bluuebunny/crossref_metadata_2025 huggingface dataset:
How young drug users view police: Canadian research study
Authors: Knopf Alison
Published: May 2022

A recent study has found that young drug users in Canada are targeted disproportionately by police, and that this targeting includes harassment and discrimination. Young people's negative encounters with police can harm their well‐being as they develop, according to researchers writing in the June issue of Contemporary Drug Problems.
New resource from NIAAA will help providers and consumers
Authors: Knopf Alison
Published: May 2022

A new online resource will help health care professionals and practices improve care for people whose alcohol consumption might be impacting their health. Recognizing alcohol's contribution to more than 200 diseases and adverse health conditions will improve clinicians' ability to serve their patients. The Healthcare Professional's Core Resource on Alcohol was developed by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health.
Wear and Corrosion Characterization of a Ti–6Al–4V Component for Automotive Applications: Forging versus Selective Laser Melting Technologies
Authors: Cecchel Silvia , Montesano Lorenzo , Cornacchia Giovanna
Published: May 2022

Selective laser melting (SLM) is applied to manufacture a Ti–6Al–4V conrod, an engine component, in order to reduce the weight respect to the original version produced by forging with the same alloy. The weight reduction is achieved through a topological optimization and is about 15%. The article focuses on an experimental study of titanium SLM and hot forging components based on evaluation and comparison of properties relevant for automotive applications: metallurgy, corrosion behavior, and wear resistance. The microstructure is duplex, composed of equiaxial α and β grains for both the technologies analyzed; different morphology and distribution of α and β phases are observed as expected. The analysis on corrosion and wear resistance against 100Cr6 highlights very similar properties for the two technologies. Finally, this study confirms that Ti–6Al–4V made by SLM can substitute the traditional forging technologies in the transport field for the properties here studied.
HAp Thermosensitive Nanohydrogel Cavities Act as Brood Pouches to Incubate and Control‐Release NSCs for Rapid Spinal Cord Injury Therapy
Authors: Hao Min , Zhang Dapeng , Wang Wenhan , Wei Zhijian , Duan Jiazhi , He Jianlong , Kong Xiaohong , Sang Yuanhua , Feng Shiqing , Liu Hong
Published: May 2022

Limitations such as the cell life span, cellular activity, and cellular diffusion outside the lesion make the direct repair of spinal cord injury (SCI) by neural stem cell (NSC) transplantation challenging. Here, an injectable hydroxyapatite (HAp) thermosensitive nanohydrogel is proposed to achieve stem cell storage and release, as well as fate regulation, for therapy. The cavities formed in situ functioned as brood pouches for cell proliferation. The enzyme‐induced collapse of cavities released mouse NSCs (mNSCs) gradually and continuously. The endocytosis of HAp nanorods by encapsulated mNSCs enhanced the property of mNSC neuronal differentiation. The HAp thermosensitive nanohydrogel with mNSCs exert an inspiring therapeutic effect on a complete transected SCI model and has prospects in material design to improve SCI therapy with stem cells.
Directing Charge Transfer in a Chemical‐Bonded BaTiO3@ReS2 Schottky Heterojunction for Piezoelectric Enhanced Photocatalysis
Authors: Liu Wei , Wang Peifang , Ao Yanhui , Chen Juan , Gao Xin , Jia Baohua , Ma Tianyi
Published: May 2022

The piezo‐assisted photocatalysis system, which can utilize solar energy and mechanical energy simulteneously, is promising but still challenging in the environmental remediation field. In this work, a novel metal–semiconductor BaTiO3@ReS2 Schottky heterostructure is designed and it shows high‐efficiency on piezo‐assisted photocatalytic molecular oxygen activation. By combining experiment and calculation results, the distorted metal‐phase ReS2 nanosheets are found to be closely anchored on the surface of the BaTiO3 nanorods, through interfacial ReO covalent bonds. The Schottky heterostructure not only forms electron‐transfer channels but also exhibits enhanced oxygen activation capacity, which are helpful to produce more superoxide radicals. The polarization field induced by the piezoelectric BaTiO3 can lower the Schottky barrier and thus reduce the transfer resistance of photogenerated electrons directing to the ReS2. As a result of the synergy effect between the two components, the BaTiO3@ReS2 exhibits untrahigh activity for degradation of pollutants with an apparent rate constant of 0.133 min−1 for piezo‐assisted photocatalysis, which is 16.6 and 2.44 times as that of piezocatalysis and photocatalysis, respectively. This performance is higher than most reported BaTiO3‐based piezo‐assisted photocatalysis systems. This work paves the way for the design of high‐efficiency piezo‐assisted photocatalytic materials for environmental remediation through using green energies in nature.
Visible‐Light‐Induced [2+2+1] Dearomative Cascade Cyclization of Indole/Furan Alkynes to Synthesize Sulfonyl Polycycles
Authors: Luo Jiajun , Zeng Guohui , Cao Xiaohui , Yin Biaolin
Published: May 2022

Herein, we report a visible‐light‐induced [2+2+1] dearomative cascade cyclization of indole/furan alkynes with NaHSO3, providing an array of diverse highly strained sulfonyl polycycles. Compared to our previous work, this method does not require the use of additional sacrificial oxidants and have wider reaction scope. Preliminary mechanistic studies suggest that the indole moiety initiated the reaction, which proceeded via single‐electron oxidation pathway. An alkenyl radical formed by intramolecular addition capture SO2, and the resulting specie is cyclized to furnish the final product. Also, DFT calculations disclosed that the groups on the indole ring or at the side chain probably affect the single electron distribution at the reaction site of IM‐RC‐I, and the distribution may be a decisive factor of spirocyclization.

magnified image
Smart Electronic Nose Enabled by an All‐Feature Olfactory Algorithm
Authors: Fang Cong , Li Hua-Yao , Li Long , Su Hu-Yin , Tang Jiang , Bai Xiang , Liu Huan
Published: May 2022

An electronic nose (e‐nose) mimics the mammalian olfactory system in identifying odors and expands human olfaction boundaries by tracing toxins and explosives. However, existing feature‐based odor recognition algorithms rely on domain‐specific expertise, which may limit the performance due to information loss during the feature extraction process. Inspired by human olfaction, a smart electronic nose enabled by an all‐feature olfactory algorithm (AFOA) is proposed, whereby all features in a gas sensing cycle of semiconductor gas sensors, including the response, equilibrium, and recovery processes are utilized. Specifically, our method combines 1D convolutional and recurrent neural networks with channel and temporal attention modules to fully utilize complementary global and dynamic information. It is further demonstrated that a novel data augmentation method can transform the raw data into a suitable representation for feature extraction. Results show that the e‐nose simply comprising of six semiconductor gas sensors achieves superior performances to state‐of‐the‐art methods on the Chinese liquor data. Ablation studies reveal the contribution of each sensor in odor recognition. Therefore, a deep‐learning‐enabled codesign of sensor arrays and recognition algorithms can reduce the heavy demand for a huge amount of highly specialized gas sensors and provide interpretable insights into odor recognition dynamics in an iterative way.
Palladium‐Catalyzed Carbonylative Cross‐Coupling of Aryl Iodides and Alkenyl Bromides with Benzyl Halides under Reductive Conditions
Authors: Lin Tingzhi , Qian Pengcheng , Wang Yan‐En , Ou Mingjie , Cui Ning , Ye Yu , Hua Rui , Xiong Dan , Xue Fei , Walsh Patrick J. , Mao Jianyou
Published: May 2022

A direct and convenient method for the palladium‐catalyzed reductive cross‐coupling of aryl iodides or alkenyl bromides and secondary benzyl halides under ambient CO pressure to generate a diverse array of aryl/alkenyl alkyl ketones has been developed. This strategy successfully achieves a three‐component carbonylative reaction with Zn as the reducing agent for C−C bond formation, overcoming the well‐known homocoupling of aryl or alkenyl halides, direct cross‐coupling between two different electrophiles and other carbonylative coupling reactions. In addition, this method avoids use of preformed organometallic nucleophiles, such as organo‐magnesium, zinc and boron reagents. This approach enables the construction of valuable aryl alkyl/alkenyl ketone derivatives (60 examples, 56–95% yields). Reactivity studies indicate that in situ formed benzylic zinc reagents are intermediates in the catalytic system.
First principles of smart manufacturing
Authors: Leiva Conrad
Published: May 2022

The democratizing of innovation and technology happens when tools and expertise are made affordable and accessible at scale to most manufacturers. To realize the democratization of smart manufacturing innovation, it is not only necessary to democratize the technology, but also necessary to provide wide access to the knowledge required to implement the strategies and leverage the solutions and insights in a more digitally enabled manufacturing ecosystem. We are at a point in the journey where it is time to converge on a concrete set of guiding principles and a framework that organizes expectations and requirements for the implementation of smart manufacturing. This paper summarizes the practices that define smart manufacturing as developed by the industry leaders, early adopters, and expert practitioners working in the ecosystem at CESMII, the smart manufacturing institute. In smart manufacturing, organizations, people, and technology work in synergy via processes and technology‐based solutions that follow these seven First Principles: Flat & real‐time, open & interoperable, proactive & semi‐autonomous, sustainable & energy efficient, secure, scalable, orchestrated & resilient. All the design principles must be considered to fully realize the vision for smart manufacturing. This paper will further explain how the seven principles work collectively to achieve new levels of connectivity, intelligence, and automation in the manufacturing ecosystem.
Layered Oxide Cathode‐Electrolyte Interface towards Na‐Ion Batteries: Advances and Perspectives
Authors: Lei Zhou‐Quan , Guo Yu‐Jie , Wang En‐Hui , He Wei‐Huan , Zhang Yu‐Ying , Xin Sen , Yin Ya‐Xia , Guo Yu‐Guo
Published: May 2022

With the ever increasing demand for low‐cost and economic sustainable energy storage, Na‐ion batteries have received much attention for the application on large‐scale energy storage for electric grids because of the worldwide distribution and natural abundance of sodium element, low solvation energy of Na+ ion in the electrolyte and the low cost of Al as current collectors. Starting from a brief comparison with Li‐ion batteries, this review summarizes the current understanding of layered oxide cathode/electrolyte interphase in NIBs, and discusses the related degradation mechanisms, such as surface reconstruction and transition metal dissolution. Recent advances in constructing stable cathode electrolyte interface (CEI) on layered oxide cathode are systematically summarized, including surface modification of layered oxide cathode materials and formulation of electrolyte. Urgent challenges are detailed in order to provide insight into the imminent developments of NIBs.
A new look at the Birnbaum–Saunders regression model
Authors: Bourguignon Marcelo , Gallardo Diego I.
Published: May 2022

Motivated by problems of vibration in commercial aircraft that caused fatigue in materials, Birnbaum and Saunders (1969a,b) proposed a family of two‐parameter distributions to model failure time due to fatigue under cyclic loading and the assumption that failure follows from the development and growth of a dominant crack. This article is cited in at least 930 scientific articles. After the work of Birnbaum and Saunders (1969a,b), the Birnbaum–Saunders model is one of the most important and used models for analyzing lifetime data. Regression analysis is commonly used when covariates are involved in the life test. In this article, we provide a comprehensive review of Birnbaum–Saunders regression models based on parameterizations of the Birnbaum–Saunders distribution in terms of central tendency measures. In particular, we propose a new and straightforward reparameterization of the Birnbaum–Saunders distribution based on an approximation to its mode. In contrast to the original parameterization, the proposed parameterization leads to regression coefficients directly associated (approximately) with the mode of the response variable. We discuss the estimation of model parameters by maximum likelihood, hypothesis testing, and residual analysis. Furthermore, we show that the proposed regression model and other parameterized Birnbaum–Saunders models have the same log‐likelihood function estimate when no covariates are used to model the shape parameter. Additionally, we propose a simple script in the R software to solve numerical problems in the Fisher information matrix for some values of the shape parameter. Finally, we present and explore two empirical applications to compare the investigated regression models.
Genome architecture and totipotency: An intertwined relation during early embryonic development
Authors: Olbrich Teresa , Ruiz Sergio
Published: May 2022

Chromosomes are not randomly packed and positioned into the nucleus but folded in higher‐order chromatin structures with defined functions. However, the genome of a fertilized embryo undergoes a dramatic epigenetic reprogramming characterized by extensive chromatin relaxation and the lack of a defined three‐dimensional structure. This reprogramming is followed by a slow genome refolding that gradually strengthens the chromatin architecture during preimplantation development. Interestingly, genome refolding during early development coincides with a progressive loss of developmental potential suggesting a link between chromatin organization and cell plasticity. In agreement, loss of chromatin architecture upon depletion of the insulator transcription factor CTCF in embryonic stem cells led to the upregulation of the transcriptional program found in totipotent cells of the embryo, those with the highest developmental potential. This essay will discuss the impact of genome folding in controlling the expression of transcriptional programs involved in early development and their plastic‐associated features.
Estimating the two graph dextran–stearic acid–spermine polymers based on iron oxide nanoparticles as carrier for gene delivery
Authors: Kazemi‐Ashtiyani Mehrnoosh , Hajipour‐Verdom Behnam , Satari Mohammad , Abdolmaleki Parviz , Hosseinkhani Saman , Shaki Hossein
Published: May 2022

Non‐viral gene carriers have shown noticeable potential in gene delivery because of limited side effects, biocompatibility, simplicity, and the ability to take advantage of electrostatic interactions. However, the low transfection rate of non‐viral vectors under physiological conditions is controversial. This study aimed to decrease the transfection time using a static magnetic field. We used self‐assembled cationic polysaccharides based on dextran–stearic acid–spermine (DSASP) conjugates associated with Fe3O4 superparamagnetic nanoparticles to investigate their potential as gene carriers to promote the target delivery. Our findings illustrate that the magnetic nanoparticles are spherical with a positive surface charge and exhibit superparamagnetic behavior. The DSASP–pDNA/Fe3O4 complexes offered a strong pDNA condensation, protection against DNase degradation, and significant cell viability in HEK 293T cells. Our results demonstrated that although conjugation of stearic acid could play a role in transfection efficiency, DSASP magnetic carriers with more spermine derivatives showed better affinity between the amphiphilic polymer and the negatively charged cell membrane.
A necroptosis‐related gene signature for predicting prognosis, immune landscape, and drug sensitivity in hepatocellular carcinoma
Authors: Chen Junliang , Wang Huaitao , Zhou Lei , Liu Zhihao , Chen Hui , Tan Xiaodong
Published: May 2022

Background

Hepatocellular carcinoma (HCC) remains a growing threat to global health. Necroptosis is a newly discovered form of cell necrosis that plays a vital role in cancer development. Thus, we conducted this study to identify a predictive signature of HCC based on necroptosis‐related genes.

Methods

The tumor samples in the liver hepatocellular carcinoma (LIHC) cohort from The Cancer Genome Atlas (TCGA) database were subtyped using the consensus clustering algorithm. Univariate Cox regression and LASSO‐Cox analysis were performed to identify a gene signature from genes differentially expressed between tumor clusters. Then, we integrated the TNM stage and the prognostic model to build a nomogram. The gene signature and the nomogram were externally validated in the GSE14520 cohort from the Gene Expression Omnibus (GEO) and the LIRP‐JP cohort from the International Cancer Genome Consortium (ICGC). Evaluations of predictive performance evaluations were conducted using Kaplan–Meier plots, time‐dependent receiver operating characteristic curves, principal component analyses, concordance indices, and decision curve analyses. The tumor microenvironment was estimated using eight published methods. Finally, we forecasted the sensitivity of HCC patients to immunotherapy and chemotherapy based on this gene signature.

Results

We identified two necroptosis‐related clusters and a 10‐gene signature (MTMR2, CDCA8, S100A9, ANXA10, G6PD, SLC1A5, SLC2A1, SPP1, PLOD2, and MMP1). The gene signature and the nomogram had good predictive ability in the TCGA, ICGC, and GEO cohorts. The risk score was positively associated with the levels of necroptosis and immune cell infiltrations (especially of immunosuppressive cells). The high‐risk group could benefit more from immunotherapy and some chemotherapeutics than the low‐risk group.

Conclusion

The necroptosis‐related gene signature provides a new method for the risk stratification and treatment optimization of HCC. The nomogram can further improve predictive accuracy.
Student safety assistants program can provide extra support within your residence halls
Authors: McCarthy Claudine
Published: May 2022

Keeping your students safe and supporting their overall well‐being on campus likely ranks as one of your top priorities. But tight budgets can interfere with taking steps to address this area of concern, such as launching new initiatives or hiring additional professional staff. If you're looking for an effective, affordable, and innovative way to support your residential students, you might want to launch a student safety assistants program, which seems to be working well at Kent State University.
Synthesis, Biological Activity and Molecular Docking Studies of Novel Sulfonate Derivatives Bearing Salicylaldehyde
Authors: Korkmaz Adem , Bursal Ercan
Published: May 2022

Enzyme activity alterations have been associated with many metabolism disorders and have crucial roles in the pathogenesis of some diseases. Tyrosinase is a key enzyme in melanin biosynthesis, which is responsible for skin pigmentation to protect the skin from solar radiation. Pancreatic lipase has been considered a key enzyme for the treatment of obesity. Herein, we reported the synthesis and enzyme inhibitions of a series of sulfonates as possible tyrosinase and pancreatic lipase inhibitors. According to the calculated IC50values, compound3f(74.1±11.1 μM) and compound3c(86.6±6.9 μM) were determined to be the best inhibitors among the synthesized compounds for the tyrosinase and pancreatic lipase enzymes, respectively. The approach yielded at extremely high level by creating very flexible structural domains for the chemically modified groups. The structural characterization of the target molecules was implemented by1H‐NMR,13C‐NMR, and HR‐MS analyses. Also, molecular docking studies of the synthesized compounds with tyrosinase and pancreatic lipase enzymes were conducted using AutoDock Vina software. Additionally, the studies of the absorption distribution, metabolism, and excretion (ADME) were performed to uncover the target compounds′ pharmacokinetics, drug similarities, and medicinal properties of the novel sulfonate derivatives bearing salicylaldehyde.
Nanomaterial Synthesis from End‐of‐Cycle Products: A Sustainable Way of Waste Valorisation
Authors: De Anindita
Published: May 2022

Waste materials are byproducts of modern technology‐driven lifestyle of mankind. They are impossible to be eliminated entirely, and often recycling of these materials into more useful products is the best way to handle them. In the last two decades, engineered nanomaterials have found application in various fields of research due to their small size and unique physical, chemical, electrical, and magnetic properties. They have potential to be used in various fields of science and technology from bench scale to industrial scale. In this review, the fabrication of nanomaterials using waste material as feedstock is elaborated. Various techniques available for nanomaterial synthesis, their application, and potential challenges of waste‐derived engineered nanomaterials are described. This field of research is highly relevant nowadays as this could prove to be a versatile and practical solution of waste management problems.
Connecting Algal Polysaccharide Degradation to Formaldehyde Detoxification
Authors: Brott Stefan , Thomas François , Behrens Maike , Methling Karen , Bartosik Daniel , Dutschei Theresa , Lalk Michael , Michel Gurvan , Schweder Thomas , Bornscheuer Uwe T.
Published: May 2022

Formaldehyde is a toxic metabolite that is formed in large quantities during bacterial utilization of the methoxy sugar 6‐O‐methyl‐d‐galactose, an abundant monosaccharide in the red algal polysaccharide porphyran. Marine bacteria capable of metabolizing porphyran must therefore possess suitable detoxification systems for formaldehyde. We demonstrate here that detoxification of formaldehyde in the marine Flavobacterium Zobellia galactanivorans proceeds via the ribulose monophosphate pathway. Simultaneously, we show that the genes encoding the key enzymes of this pathway are important for maintaining high formaldehyde resistance. Additionally, these genes are upregulated in the presence of porphyran, allowing us to connect porphyran degradation to the detoxification of formed formaldehyde.
PIMesh: An automatic point cloud and unstructured mesh generation algorithm for meshless methods and finite element analysis–with applications in surgical simulations
Authors: Wang Zhujiang , Srinivasa Arun R. , Reddy Junuthula N. , Dubrowski Adam
Published: May 2022

We propose a point cloud and mesh generation algorithm, particle injection mesh generator (PIMesh), that can be used to generate optimized high‐quality point clouds and unstructured meshes for domains in any shape with minimum (or even no) user intervention. The domains can be scanned images in OBJ format in 2D and 3D or just a line drawing in 2D. Mesh grading can also be easily controlled. The PIMesh is robust and easy to be implemented and is useful for a variety of applications, ranging from generating point clouds for meshless methods, mesh generation for finite element methods, computer graphics applications and surgical simulators. The core idea of the PIMesh is that a mesh domain is considered as an “airtight container” into which particles are “injected” at one or multiple selected interior points. The motion of the particles is controlled by a pseudo‐molecular dynamics (PMD) formulation with a pairwise purely repelling “force” moderated by an absolute velocity dependent drag force. The particles repel each other and occupy the whole domain somewhat like blowing up a balloon. When the container is full of particles and the motion is stopped (the particles can be considered as a point cloud), a Delaunay triangulation algorithm is employed to link the particles together to generate an unstructured mesh. The performance of the PIMesh and the comparison with other unstructured mesh generation approaches are demonstrated through generating node distributions and meshes for several 2D and 3D object domains including a scanned image of bones and others.
Bridging Efficacy of Tofacitinib Immediate‐Release to Extended‐Release Formulations for Treatment of Ulcerative Colitis: Application of a Model‐Informed Drug Development Approach
Authors: Mukherjee Arnab , Tsuchiwata Shinichi , Chang Cheng , Nicholas Timothy , Su Chinyu , Le Vu H. , Kushner Joseph , Kulisek Nicole
Published: May 2022

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We report a model‐informed drug development approach for bridging efficacy from immediate‐release (IR) to extended‐release (XR) tofacitinib formulations in patients with UC. IR‐XR efficacy bridging was supported by exposure‐response analysis of phase 3 induction/maintenance studies of the IR formulation in UC to identify exposure metrics relevant for efficacy. Pharmacokinetic studies in healthy subjects were used to confirm similarity of relevant exposure metrics of tofacitinib IR 5 mg twice daily to XR 11 mg once daily, and tofacitinib IR 10 mg twice daily to XR 22 mg once daily, thereby bridging efficacy between IR and XR formulations. Food effect was evaluated at both XR formulation dose levels. Exposure‐response analysis demonstrated that area under the plasma concentration–time curve (average plasma concentration) was a relevant predictor of efficacy. Pharmacokinetic studies demonstrated that area under the plasma concentration–time curve was equivalent between formulations under single‐dose and steady‐state conditions, and other exposure metrics were also similar. These results also supported bridging of safety data for IR‐XR formulations. Food had no impact on tofacitinib XR exposure. These data support efficacy/safety bridging of IR‐XR formulations in patients with UC.
Detection of diabetic retinopathy and related retinal disorders using fundus images based on deep learning and image processing techniques: A comprehensive review
Authors: Lalithadevi Balakrishnan , Krishnaveni Sivamohan
Published: May 2022

Diabetes mellitus is a chronic disorder disease in which a person's body fails to adhere insulin produced by their pancreas or unable to segregate enough insulin due to harmonic imbalance. Diabetic people are suffering from eye disorders like diabetic retinopathy (DR), glaucoma and various diseases such as neuropathy, nephropathy, cardiomyopathy over long intervals. One of the most prevalent diabetic consequence is DR. Detecting the morphological variations in retina is difficult and requires an effective automated detection system. DR can be predicted in earlier stage using tremendous development of deep learning models and image processing techniques. Recently, many research articles have been published in DR diagnosis system. This article shows a comprehensive review of automated diagnostic methods for DR detection and other related eye disorders from several points: Causes for DR, publicly available datasets, image preprocessing, segmentation of various DR lesions, feature optimization, various deep learning models, and open research challenges. The study offers a thorough overview of DR detection techniques, which delivers valuable information for researchers, medical professionals, and DR affected patients.
A top‐down enriching approach for ontology learning from text
Authors: Tissaoui Anis , Sassi Salma , Chbeir Richard , Mechergui Ameni
Published: May 2022

To allow better communications between computers and people, ontologies have been adopted in several application domains (web, medicine, industry, etc.). Ontology building exhibits a structural and logical complexity. To the end of making high quality domain ontologies, effective and usable methodologies are needed to facilitate their building process. In this article, we propose to extend the classical methods of ontology construction to design semantically richer ontologies. The objective of this article is to study the relevance of the latent Dirichlet allocation model that generates probabilistic topic models for each enrichment proposal by adopting a domain independent core ontology model. The fitted model can be used to estimate the similarity between documents as well as between a set of specified words/terms using an additional layer of latent variables which are referred to as topics. Experiments were conducted to measure the quality of our proposal against other solutions. Obtained results discussed here are satisfactory.
Population Pharmacokinetics and Pharmacodynamics of the Therapeutic and Adverse Effects of Ketamine in Patients With Treatment‐Refractory Depression
Authors: Abuhelwa Ahmad Y. , Somogyi Andrew A. , Loo Colleen K. , Glue Paul , Barratt Daniel T. , Foster David J.R.
Published: May 2022

We aimed to develop population pharmacokinetic/pharmacodynamic (PK/PD) models that can effectively describe ketamine and norketamine PK/PD relationships for Montgomery–Åsberg Depression Rating Scale (MADRS) scores, blood pressure (BP), and heart rate (HR) following i.v., s.c., and i.m. ketamine administration in patients with treatment‐refractory depression. Ketamine PK/PD data were collected from 21 treatment‐refractory depressed participants who received ketamine (dose titration 0.1–0.5 mg/kg as single doses) by i.v., s.c., or i.m. administration. Model development used nonlinear mixed effect modeling. Ketamine and norketamine PK were best described using two‐compartment models with first‐order absorption after s.c. and i.m. administration. Estimated ketamine bioavailability after i.m. and s.c. was ~ 64% with indistinguishable first‐order absorption rate constants. Allometric scaling of body weight on all clearance and volumes of distribution improved the model fit. The delay in the concentration‐response relationship for MADRS scores was best described using a turnover model (turnover time ~ 42 hours), whereas for the BP and HR rates this was an immediate effect model. For all PD effects, ketamine alone was superior to models with norketamine concentration linked to an effect. No covariates were identified for PD effects. The estimated half‐maximal effective concentration from the MADRS score, BP, and HR were 0.44, 468, and 7,580 ng/mL, respectively. The integrated population models were able to effectively describe the PK/PD relationships for MADRS scores, BP, and HR after i.v., s.c., and i.m. ketamine administration. These findings allow for a deeper understanding of the complex relationships between route of ketamine administration and clinical response and safety.
Clinical Implications of Altered Drug Transporter Abundance/Function and PBPK Modeling in Specific Populations: An ITC Perspective
Authors: Chu Xiaoyan , Prasad Bhagwat , Neuhoff Sibylle , Yoshida Kenta , Leeder James Steven , Mukherjee Dwaipayan , Taskar Kunal , Varma Manthena V. S. , Zhang Xinyuan , Yang Xinning , Galetin Aleksandra
Published: May 2022

The role of membrane transporters on pharmacokinetics (PKs), drug–drug interactions (DDIs), pharmacodynamics (PDs), and toxicity of drugs has been broadly recognized. However, our knowledge of modulation of transporter expression and/or function in the diseased patient population or specific populations, such as pediatrics or pregnancy, is still emerging. This white paper highlights recent advances in studying the changes in transporter expression and activity in various diseases (i.e., renal and hepatic impairment and cancer) and some specific populations (i.e., pediatrics and pregnancy) with the focus on clinical implications. Proposed alterations in transporter abundance and/or activity in diseased and specific populations are based on (i) quantitative transporter proteomic data and relative abundance in specific populations vs. healthy adults, (ii) clinical PKs, and emerging transporter biomarker and/or pharmacogenomic data, and (iii) physiologically‐based pharmacokinetic modeling and simulation. The potential for altered PK, PD, and toxicity in these populations needs to be considered for drugs and their active metabolites in which transporter‐mediated uptake/efflux is a major contributor to their absorption, distribution, and elimination pathways and/or associated DDI risk. In addition to best practices, this white paper discusses current challenges and knowledge gaps to study and quantitatively predict the effects of modulation in transporter activity in these populations, together with the perspectives from the International Transporter Consortium (ITC) on future directions.
Pleural fluid metastasis of plasmacytoid urothelial carcinoma in comparison to micropapillary and conventional high‐grade urothelial carcinoma: Cytologic and immuonohistochemical findings
Authors: Wang Brant G. , Woodward Kimberly , Menezes Geetha , Wang Zoe Q. , He Rui , Li Wenping
Published: May 2022

Plasmacytoid urothelial carcinoma (PUC) is a rare but clinically aggressive variant of high‐grade urothelial carcinoma (HGUC). Cytological features include single plasmacytoid neoplastic cells with N:C ratio around 0.5, eccentric nuclei, nuclear hyperchromasia, irregular nuclear membrane, and vacuolated cytoplasm. Micropapillary urothelial carcinoma (MPUC) is another clinically aggressive variant of HGUC that shares some overlapping features of PUC. The diagnosis of these two aggressive variants in pleural effusions can be challenging due to features mimicking adenocarcinoma, unusual immunochemistry profile, and confusion with differential diagnoses, especially when pertinent clinical information is unavailable. We present report on one case each of pleural fluid metastasis of PUC and MPUC respectively, and compare the findings with that of a metastatic conventional HGUC originally thought to be metastatic adenocarcinoma. The diagnosis of PUC was confirmed with immunohistochemical studies showing expression for cytokeratin, GATA‐3, uroplakin II, and CD138, diminished or loss of E‐cadherin membranous expression, negative expression for p63, p53, Epicam‐BerEP4, Epicam‐MOC31, and p120. The diagnosis of MPUC was confirmed with immunostain profile similar to that of PUC except positive stain for E‐cadherin, p120, and p53. The diagnosis of HGUC was confirmed with immunohistochemical studies showing expression for cytokeratin, GATA‐3, uroplakin II, p63, Epicam‐BerEP4 (focal weak), and Epicam‐MOC31. Our cases of metastatic urothelial carcinoma showed features mimicking adenocarcinoma and others, especially the MPUC and HGUC were diagnosed without prior tissue diagnosis of urothelial carcinoma. This report emphasizes the cytohistological and immunohistochemical details of urothelial carcinoma involving effusion fluid and discusses potential pitfalls in diagnosis.
Cannabinoid receptor activation potential of the next generation, generic ban evading OXIZID synthetic cannabinoid receptor agonists
Authors: Deventer Marie H. , Van Uytfanghe Katleen , Vinckier Inge M. J. , Reniero Fabiano , Guillou Claude , Stove Christophe P.
Published: May 2022

In recent years, several nations have implemented various measures to control the surge of new synthetic cannabinoid receptor agonists (SCRAs) entering the recreational drug market. In July 2021, China put into effect a new generic legislation, banning SCRAs containing one of seven general core scaffolds. However, this has driven manufacturers towards the synthesis of SCRAs with alternative core structures, exemplified by the recent emergence of “OXIZID SCRAs.” Here, using in vitro β‐arrestin2 recruitment assays, we report on the CB1 and CB2 potency and efficacy of five members of this new class of SCRAs: BZO‐HEXOXIZID, BZO‐POXIZID, 5‐fluoro BZO‐POXIZID, BZO‐4en‐POXIZID, and BZO‐CHMOXIZID. All compounds behaved as full agonists at CB1 and partial agonists at CB2. Potencies ranged from 84.6 to 721 nM at CB1 and 2.21 to 25.9 nM at CB2. Shortening the n‐hexyl tail to a pentyl tail enhanced activity at both receptors. Fluorination of this pentyl analog did not yield a higher receptor activation potential, whereas an unsaturated tail resulted in decreased potency and efficacy at CB1. The cyclohexyl methyl analog BZO‐CHMOXIZID was the most potent compound at both receptors, with EC50 values of 84.6 and 2.21 nM at CB1 and CB2, respectively. Evaluation of the activity of a seized powder containing BZO‐4en‐POXIZID suggested a high purity, in line with high‐performance liquid chromatography coupled to diode‐array detection (HPLC‐DAD), gas chromatography coupled to mass spectrometry (GC–MS), liquid chromatography coupled to time‐of‐flight mass spectrometry (LC‐QTOF‐MS), and Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR) analysis. Furthermore, all tested compounds showed a preference for CB2, except for BZO‐POXIZID. Overall, these findings inform public health officials, law enforcement agencies, and clinicians on these newly emerging SCRAs.
Application of modern coexistence theory to rare plant restoration provides early indication of restoration trajectories
Authors: Aoyama Lina , Shoemaker Lauren G. , Gilbert Benjamin , Collinge Sharon K. , Faist Akasha M. , Shackelford Nancy , Temperton Vicky M. , Barabás György , Larios Loralee , Ladouceur Emma , Godoy Oscar , Bowler Catherine , Hallett Lauren M.
Published: May 2022

Restoration ecology commonly seeks to re‐establish species of interest in degraded habitats. Despite a rich understanding of how succession influences re‐establishment, there are several outstanding questions that remain unaddressed: are short‐term abundances sufficient to determine long‐term re‐establishment success, and what factors contribute to unpredictable restorations outcomes? In other words, when restoration fails, is it because the restored habitat is substandard, because of strong competition with invasive species, or alternatively due to changing environmental conditions that would equally impact established populations? Here, we re‐purpose tools developed from modern coexistence theory to address these questions, and apply them to an effort to restore the endangered Contra Costa goldfields (Lasthenia conjugens) in constructed (“restored”) California vernal pools. Using 16 years of data, we construct a population model of L. conjugens, a species of conservation concern due primarily to habitat loss and invasion of exotic grasses. We show that initial, short‐term appearances of restoration success from population abundances is misleading, as year‐to‐year fluctuations cause long‐term population growth rates to fall below zero. The failure of constructed pools is driven by lower maximum growth rates compared with reference (“natural”) pools, coupled with a stronger negative sensitivity to annual fluctuations in abiotic conditions that yield decreased maximum growth rates. Nonetheless, our modeling shows that fluctuations in competition (mainly with exotic grasses) benefit L. conjugens through periods of competitive release, especially in constructed pools of intermediate pool depth. We therefore show how reductions in invasives and seed addition in pools of particular depths could change the outcome of restoration for L. conjugens. By applying a largely theoretical framework to the urgent goal of ecological restoration, our study provides a blueprint for predicting restoration success, and identifies future actions to reverse species loss.
Impacts of seasonality on gene expression in the Chinese horseshoe bat
Authors: Chen Wenli , Mao Xiuguang
Published: May 2022

Seasonality can cause changes in many environmental factors which potentially affects gene expression. Here, we used a bat species (Rhinolophus sinicus) from eastern China as a model to explore the molecular mechanisms of seasonal effects, in particular during phenological shifts in the spring and autumn. Based on the analysis of 45 RNA‐seq samples, we found strong seasonal effects on gene expression, with a large number of genes identified as either specific or biased to each season. Weighted gene co‐expression network analysis also identified multiple modules significantly associated with each season. These seasonal genes were further enriched into different functional categories. Consistent with effects of phenological shifts on bats, we found that genes related to promoting food intake were highly expressed in both autumn and spring. In addition, immunity genes were also highly expressed in both seasons although this seasonal immune response had tissue specificity in different seasons. In female bats, genes related to the delay of ovulation (e.g., NPPC, natriuretic peptide precursor type C) were highly expressed in October, while genes associated with the promotion of reproduction (e.g., DIO2, iodothyronine deiodinase 2) were biasedly expressed in April. Lastly, we found multiple known core clock genes in both October‐biased and April‐biased expressed genes, which may be involved in regulating the start and end of hibernation, respectively. Overall, together with studies in other land and aquatic animals, our work supports that seasonal gene expression variations may be a general evolutionary response to environmental changes in wild animals.
Using wildfire as a management strategy to restore resiliency to ponderosa pine forests in the southwestern United States
Authors: Young Jesse D. , Ager Alan A. , Thode Andrea E.
Published: May 2022

The long‐term outcome from accelerated forest restoration using resource objective wildfire in combination with fuel management on fire‐excluded landscapes is not well studied. We used simulation modeling to examine long‐term trade‐offs and synergies of alternative land management strategies by combining two wildfire management alternatives with three levels of contemporary forest restoration treatments on a 778,000‐ha landscape over 56 years. We found that managing wildfires for resource objectives diminished the likelihood of irregular fire events over time by making wildfire activity more predictable. Overall, adding resource objective wildfire reduced the proportion of high‐severity fire in relation to total area burned, but increased total area burned and the area of high‐severity fire. We also found resource objective wildfire changed the distribution of high‐severity burn patches by increasing their total number and range, their likelihood of containing disjunct core areas, and their edge complexity. The results suggested that alongside the current pace of active forest management, expanding the fire footprint to achieve low‐cost restoration carries the potential for increased high‐severity fire and associated impacts to ecological values including old forest structure and wildlife habitat. Concurrently, adding resource objective wildfire expanded the footprint of conventional restoration treatments by fivefold, and restoration objectives were achieved in 25 years when managing resource objective wildfires alongside restoration treatments five times the current pace. This study demonstrates the first fire suppression model to replicate local decision making by fire managers during simulated fire events to manage risk by considering both fire proximity to values at risk, and daily weather conditions. The study paves the way for further investigations of the synergies between wildfires and conventional forest restoration to improve resiliency in fire‐excluded pine forests.
Fuel reduction treatments reduce modeled fire intensity in the sagebrush steppe
Authors: Ellsworth L. M. , Newingham B. A. , Shaff S. E. , Williams C. L. , Strand E. K. , Reeves M. , Pyke D. A. , Schupp E. W. , Chambers J. C.
Published: May 2022

Increased fire size and frequency coupled with annual grass invasion pose major challenges to sagebrush (Artemisia spp.) ecosystem conservation, which is currently focused on protecting sagebrush community composition and structure. A common strategy for mitigating potential fire is to use fuel treatments that alter the structure and amount of burnable material, thus reducing fire behavior and creating access points for fire suppression resources. While there is some recent information on the impacts of fuel treatments on ecological communities, we have little information on fuel treatment effectiveness at modifying fire behavior in sagebrush ecosystems. We present 10 years of data on fuel accumulation and the resultant modeled fire behavior in prescribed fire, mowed, herbicide (tebuthiuron or imazapic), and untreated control plots in the Sagebrush Treatment Evaluation Project (SageSTEP) network in the Great Basin, USA. Fuel data (i.e., aboveground burnable live and dead biomass) were collected in each treatment plot at Years 0 (pretreatment), 1, 2, 3, 6, and 10 posttreatment. We used the Fuel and Fire Tool fire behavior modeling program to test whether treatments impacted potential fire behavior. Prescribed fire initially removed 49% of the total fuel load and 75% of shrubs, and fuel loads remained reduced through Year 10. Mowing shifted fuels from the shrub canopy to the ground surface but did not change the total fuel amount. Prescribed fire and mowing increased herbaceous fuel by the second posttreatment year and that trend persisted through Year 10. Tebuthiuron treatments were ineffective at altering fuel loads. Imazapic suppressed herbaceous vegetation by 30% in Years 2 and 3 following treatment. The modified fuel beds in fire and mow treatments resulted in modeled flame lengths that were significantly lower than untreated control plots for the duration of the study, with shorter term reductions in reaction intensity and rate of spread. Understanding fuel treatment effectiveness will allow natural resource managers to evaluate trade‐offs between protecting wildlife habitat and reducing the potential for high‐intensity wildfire.