bluuebunny/crossref_metadata_2025 huggingface dataset:
Long noncoding RNAs implicated in embryonic development in Ybx1 knockout zebrafish
Authors: Huang Chen , Zhu Bo , Leng Dongliang , Ge Wei , Zhang Xiaohua Douglas
Published: December 2020

Y‐box‐binding protein 1 (Ybx1, YB‐1), also known as Y‐box transcription factor, is involved in a variety of biological processes (BPs) and pathways, including embryogenesis, reproduction and development in vertebrates. Several noncoding RNAs regulate Ybx1 signaling. However, the role of long noncoding RNAs (lncRNAs) in embryogenesis remains incompletely understood. Here, we investigated the possible involvement of lncRNAs in Ybx1‐mediated regulation of vertebrate development by performing systematic transcriptome analysis of RNA sequencing data derived from ybx1 homozygous mutant zebrafish on day 5 (day5_ybx1−/−) and wild‐type zebrafish on days 5 and 6 (day5_ybx1+/+ and day6_ybx1+/+). We identified several lncRNAs affected by ybx1 disruption that may target reduction–oxidation‐related genes, such as duox (NADPH oxidase) and noxo1a (NADPH oxidase organizer). Knockdown of three selected lncRNAs led to morphological deformation of larvae, implying an involvement of these lncRNAs in zebrafish embryo development. In summary, our study provides new insights into the lncRNA‐mediated mechanisms underlying development in Ybx1‐deficient zebrafish larvae.
The Earth's Lithosphere Inspires Materials Design
Authors: Beygelzimer Yan , Kulagin Roman , Fratzl Peter , Estrin Yuri
Published: December 2020

Structural patterns found in living organisms have long been inspiring biomimetic materials design. Here, it is suggested that a rich palette of patterns occurring in inanimate Nature, and especially in the Earth's lithosphere, could be not less inspirational for design of novel architectured materials. This materials design paradigm is referred to as lithomimetics and it is demonstrated that some of the patterns found in the lithosphere can be emulated by established processes of severe plastic deformation. This opens up interesting avenues for materials design in which potentially promising structural patterns are borrowed from the lithosphere's repository. The key aim here is to promulgate the “lithomimetics” paradigm as a promising approach to developing novel architectured materials.
Roles of MACl in Sequentially Deposited Bromine‐Free Perovskite Absorbers for Efficient Solar Cells
Authors: Ye Feihong , Ma Junjie , Chen Cong , Wang Haibing , Xu Yuhao , Zhang Shunping , Wang Ti , Tao Chen , Fang Guojia
Published: December 2020

So far, the combination of methylammonium bromide/methylammonium chloride (MABr/MACl) or methylammonium iodide (MAI)/MACl is the most frequently used additives to stabilize formamidinium lead iodide (FAPbI3) fabricated by the sequential deposition method. However, the enlarged bandgap due to the addition of bromide and the ambiguous functions of these additives in lead iodide (PbI2) transformation are still worth considering. Herein, the roles of MACl in sequentially deposited Br‐free FA‐based perovskites are systematically investigated. It is found that MACl can finely regulate the PbI2/FAI reaction, tune the phase transition at room temperature, and adjust intermediate‐related perovskite crystallization and decomposition during thermal annealing. Compared to FAPbI3, the perovskite with MACl exhibits larger grain, longer carrier lifetime, and reduced trap density. The resultant solar cell therefore achieves a champion power conversion efficiency (PCE) of 23.1% under reverse scan with a stabilized power output of 23.0%. In addition, it shows much improved photostability under 100 mW cm−2 white illumination (xenon lamp) in nitrogen atmosphere without encapsulation.
Dimensional Stacking for Machine Learning in ToF‐SIMS Analysis of Heterostructures
Authors: Abbasi Kevin , Smith Hugh , Hoffman Matthew , Farghadany Elahe , Bruckman Laura S. , Sehirlioglu Alp
Published: December 2020

Output from multidimensional datasets obtained from spectroscopic imaging techniques provides large data suitable for machine learning techniques to elucidate physical and chemical attributes that define the maximum variance in the specimens. Here, a recently proposed technique of dimensional stacking is applied to obtain a cumulative depth over several LaAlO3/SrTiO3 heterostructures with varying thicknesses. Through dimensional reduction techniques via non‐negative matrix factorization (NMF) and principal component analysis (PCA), it is shown that dimensional stacking provides much more robust statistics and consensus while still being able to separate different specimens of varying parameters. The results of stacked and unstacked samples as well as the dimensional reduction techniques are compared. Applied to four LaAlO3/SrTiO3 heterostructures with varying thicknesses, NMF is able to separate 1) surface and film termination; 2) film; 3) interface position; and 4) substrate attributes from each other with near perfect consensus. However, PCA results in the loss of data related to the substrate.
Hydroxyl Assisted, Photoredox/Cobalt Co‐catalyzed Semi‐Hydrogenation and Tandem Cyclization of o‐Alkynylphenols for Access to 2,3‐Dihydrobenzofurans
Authors: Tian Wan‐Fa , Zhu Yao , He Yong‐Qin , Wang Mei , Song Xian‐Rong , Bai Jiang , Xiao Qiang
Published: December 2020

Herein, a hydroxyl assisted, photoredox/cobalt co‐catalyzed semi‐hydrogenation and tandem cyclization of o‐alkynylphenols is developed towards direct assembly of 2,3‐dihydrobenzofurans. Moderate to good yields were obtained for a range of sterically and electronically diverse 2‐propynolphenols under mild conditions. Mechanistic studies demonstrated the inevitable role of the alcoholic hydroxyl group with (Z)‐alkene as the real intermediate. Finally, a key low‐valent cobalt catalyzed intramolecular hydroetherification of alkene is proposed.

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Effective C5‐Arylation of Peptide‐Integrated Oxazoles: Almazole D
Authors: Oberheide Ansgar , Arndt Hans‐Dieter
Published: December 2020

An efficient functionalization approach of oxazoles by using Pd‐catalyzed cross‐coupling reactions is reported. Oxazolone formation and subsequent sulfamoylation in situ are facilitated by employing N,N‐diethylsulfamoyl imidazolium triflate. Cross‐couplings provide both oxazole‐arenes and oxazole‐heteroarenes and were compatible with sensitive and epimerization‐prone substrates, as exemplified by the total synthesis of the natural product almazole D.

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Visible‐Light Photoredox‐Catalyzed Tandem Trifluoro‐methylation/Cyclization/Remote Oxidation of 1,6‐Dienes: Access to CF3‐Containing Five‐Membered Heterocycles
Authors: Chun Jianlin , Zhang Honglin , Meng Fei , Guo Kang , Cao Shujun , Fang Qin , Li Jie , Zhu Yingguang
Published: December 2020

A visible‐light photoredox‐catalyzed tandem trifluoromethylation/cyclization/remote oxidation of 1,6‐dienes has been achieved. A broad range of trifluoromethyl group‐containing tetrahydrofurans or tetrahydropyrroles could be generated in good yields and with excellent diastereoselectivity by using dimethyl sulfoxide (DMSO) as the oxidant. The mild and facile protocol affords direct access to trifluoromethyl group‐bearing tetrahydrofurans and tetrahydropyrroles via difunctionalization of olefins.

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Synthesis of Nitro Alcohols by Riboflavin Promoted Tandem Nef‐Henry Reactions on Nitroalkanes
Authors: Lupidi Gabriele , Palmieri Alessandro , Petrini Marino
Published: December 2020

We disclose a unprecedented riboflavin promoted Nef reaction of primary nitroalkanes coupled with a nitroaldol reaction. This tandem process allows the synthesis of functionalized nitro alcohols under mild reaction conditions. Secondary nitroalkanes fail to give the expected nitroaldol products although they are consumed under the reaction conditions.

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Changes in Consumer Preferences toward Non‐GM Foods within an Information‐Rich Environment: The Case of the Washington State Ballot Initiative
Authors: Magnier Alexandre , Kalaitzandonakes Nicholas , Lusk Jayson
Published: December 2020

In this study, we investigate the impact of information on consumer preference for GM foods. In November 2013, the state of Washington voted on ballot initiative I‐522, which would have required the labeling of GM foods. The political campaign preceding the vote gave rise to an information‐rich environment where positive and negative information about GM foods became available to consumers in this state. We estimated the WTP for avoiding GM ingredients before and at the time of the vote and found that the WTP for non‐GM foods declined. This result is consistent with the proposition that information can affect consumer preferences for GM foods.
Expression patterns of the ZmASR family during simulated drought stress in maize
Authors: Zhang Lili , Yi Xiaoping , Guo Jingyuan , Zhao Hui , Xia Qiyu , He Pingping , Huo Shanshan , Qu Jing , Cao Yang , Tan Yanhua , Guo Anping
Published: December 2020

Maize (Zea mays L.) is an important food crop. Maize production is adversely affected by abiotic stress, especially drought stress. The screening and characterization of the roles of stress‐related genes in maize are thus essential for improving abiotic stress resistance. Abscisic acid‐stress‐ripening (ASR)‐induced proteins with abscisic acid/water deficit stress (ABA/WDS) domains are a class of plant‐specific transcription factors that play an important role in plant development, growth, and abiotic stress responses. In this study, nine members of the ASR‐induced protein in maize (ZmASR) family were predicted and analyzed in maize in terms of gene structure, subcellular localization, amino acid sequence, physical and chemical properties, secondary structure, tertiary structure, and phosphorylation modification sites by bioinformatics. Analysis of regulatory promoter elements was performed to provide additional information about their distinctive tissue‐specific expression and possible functions. To further investigate the function of these proteins in maize, the expression levels of ZmASRs in different tissues and in response to different drought stress treatments were analyzed using quantitative real‐time polymerase chain reaction (qRT‐PCR). The results showed that the nine members of the maize ZmASR family have very different expression levels in different organs and under different degrees of drought stress. Moreover, the expression levels of the nine members in the same organ also varied greatly with leaf age. These findings provide a reference for functional research of the maize ZmASR gene family. Our findings have important theoretical and practical significance for cultivating new drought‐resistant maize varieties and promoting the development of the maize industry.
Optional tool use: The case of wild bearded capuchins (Sapajus libidinosus) cracking cashew nuts by biting or by using percussors
Authors: Visalberghi Elisabetta , Barca Virginia , Izar Patricia , Fragaszy Dorothy , Truppa Valentina
Published: December 2020

Tool use in humans can be optional, that is, the same person can use different tools or no tool to achieve a given goal. Strategies to reach the same goal may differ across individuals and cultures and at the intra‐individual level. This is the first experimental study at the intra‐individual level on the optional use of a tool in wild nonhuman primates. We investigated optional tool use by wild bearded capuchins (Sapajus libidinosus) of Fazenda Boa Vista (FBV; Piauí, Brazil). These monkeys habitually succeed in cracking open the mesocarp of dry cashew nuts (Anacardiumspp.) by pounding them with stones and/or by biting. We assessed whether availability of a stone and resistance of the nut affected capuchins' choice to pound or to bite the nuts and their rates of success. Sixteen capuchins (1–16 years) received small and large dry cashew nuts by an anvil together with a stone (Stone condition) or without a stone (No‐Stone condition). In the Stone conditions, subjects used it to crack the nut in 89.1% (large nuts) and 90.1% (small nut) of the trials. Nut size significantly affected the number of strikes used to open it. Availability of the stone significantly increased the average percent of success. In the No‐Stone conditions, monkeys searched for and used other percussors to crack the nuts in 54% of trials. In all conditions, age affects percentage of success and number of strikes to reach success. We argue that exclusive use of stones in other sites may be due to the higher abundance of stones at these sites compared with FBV. Since capuchins opened cashews with a tool 1–2 years earlier than they succeed at cracking more resistant palm nuts, we suggest that success at opening cashew nuts with percussors may support the monkeys' persistent efforts to crack palm nuts.
Optimization of Deodorization Design for Four Different Kinds of Vegetable Oil in Industrial Trial to Reduce Thermal Deterioration of Product
Authors: Liu Xiaojun , Zhou Shengmin , Jiang Yuanrong , Xu Xuebing
Published: December 2020

Trans fatty acids (TFA) have been shown to be associated with various health disorders. Due to thermal stress, one major source of dietary TFA is high‐temperature deodorization of vegetable oils. In this study, precision minimal deodorization was proposed to obtain healthier “zero‐TFA” vegetable oils (TFA ≤0.3%). By optimizing temperatures for different deodorizers, dual columns with dual temperatures (DCDT) deodorizers were proposed, transformed, and industrially implemented among dozens of plants. The deodorization temperatures were optimized and customized, respectively, for four kinds of vegetable oil (soybean oil and rapeseed oil: tray column 205 °C and packed column 225 °C, maize oil and sunflower seed oil: tray column 210 °C and packed column 230 °C). Industrial trials showed that all four kinds of oils can achieve “zero‐TFA” by DCDT deodorization at the customized mild temperatures, and meanwhile oil physicochemical qualities and shelf‐life stabilities were compared with corresponding conventional refining oils. The initial free fatty acid and color were a little higher than that of conventional refining oils, but no significant differences were shown in change trends of these physicochemical indexes during the shelf life, which indicated a good and stable oil quality of “zero‐TFA” oils for future industrial productions and sales.
Engineering multistructure poly(vinylidene fluoride) membranes modified by polydopamine to achieve superhydrophilicity, excellent permeability, and antifouling properties
Authors: Ding Jie , Zeng Jianxian , Zeng Yajie , Yuan Zhengqiu , Huang Xiaoping , Wu Yanna
Published: December 2020

Polydopamine (PDA) was coated on poly(vinylidene fluoride) (PVDF) membranes with different structures to select the most suitable structure for achieving outstanding hydrophilicity, permeability, stability, and antifouling properties. PVDF membranes were prepared with different solvents (N‐methyl‐2‐pyrrolidone [NMP], N,N‐dimethylacetamide [DMAc], N,N‐dimethylformamide [DMF], NMP/DMAc, NMP/DMF, DMAc/DMF, and NMP/DMAc/DMF), and the factors that influenced the phase inversion were discussed. Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and atomic force microscopy (AFM) were employed to characterize various membranes. Results indicated that PDA was coated on PVDF membrane surface and formed a smoother PDA layer. Water contact angle measurement confirmed the increased hydrophilicity of PDA modified membranes, but water flux decreased due to the adhesion of PDA on pore walls. The decrease of static adsorption of bovine serum albumin (BSA), the increase of flux recovery ratio (FRR), and the decline of fouling resistance for PDA modified membranes demonstrated that their antifouling properties have been improved significantly. The membrane prepared with NMP/DMAc displayed the highest decay rate of contact angle (16.6 ± 1.27%), the higher water flux (1358.5 ± 33.87 L m−2 h−1), the highest decrease of BSA adsorption (129.3 ± 5.02 μg cm−2), the highest increase rate of BSA rejection (13.6 ± 0.42%), and the highest FRR (92.8 ± 1.42%). This indicated that NMP/DMAc membrane possessed the most suitable structure to improve membrane performances by PDA coating.
Inauthenticity aversion: Moral reactance toward tainted actors, actions, and objects
Authors: Silver Ike , Newman George , Small Deborah A.
Published: December 2020

Theories of authenticity usually try to explain what leads consumers to see something as authentic. Here, we address the inverse question instead: What makes a brand, individual, or product seem inauthentic? This shift in focus reveals a distinct psychology that is more than just the absence or inverse of responses to authenticity. Whereas authenticity typically confers meaning and value, invoking inauthenticity typically implies the detection of a moral violation. Specifically, consumers judge an entity to be inauthentic if they perceive a mismatch between what that entity claims to be (e.g., a socially responsible apparel brand, 100% orange juice) and what it really is upon closer scrutiny. Such judgments give rise to a powerful, non‐compensatory reactance we term inauthenticity aversion. We segment inauthenticity violations into three principle types: deceptions, ulterior motives, and adulterations. This conceptualization allows us to capture a wide variety of inauthenticity cases and outline psychological commonalities across them. It also helps to explain the powerful outrage consumers display at perceived inauthenticity and illuminates potential hazards in common marketing approaches.
RTA‐408 protects against propofol‐induced cognitive impairment in neonatal mice via the activation of Nrf2 and the inhibition of NF‐κB p65 nuclear translocation
Authors: Zhang Ling , Zhou Qian , Zhou Chun‐Li
Published: December 2020

Objective

To explore the effect of RTA‐408 on the propofol‐induced cognitive impairment of neonatal mice via regulating Nrf2 and NF‐κB p65 nuclear translocation.

Methods

C57BL/6 neonatal mice were randomized into intralipid, propofol, vehicle + propofol, and RTA‐408 + propofol groups. The learning and memory ability was inspected by Morries water maze (MWM) test. TUNEL staining was performed to examine the apoptosis of neurons in hippocampus. The gene and protein expressions in hippocampus were detected by immunohistochemistry, qRT‐PCR, or Western blotting. The activities of glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) were tested by the corresponding kits.

Results

Propofol prolonged escape latency of mice, decreased the times of crossing the platform, and shortened the time of staying in the target quadrant, while RTA‐408 treatment improved the above‐mentioned situation. Besides, Nrf2 protein in hippocampus of mice induced by propofol was decreased with the increased NF‐κB p65 nuclear translocation, which was reversed by RTA‐408. Meanwhile, RTA‐408 decreased the apoptosis of neurons accompanying with the down‐regulation of Caspase‐3 and the up‐regulations of neuronal‐specific nuclear protein (NeuN), microtubule‐associated protein 2 (Map2), Ca2+/Calmodulin‐dependent Protein Kinase II (CaMKII), and parvalbumin (PV) immunostaining in hippocampus. Besides, propofol‐induced high levels of proinflammatory cytokines and antioxidase activities in hippocampus were reduced by RTA‐408.

Conclusion

RTA‐408 improved propofol‐induced cognitive impairment in neonatal mice via enhancing survival of neurons, reducing the apoptosis of hippocampal neurons, mitigating the inflammation and oxidative stress, which may be correlated with the activation of Nrf2 and the inhibition of NF‐κB p65 nuclear translocation.
The critical impact of tumor size in predicting cancer special survival for T3aM0M0 renal cell carcinoma: A proposal of an alternative T3aN0M0 stage
Authors: Li Luping , Shi Lei , Zhang Junjie , Fan Yingzhong , Li Qi
Published: December 2020

Objective

Based on the eighth TNM staging system, T3a renal cell carcinoma (RCC) is identified as an anatomical extrarenal invasion and does not consider the size of the tumor; however, it may not fully predict the prognosis of the patient. The objective of this study was to evaluate the prognostic value of tumor size effects on prognosis in T3a RCC and propose an alternative tumor stage system combined with T1‐2.

Methods

Data relating to T1‐3aN0M0 RCC (n = 49586) were obtained from the Surveillance, Epidemiology, and End Results database (2004–2015). Survival analyses were conducted by Cox regression and Fine and Gray regression. Harrell's concordance index (c‐index) was used to assess the discriminatory ability of the prognostic factors.

Results

A 1‐cm increase in T3a RCC resulted in an 8% increase in all‐cause mortality (hazard ratio [HR]: 1.08; 95% confidence interval [CI]: 1.06–1.10, p < 0.001) and 14% increase in the risk of RCC‐specific mortality (sub‐distribution HR [sHR]: 1.14; 95% CI: 1.11–1.16, p < 0.001). T3a tumor size stratified by the cutoff of 4 cm and 7 cm showed a better prediction of RCC‐special survival (c‐index: 0.644), compared with a cutoff just by 4 cm (c‐index: 0.571) or by 7 cm (c‐index: 0.602). Compared with T1b tumors, T3a RCC ≤4 cm showed no differences in terms of all‐cause mortality (HR: 0.93; 95% CI: 0.79–1.09; p = 0.37) and mortality caused by RCC (sHR: 0.91; 95% CI: 0.70–1.19; p = 0.50). Last, the alternative T‐staging system (T1a, a combination of T1b and T3a [≤4 cm], T2a, T2b, T3a [4–7 cm], and T3a [>7] cm) demonstrated good RCC‐special survival predictive accuracy (c‐index: 0.729), which was higher than that shown by the current eighth edition T‐staging system (c‐index: 0.720).

Conclusion

Tumor size should be taken into consideration for T3aN0M0 RCC rather than based on anatomical features alone.
Philadelphia‐negative myeloproliferative neoplasms among Kuwaiti Nationals
Authors: Alshemmari Salem , Almazyad Mazyad , Alwehaib Aisha , Ameen Reem
Published: December 2020

The epidemiology, genetics, and thrombosis risk of MPNs among Arabs are largely unknown. This may be attributed to scarce epidemiological data, particularly from our region. Our study included 381 Kuwaiti nationals with Ph‐negative MPNs and a confirmed driver mutation involving JAK2 (exon 12 14), CALR, or MPL. This first regional study examines the demographics, clinical parameters, and thrombosis‐related attributes of the participants. This study reported a median age of 58 years, with females and males representing 54.9% and 45.1%, respectively. ET was the most frequent subtype of Ph‐negative MPNs in our population, accounting for 52.0% of the cases, followed by PV, found in 34.6% of the participants, and PMF, found in 8.4% of participants. The crude annual cumulative incidence of Ph‐negative MPNs in Kuwait ranged from 0.674 to 3.177 per 100,000 population across the study period. The most common driver mutation was JAK2V617F, with a frequency of 89.5%. At diagnosis, 19.2% of the patients presented with unexplained thrombosis, and almost half were of arterial origins. Males were more likely to present with arterial thrombosis than females (61.5% vs. 35.3%), whereas venous thrombotic events were more common in females than in males (47.1% vs. 17.9%; p‐value = 0.025). Ph‐negative MPNs in Kuwait are rare; however, thrombosis is a frequent complication, being documented in up to 19.2% of cases at presentation, more commonly at arterial sites. These findings call for thorough evaluation of patients with unexplained derangements in their hematological parameters during follow‐ups.
Bone marrow mesenchymal stem cells‐derived exosomes reduce Aβ deposition and improve cognitive function recovery in mice with Alzheimer's disease by activating sphingosine kinase/sphingosine‐1‐phosphate signaling pathway
Authors: Wang Xinhui , Yang Guojie
Published: December 2020

Exosomes are associated with the development and progression of Alzheimer's disease (AD), although the impact of these extracellular vesicles in brain pathological condition remains incompletely understood. Therefore, this study aimed to investigate the role and mechanism of exosomes signaling in AD. Double transgenic APP/PS1 mice were injected with bone marrow mesenchymal stem cells (BM‐MSCs)‐derived exosomes or combined with SKI‐Ⅱ (sphingosine kinase [SphK] inhibitor) or VPC23019 (sphingosine‐1‐phosphate [S1P] 1 receptor blocker). We observed the spatial learning and memory ability of mice, and assessed the levels of amyloid and proteins. We found that exosomes improved spatial learning and memory ability of APP/PS1 mice, and enhanced the expression of SphK1 and S1P1. Moreover, exosomes inhibited the levels of amyloid and enhanced the expression of NeuN in cortex and hippocampus of APP/PS1 mice. Exosomes repressed the levels of Aβ1‐40, Aβ1‐42, BACE1, and PS1, and promoted the expression of neprilysin in APP/PS1 mice. The influence conferred by exosomes was abolished by SKI‐Ⅱ or VPC23019. In conclusion, our article confirms that BM‐MSCs‐derived exosomes reduce Aβ deposition and promote cognitive function recovery in AD mice by activating SphK/S1P signaling pathway. Thus, our data suggest that S1P/SphK‐containing exosomes should be explored as potential AD cure.
Structural and Electronic Control of the Bidentate 1‐(2‐pyridyl)benzotriazole Ligand in Copper Chemistry with Application to Catalysis in the A3 Coupling Reaction
Authors: Sampani Stavroula I. , Zdorichenko Victor , Devonport Jack , Rossini Gioia , Leech Matthew C. , Lam Kevin , Cox Brian , Abdul‐Sada Alaa , Vargas Alfredo , Kostakis George E.
Published: December 2020

The hybrid bidentate 1‐(2‐pyridyl)benzotriazole (pyb) ligand was introduced into 3d transition metal catalysis. Specifically, [CuII(OTf)2(pyb)2]⋅2 CH3CN (1) enables the synthesis of a wide range of propargylamines by the A3 coupling reaction at room temperature in the absence of additives. Experimental and high‐level theoretical calculations suggest that the bridging N atom of the ligand imposes exclusive trans coordination at Cu and allows ligand rotation, while the N atom of the pyridine group modulates charge distribution and flux, and thus orchestrates structural and electronic precatalyst control permitting alkyne binding with simultaneous activation of the C−H bond via a transient CuI species.
A short‐term deep learning model for urban pollution forecasting with incomplete data
Authors: Colorado Cifuentes Gerson Uriel , Flores Tlacuahuac Antonio
Published: December 2020

A deep neural network model for the short term prediction of ozone, 10 μm particulate matter, and 2.5 μm particulate matter concentrations in a major northwestern metropolitan area of México is developed. In order to formulate such a model, the data available from the local air quality automatic network monitoring system are used for training, validation, and testing purposes. Such time series data are incomplete and a procedure of missing data imputation is carried out. The model predicts with high accuracy the concentration of the target pollutants, and the training procedure, performance metrics, and tools used are discussed in this work. Such a model can be deployed for the implementation and evaluation of public politics for improving population health, and reducing the potential negative impacts of harmful pollutants by issuing early warnings on dangerous pollution levels.
The phosphatase inhibitor Sds23 promotes symmetric spindle positioning in fission yeast
Authors: Schutt Katherine L. , Moseley James B.
Published: December 2020

A hallmark of cell division in eukaryotic cells is the formation and elongation of a microtubule (MT)‐based mitotic spindle. Proper positioning of the spindle is critical to ensure equal segregation of the genetic material to the resulting daughter cells. Both the timing of spindle elongation and constriction of the actomyosin contractile ring must be precisely coordinated to prevent missegregation or damage to the genetic material during cellular division. Here, we show that Sds23, an inhibitor of protein phosphatases, contributes to proper positioning of elongating spindles in fission yeast cells. We found that sds23∆ mutant cells exhibit asymmetric spindles that initially elongate asymmetrically toward one end of the dividing cell. Spindle asymmetry in sds23∆ cells results from a defect that is distinct from previously identified mechanisms, including MT protrusions and enlarged vacuoles. Combined with our previous work, this study demonstrates that Sds23, an inhibitor of PP2A‐family protein phosphatases, promotes proper positioning of both the bipolar spindle and cytokinetic ring during fission yeast cell division. These two steps ensure the overall symmetry and fidelity of the cell division process.
The Question‐prompt list (QPL): Why it is needed in the Indian oncology setting?
Authors: Chawak Shweta , Chittem Mahati , Maya Sravannthi , Dhillon Haryana M. , Butow Phyllis N.
Published: December 2020

Background

In India, caregivers are an integral part of the illness experience, especially in cancer, to the extent that they can become proxy decision‐makers for the patient. Further, owing to acute resource constraints in the Indian healthcare system, it may be difficult for oncologists to assess and elicit questions from each patient/caregiver. Consequently, there is a need to address these unique aspects of oncology care in India to improve patient outcomes and understanding of their illness and treatment. This can be achieved through a Question Prompt List (QPL), a checklist used by care recipients during medical consultations.

Recent Findings

This narrative review will first introduce research on the development and effectiveness of the QPL, and then it will highlight current gaps in oncology care in India and explore how the QPL may aid in closing these gaps.

A literature search of the empirical research focused on the development, feasibility and acceptability of the QPL in oncology settings was conducted. The final review included 40 articles pertaining to QPL research. Additionally, psycho‐oncology research in India centered on information needs and experiences was reviewed.

Current Indian psycho‐oncology research reports patients' want to be actively involved in their cancer care and a need for more illness information. However, a high demand on physicians' resources and the family caregivers' interference can be barriers to meeting patients' information/communication needs. International research demonstrates that a QPL helps structure and decrease consultation time, improves patient satisfaction with care, and improves the quality of communication during medical encounters.

Conclusion

QPLs for Indian patients and caregivers may focus on the scope of medical consultations to address patient needs while influencing the course and content of the patient‐caregiver‐physician interactions. Further, it can address the resource constraints in Indian oncology care settings, thus reducing the physician's burden.
Physiologically Based Precision Dosing Approach for Drug‐Drug‐Gene Interactions: A Simvastatin Network Analysis
Authors: Wojtyniak Jan‐Georg , Selzer Dominik , Schwab Matthias , Lehr Thorsten
Published: December 2020

Drug‐drug interactions (DDIs) and drug‐gene interactions (DGIs) are well known mediators for adverse drug reactions (ADRs), which are among the leading causes of death in many countries. Because physiologically based pharmacokinetic (PBPK) modeling has demonstrated to be a valuable tool to improve pharmacotherapy affected by DDIs or DGIs, it might also be useful for precision dosing in extensive interaction network scenarios. The presented work proposes a novel approach to extend the prediction capabilities of PBPK modeling to complex drug‐drug‐gene interaction (DDGI) scenarios. Here, a whole‐body PBPK network of simvastatin was established, including three polymorphisms (SLCO1B1 (rs4149056), ABCG2 (rs2231142), and CYP3A5 (rs776746)) and four perpetrator drugs (clarithromycin, gemfibrozil, itraconazole, and rifampicin). Exhaustive network simulations were performed and ranked to optimize 10,368 DDGI scenarios based on an exposure marker cost function. The derived dose recommendations were translated in a digital decision support system, which is available at simvastatin.precisiondosing.de. Although the network covers only a fraction of possible simvastatin DDGIs, it provides guidance on how PBPK modeling could be used to individualize pharmacotherapy in the future. Furthermore, the network model is easily extendable to cover additional DDGIs. Overall, the presented work is a first step toward a vision on comprehensive precision dosing based on PBPK models in daily clinical practice, where it could drastically reduce the risk of ADRs.
Developing and Validating a Clinical Warfarin Dose‐Initiation Model for Black‐African Patients in South Africa and Uganda
Authors: Asiimwe Innocent G. , Waitt Catriona , Sekaggya‐Wiltshire Christine , Hutchinson Claire , Okello Emmy , Zhang Eunice J. , Semakula Jerome R. , Mouton Johannes P. , Cohen Karen , Blockman Marc , Lamorde Mohammed , Jorgensen Andrea L. , Pirmohamed Munir
Published: December 2020

Warfarin remains the oral anticoagulant of choice in sub‐Saharan Africa. However, dosing is challenging due to a highly variable clinical response for a given dose. This study aimed to develop and validate a clinical warfarin dose‐initiation model in sub‐Saharan Black‐African patients. For the development cohort, we used data from 364 patients who were recruited from 8 outpatient clinics and hospital departments in Uganda and South Africa (June 2018–July 2019). Validation was undertaken using the International Warfarin Pharmacogenetics Consortium (IWPC) dataset (690 black patients). Four predictors (age, weight, target International Normalized Ratio range, and HIV status) were included in the final model, which achieved mean absolute errors (MAEs; mean of absolute differences between true dose and dose predicted by the model) of 11.6 (95% confidence interval (CI) 10.4–12.8) and 12.5 (95% CI 11.6–13.4) mg/week in the development and validation cohorts, respectively. Two other clinical models, IWPC and Gage, respectively, obtained MAEs of 12.5 (95% CI 11.3–13.7) and 12.7 (95% CI 11.5–13.8) mg/week in the development cohort, and 12.1 (95% CI 11.2–13.0) and 12.2 (95% CI 11.4–13.1) mg/week in the validation cohort. Compared with fixed dose‐initiation, our model decreased the percentage of patients at high risk of suboptimal anticoagulation by 7.5% (1.5–13.7%) and 11.9% (7.1–16.8%) in the development and validation cohorts, respectively. The clinical utility of this model will be tested in a prospective study.

Study Highlights

WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Warfarin dosing remains challenging due to a highly variable clinical response for a given dose.

WHAT QUESTION DID THIS STUDY ADDRESS?

☑ Can a clinical dose‐initiation model be developed and validated for sub‐Saharan Black‐African patients?

WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ We have developed the first warfarin dose‐initiation clinical model for Black‐African patients in Uganda and South Africa.

HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ We will be implementing and validating this model in a prospective cohort to inform future large‐scale implementation. More optimized dosing should improve the quality of warfarin anticoagulation in these two developing countries.
Thromboembolic and Hemorrhagic Outcomes in the Direct Oral Anticoagulant Trials Across the Spectrum of Kidney Function
Authors: Limdi Nita A. , Beasley Timothy Mark , Sun Jielin , Stockbridge Norman , Pacanowski Michael , Florian Jeffry
Published: December 2020

Chronic kidney disease is a common comorbidity among patients taking direct‐acting oral anticoagulants (DOACs). Herein, we evaluate the influence of kidney function on stroke or systemic embolism (SEE), hemorrhage, and composite end points (stroke/SEE/hemorrhage/death and stroke/SEE/death) among patients on DOACs and warfarin. Baseline kidney function was categorized as glomerular filtration rate (GFR) ≥ 60 (reference), 45–59, and < 45mL/min/1.73 m2 for participants in the Randomized Evaluation of Long‐Term Anticoagulant Therapy (RE‐LY) (n = 18,049), Apixaban for Reduction in Stroke and Other Thromboembolic Events (ARISTOTLE) (n = 18,187), and The Effective Anticoagulation with Factor Xa Next Generation in AF (ENGAGE AF) (n = 20,798) trials. Incidence of events was compared across GFR categories. Hazard ratios for events were estimated using Cox regression using intention‐to‐treat analysis adjusting for known predictors. A large proportion of participants had GFR < 60 (25–29% had 45 ≤ GFR < 60 and 9.5–12.6% with GFR < 45). Compared with patients with GFR ≥ 60, warfarin users across the trials with GFR ≥ 45–59 and GFR < 45 had a higher incidence of hemorrhage (P values < 0.0001) and warfarin users in the ARISTOTLE and ENGAGE trials had higher incidence of stroke/SEE (P values ≤ 0.05). Compared with patients with GFR ≥ 60, dabigatran users with GFR ≥ 45–59 and GFR < 45 had a higher incidence of stroke/SEE (P ≤ 0.02), hemorrhage (P < 0.001), and both composite end points (P < 0.0001). Compared with patients with GFR ≥ 60, apixaban and edoxaban users with GFR ≥ 45–59 and GFR < 45 had a higher incidence of hemorrhage (P values ≤ 0.05) and composite end points (P values ≤ 0.05). After adjustment, compared with patients with GFR ≥ 60, warfarin users with GFR < 60 in the ARISTOTLE and RE‐LY trials had a higher risk of hemorrhage (P < 0.05), as did dabigatran (P < 0.001) and edoxaban (P ≤ 0.005) users, while apixaban users did not exhibit an increased risk (P = 0.08 GFR ≥ 45–59; P = 0.71 GFR < 45). Kidney function significantly influences the safety and efficacy of oral anticoagulants.
Identification of tumor‐associated macrophage subsets that are associated with breast cancer prognosis
Authors: Strack Elisabeth , Rolfe P. Alexander , Fink Annika F. , Bankov Katrin , Schmid Tobias , Solbach Christine , Savai Rajkumar , Sha Weixiao , Pradel Leon , Hartmann Sylvia , Brüne Bernhard , Weigert Andreas
Published: December 2020

Background

Breast cancer is the leading cause of cancer‐related deaths in women, demanding new treatment options. With the advent of immune checkpoint blockade, immunotherapy emerged as a treatment option. In addition to lymphocytes, tumor‐associated macrophages exert a significant, albeit controversial, impact on tumor development. Pro‐inflammatory macrophages are thought to hinder, whereas anti‐inflammatory macrophages promote tumor growth. However, molecular markers to identify prognostic macrophage populations remain elusive.

Methods

We isolated two macrophage subsets, from 48 primary human breast tumors, distinguished by the expression of CD206. Their transcriptomes were analyzed via RNA‐Seq, and potential prognostic macrophage markers were validated by PhenOptics in tissue microarrays of patients with invasive breast cancer.

Results

Normal human breast tissue contained mainly CD206+ macrophages, while increased relative amounts of CD206− macrophages were observed in tumors. The presence of CD206+ macrophages correlated with a pronounced lymphocyte infiltrate and subsets of CD206+ macrophages, expressing SERPINH1 and collagen 1, or MORC4, were unexpectedly associated with improved survival of breast cancer patients. In contrast, MHCIIhi CD206− macrophages were linked with a poor survival prognosis.

Conclusion

Our data highlight the heterogeneity of tumor‐infiltrating macrophages and suggest the use of multiple phenotypic markers to predict the impact of macrophage subpopulations on cancer prognosis. We identified novel macrophage markers that correlate with the survival of patients with invasive mammary carcinoma.
Little to no expression of angiotensin‐converting enzyme‐2 on most human peripheral blood immune cells but highly expressed on tissue macrophages
Authors: Song Xiang , Hu Wei , Yu Haibo , Zhao Laura , Zhao Yeqian , Zhao Xin , Xue Hai‐Hui , Zhao Yong
Published: December 2020

Angiotensin‐converting enzyme‐2 (ACE2) has been recognized as the binding receptor for the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Flow cytometry demonstrated that there was little to no expression of ACE2 on most of the human peripheral blood‐derived immune cells including CD4+ T, CD8+ T, activated CD4+/CD8+ T, Tregs, Th17, NKT, B, NK cells, monocytes, dendritic cells, and granulocytes. There was no ACE2 expression on platelets and very low level of ACE2 protein expression on the surface of human primary pulmonary alveolar epithelial cells. The ACE2 expression was markedly upregulated on the activated type 1 macrophages (M1). Immunohistochemistry demonstrated high expressions of ACE2 on human tissue macrophages, such as alveolar macrophages, Kupffer cells within livers, and microglial cells in brain at steady state. The data suggest that alveolar macrophages, as the frontline immune cells, may be directly targeted by the SARS‐CoV‐2 infection and therefore need to be considered for the prevention and treatment of COVID‐19.
Flow cytometric measurement of STAT5 phosphorylation in cytomegalovirus‐stimulated T cells
Authors: Bitar Michael , Boettcher Marcus , Boldt Andreas , Hauck Fabian , Köhl Ulrike , Liebert Uwe G. , Magg Thomas , Schulz Marian S. , Sack Ulrich
Published: December 2020

Cytomegalovirus (CMV)‐specific T cells expand with CMV reactivation and are probably prerequisite for control and protection. Given the critical role STAT5A phosphorylation (pSTAT5A) in T cell proliferation, this study presents a simple and sensitive flow cytometric‐based pSTAT5A assay to quickly identify CMV‐specific T cell proliferation. We determined pSTAT5A in T cells treated with CMV‐specific peptide mix (pp65 + IE1 peptides) from 20 healthy adult subjects and three immunodeficient patients with CARMIL‐2 mutation. After stimulation, the percentage of pSTAT5A+ T cells in CMV‐seropositive (CMV+) subjects significantly increased from 3.0% ± 1.9% (unstimulated) to 11.4% ± 5.9% (stimulated) for 24 h. After 7 days of stimulation, the percentage of expanded T cells amounted to 26% ± 17.2%. Conversely, the percentage of pSTAT5A+ T cells and T cell proliferation from CMV‐seronegative (CMV−) subjects hardly changed (from 3.0% ± 1.3% to 3.7% ± 1.8% and from 4.3% ± 2.1% to 5.7% ± 1.7%, respectively). We analyzed the correlation between the percentage of pSTAT5A+ T cells versus (1) CMV‐IgG concentrations versus (2) the percentage of expanded T cells and versus (3) the percentage of initial CMV‐specific T cells. In immunodeficient patients with CARMIL‐2 mutation, CMV‐specific pSTAT5A and T cell proliferation were completely deficient. In conclusion, flow cytometric‐based pSTAT5A assay represents an appropriate tool to quickly identify CMV‐specific T cell proliferation and helps to understand dysfunctions in controlling other pathogens. Flow cytometric‐based pSTAT5A assay may be a useful test in clinical practice and merits further validation in large studies.
RHAPSODY, Biomarkers and Novel Clinical Trial design in type 2 diabetes (T2D) and prediabetes
Authors: Adams Rachel , Daly Nicole , Robertson Elizabeth , Giordano Giuseppe N.
Published: December 2020

Developing a novel therapeutic product for the treatment of type 2 diabetes (T2D) is a long, resource‐intensive process. Novel biomarkers could potentially aid clinical trial design by shortening clinical trials or enabling better prediction of at‐risk populations and/or disease progression. Novel clinical trial designs could lead to reduced costs of development and less burden to patients, due to shorter trial duration, and/or less burdensome assessments.
Predominant subtype of heart failure after acute myocardial infarction is heart failure with non‐reduced ejection fraction
Authors: Kamon Daisuke , Sugawara Yu , Soeda Tsunenari , Okamura Akihiko , Nakada Yasuki , Hashimoto Yukihiro , Ueda Tomoya , Nishida Taku , Onoue Kenji , Okayama Satoshi , Watanabe Makoto , Kawakami Rika , Saito Yoshihiko
Published: December 2020

Aims

Patients who survive acute myocardial infarction (AMI) are at risk of being rehospitalized owing to the occurrence of acute decompensated heart failure (HF). However, the clinical characteristics of HF after AMI, especially the frequency of each HF subtype, are unclear.

Methods and results

We retrospectively studied 1055 patients with AMI. We excluded 257 patients, who were admitted >48 h after the onset of AMI, died during hospitalization or after discharge, and whose echocardiogram data at index hospitalization and follow‐up data were missing. The remaining 798 patients (mean age: 66.5 ± 11.7 years) were investigated for a mean follow‐up period of 4.9 years. All patients underwent emergency coronary angiography. The mean maximum creatine kinase levels were 2898 ± 2627 IU/L, and mean left ventricular ejection fraction (LVEF) was 58.9 ± 10.2%. Eighty‐one patients (10.2%) were rehospitalized because of unexpected worsening of HF. Echocardiography data were available for 74 of the 81 patients during the acute phase of the second hospitalization, of which 30, 20, and 24 patients (41%, 27%, and 32%, respectively) were diagnosed as having HF with preserved LVEF (LVEF ≥ 50%), HF with mid‐range LVEF (40% ≤ LVEF < 50%), and HF with reduced LVEF (LVEF < 40%), respectively. The ejection fraction during index hospitalization was 58.3 ± 9.7% in the HF with preserved LVEF group, 53.3 ± 10.2% in the HF with mid‐range LVEF group, and 43.3 ± 10.5% in the HF with reduced LVEF group (P < 0.001).

Conclusions

The predominant subtypes of HF after AMI were HF with mid‐range ejection fraction and preserved ejection fraction, or HF with non‐reduced ejection fraction.
How many types of circulation can a boy have during his life? A case of aortic stenosis with a borderline left ventricle
Authors: Koubský Karel , Tláskal Tomáš , Chaloupecký Václav , Janoušek Jan
Published: December 2020

Severe aortic stenosis can be accompanied by various degrees of left ventricular underdevelopment. The assessment whether a borderline‐sized left ventricle can or cannot support the systemic circulation is crucial. The decision‐making still remains challenging. We present a case that illustrates that the development of haemodynamic parameters can be difficult to estimate, even in the long term. The patient went from biventricular to univentricular circulation and back and could finally be palliated by heart transplantation. Modern technology including long‐term mechanical cardiac support as a bridge to candidacy and drug therapy for pulmonary hypertension were vital to successfully combat a previously lethal disease.