of magnetically-tunable hybrid piezoelectric-triboelectric energy harvester
Authors: Ganapathy Satish Rao , Salleh Hanim , Azhar Mohammad Khairul Azwan 
Published: February 2021

AbstractThe demand for energy harvesting technologies has been increasing over the years that can be attributed to its significance to low power applications. One of the key problems associated with the available vibration-based harvester is the maximum peak power can only be achieved when the device frequency matches the source frequency to generate low usable power. Therefore, in this study, a magnetically-tunable hybrid piezoelectric-triboelectric energy harvester (MT-HPTEH) was designed and optimised. Four key design factors: mass placement, triboelectric surface area, extension length and magnetic stiffness were investigated and optimised. The voltage generation from piezoelectric and triboelectric mechanisms was determined individually to understand the effect of each design factor on the mechanisms. An output power of 659 µW at 180 kΩ at 44 Hz was obtained from the optimised MT-HPTEH with a theoretical–experimental discrepancy of less than 10%. The added magnetically-tunable feature enabled the harvester to work at the desired frequency range with an open circuit voltage between 7.800 and 20.314 V and a frequency range from 38 to 54 Hz. This MT-HPTEH can power at least six wireless sensor networks and can be used for low power applications such as RFID tags. Future work may include designing of energy-saving and sustainable harvester.
Association of coagulation dysfunction with cardiac injury among hospitalized patients with COVID-19
Authors: Chen Liang , Hu Wei , Guo Xiaoxiao , Zhao Ping , Tang Jia , Gu Yuwei , Huang Ninghao , Wang Chao , Cui An , Zhang Dian , Hu Linjie , Feng Yi , Hu Shengshou , Chen Mingquan , Duru Firat , Xiong Chenglong 
Published: February 2021

AbstractCardiac injury is a common complication of the coronavirus disease 2019 (COVID-19), and is associated with adverse clinical outcomes. In this study, we aimed to reveal the association of cardiac injury with coagulation dysfunction. We enrolled 181 consecutive patients who were hospitalized with COVID-19, and studied the clinical characteristics and outcome of these patients. Cardiac biomarkers high-sensitivity troponin I (hs-cTnI), myohemoglobin and creatine kinase-myocardial band (CK-MB) were assessed in all patients. The clinical outcomes were defined as hospital discharge or death. The median age of the study cohort was 55 (IQR, 46–65) years, and 102 (56.4%) were males. Forty-two of the 181 patients (23.2%) had cardiac injury. Old age, high leukocyte count, and high levels of aspartate transaminase (AST), D-dimer and serum ferritin were significantly associated with cardiac injury. Multivariate regression analysis revealed old age and elevated D-dimer levels as being strong risk predictors of in-hospital mortality. Interleukin 6 (IL6) levels were comparable in patients with or without cardiac injury. Serial observations of coagulation parameters demonstrated highly synchronous alterations of D-dimer along with progression to cardiac injury. Cardiac injury is a common complication of COVID-19 and is an independent risk factor for in-hospital mortality. Old age, high leukocyte count, and high levels of AST, D-dimer and serum ferritin are significantly associated with cardiac injury, whereas IL6 are not. Therefore, the pathogenesis of cardiac injury in COVID-19 may be primarily due to coagulation dysfunction along with microvascular injury.
Insights in genetic diversity of German and Italian grape berry moth (Eupoecilia ambiguella) populations using novel microsatellite markers
Authors: Reineke Annette , Pozzebon Alberto , Herczynski Olivia , Duso Carlo 
Published: February 2021

AbstractThe grape berry moth Eupoecilia ambiguella (Lepidoptera: Tortricidae) is causing significant damage to grape berries, however, little is known on population genetics of this lepidopteran pest insect, hindered so far by the lack of suitable molecular markers. Here we report on the development of ten microsatellite markers of which six were used to characterise 21 E. ambiguella populations obtained from two viticultural regions in Germany and Italy. Moths were sampled during two subsequent generations (flights) in the same vineyard as well as in vineyards surrounded by different landscape types. German and Italian populations were genetically differentiated and a significant isolation by distance was evident. No significant divergence was observed among the populations from first or second flight moths, however, inbreeding was higher in first than in second flight populations. Moreover, inbreeding was influenced by habitat composition and complexity of landscape around vineyards, being positively associated with the percentage of area covered by grapevine. Population genetics of E. ambiguella could thus be affected by the presence of alternative host plants in viticultural landscapes, which is important in the light of both insecticide resistance management and sustainable pest management.
Stable isotope turnover rates and fractionation in captive California yellowtail (Seriola dorsalis): insights for application to field studies
Authors: Madigan Daniel J. , Snodgrass Owyn E. , Hyde John R. , Dewar Heidi 
Published: February 2021

AbstractStable isotope analysis (SIA) measurements from long-term captivity studies provide required parameters for interpretation of consumer SIA data. We raised young-of-the-year (14–19 cm) California yellowtail (Seriola dorsalis) on a low δ15N and δ13C diet (pellet aquaculture feed) for 525 days, then switched to a high δ15N and δ13C diet (mackerel and squid) for 753 days. Yellowtail muscle was sequentially sampled from each individual after the diet switch (0 to 753 days) and analyzed for δ15N and δ13C, allowing for calculation of diet-tissue discrimination factors (DTDFs) from two isotopically different diets (low δ15N and δ13C: pellets; high δ15N and δ13C: fish/squid) and turnover rates of 15N and 13C. DTDFs were diet dependent: Δ15N = 5.1‰, Δ13C = 3.6‰ for pellets and Δ15N = 2.6‰, Δ13C = 1.3‰ for fish/squid. Half-life estimates from 15N and 13C turnover rates for pooled yellowtail were 181 days and 341 days, respectively, but varied considerably by individual (15N: 99–239 d; 13C: 158–899 d). Quantifying DTDFs supports isotopic approaches to field data that assume isotopic steady-state conditions (e.g., mixing models for diet reconstruction). Characterizing and quantifying turnover rates allow for estimates of diet/habitat shifts and “isotopic clock” approaches, and observed inter-individual variability suggests the need for large datasets in field studies. We provide diet-dependent DTDFs and growth effects on turnover rates, and associated error around these parameters, for application to field-collected SIA data from other large teleosts.
Continuous glucose monitoring during pregnancy in healthy mice
Authors: Wuyts Caroline , Simoens Caroline , Pinto Silvia , Philippaert Koenraad , Vennekens Rudi 
Published: February 2021

AbstractDuring pregnancy, metabolic adaptations occur to maintain the balance between maternal and foetal growth, including increased insulin secretion and decreased insulin sensitivity. When the body fails to adjust, gestational diabetes mellitus develops. To gain insight in the pregnancy-induced adaptations, we applied continuous glucose monitoring via telemetric transmitters. We show that continuous glucose monitoring in conscious, non-stressed, freely moving mice throughout the full pregnancy is feasible, accurate and safe. We show that healthy mice during a full pregnancy develop adaptations in glucose homeostasis reminiscent of those in pregnant women. Furthermore, continuous glucose monitoring allows the complete analysis of all aspects of glucose excursions associated with spontaneous feeding episodes, and the thorough analysis of glycaemic variability. In conclusion, continuous glucose monitoring allows a detailed description of the glycaemic status during pregnancy, which will help to unravel specific mechanisms for gestational diabetes mellitus.
Behavioral effects of continuous theta-burst stimulation in macaque parietal cortex
Authors: Merken Lara , Davare Marco , Janssen Peter , Romero Maria C. 
Published: February 2021

AbstractThe neural mechanisms underlying the effects of continuous Theta-Burst Stimulation (cTBS) in humans are poorly understood. Animal studies can clarify the effects of cTBS on individual neurons, but behavioral evidence is necessary to demonstrate the validity of the animal model. We investigated the behavioral effect of cTBS applied over parietal cortex in rhesus monkeys performing a visually-guided grasping task with two differently sized objects, which required either a power grip or a pad-to-side grip. We used Fitts’ law, predicting shorter grasping times (GT) for large compared to small objects, to investigate cTBS effects on two different grip types. cTBS induced long-lasting object-specific and dose-dependent changes in GT that remained present for up to two hours. High-intensity cTBS increased GTs for a power grip, but shortened GTs for a pad-to-side grip. Thus, high-intensity stimulation strongly reduced the natural GT difference between objects (i.e. the Fitts’ law effect). In contrast, low-intensity cTBS induced the opposite effects on GT. Modifying the coil orientation from the standard 45-degree to a 30-degree angle induced opposite cTBS effects on GT. These findings represent behavioral evidence for the validity of the nonhuman primate model to study the neural underpinnings of non-invasive brain stimulation.
Pathologically phosphorylated tau at S396/404 (PHF-1) is accumulated inside of hippocampal synaptic mitochondria of aged Wild-type mice
Authors: Torres Angie K. , Jara Claudia , Olesen Margrethe A. , Tapia-Rojas Cheril 
Published: February 2021

AbstractBrain aging is a natural process characterized by cognitive decline and memory loss. This impairment is related to mitochondrial dysfunction and has recently been linked to the accumulation of abnormal proteins in the hippocampus. Age-related mitochondrial dysfunction could be induced by modified forms of tau. Here, we demonstrated that phosphorylated tau at Ser 396/404 sites, epitope known as PHF-1, is increased in the hippocampus of aged mice at the same time that oxidative damage and mitochondrial dysfunction are observed. Most importantly, we showed that tau PHF-1 is located in hippocampal mitochondria and accumulates in the mitochondria of old mice. Finally, since two mitochondrial populations were found in neurons, we evaluated tau PHF-1 levels in both non-synaptic and synaptic mitochondria. Interestingly, our results revealed that tau PHF-1 accumulates primarily in synaptic mitochondria during aging, and immunogold electron microscopy and Proteinase K protection assays demonstrated that tau PHF-1 is located inside mitochondria. These results demonstrated the presence of phosphorylated tau at PHF-1 commonly related to tauopathy, inside the mitochondria from the hippocampus of healthy aged mice for the first time. Thus, this study strongly suggests that synaptic mitochondria could be damaged by tau PHF-1 accumulation inside this organelle, which in turn could result in synaptic mitochondrial dysfunction, contributing to synaptic failure and memory loss at an advanced age.
Interaction between cognitive reserve and age moderates effect of lesion load on stroke outcome
Authors: Umarova Roza M. , Schumacher Lena V. , Schmidt Charlotte S. M. , Martin Markus , Egger Karl , Urbach Horst , Hennig Jürgen , Klöppel Stefan , Kaller Christoph P. 
Published: February 2021

AbstractThe concepts of brain reserve and cognitive reserve were recently suggested as valuable predictors of stroke outcome. To test this hypothesis, we used age, years of education and lesion size as clinically feasible coarse proxies of brain reserve, cognitive reserve, and the extent of stroke pathology correspondingly. Linear and logistic regression models were used to predict cognitive outcome (Montreal Cognitive Assessment) and stroke-induced impairment and disability (NIH Stroke Scale; modified Rankin Score) in a sample of 104 chronic stroke patients carefully controlled for potential confounds. Results revealed 46% of explained variance for cognitive outcome (p < 0.001) and yielded a significant three-way interaction: Larger lesions did not lead to cognitive impairment in younger patients with higher education, but did so in younger patients with lower education. Conversely, even small lesions led to poor cognitive outcome in older patients with lower education, but didn’t in older patients with higher education. We observed comparable three-way interactions for clinical scores of stroke-induced impairment and disability both in the acute and chronic stroke phase. In line with the hypothesis, years of education conjointly with age moderated effects of lesion on stroke outcome. This non-additive effect of cognitive reserve suggests its post-stroke protective impact on stroke outcome.