bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rational Design of Azastatin as a Potential ADC Payload with Reduced Bystander Killing
Authors: Hartmann Rafael W. , Fahrner Raphael , Shevshenko Denys , Fyrknäs Mårten , Larsson Rolf , Lehmann Fredrik , Odell Luke R. 
Published: October 2020

AbstractAuristatins are a class of ultrapotent microtubule inhibitors, whose growing clinical popularity in oncology is based upon their use as payloads in antibody‐drug conjugates (ADCs). The most widely utilized auristatin, MMAE, has however been shown to cause apoptosis in non‐pathological cells proximal to the tumour (“bystander killing”). Herein, we introduce azastatins, a new class of auristatin derivatives encompassing a side chain amine for antibody conjugation. The synthesis of Cbz‐azastatin methyl ester, which included the C2‐elongation and diastereoselective reduction of two proteinogenic amino acids as key transformations, was accomplished in 22 steps and 0.76 % overall yield. While Cbz‐protected azastatin methyl ester (0.13–3.0 nM) inhibited proliferation more potently than MMAE (0.47–6.5 nM), removal of the Cbz‐group yielded dramatically increased IC50‐values (9.8–170 nM). We attribute the reduced apparent cytotoxicity of the deprotected azastatin methyl esters to a lack of membrane permeability. These results clearly establish the azastatins as a novel class of cytotoxic payloads ideally suited for use in next‐generation ADC development.
Broad‐Spectrum Antifungal Agents: Fluorinated Aryl‐ and Heteroaryl‐Substituted Hydrazones
Authors: Thamban Chandrika Nishad , Dennis Emily K. , Brubaker Katelyn R. , Kwiatkowski Stefan , Watt David S. , Garneau‐Tsodikova Sylvie 
Published: October 2020

AbstractFluorinated aryl‐ and heteroaryl‐substituted monohydrazones displayed excellent broad‐spectrum activity against various fungal strains, including a panel of clinically relevant Candida auris strains relative to a control antifungal agent, voriconazole (VRC). These monohydrazones displayed less hemolysis of murine red blood cells than that of VRC at the same concentrations, possessed fungicidal activity in a time‐kill study, and exhibited no mammalian cell cytotoxicity. In addition, these monohydrazones prevented the formation of biofilms that otherwise block antibiotic effectiveness and did not trigger the development of resistance when exposed to C. auris AR Bank # 0390 over 15 passages.
Maize nitrogen management in soils with influencing water tables within optimum depth
Authors: Ruiz Alejo , Salvagiotti Fernando , Gambin Brenda L. , Borrás Lucas 
Published: October 2020

AbstractThe central temperate Argentinean region is currently affected by rising water tables, allowing higher and more stable maize yields (Zea maysL) when they fluctuate within optimum depth. However, limited information was available for optimizing N management in these environments. Yield response to N rates was explored in soils with influencing groundwater (always <3.5 m depth), and different environment and management variables were examined to help explain differential yield responses across sites. A total of 15 rainfed experiments (site × year combinations) were conducted with five N rates (0–240 kg N ha−1) tested at two different timings (sowing and V7) in a factorial design. A consistent yield response to N rate was evident, increasing yields from 2,300 to 6,900 kg ha−1across sites. Yields at maximum N levels ranged from 13,700 to 16,900 kg ha−1. Fertilization timing had a minor and inconsistent effect on yield across sites. At a maize grain/fertilizer N price ratio of 10, the economically optimal N rate ranged from 117 to 206 kg N ha−1. Soil N‐NO3at sowing, previous crop, and apparent–indigenous N supply (INS) helped explain differential yield responses across sites, and response models for obtaining economic optimum rates considering the influence of these variables are provided. These results highlight the relevance of N rate, rather than timing, as a critical crop management decision in environments with high water availability and yield.
Recent Developments in Metalloporphyrin Electrocatalysts for Reduction of Small Molecules: Strategies for Managing Electron and Proton Transfer Reactions
Authors: Zhang Rui , Warren Jeffrey J. 
Published: October 2020

AbstractPorphyrins are archetypal ligands in inorganic chemistry. The last 10 years have seen important new advances in the use of metalloporphyrins as catalysts in the activation and reduction of small molecules, in particular O2 and CO2. Recent developments of new molecular designs, scaling relationships, and theoretical modeling of mechanisms have rapidly advanced the utility of porphyrins as electrocatalysts. This Minireview focuses on the summary and evaluation of recent developments of metalloporphyrin O2 and CO2 reduction electrocatalysts, with an emphasis on contrasting homogeneous and heterogeneous electrocatalysis. Comparisons for proposed reaction mechanisms are provided for both CO2 and O2 reduction, and ideas are proposed about how lessons from the last decade of research can lead to the development of practical, applied porphyrin‐derived catalysts.
Regulation of zebrafish fin regeneration by vitamin D signaling
Authors: Chen Anzhi , Han Yanchao , Poss Kenneth D. 
Published: October 2020

AbstractBackgroundVitamin D is an essential nutrient that has long been known to regulate skeletal growth and integrity. In models of major appendage regeneration, treatment with vitamin D analogs has been reported to improve aspects of zebrafish fin regeneration in specific disease or gene misexpression contexts, but also to disrupt pattern in regenerating salamander limbs. Recently, we reported strong mitogenic roles for vitamin D signaling in several zebrafish tissues throughout life stages, including epidermal cells and osteoblasts of adult fins. To our knowledge, molecular genetic approaches to dissect vitamin D function in appendage regeneration have not been described.ResultsUsing a knock‐in GFP reporter for the expression of the vitamin D target gene and negative regulator cyp24a1, we identified active vitamin D signaling in adult zebrafish fins during tissue homeostasis and regeneration. Transgenic expression of cyp24a1 or a dominant‐negative vitamin D receptor (VDR) inhibited regeneration of amputated fins, whereas global vitamin D treatment accelerated regeneration. Using tissue regeneration enhancer elements, we found that local enhancement of VDR expression could improve regeneration with low doses of a vitamin D analog.ConclusionsVitamin D signaling enhances the efficacy of fin regeneration in zebrafish.
DNA diet profiles with high‐resolution animal tracking data reveal levels of prey selection relative to habitat choice in a crepuscular insectivorous bird
Authors: Evens Ruben , Conway Greg , Franklin Kirsty , Henderson Ian , Stockdale Jennifer , Beenaerts Natalie , Smeets Karen , Neyens Thomas , Ulenaers Eddy , Artois Tom 
Published: October 2020

AbstractGiven the global decline of many invertebrate food resources, it is fundamental to understand the dietary requirements of insectivores. We give new insights into the functional relationship between the spatial habitat use, food availability, and diet of a crepuscular aerial insectivore, the European Nightjar (Caprimulgus europaeus) by relating spatial use data with high‐throughput sequencing (HTS) combined with DNA metabarcoding. Our study supports the predictions that nightjars collect a substantial part of their daily nourishment from foraging locations, sometimes at considerable distance from nesting sites. Lepidopterans comprise 65% of nightjars' food source. Nightjars tend to select larger species of Lepidoptera (>19 mm) which suggests that nightjars optimize the efficiency of foraging trips by selecting the most energetically favorable—larger—prey items. We anticipate that our findings may shed additional light on the interactions between invertebrate communities and higher trophic levels, which is required to understand the repercussions of changing food resources on individual‐ and population‐level processes.
Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity
Authors: Baars Matthijs J.D. , Douma Thera , Simeonov Dimitre R. , Myers Darienne R. , Kulhanek Kayla , Banerjee Saikat , Zwakenberg Susan , Baltissen Marijke P. , Amini Mojtaba , de Roock Sytze , van Wijk Femke , Vermeulen Michiel , Marson Alexander , Roose Jeroen P. , Vercoulen Yvonne 
Published: October 2020

AbstractRasGRP1 is a Ras guanine nucleotide exchange factor, and an essential regulator of lymphocyte receptor signaling. In mice, Rasgrp1 deletion results in defective T lymphocyte development. RASGRP1‐deficient patients suffer from immune deficiency, and the RASGRP1 gene has been linked to autoimmunity. However, how RasGRP1 levels are regulated, and if RasGRP1 dosage alterations contribute to autoimmunity remains unknown. We demonstrate that diminished Rasgrp1 expression caused defective T lymphocyte selection in C57BL/6 mice, and that the severity of inflammatory disease inversely correlates with Rasgrp1 expression levels. In patients with autoimmunity, active inflammation correlated with decreased RASGRP1 levels in CD4+ T cells. By analyzing H3K27 acetylation profiles in human T cells, we identified a RASGRP1 enhancer that harbors autoimmunity‐associated SNPs. CRISPR‐Cas9 disruption of this enhancer caused lower RasGRP1 expression, and decreased binding of RUNX1 and CBFB transcription factors. Analyzing patients with autoimmunity, we detected reduced RUNX1 expression in CD4+ T cells. Lastly, we mechanistically link RUNX1 to transcriptional regulation of RASGRP1 to reveal a key circuit regulating RasGRP1 expression, which is vital to prevent inflammatory disease.
Nerve growth factor sensitizes nociceptors to C‐fibre selective supra‐threshold electrical stimuli in human skin
Authors: Schnakenberg Mark , Thomas Christian , Schmelz Martin , Rukwied Roman 
Published: October 2020

AbstractBackgroundIntradermal injection of 1 µg nerve growth factor (NGF) causes sustained nociceptor sensitization. Slowly depolarizing electrical current preferentially activates C‐nociceptors.MethodsWe explored the differential contribution of A‐delta and C‐nociceptors in NGF‐sensitized skin using slowly depolarizing transcutaneous electrical current stimuli, CO2 laser heat, mechanical impact, and A‐fibre compression block. In 14 healthy volunteers, pain rating was recorded on a numeric scale at days 1–14 after NGF treatment. Ratings during A‐fibre conduction block were investigated at days 3 and 7 post‐NGF.ResultsPain ratings to electrical, CO2 heat and mechanical impact stimuli were enhanced (>30%, p < .0005, ANOVA) at NGF‐injection sites. Axon reflex erythema evoked by electrical stimulation was also larger at NGF‐injection sites (p < .02, ANOVA). Diminution of pain during continuous (1 min) sinusoidal current stimulation at 4 Hz was less pronounced after NGF (p < .05, ANOVA). Pain ratings to electrical sinusoidal and mechanical impact stimuli during A‐fibre conduction block were significantly elevated at the NGF sites compared to NaCl‐treated skin (p < .05, ANOVA).ConclusionsNGF‐induced sensitization of human skin to electrical and mechanical stimuli is primarily driven by C‐nociceptors with little contribution from A‐delta fibres. Less‐pronounced accommodation during ongoing sinusoidal stimulation suggests that NGF could facilitate axonal spike generation and conduction in primary afferent nociceptors in humans. Further studies using this sinusoidal electrical stimulation profile to investigate patients with chronic inflammatory pain may allow localized assessment of skin C‐nociceptors and their putative excitability changes under pathologic conditions.SignificanceThe application of novel slowly depolarizing electrical stimuli demonstrated a predominant C‐nociceptor sensitization in NGF‐treated skin. Increased pain ratings, larger axon reflex erythema and less accommodation of C‐fibres to ongoing sinusoidal stimulation all indicated an enhanced nociceptor discharge after NGF. A‐fibre conduction block had little effect on electrical and mechanical hyperalgesia skin in NGF‐treated compared to NaCl‐treated skin. This electrical stimulus profile may be applicable for patients with chronic inflammatory pain, allowing localized assessment of skin C‐nociceptors and their putative excitability changes under pathologic conditions.
Comparison of methane production performance of vinegar residue under liquid‐ and solid‐state conditions
Authors: Song Chao , Feng Jiayu , Wang Ligong , Cai Fanfan , Chen Chang , Liu Guangqing 
Published: October 2020

AbstractVinegar residue (VR), a major by‐product in the vinegar brewing process, is generated at least three million tons annually in China. Currently major part of the disposal of VR is fulfilled by landfill and incineration, however, serious environment pollution along with such processes is a challenging issue. Anaerobic digestion (AD) can provide benefits of environment and renewable methane generation, which seems to be a reasonable alternative to traditional treatment. Noticeably, total solids (TS) is an important influential parameter to AD performance. Therefore, VR was evaluated for methane production and associated kinetic characteristics during the liquid‐state AD (LS‐AD) and solid‐state AD (SS‐AD) in this study. The results indicated that the highest specific methane yield of 194.8 mL gVS−1 and volumetric methane yield of 9.4 Lmethane Lreactor volume−1 were achieved in LS‐AD (TS = 10%) and SS‐AD (TS = 20%), respectively. The kinetic analysis showed a higher specific methane production rate for LS‐AD than SS‐AD, while volumetric methane production rate presented a reverse trend. This study provides useful guidance for the sustainable utilization of VR while contributes to environmental protection and alleviates the dependence on fossil fuels.
Memristor‐based 2D1M architecture: Solution to sneak paths in multilevel memory
Authors: Ravi V. , Singh Shivendra , Sofana Reka S. 
Published: October 2020

AbstractThe memristor, the fourth fundamental elements have shown the potential to revolutionize the present storage, analog, and digital computational technologies. The ability to remember its previous state in the absence of any stimuli has made the memristor as a prime candidate for nonvolatile memory. However, the sneak path is one of the main problems hampering the implementation of memristor‐based crossbar memories. In this article, we introduce a new crossbar architecture that is capable of storing multibit per cell and eliminates the sneak paths without adding any complex circuitry. The approximate write delay of the proposed memory cell is 20 mS which is very close to the delay of the single bit cell. The proposed architecture was validated by storing four different logic states in each cell of the 4 × 4 memory. Hence, one memory cell of the proposed architecture replaces four cells of the single‐bit memory at the cost of one additional diode per cell. Therefore, the proposed scheme saves considerable area when compared with the conventional single‐bit memory array. The write/read operations are validated by a generic, accurate, and efficient “voltage threshold adaptive memristor” (VTEAM) model. The simulation results prove that the proposed circuitry can read the memory content even after 2000 cycles without any sneak paths problem.
Dynamic neural circuit disruptions associated with antisocial behaviors
Authors: Jiang Weixiong , Zhang Han , Zeng Ling‐Li , Shen Hui , Qin Jian , Thung Kim‐Han , Yap Pew‐Thian , Liu Huasheng , Hu Dewen , Wang Wei , Shen Dinggang 
Published: October 2020

AbstractAntisocial behavior (ASB) is believed to have neural substrates; however, the association between ASB and functional brain networks remains unclear. The temporal variability of the functional connectivity (or dynamic FC) derived from resting‐state functional MRI has been suggested as a useful metric for studying abnormal behaviors including ASB. This is the first study using low‐frequency fluctuations of the dynamic FC to unravel potential system‐level neural correlates with ASB. Specifically, we individually associated the dynamic FC patterns with the ASB scores (measured by Antisocial Process Screening Device) of the male offenders (age: 23.29 ± 3.36 years) based on machine learning. Results showed that the dynamic FCs were associated with individual ASB scores. Moreover, we found that it was mainly the inter‐network dynamic FCs that were negatively associated with the ASB severity. Three major high‐order cognitive functional networks and the sensorimotor network were found to be more associated with ASB. We further found that impaired behavior in the ASB subjects was mainly associated with decreased FC dynamics in these networks, which may explain why ASB subjects usually have impaired executive control and emotional processing functions. Our study shows that temporal variation of the FC could be a promising tool for ASB assessment, treatment, and prevention.
Experimental investigation of internal erosion behaviours in inclined seepage flow
Authors: Liang Yue , Yeh Tian‐Chyi J. , Ma Chen , Zhang Qiang , Yang Dehong , Hao Yonghong 
Published: October 2020

AbstractInternal erosion is one of the most common causes of failure in hydraulic engineering structures, such as embankments and levees. It also plays a vital role in the geohazards (such as landslides and sinkhole developments) and more importantly, the earth landscape evolution, which has a broad environmental and ecosystem impacts. The groundwater seepage is multi‐directional, and its multi‐dimensional nature could affect the initiation and the progression of internal erosion. With a newly developed apparatus, we carry out nine internal erosion experiments under five different seepage directions. The results reveal that the critical hydraulic gradient increases as the seepage direction varies from the horizontal to the vertical. After a global erosion is triggered, preferential erosion paths distribute randomly from the bottom to the top of the specimen. If the seepage direction is not vertical, small preferential erosion paths merge into a large erosion corridor, in which the loss of fine particles is significant but negligible outside. Results of experiments manifest that the erosion is heterogeneous and three‐dimensional, even in the unidirectional seepage flow. The particles are rapidly eroded at the early stage of the erosion, indicating a high erosion rate. With the erosion time increasing, the particle loss slows down and even ceases if the time is long enough. The erosion rate increases if the seepage direction approaches a vertical direction. Overall, the erosion rate approximately decreases with erosion time exponentially. We proposed exponential equations to illustrate the variation of the erosion rate in the erosion process.
Analgesia for vaginal birth: Secondary analysis from the WHO Multicountry Survey on Maternal and Newborn Health
Authors: Souza Marcio A. , Cecatti Jose G. , Guida Jose P. , Souza Joao P. , Gulmezoglu Ahmet M. , Betran Ana P. , R.Torloni Maria , Vogel Joshua P. , Costa Maria L. ,   for the WHO‐MCS study group
Published: October 2020

AbstractObjectiveTo evaluate the use of analgesia during labor in women who had a vaginal birth and to determine the factors associated with its use.MethodsA secondary analysis was performed of the WHO Multicountry Survey on Maternal and Newborn Health, a cross‐sectional, facility‐based survey including 359 healthcare facilities in 29 countries. The prevalence of analgesia use for vaginal birth in different countries was reported according to the Human Development Index (HDI). Sociodemographic and obstetric characteristics of the participants with and without analgesia were compared. The prevalence ratios were compared across countries, HDI groups, and regions using a design‐based χ2 test.ResultsAmong the 221 345 women who had a vaginal birth, only 4% received labor analgesia, mainly epidural. The prevalence of women receiving analgesia was significantly higher in countries with a higher HDI than in countries with a lower HDI. Education was significantly associated with increased use of analgesia; nulliparous women and women undergoing previous cesarean delivery had a significantly increased likelihood of receiving analgesia.ConclusionUse of analgesia for women undergoing labor and vaginal delivery was low, specifically in low‐HDI countries. Whether low use of analgesia reflects women’s desire or an unmet need for pain relief requires further studies.
Diagnosing colorectal abnormalities using scattering coefficient maps acquired from optical coherence tomography
Authors: Zeng Yifeng , Chapman William C. , Lin Yixiao , Li Shuying , Mutch Matthew , Zhu Quing 
Published: October 2020

AbstractOptical coherence tomography (OCT) has shown potential in differentiating normal colonic mucosa from neoplasia. In this study of 33 fresh human colon specimens, we report the first use of texture features and computer vision‐based imaging features acquired from en face scattering coefficient maps to characterize colorectal tissue. En face scattering coefficient maps were generated automatically using a new fast integral imaging algorithm. From these maps, a gray‐level cooccurrence matrix algorithm was used to extract texture features, and a scale‐invariant feature transform algorithm was used to derive novel computer vision‐based features. In total, 25 features were obtained, and the importance of each feature in diagnosis was evaluated using a random forest model. Two classifiers were assessed on two different classification tasks. A support vector machine model was found to be optimal for distinguishing normal from abnormal tissue, with 94.7% sensitivity and 94.0% specificity, while a random forest model performed optimally in further differentiating abnormal tissues (i.e., cancerous tissue and adenomatous polyp) with 86.9% sensitivity and 85.0% specificity. These results demonstrated the potential of using OCT to aid the diagnosis of human colorectal disease.
miR‐301b and NR3C2 co‐regulate cells malignant properties and have the potential to be independent prognostic factors in breast cancer
Authors: Peng Yun , Xi Xun , Li Juntao , Ni Jun , Yang Hongbiao , Wen Changyong , Wen Meiling 
Published: October 2020

AbstractThis study intends to address the function of miR‐301b/nuclear receptor subfamily 3 group C member 2 (NR3C2) in breast cancer. The Cancer Genome Atlas database was processed to investigate the expression of miR‐301b/NR3C2 in breast cancer samples, as well as the relationship between their expression and the prognosis of the patients. Cox regression analysis was performed to determine whether miR‐301b/NR3C2 was an independent predictor of the patient's prognosis. Associations between miR‐301b and NR3C2 were analyzed by prediction website, dual‐luciferase assay, and Pearson correlation coefficient. Quantitative polymerase chain reaction and Western blot analyses were implemented to detect gene expression. The relevant biological characteristics of MCF7 and BCAP‐37 cells were tested by cell counting kit‐8, colony formation, and transwell assays. Lower expression of NR3C2, which was closely related to the bad prognosis of breast cancer patients, was presented in breast cancer samples and can be used as an independent predictor. miR‐301b, as an upstream regulator of NR3C2, was highly expressed in breast cancer samples and can be used as an independent predictor as well. Notably, a higher level of miR‐301b and lower level of NR3C2 were related to the reduced overall survival in patients with breast cancer. The proliferative and migratory behaviors of cells were elevated or blocked after overexpression of miR‐301b or NR3C2, respectively. However, the above situation was attenuated after together upregulation of miR‐301b and NR3C2. The present data afforded evidence that miR‐301b may be a tumor‐promoting miRNA in breast cancer, and that miR‐301b/NR3C2 axis mediated tumor development from cell proliferation and migration.