bluuebunny/crossref_metadata_2025 huggingface dataset:
Quality of Life after Ablation vs Medication Therapy in Patients With Supraventricular Tachycardia
Authors: Mueed Abdul , Rathi Nandlal , Shahzad . , Ashraf Jibran , Ahmed Salman , Rai Lajpat
Published: June 2021

Objective: Supraventricular tachycardia (SVT) is the most common presentation of patients at cardiac emergency department. This study aims to determine the quality of life in patients with supraventricular tachycardia after they treated with medicines vs. ablation therapy.

Methods: This prospective clinical comparative study was held at the National Institute of Cardiovascular Diseases (NICVD). Patients 18 years or older of either gender presenting with the two most common variants of SVT i.e. Atrioventricular nodal reentry tachycardia (AVNRT) and Atrioventricular reentry tachycardia (AVRT) were eligible to be included into the study. Once stabilized at the emergency department (ED) the patients were given the option to undergo electrophysiology study and radiofrequency ablation (EPS and RFA) (group A) or opt for medications only (group B). Quality of life (sense of personal well being, impact on social life, fear of mortality or anxiety about the disease, recurrence of episodes of arrhythmia, and visits to ED) was assessed through a questionnaire filled after six months of receiving treatment.

Results: A total of 120 patients were included into our study. Group A and group B were evenly divided with 60 patients each. The overall mean age of the participants and duration of cardiac illness were 44.67±18.91 and 5.42±3.13 years, respectively. Patients who received EPS and RFA (group A) had superior and statistically significant scores (better QoL) for sense of personal well being, impact on social life, fear of mortality or anxiety levels, recurrence of arrhythmia, and visits to the ED as compared to those who received medications alone, p<0.05.

Conclusion: EPS and RFA vastly improved the quality of life in patients with SVT post treatment. Medications alone are associated with a high number of post treatment sequels and adverse events; therefore they are best avoided in patients with SVT.
Study of Heavy Metals Bio Toxicity Present in Locally Produced Palm Kernel Oil in Osun State, Nigeria
Authors: Ajibade Oluwadamilola Ayoola , Tchokossa Pascal , Oluwasusi Taye Victoria , Adeleye Michael Oluwasanmi , Okparaocha Funmilayo Joke
Published: June 2021

This study investigates the heavy metals content presents in locally produced Palm Kernel Oil in Osun State, Nigeria. 16 samples were collected from four major factories in four towns in the study area.  Atomic Absorption Spectrometry (AAS) was used for the concentration of the heavy metals analysis in the samples. The results show the contents of the heavy metal present were 0.022, 0.018, 0.090, 0.071, 0.166 and 0.010 ppm for Cd, As, Fe, Zn, Cu and Pb, respectively. The range of measured concentration of heavy metal contents in the palm kernel oil varies within the same factory which may be due to the fact that the production processes and most especially the source of the palm kernel used by the factories and nature of the soil where the palm tree is planted varied. The mean concentration of Cd, Zn, As, Fe and Pb were below the bio-recommended limit published by joint FAO/WHO. Only Cu is well above the permissible limit.
Impact of Stocking Density as the Growth and Biomass Production of Hybrid Tilapia (Red Strain) in Cages
Authors: Debbarma Alish , Kumar Stephen Sampath , Kumar J. V. Senthil , Tripura Anupam
Published: June 2021

The study was conducted to evaluate the effect of stocking density influencing the growth of Hybrid Tilapia (Red strain) in cages for culture period of 120 days. The experiment is conducted in Thanjavur Center for sustainable Aquaculture, Sorrokottai, Tamil Nadu, India. Hybrid Tilapia fingerling ABW of (3.3+0.01 g) were stocked at 20/m3 (T1), 30/m3 (T2) and 40/m3 (T3) and fed 3 times daily (9:00, 12:00 and 17:00 H) with a commercial food 40% protein gradually reduce to 35 to 30% protein and stock was sampled fortnight. Among three stocking densities, 20 fish/m3 was found to be the best for the growth in cages, while the FCR and net biomass production were found higher in high stocking densities fishes (30, 40 fish/m3). The best FCR was 1.08 +0.06 from T1 (20 fish/m3) with 92.5+0.04% of FCE. The highest net biomass production was 19 kg (3.16 kg/m3) from T2 (30 fish/m3). Present study reveal that stocking density has negative effect on bio-growth parameters but biomass production has positive effect with stocking density.
Re-interpretation of the Two-World Background of Special Relativity as Four-World Background II
Authors: Joseph O. Akindele Adekugbe
Published: June 2021

Coexisting four universes in separate four-dimensional spacetimes constitute four-world background for the special theory of relativity (SR) in each universe, as developed in previous papers. The fact that the four universes exhibit perfect symmetry of state and perfect symmetry of natural laws is shown in this paper. The many universes concept involved is entitled compartment universes. Compartment universes are coexisting symmetrical universes in different fourdimensional spacetimes of identical extents. Material particles and bodies are symmetrically distributed in spacetimes and the same natural laws take on identical forms in compartment universes. These features differentiate the compartment universes concept from the multiverse of inflationary cosmology and the parallel branes of M-theory. The compartment universes concept opens new vista for many-world interpretations of the natural laws, as demonstrated for the special theory of relativity already, and it is a potential platform for the uniform formulation of the natural laws. Investigation of the possible existence of larger number of compartment universes than four and many-world interpretations of gravitation and other natural laws in the compartment universes picture are recommended.
Implementation of Coulomb Counting Method for Estimating the State of Charge of Lithium-Ion Battery
Authors: Ndeche Kevin C. , Ezeonu Stella O.
Published: June 2021

An accurate estimate of the state of charge, which describes the remaining percentage of a battery’s capacity, has been an important and ever existing problem since the invention of the electrochemical cell. State of charge estimation is one of the important function of a battery management system which ensures the safe, efficient and reliable operation of a battery. In this paper, the coulomb counting method is implemented for the estimation of the state of charge of lithium-ion battery. The hardware comprises an Arduino based platform for control and data processing, and a 16-bit analog to digital converter for current and voltage measurement. The embedded algorithm initializes with a self-calibration phase, during which the battery capacity, coulombic efficiency and initial state of charge are evaluated. The initial state of charge is determined at the fully charged state (100% state of charge) or the fully discharged state (0% state of charge). The cumulative error of this method was addressed by routine recalibration of the capacity, coulombic efficiency and state of charge at the fully-charged and fully-discharged states. The algorithm was validated by charging/discharging a lithium-ion battery through fifty complete cycles and evaluating the error in the estimated state of charge. The result shows a mean absolute error of 0.35% in the estimated state of charge during the test. Further analysis, considering prolonged battery operation without parameters recalibration, suggests that error in the coulombic efficiency term contributes the most to the increasing error in the estimated state of charge with each cycle.
Study the Meteorological Environment on Physical and Mental Well-Being (Ayurveda and Modern View)-A Conceptual Study
Authors: Dharmarathna A. B. , Edirisinghe B. L. , Kulathunga W. M. S. S. K.
Published: June 2021

Introduction: Ritucharya (seasonal regimen) have been mentioned in the classics of Ayurveda. According to Ayurveda tridoshas (Three body humors)plays important role in maintaining physiological state of an individuals. But chaya(Accumilation), prakopa(Unbalanced) and prasmana(Balanced) of doshas takes place naturally by seasonal changes. A year is divided into 2 Kaals (time periods-Uththarayanaya/Adana kaal and Dakshinayanaya/Visaraga kaal). Each Kaal comprises of 3 seasons which gives a total of 6 seasons in a year. Each season lasts for two months The impacts of climate change include warming temperatures, changes in precipitation, increases in the frequency or intensity of some extreme weather events, and rising sea levels. These impacts threaten our health by affecting the food , the water, the air and the weather we experience.

Objectives: To identify the Meteorological environment on Physical and Mental well-being (Ayurveda and Modern view)

Methodology: Literature review was done from classical Ayurvedic texts,web references and modern literature regarding selected Scientific Research articles published in PubMed, Research gate, Google scholar, Science direct, Elsevier, Cochrane library and PMC,including health impact of meteorological changes.

Results: According to Ayurveda tridoshas plays important role in maintaining physiological state of an individuals. But chaya, prakopa and prasmana of doshas takes place naturally by seasonal changes. In the beginning of visarga kala and at the end of adana kala, human beings on the Earth experience weakness. In the middle of these two periods, humans possess medium strength. At the end of the visarga kala and at the beginning of adana kala the strength in human beings is maximum. The impacts of climate change include warming temperatures, changes in precipitation, increases in the frequency or intensity of some extreme weather events, and rising sea levels. These impacts threaten our health by affecting the food we eat, the water we drink, the air we breathe, and the weather we experience.

Conclusion: Lifestyle disorders are very common in the present era, basically originating from lack of following seasonal regimens due to lack of concentration in seasonal characteristics In this study reflect that meteorological environment effect on both physical and mental health.
Alkene Cross‐Metathesis Reactions
Authors: Grela Karol , Kajetanowicz Anna , Szadkowska Anna , Czaban‐Jóźwiak Justyna
Published: June 2021

This chapter describes olefin cross‐metathesis (CM) reactions catalyzed by ruthenium, molybdenum, and tungsten complexes and surveys the literature from 1993 through 2020. Cross‐metathesis has been applied to the synthesis of a wide range of functionalized alkenes, including natural and biologically active products. Due to its simplicity and inherit atom economy, CM has found applications in the preparation of fine chemicals and various building blocks, and in transformations of biomass. Tandem reactions involving CM as the key step are also reviewed. Examples discussed in this chapter serve to illustrate how the reactivity of alkene substrates in CM depends on the presence of functional groups and steric congestion in the proximity of the reacting double bonds. A discussion of the mechanism of olefin metathesis is also included.
Mutation of aspartic acid 199 in USP1 disrupts its deubiquitinating activity and impairs DNA repair
Authors: Jang Seok Won , Kim Jung Min
Published: June 2021

The deubiquitinating enzyme USP1 contains highly conserved motifs forming its catalytic center. Recently, the COSMIC mutation database identified a mutation in USP1 at Asp‐199 in endometrial cancer. Here, we investigated the role of Asp‐199 for USP1 function. The mutation of aspartic acid to alanine (D199A) resulted in failure of USP1 to undergo autocleavage and form a complex with ubiquitin, indicating D199A Usp1 is catalytically inactive. The D199A mutation did not affect the interaction with Uaf1. Moreover, D199A Usp1 had defects in deubiquitination of FANCD2 and PCNA and displayed reduced FANCD2 foci formation and DNA repair efficiency. Furthermore, mutation of Asp‐199 to glutamic acid resulted in phenotypes similar to the D199A mutation. Collectively, our findings demonstrate the importance of Asp‐199 for USP1 activity and suggest the implications of USP1 downregulation in cancer.
Nuclear Magnetic Resonance Spectroscopic and Infrared Spectroscopic Characterization of Poly(

N
‐Vinyl

Pyrrolidone) and Poly(

N
‐Vinyl

Caprolactam) Polymers
Authors: Clark Raymond B. , McMullen Roger L.
Published: June 2021

Nuclear magnetic resonance (NMR) and mid‐infrared (IR) spectroscopy have been instrumental in the characterization of poly(N‐vinyl pyrrolidone) (PVP) and poly(N‐vinyl caprolactam) (PVCL) polymers. NMR and IR spectroscopy are proven to be valuable analytical techniques to study polymers qualitatively and quantitatively on a macrostructural level. This chapter discusess the benefit of various hyphenated analytical techniques using NMR and IR spectroscopy to analyze and characterize macromolecules to provide a better understanding of various aspects of PVP and PVCL polymers. A polymer's microstructural features affect its overall chemical and physical properties and dictate its various performance attributes. Copolymers are polymers consisting of two or more monomers and can be described as being random, regular, block, or graft. Controlling the polymerizations and especially the comonomer composition provides a polymer that exhibits specific properties that optimize performance attributes in the specific application. Block copolymers are described as polymers comprised of two or more different homopolymer subunits linked by covalent bonds.
Never quit on hills: John M. Graham, Jr. MD, ScD, as mentor
Authors: Burkardt Deepika D.
Published: June 2021

John M. Graham, Jr. MD, ScD, pediatrician, Clinical Geneticist and Dysmorphologist, fellow of David Weyhe Smith, one of the founding members of the American College of Medical Genetics, father, grandfather, and perpetually optimistic Dodgers fan, has launched many careers. Through his long and productive career, he has demonstrated and fostered the values of kindness, respect, inclusivity, and resilience. His teaching, mentorship, and collaborative efforts have contributed to the very fabric of the field of Medical Genetics and the congenial zeitgeist of Dysmorphology. In this age of pandemonium, it is perhaps appropriate to reflect on the intentional (and sometimes unintentional) lessons of John M. Graham, Jr MD, ScD, and his contribution as a physician, teacher, mentor, and successful collaborator across traditional barriers.
Selective Synthesis of Trisubstituted Imidazoles by Iodine‐Catalyzed [3+2] Cycloadditions
Authors: Zhan Zhenzhen , Zhang Mingming , Jiang Pengbo , He Jianping , Luo Nan , Wang Hesong , Wang Meng , Huang Guosheng
Published: June 2021

In this paper, two novel and efficient methods for the synthesis of trisubstituted imidazoles have been developed through iodine‐catalyzed [3+2] cycloaddition. By controlling one of the reaction materials, we selectively synthesized 1,2,4‐trisubstituted imidazoles and 1,2,5‐trisubstituted imidazoles. The desired products were obtained in moderate to good yields with wide functional groups compatibility under standard conditions.
The functional morphology of the postpulmonary septum of the American alligator (Alligator mississippiensis)
Authors: Cramberg Michael , Greer Skye , Young Bruce A.
Published: June 2021

The American alligator (Alligator mississippiensis) has a postpulmonary septum (PPS) that partitions the intracoelomic cavity. The PPS adheres to the capsule of the liver caudally and to the visceral pleura of the lung cranially; the ventrolateral portions of the PPS are invested with smooth muscle, the remainder is tendinous. Differential pressure transducers were used to record the intrathoracic (ITP) and intraperitoneal (IPP) pressures, and determine the transdiaphragmatic pressure (TDP). Each ventilatory pulse resulted in a pulse in ITP and a significantly lower pulse in IPP; meaning that a TDP was established, and that the pleural and peritoneal cavities were functionally isolated. The anesthetized alligators were tilted 30° head‐up or head‐down in order to displace the liver. Head‐up rotations caused a significant increase in IPP, and a significant decrease in ITP (which became negative); head‐down rotations produced the opposite effect. During these rotations, the PPS maintained opposite pressures (positive or negative) in the pleural and peritoneal cavities, and established TDPs greater than have been reported for some mammals. Two types of “breaths” were recorded during these experiments. The first was interpreted as a contraction of the diaphragmaticus muscle, which displaces the liver caudally; these breaths had the same effect as the head‐up rotations. The second type of breath was interpreted as constriction of the thoracic and abdominal body walls; this type of breath produced pronounced, long‐duration, roughly parallel, increases in ITP and IPP. The smooth muscle within the PPS is suggestive of higher‐order adjustment or tuning of the PPS's tensile state.
Design, synthesis, and biological evaluation of novel benzimidazole derivatives as sphingosine kinase 1 inhibitor
Authors: Khairat Sarah H. M. , Omar Mohamed A. , Ragab Fatma A. F. , Roy Sonam , Turab Naqvi Ahmad A. , Abdelsamie Ahmed S. , Hirsch Anna K. H. , Galal Shadia A. , Hassan Md. Imtaiyaz , El Diwani Hoda I.
Published: June 2021

Sphingosine kinase 1 (SphK1) has emerged as an attractive drug target for different diseases. Recently, discovered SphK1 inhibitors have been recommended in cancer therapeutics; however, selectivity and potency are great challenges. In this study, a novel series of benzimidazoles was synthesized and evaluated as SphK1 inhibitors. Our design strategy is twofold: It aimed first to study the effect of replacing the 5‐position of the benzimidazole ring with a polar carboxylic acid group on the SphK1‐inhibitory activity and cytotoxicity. Our second aim was to optimize the structures of the benzimidazoles through the elongation of the chain. The enzyme inhibition potentials against all the synthesized compounds toward SphK1 were evaluated, and the results revealed that most of the studied compounds inhibited SphK1 effectively. The binding affinity of the benzimidazole derivatives toward SphK1 was measured by fluorescence binding and molecular docking. Compounds 33, 37, 39, 41, 42, 43, and 45 showed an appreciable binding affinity. Therefore, the SphK1‐inhibitory potentials of compounds 33, 37, 39, 41, 42, 43, and 45 were studied and IC50 values were determined, to reveal high potency. The study showed that these compounds inhibited SphK1 with effective IC50 values. Among the studied compounds, compound 41 was the most effective one with the lowest IC50 value and a high cytotoxicity on a wide spectrum of cell lines. Molecular docking revealed that most of these compounds fit well into the ATP‐binding site of SphK1 and form hydrogen bond interactions with catalytically important residues. Overall, the findings suggest the therapeutic potential of benzimidazoles in the clinical management of SphK1‐associated diseases.
Comment on “Open is not forever: A study of vanished open access journals”
Authors: Shelomi Matan
Published: June 2021

This letter comments on a recent article by Laakso et al. (10.1002/asi.24460), in which the disappearance of 176 open access journals from the Internet is noted. One reason these journals may have vanished is that they were predatory journals: a possibility the original paper did not consider. The delisting of predators from the Directory of Open Access Journals in 2014 and the abundance of predatory journals and awareness thereof in North America parsimoniously explain the temporal and geographic patterns Laakso et al. observed.
Overcoming stochastic variations in culture variables to quantify and compare growth curve data
Authors: Sausen Christopher W. , Bochman Matthew L.
Published: June 2021

The comparison of growth, whether it is between different strains or under different growth conditions, is a classic microbiological technique that can provide genetic, epigenetic, cell biological, and chemical biological information depending on how the assay is used. When employing solid growth media, this technique is limited by being largely qualitative and low throughput. Collecting data in the form of growth curves, especially automated data collection in multi‐well plates, circumvents these issues. However, the growth curves themselves are subject to stochastic variation in several variables, most notably the length of the lag phase, the doubling rate, and the maximum expansion of the culture. Thus, growth curves are indicative of trends but cannot always be conveniently averaged and statistically compared. Here, we summarize a simple method to compile growth curve data into a quantitative format that is amenable to statistical comparisons and easy to graph and display.
Interleukin‐25: New perspective and state‐of‐the‐art in cancer prognosis and treatment approaches
Authors: Gowhari Shabgah Arezoo , Amir Azwar , Gardanova Zhanna R. , Olegovna Zekiy Angelina , Thangavelu Lakshmi , Ebrahimi Nik Maryam , Ahmadi Majid , Gholizadeh Navashenaq Jamshid
Published: June 2021

Cancer is a leading cause of death which imposes a substantial financial burden. Among the several mechanisms involved in cancer progression, imbalance of immune cell‐derived factors such as cytokines and chemokines plays a central role. IL‐25, as a member of the IL‐17 cytokine subfamily, exerts a paradoxical role in cancer, including tumor supportive and tumor suppressive. Hence, we have tried to clarify the role of IL‐25 and its receptor in tumor progression and cancer prognosis. It has been confirmed that IL‐25 exerts a tumor‐suppressive role through inducing infiltration of eosinophils and B cells into the tumor microenvironment and activating the apoptotic pathways. In contrast, the tumor‐supportive function has been implemented by activating inflammatory cascades, promoting cell cycle, and inducing type‐2 immune responses. Since IL‐25 has been dysregulated in tumor tissues and this dysregulation is involved in cancer development, its examination can be used as a tumor diagnostic and prognostic biomarker. Moreover, IL‐25‐based therapeutic approaches have shown promising results in cancer inhibition. In cancers in which IL‐25 has a tumor‐suppressive function, employing IL‐25‐enhancing approaches, such as Virulizin® and dihydrobenzofuran administration, has potentially inhibited tumor cell growth. On the other hand, in the case of IL‐25‐dependent tumor progression, using IL‐25 blocking methods, including anti‐IL‐25 antibodies, might be a complementary approach to the other anticancer agent. Collectively, it is hoped, IL‐25 might be a promising target in cancer treatment.
Immune infiltration phenotypes of prostate adenocarcinoma and their clinical implications
Authors: Ma Zehua , Cheng Xiankui , Yue Ting , Shangguan Xun , Xin Zhixiang , Zhang Weiwei , Pan Jiahua , Wang Qi , Xue Wei
Published: June 2021

Background

Tumor‐infiltrating immune cells participate in the initiation and progression of prostate adenocarcinoma (PRAD). However, it is not fully known how immune infiltration affects the development of PRAD and its clinical presentation.

Methods

Herein, we investigated the immune infiltration phenotypes in PRAD based on transcriptome profiles, methylation profiles, somatic mutation, and copy number variations. We also developed an immune prognostic model (IPM) to identify unfavorable prognosis. To verify this model, immunohistochemistry staining was performed on a cohort of PRAD samples. Moreover, we constructed a nomogram to assess the survival of PRAD incorporating immune infiltration and other clinical features.

Results

We categorized PRAD patients into high and low‐level clusters based on immune infiltration phenotypes. The patients in the high‐level clusters had worse survival than their low‐level counterparts. Gene set enrichment analysis indicated that both anti‐ and pro‐tumor terms were enriched in high‐level cluster. Moreover, we identified a positive correlation between anti‐ and pro‐tumor immune cells in PRAD microenvironment. Notably, Somatic mutation analysis showed patients in high‐level cluster had a higher somatic mutation burden of KMT2D, HSPA8, CHD7, and MAP1A. In addition, we developed an IPM with robust predictive ability. The model can distinguish high‐risk PRAD patients with poor prognosis from low‐risk PRAD patients in both training and another three independent validation datasets. Besides, we constructed a nomogram incorporating Gleason score, pathological T stage, and IPM for the prognosis prediction of PRAD patients, which displayed robust predictive ability and might contribute to clinical practice.

Conclusion

Our work illustrated the immune infiltration phenotypes strongly related to the poor prognosis of PRAD patients, and highlighted the potential of the IPM to identify unfavorable tumor features.
Real time identification of anomalous events in coastal regions using deep learning techniques
Authors: Perumal Varalakshmi , Murugaiyan SureshKumar , Ravichandran Pavithran , Venkatesan R. , Sundar R.
Published: June 2021

The present existing weather prediction systems deployed by weather forecasting agencies predict the anomalous events using numerical simulation models developed based on geophysics and oceanographic theories. The major disadvantage with existing models is that are explicit simulation models. So, we try to build a real time prediction system that will automatically predict the intensity of any marine natural disaster events and alert the authorities to take necessary actions using a satellite and observational real time data set including moored met ocean data. We propose a novel hybrid model which is a combination of Convolutional Neural Network (CNN) and Long Short‐Term Memory (LSTM). The paper analyzes various other models such as Gated Recurrent Unit (GRU), Bidirectional LSTM (Bi‐LSTM) Recurrent Neural Network (RNN), and Extreme Learning Machine. In addition the other standard CNN architectures are also analyzed. Since the residual CNN network is the most effective architecture, the paper proposes a modification of the residual CNN network by combining the residual CNN network with LSTM/GRU RNN network along with a proposed new activation function which was experimentally proved to be more effective than the deep learning community standard activation function ReLU. The proposed new activation function overcomes the dead neuron propagation problem in ReLU activation function and hence the model's accuracy is increased by more than 1%. The proposed CNN + LSTM/GRU model is benchmarked with UCR time series benchmark dataset and it is experimentally seen that the model performs better than all existing algorithms.
Lightweight fog‐centric auditing scheme to verify integrity of IoT healthcare data in the cloud environment
Authors: Yoosuf Mohamed Sirajudeen , R Anitha
Published: June 2021

IoT healthcare applications have become very popular among medical societies. At regular intervals, the healthcare IoT devices collect the patient's health information and transfer it to cloud storage. Storing the health records in the cloud environment increases the vulnerability. Integrity verification performed at regular intervals ensures the safety and security of the healthcare data stored in the cloud. Existing schemes use RSA and BLS signatures to verify the authenticity. However, the size of the signature is too large in RSA and BLS schemes. Using large signatures for proving the authenticity increases the computation overhead. IoT devices have minimal resource capacity, hence performing heavily weighted integrity schemes will create an unbearable workload. Likewise, private auditing increases the communication overhead between IoT devices and cloud storage. To overcome these issues, a fog‐centric auditing scheme is proposed based on the Cramer–Shoup cryptosystem. The proposed scheme allows the fog nodes to perform integrity verification without compromising security. It reduces the communication overhead by 55%–60%. The size of the CS signature used in the scheme is far lesser than the existing signatures. Moreover, performing the inline deduplication on the fog layer improves the efficiency of cloud storage by 30%.
Pharmacogenetics‐Guided Advances in Antipsychotic Treatment
Authors: Islam Farhana , Men Xiaoyu , Yoshida Kazunari , Zai Clement C. , Müller Daniel J.
Published: June 2021

Pharmacogenetics (PGx) research over the past 2 decades has produced extensive evidence for the influence of genetic factors on the efficacy and tolerability of antipsychotic treatment. However, the application of these findings to optimize treatment outcomes for patients in clinical practice has been limited. This paper presents a meta‐review of key PGx findings related to antipsychotic response and common adverse effects, including antipsychotic‐induced weight gain, tardive dyskinesia (TD), and clozapine‐induced agranulocytosis (CIAG), and highlights advances and challenges in clinical implementation. Most robust findings from candidate gene and genomewide association studies were reported for associations between polymorphisms in CYP2D6 and exposure and response to specific antipsychotics. As a result, product labels and guidelines from various PGx expert groups have provided selection and dosing recommendations based on CYP2D6 metabolizer phenotypes for commonly prescribed antipsychotics. Other interesting genetic targets include DRD2 for antipsychotic response, SLC18A2 for TD, and the human leukocyte antigen (HLA) genes, HLA‐DQB1 and HLA‐B, for CIAG. Well‐designed studies using large, well‐characterized samples that leverages international collaborations are needed to validate previous findings, as well as discover new genetic variants involved in antipsychotic response and adverse effects.
Next‐generation Bruton's tyrosine kinase inhibitor BIIB091 selectively and potently inhibits B cell and Fc receptor signaling and downstream functions in B cells and myeloid cells
Authors: Bame Eris , Tang Hao , Burns Jeremy C , Arefayene Million , Michelsen Klaus , Ma Bin , Marx Isaac , Prince Robin , Roach Allie M , Poreci Urjana , Donaldson Douglas , Cullen Patrick , Casey Fergal , Zhu Jing , Carlile Thomas M , Sangurdekar Dipen , Zhang Baohong , Trapa Patrick , Santoro Joseph , Muragan Param , Pellerin Alex , Rubino Stephen , Gianni Davide , Bajrami Bekim , Peng Xiaomei , Coppell Alex , Riester Katherine , Belachew Shibeshih , Mehta Devangi , Palte Mike , Hopkins Brian T , Scaramozza Matthew , Franchimont Nathalie , Mingueneau Michael
Published: June 2021

Objectives

Bruton's tyrosine kinase (BTK) plays a non‐redundant signaling role downstream of the B‐cell receptor (BCR) in B cells and the receptors for the Fc region of immunoglobulins (FcR) in myeloid cells. Here, we characterise BIIB091, a novel, potent, selective and reversible small‐molecule inhibitor of BTK.

Methods

BIIB091 was evaluated in vitro and in vivo in preclinical models and in phase 1 clinical trial.

Results

In vitro, BIIB091 potently inhibited BTK‐dependent proximal signaling and distal functional responses in both B cells and myeloid cells with IC50s ranging from 3 to 106 nm, including antigen presentation to T cells, a key mechanism of action thought to be underlying the efficacy of B cell‐targeted therapeutics in multiple sclerosis. BIIB091 effectively sequestered tyrosine 551 in the kinase pocket by forming long‐lived complexes with BTK with t1/2 of more than 40 min, thereby preventing its phosphorylation by upstream kinases. As a key differentiating feature of BIIB091, this property explains the very potent whole blood IC50s of 87 and 106 nm observed with stimulated B cells and myeloid cells, respectively. In vivo, BIIB091 blocked B‐cell activation, antibody production and germinal center differentiation. In phase 1 healthy volunteer trial, BIIB091 inhibited naïve and unswitched memory B‐cell activation, with an in vivo IC50 of 55 nm and without significant impact on lymphoid or myeloid cell survival after 14 days of dosing.

Conclusion

Pharmacodynamic results obtained in preclinical and early clinical settings support the advancement of BIIB091 in phase 2 clinical trials.
Spatial Gaussian processes improve multi‐species occupancy models when range boundaries are uncertain and nonoverlapping
Authors: Wright Wilson J. , Irvine Kathryn M. , Rodhouse Thomas J. , Litt Andrea R.
Published: June 2021

Species distribution models enable practitioners to analyze large datasets of encounter records and make predictions about species occurrence at unsurveyed locations. In omnibus surveys that record data on multiple species simultaneously, species ranges are often nonoverlapping and misaligned with the administrative unit defining the spatial domain of interest (e.g., a state or province). Consequently, some species display differentially restricted extents within a study area. Assuming hard boundaries based on expert opinion or published range maps to restrict species occurrence predictions implies a false sense of certainty in model‐based inferences.

We propose a multi‐species occupancy model with a spatial Gaussian process on site‐specific effects for each species as a model‐based solution. Specifying informative Bayesian hyperpriors on the spatial hyperparameters encapsulates broad‐scale correlation among site occupancy probabilities for each species. We fit this model to acoustic detection/nondetection data collected with autonomous recording units during summer of 2016–2019 throughout Oregon and Washington, USA, on 15 bat species.

We found vast improvements in spatial predictions of spotted bat (Euderma maculatum), canyon bat (Parastrellus hesperus), and Brazilian free‐tailed bat (Tadarida brasiliensis) when the available environmental predictors were insufficient for characterizing their restricted ranges within the region.

In contrast, widespread species (Lasionycteris noctivagans, Myotis californicus, Myotis evotis, Myotis volans) were appropriately modeled using only environmental predictors, such as percentage forest cover and cliff and canyon cover.

Utilizing spatial Gaussian processes within a community or multi‐species model incorporates uncertainty in range boundaries and allows for simultaneous predictions for the entire faunal assemblage even if species have nonoverlapping or restricted ranges within a spatial domain of interest. Such modeling improvements are essential if species distribution models are to accurately inform monitoring, species recovery plans, and other conservation efforts.
Exposure to a common antidepressant alters crayfish behavior and has potential subsequent ecosystem impacts
Authors: Reisinger Alexander J. , Reisinger Lindsey S. , Richmond Erinn K. , Rosi Emma J.
Published: June 2021

Pharmaceuticals are ubiquitous in aquatic environments, yet little is known regarding their impacts on ecological processes. Selective serotonin reuptake inhibitors (SSRIs) are frequently prescribed human antidepressants and have been shown to alter crayfish behavior. These behavioral alterations are particularly relevant as crayfish play a central role in freshwater ecosystems and often reach high biomass in anthropogenically influenced environments commonly exposed to pharmaceutical contamination. Using a 14‐d artificial stream experiment, we exposed spinycheek crayfish (Faxonius limosus) to citalopram, a common SSRI, at an environmentally realistic concentration (0.5 µg/L). We used a Y‐shaped flume to quantify the effects of SSRI exposure on crayfish behavior and food/conspecific preference. We also tested the interacting effects of citalopram and crayfish on habitat‐specific and whole‐stream ecosystem functions and biomass. Crayfish exposed to SSRIs exhibited increased boldness (time to emerge from shelters;P < 0.05) and spent more time orienting to food resources than nonexposed crayfish. Crayfish increased water column chlorophylla(P < 0.01) and benthic organic matter (P = 0.03). Furthermore, crayfish potentially increased water column respiration (P = 0.09) and potentially decreased nitrate uptake (P = 0.05). SSRI exposure exhibited a potential effect of decreasing benthic chlorophylla(P = 0.07), but there were no significant CRAY+SSRI interactions. Neither crayfish nor SSRI treatments affected whole‐stream metabolism. These results suggest that citalopram has the potential to affect algal biomass but did not affect ecosystem functioning. However, alterations to crayfish behavior driven by SSRI exposure could lead to subsequent ecosystem‐level effects as crayfish did affect various response metrics. We were unable to detect the effects of altered crayfish behavior at the ecosystem scale during our study, likely due to the short time frame (2 weeks) of our experiment. Further work is needed to quantify longer‐term ecosystem consequences of sublethal effects of pharmaceuticals, but these results show that ecological responses to pharmaceuticals should consider the entire ecosystem.
Low‐density aspen seedling establishment is widespread following recent wildfires in the western United States
Authors: Kreider Mark R. , Yocom Larissa L.
Published: June 2021

Sexual regeneration is increasingly recognized as an important regeneration pathway for aspen in the western United States, a region previously thought to be too dry for seedling establishment except for during unusually wet periods. Because of this historical assumption, information on aspen seedling establishment and factors influencing its occurrence is limited and frequently anecdotal. We conducted a systematic field survey of 15 recent fire footprints that burned in 2018 in the western United States to quantify how common aspen seedling establishment is following fire and to identify factors associated with establishment. We found aspen seedling establishment in 12 of 15 (80%) of fire footprints surveyed, although densities were mostly low. Establishment probability was positively associated with mean annual precipitation and negatively associated with seed‐source distance and the density of asexual aspen regeneration. Our results suggest that aspen seedling establishment may be a widespread, if often low‐density, feature in postdisturbance areas. Even in low numbers, aspen seedlings may play a disproportionately large role in aspen regeneration ecology, providing adaptive capacity and facilitating local range expansion.
Controlling the Activity of a Caged Cobalt‐Porphyrin‐Catalyst in Cyclopropanation Reactions with Peripheral Cage Substituents
Authors: Mouarrawis Valentinos , Bobylev Eduard O. , de Bruin Bas , Reek Joost N. H.
Published: June 2021

In this study, three novel cubic cages were synthesized and utilized to encapsulate a catalytically active cobalt(II) meso‐tetra(4‐pyridyl)porphyrin guest. The newly developed caged catalysts (Co‐G@Fe8(Zn‐L ⋅ 1)6, Co‐G@Fe8(Zn‐L ⋅ 2)6 and Co‐G@Fe8(Zn‐L ⋅ 3)6) can be easily synthesized and differ in exo‐functionalization, which are either none, polar or apolar groups. This leads to a different polarity of the peripheral environment surrounding the cage, which affects the (relative) local concentration of the substrates surrounding the cage and hence indirectly influences the substrate availability of the catalysis embedded in the active site of the caged catalyst systems. The resulting increased local substrate concentrations give rise to higher catalytic activities of the respective caged catalyst in metalloradical catalyzed cyclopropanation reactions. Interestingly, the catalytic activity is the highest when the apolar cage catalyst (Co‐G@Fe8(Zn‐L ⋅ 1)6) is used, and lowest with the polar analog (Co‐G@Fe8(Zn‐L ⋅ 3)6). In addition, the catalytic activity of the cage without exo‐functionalities (Co‐G@Fe8(Zn‐L ⋅ 2)6) is nearly two times lower than that of Co‐G@Fe8(Zn‐L ⋅ 1)6 and three times higher than that of Co‐G@Fe8(Zn‐L ⋅ 3)6, which further demonstrates the effect of the peripheral functionalities on the cyclopropanation reaction.
Hexadentate Poly‐Lewis Acids Based on 1,3,5‐Trisilacyclohexane
Authors: Schäfer Fabian , Neumann Beate , Stammler Hans‐Georg , Mitzel Norbert W.
Published: June 2021

We report the preparation of hexadentate poly‐Lewis acids (PLA) based on 1,3,5‐trisilacyclohexane backbones bearing two alkynyl groups attached to each of the silicon atoms. A rigid hexadentate PLA bearing six Lewis‐acidic catecholatoboryl‐substituents was prepared by a tin‐boron exchange reaction. Its structure, determined by X‐ray diffraction, is the first of a Lewis‐acid‐functionalised donor‐free trisilacyclohexane. Flexible hexadentate PLA were prepared by hydroboration or hydrosilylation of hexavinyltrisilacyclohexane, resulting in PLA with six 9‐BBN, SiCl3, SiCl2Me or SiClMe2 groups. The Lewis‐acidity of the last one was increased by conversion with silver triflate, resulting in a PLA with six highly acidic silyl triflate groups attached to the 1,3,5‐trisilacyclohexane unit as TfOSiMe2‐C2H4‐ groups. Host‐guest experiments of the above PLA demonstrated the suitability of the flexible representatives for complexation of neutral Lewis‐based guest molecules under formation of 1 : 6 adducts (host: guest).
Pd0‐Mediated Cross‐Coupling of [11C]Methyl Iodide with Carboxysilane for Synthesis of [11C]Acetic Acid and its Active Esters: 11C‐Acetylation of Small, Medium, and Large Molecules
Authors: Doi Hisashi , Goto Miki , Sato Yuzuru
Published: June 2021

A rapid Pd0‐mediated cross‐coupling of [11C]CH3I with carboxytriphenylsilane (1) to synthesize [2‐11C]acetic acid ([11C]2) and its corresponding imidyl esters as radiolabeling reagents for 11C‐acetylation is reported. The reaction of [11C]CH3I with 1 using a Pd2(dibenzylideneacetone)3/P(o‐tolyl)3 (1 : 4) catalyst in tetrahydrofuran/H2O (9 : 1) at 90 °C for 4 min afforded [11C]2 having satisfactory radioactivity and a good yield. The coupling of the cationic carbon atom of methyl iodide and the carboxyl group in 1 is an ionicity‐driven reversed‐polarity reaction. An injectable radiopharmaceutical formulation of [11C]2 prepared using 33 GBq of [11C]CH3I had a radioactivity of 7.4–7.8 GBq, and the decay‐corrected radiochemical yield of [11C]CH3I into [11C]2 was 63–73 %. [11C]2 was converted to [2‐11C]acetic acid phthalimidyl ester ([11C]3) or its succinimidyl ester ([11C]10), which were used for the 11C‐acetylation of 4‐aminophenol, oxytocin, and albumin. Injectable solutions of these products (0.25–2.0 GBq) are suitable for in vivo positron emission tomography studies.
The genomic origin of Zana of Abkhazia
Authors: Margaryan Ashot , Sinding Mikkel‐Holger S. , Carøe Christian , Yamshchikov Vladimir , Burtsev Igor , Gilbert M. Thomas P.
Published: June 2021

Enigmatic phenomena have sparked the imagination of people around the globe into creating folkloric creatures. One prime example is Zana of Abkhazia (South Caucasus), a well‐documented 19th century female who was captured living wild in the forest. Zana's appearance was sufficiently unusual, that she was referred to by locals as an Almasty—the analog of Bigfoot in the Caucasus. Although the exact location of Zana's burial site was unknown, the grave of her son, Khwit, was identified in 1971. The genomes of Khwit and the alleged Zana skeleton were sequenced to an average depth of ca. 3× using ancient DNA techniques. The identical mtDNA and parent‐offspring relationship between the two indicated that the unknown woman was indeed Zana. Population genomic analyses demonstrated that Zana's immediate genetic ancestry can likely be traced to present‐day East‐African populations. We speculate that Zana might have had a genetic disorder such as congenital generalized hypertrichosis which could partially explain her strange behavior, lack of speech, and long body hair. Our findings elucidate Zana's unfortunate story and provide a clear example of how prejudices of the time led to notions of cryptic hominids that are still held and transmitted by some today.
Enrichment of polychlorinated biphenyls in river water by using magnetic adsorbents with high selectivity to nonplanar aromatic compounds and their analysis with gas chromatography–mass spectrometry
Authors: Wang Xuesong , Li Chunyan , Wu Dan , Shen Jiwei , Wei Yinmao , Wang Chaozhan
Published: June 2021

Previously our group reported a magnetic adsorbent, magGO@bottlebrush, which has high selectivity to nonplanar aromatic compounds with two or more phenyl rings. In this work, the magGO@bottlebrush was used for pre‐concentration of seven frequently concerned polychlorinated biphenyls (PCB28, PCB52, PCB101, PCB118, PCB138, PCB153, and PCB180) from river water samples, considering PCBs are hydrophobic compounds with two substituted benzene rings and have nonplanar structure, and gas chromatography–mass spectrometry (GC–MS) was used for the quantification. Several parameters affecting the extraction efficiency of the seven PCBs were investigated, under the best concerned extraction conditions, the developed method had excellent linearity (R2 > 0.9951) within the range of 1–100 pg/ml, it also possessed low limits of detection (0.33–0.90 pg/ml, S/N = 3) for the PCBs. Then, the enrichment and detection methods were applied to determine PCBs in two local rivers. PCB101, PCB118, and PCB138 were detected in one river, and their concentrations were 1.31, 0.69, and 10.01 pg/ml, respectively. The spiked recoveries of the river water samples were 63.33–119.29%, and the relative SD values were less than 17.33%. These results show that the proposed method has great potential application for the analysis of PCBs in river water samples.
Energy metabolism during exercise in patients with β‐enolase deficiency (GSDXIII)
Authors: Buch Astrid Emilie , Musumeci Olimpia , Wigley Ralph , Stemmerik Mads Peter Godtfeldt , Eisum Anne‐Sofie Vibæk , Madsen Karen Lindhardt , Preisler Nicolai , Hilton‐Jones David , Quinlivan Ros , Toscano Antonio , Vissing John
Published: June 2021

Aim

To investigate the in vivo skeletal muscle metabolism in patients with β‐enolase deficiency (GSDXIII) during exercise, and the effect of glucose infusion.

Methods

Three patients with GSDXIII and 10 healthy controls performed a nonischemic handgrip test as well as an incremental cycle ergometer test measuring maximal oxidative consumption (VO2max) and a 1‐hour submaximal cycle test at an intensity of 65% to 75% of VO2max. The patients repeated the submaximal exercise after 2 days, where they received a 10% iv‐glucose supplementation.

Results

Patients had lower VO2max than healthy controls, and two of three patients had to stop prematurely during the intended 1‐hour submaximal exercise test. During nonischemic forearm test, all patients were able to produce lactate in normal amounts. Glucose infusion had no effect on patients' exercise capacity.

Conclusions

Patients with GSDXIII experience exercise intolerance and episodes of myoglobinuria, even to the point of needing renal dialysis, but still retain an almost normal anaerobic metabolic response to submaximal intensity exercise. In accordance with this, glucose supplementation did not improve exercise capacity. The findings show that GSDXIII, although causing episodic rhabdomyolysis, is one of the mildest metabolic myopathies affecting glycolysis.