bluuebunny/crossref_metadata_2025 huggingface dataset:
Semiparametric marginal methods for clustered data adjusting for informative cluster size with nonignorable zeros
Authors: Shen Biyi , Chen Chixiang , Chinchilli Vernon M. , Ghahramani Nasrollah , Zhang Lijun , Wang Ming
Published: March 2022

Clustered or longitudinal data are commonly encountered in clinical trials and observational studies. This type of data could be collected through a real‐time monitoring scheme associated with some specific event, such as disease recurrence, hospitalization, or emergency room visit. In these contexts, the cluster size could be informative because of its potential correlation with disease status, since more frequency of observations may indicate a worsening health condition. However, for some clusters/subjects, there are no measures or relevant medical records. Under such circumstances, these clusters/subjects may have a considerably lower risk of an event occurrence or may not be susceptible to such events at all, indicating a nonignorable zero cluster size. There is a substantial body of literature using observations from those clusters with a nonzero informative cluster size only, but few works discuss informative nonignorable zero‐sized clusters. To utilize the information from both event‐free and event‐occurring participants, we propose a weighted within‐cluster‐resampling (WWCR) method and its asymptotically equivalent method, dual‐weighted generalized estimating equations (WWGEE) by adopting the inverse probability weighting technique. The asymptotic properties are rigorously presented theoretically. Extensive simulations and an illustrative example of the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS‐AKI) study are performed to analyze the finite‐sample behavior of our methods and to show their advantageous performance compared to the existing approaches.
Erbium(III) ion‐doped borate‐based glasses for 1.53 μm broad band applications
Authors: Nayab Rasool Shaik , Shabeena Shaik , Kesavulu Culala Rajasekharaudayar , Babu Singarapu , Mohan Babu Asanapuram , Venkatramu Vemula
Published: March 2022

Novel erbium(III) ion‐doped borate‐based glasses (Er3+:BCNF) by conventional melt‐quenching technique were designed and synthesized. The glasses were characterized for their structural, vibrational and spectroscopic properties. The nephelauxetic ratio, bonding parameters, and Judd–Ofelt (JO) intensity parameters (Ωλ λ = 2, 4 and 6) were determined by using absorption spectrum of 1 mol% Er2O3 doped glass. These JO parameters were utilized to derive radiative properties for various excited states of erbium(III) ions. Emission cross‐section for 4I13/2 → 4I15/2 transition of erbium(III) ions was computed through McCumber theory. The decay curves for (2H11/2, 4S3/2) and 4I13/2 levels were recorded and analysed. All the results of Er3+:BCNF glasses revealed that the studied glasses are efficient and thermally stable and could be suitable for display devices, optical amplification and green laser applications.
A Comparative Study of Chemical Profiling and Biological Effects ofDoronicum orientaleExtracts
Authors: Zengin Gokhan , Mahoomodally Mohamad Fawzi , Sinan Kouadio Ibrahime , Bakar Kassim , Jugreet Sharmeen , Yildiztugay Evren , Angeloni Simone , Mustafa Ahmed M. , Caprioli Giovanni
Published: March 2022

In this study, phytochemical and pharmacological screening of the aerial part and roots extracts fromDoronicum orientaleHoffm. (Asteraceae) was carried out. Plant extracts were obtained using solvents of different polarity (hexane, ethyl acetate, ethanol, ethanol/water, water) for selection the most optimal solvent for the extraction of active compounds. For instance, the extracts yielded total phenolic and flavonoid contents in the range of 12.13–45.67 mg GAE/g and 0.75–12.44 mg QE/g, respectively, while the total antioxidant capacity of the extracts determined by the phosphomolybdenum assay ranged from 0.88–2.53 mmol TE/g. HPLC/MS/MS analysis revealed 5‐caffeoylquinic acid (2.52–337.05 μg/g) and 3,5‐dicaffeoylquinic acid (3.12–299.36 μg/g) to be the major components present in the investigated extracts. Antioxidant activity in terms of radical scavenging ability of the extracts ranged from 0.82–45.56 mg TE/g in DPPH assay and from 5.07–104.58 mg TE/g in ABTS assay. The tested extracts were found to inhibit acetylcholinesterase (aerial part: 0.50–2.33 mg GALAE/g; roots: 0.40–2.43 mg GALAE/g), while with the exception of the water extracts, the other extracts showed butyrylcholinesterase inhibition (aerial part: 2.46–5.02 mg GALAE/g; root: 2.93–4.17 mg GALAE/g). Overall, this study presented an interesting scope of this species in phytomedicine with preliminary data demonstrating some of the tested extracts to possess high bioactive contents, antioxidant potential and enzyme inhibitory activity. Thus, additional investigations are necessary to confirm their safety in herbal drug applications.
Mammalian target of rapamycin (mTOR) signaling pathway and traumatic brain injury: A novel insight into targeted therapy
Authors: Movahedpour Ahmad , Vakili Omid , Khalifeh Masoomeh , Mousavi Pegah , Mahmoodzadeh Amir , Taheri‐Anganeh Mortaza , Razmeh Saeed , Shabaninejad Zahra , Yousefi Fatemeh , Behrouj Hamid , Ghasemi Hassan , Khatami Seyyed Hossein
Published: March 2022

Traumatic brain injury (TBI) is one of the most concerning health issues in which the normal brain function may be disrupted as a result of a blow, bump, or jolt to the head. Loss of consciousness, amnesia, focal neurological defects, alteration in mental state, and destructive diseases of the nervous system such as cognitive impairment, Parkinson's, and Alzheimer's disease. Parkinson's disease is a chronic progressive neurodegenerative disorder, characterized by the early loss of striatal dopaminergic neurons. TBI is a major risk factor for Parkinson's disease. Existing therapeutic approaches have not been often effective, indicating the necessity of discovering more efficient therapeutic targets. The mammalian target of rapamycin (mTOR) signaling pathway responds to different environmental cues to modulate a large number of cellular processes such as cell proliferation, survival, protein synthesis, autophagy, and cell metabolism. Moreover, mTOR has been reported to affect the regeneration of the injured nerves throughout the central nervous system (CNS). In this context, recent evaluations have revealed that mTOR inhibitors could be potential targets to defeat a group of neurological disorders, and thus, a number of clinical trials are investigating their efficacy in treating dementia, autism, epilepsy, stroke, and brain injury, as irritating neurological defects. The current review describes the interplay between mTOR signaling and major CNS‐related disorders (esp. neurodegenerative diseases), as well as the mTOR signaling–TBI relationship. It also aims to discuss the promising therapeutic capacities of mTOR inhibitors during the TBI.
Linkage‐Specific Synthesis of Di‐ubiquitin Probes Enabled by the Incorporation of Unnatural Amino Acid ThzK
Authors: Zhou Han , Carpenter Tomaya , Fu Xuan , Jin Bo , Ody Britton , Hassan Mohammad Sazid , Jacobs Savannah E. , Cheung Jenny , Nicholson Eve M. , Turlington Mark , Zhao Bo , Lorenz Sonja , Cropp T. Ashton , Yin Jun
Published: March 2022

Di‐ubiquitin (diUB) conjugates of defined linkages are useful tools for probing the functions of UB ligases, UB‐binding proteins and deubiquitinating enzymes (DUBs) in coding, decoding and editing the signals carried by the UB chains. Here we developed an efficient method for linkage‐specific synthesis of diUB probes based on the incorporation of the unnatural amino acid (UAA) Nϵ‐L‐thiaprolyl‐L‐Lys (L‐ThzK) into UB for ligation with another UB at a defined Lys position. The diUB formed by the UAA‐mediated ligation reaction has a G76C mutation on the side of donor UB for conjugation with E2 and E3 enzymes or undergoing dethiolation to generate a covalent trap for DUBs. The development of UAA mutagenesis for diUB synthesis provides an easy route for preparing linkage‐specific UB‐based probes to decipher the biological signals mediated by protein ubiquitination.
Can hypoosmotic shock and calcium influx lead to translocation of aquaporin‐1 in shrimp muscle cells?
Authors: Foguesatto Kamila , Lopes Fernanda Moreira , Boyle Robert Tew , Nery Luiz Eduardo Maia , Souza Marta Marques
Published: March 2022

The physiological variations during the crustacean molting cycle have intrigued researchers for many years. Maintaining osmotic homeostasis in the face of hemolymph dilution and dealing with dynamic intracellular and extracellular calcium fluctuations are challenges these animals continuously confront. It has recently been shown that water channels present in the cell membrane (aquaporins) are essential for water uptake during premolt and postmolt. This study aims to investigate whether hypoosmotic shock and intracellular and extracellular calcium variations can lead to translocation of Aquaporin 1 (AQP‐1) from the intracellular region to the plasma membrane during premolt and postmolt, thus allowing increased water flow in these stages. For this, we investigate in vitro the rapid change of AQP‐1 positions in the abdominal muscle cells in the freshwater shrimp, Palaemon argentinus. Using cell volume analysis and immunohistochemistry, we show that hypoosmotic conditions and an elevation of the intracellular and extracellular calcium concentrations are concurrent with the translocation of AQP‐1 to the plasma membrane. These results indicate that calcium flux and hypoosmotic shock may be regulators of AQP 1 in the translocation process.
ARID3A promotes the chemosensitivity of colon cancer by inhibiting AKR1C3
Authors: Li Yafei , Tang Jing , Li Jing , Du Yaru , Bai Fuqiang , Yang Lirui , Li Xiaobo , Jin Xiaoming , Wang Tianzhen
Published: March 2022

ARID3A is upregulated in colorectal cancer and can promote the proliferation and metastasis of cancer cells. However, patients with higher level of ARID3A have a better prognosis. This study aimed to uncover the mechanism by which ARID3A benefits the prognosis of colon cancer. Our results indicated that ARID3A upregulation enhanced the chemosensitivity of colon cancer cells to 5‐fluorouracil (5‐FU), whereas ARID3A downregulation inhibited the chemosensitivity of colon cancer cells to 5‐FU. Through database analysis, we found that AKR1C3, a drug resistance‐related gene, was the target of ARID3A. Moreover, AKR1C3 was downregulated in colon cancer tissues compared to normal tissues. Next, we assessed the interaction between AKR1C3 and ARID3A, and found that ARID3A inhibited the transcription of AKR1C3, leading to the downregulation of AKR1C3 in colon cancer cells. We also verified that AKR1C3 inhibited the chemosensitivity of colon cancer cells to 5‐FU. Moreover, patients with higher ratio of ARID3A to AKR1C3 had a better prognosis. This study suggested that ARID3A promoted chemosensitivity of colon cancer cells by inhibiting AKR1C3 in colon cancer. The ratio of ARID3A to AKR1C3 is a good marker to predict the prognosis of colon cancer patients.
Controllable Intercalated Polyaniline Nanofibers Highly Enhancing the Utilization of Delaminated RuO2 Nanosheets for High‐Performance Hybrid Supercapacitors
Authors: Zhang Gaini , Deng Lingjuan , Liu Jinqian , Zhang Jianhua , Wang Jingjing , Li Wenbin , Li Xifei
Published: March 2022

Ruthenium oxide (RuO2) and polyaniline (PANI) are attracting extensive attention as electrode materials due to their remarkable pseudocapacitance. However, RuO2 suffers from low utilization and PANI sustains poor stability. Herein, both defects were optimized by designing intercalated‐structure PANI/RuO2 composites, which were fabricated for the first time by controllable chemical polymerization of aniline on the delaminated RuO2 nanosheets. Intercalated PANI nanofibers not only highly prevent the RuO2 nanosheets from their reassembling as well as increase the interlayer spacing among RuO2 nanosheets but also alleviate the swelling/shrinking of PANI during charge‐discharge progress. In comparison to the pristine RuO2 nanosheets, the obtained intercalated structure is beneficial for creating channels for better ion transfer and electron transport, which leads to a high‐efficiency utilization of RuO2 nanosheets. The optimized PANI/RuO2‐38 electrode with a RuO2 content of 61.7 wt% shows the highest utilization of 72.1 % of RuO2, resulting in the highest specific capacity of 816 F g−1. The asymmetric supercapacitor PANI/RuO2//AC offers a high energy density of 25.7 Wh kg−1 at 375 kW kg−1, further indicating a good potential as energy‐storage device.
Polycations Stabilised by Borosulfates: [Au3Cl4][B(S2O7)2] and the One‐Dimensional Metal [Au2Cl4][B(S2O7)2](SO3)
Authors: Sutorius Stefan , van Gerven David , Olthof Selina , Rasche Bertold , Bruns Jörn
Published: March 2022

(SO4)‐rich silicate analogue borosulfates are able to stabilise cationic cluster‐like and chain‐like aggregates. Single crystals of [Au3Cl4][B(S2O7)2] and [Au2Cl4][B(S2O7)2](SO3) were obtained by solvothermal reaction with SO3, and the electronic properties were investigated by means of density functional theory–based calculations. [Au3Cl4][B(S2O7)2] exhibits a cluster‐like cation, and the cationic gold‐chloride strands in [Au2Cl4][B(S2O7)2](SO3) are found to resemble one‐dimensional metallic wires. This is confirmed by polarisation microscopy.
The impact of whole genome and transcriptome analysis (WGTA) on predictive biomarker discovery and diagnostic accuracy of advanced malignancies
Authors: Tessier‐Cloutier Basile , Grewal Jasleen K , Jones Martin R , Pleasance Erin , Shen Yaoqing , Cai Ellen , Dunham Chris , Hoang Lynn , Horst Basil , Huntsman David G , Ionescu Diana , Karnezis Anthony N , Lee Anna F , Lee Cheng Han , Lee Tae Hoon , Twa David DW , Mungall Andrew J , Mungall Karen , Naso Julia R , Ng Tony , Schaeffer David F , Sheffield Brandon S , Skinnider Brian , Smith Tyler , Williamson Laura , Zhong Ellia , Regier Dean A , Laskin Janessa , Marra Marco A , Gilks C Blake , Jones Steven JM , Yip Stephen
Published: March 2022

In this study, we evaluate the impact of whole genome and transcriptome analysis (WGTA) on predictive molecular profiling and histologic diagnosis in a cohort of advanced malignancies. WGTA was used to generate reports including molecular alterations and site/tissue of origin prediction. Two reviewers analyzed genomic reports, clinical history, and tumor pathology. We used National Comprehensive Cancer Network (NCCN) consensus guidelines, Food and Drug Administration (FDA) approvals, and provincially reimbursed treatments to define genomic biomarkers associated with approved targeted therapeutic options (TTOs). Tumor tissue/site of origin was reassessed for most cases using genomic analysis, including a machine learning algorithm (Supervised Cancer Origin Prediction Using Expression [SCOPE]) trained on The Cancer Genome Atlas data. WGTA was performed on 652 cases, including a range of primary tumor types/tumor sites and 15 malignant tumors of uncertain histogenesis (MTUH). At the time WGTA was performed, alterations associated with an approved TTO were identified in 39 (6%) cases; 3 of these were not identified through routine pathology workup. In seven (1%) cases, the pathology workup either failed, was not performed, or gave a different result from the WGTA. Approved TTOs identified by WGTA increased to 103 (16%) when applying 2021 guidelines. The histopathologic diagnosis was reviewed in 389 cases and agreed with the diagnostic consensus after WGTA in 94% of non‐MTUH cases (n = 374). The remainder included situations where the morphologic diagnosis was changed based on WGTA and clinical data (0.5%), or where the WGTA was non‐contributory (5%). The 15 MTUH were all diagnosed as specific tumor types by WGTA. Tumor board reviews including WGTA agreed with almost all initial predictive molecular profile and histopathologic diagnoses. WGTA was a powerful tool to assign site/tissue of origin in MTUH. Current efforts focus on improving therapeutic predictive power and decreasing cost to enhance use of WGTA data as a routine clinical test.
An Assessment of Zinc Fluxes by Analyzing Monthly, Weekday, and Weekend Levels in a River
Authors: Andarani Pertiwi , Yokota Kuriko , Inoue Takanobu , Alimuddin Hardianti , Nguyen Minh Ngoc
Published: March 2022

Unlike other potentially toxic metals, zinc (Zn) is indispensable to life but also poses environmental risks to aquatic organisms. Aichi Prefecture has the Japan's fourth‐highest discharges of Zn into water bodies. It is likely that the Zn fluxes in Aichi's water bodies originate from industrial wastewater. This study evaluates the spatial‐temporal and diel variability of Zn on sunny days during weekdays and weekends in the Umeda River. The most downstream point is considered as the most polluted section according to the monthly survey [dissolved Zn (D‐Zn): 0.0046–0.0719 mg L−1, particulate Zn (P‐Zn): 0.42–2.01 mg g−1] that varied between seasons (coefficient of variation: 95% for D‐Zn; 53% for P‐Zn). The total Zn (T‐Zn) concentrations on weekdays (0.015–0.043 mg L−1) at the most downstream point exhibit much higher concentrations than those during the weekends (undetected–0.032 mg L−1). Given the dissolved phase of these Zn levels (77 ± 11%), the Zn are likely discharged by industrial facilities on weekdays. The T‐Zn loading on weekdays (56 g km−2 d−1) is approximately three times higher than that on weekends. At least 67% of the T‐Zn and 70% of the D‐Zn fluxes from industrial point sources are potentially discharged on weekdays.
Highly Stable Nanostructured Magnetic Vesicles as Doxorubicin Carriers for Field‐assisted Therapies
Authors: Andrada Heber E. , Venosta Lisandro , Jacobo Silvia E. , Fernando Silva O. , Darío Falcone R. , Bercoff Paula G.
Published: March 2022

In this work, magnetic vesicles were produced using magnetite (Fe3O4) nanoparticles and 1‐methylimidazolium bis‐ (2‐ethylhexyl) phosphate (imim‐DEHP) as surfactant. Some of the vesicles were subsequently coated with chitosan to improve their stability and biocompatibility. A physicochemical characterization of the prepared systems was carried out using several techniques, which allowed verifying that the magnetic nanoparticles were successfully encapsulated. Finally, the vesicles were loaded with an antitumor drug (doxorubicin) by swelling in order to perform release studies. The Korsmeyer‐Peppas model was used to fit the doxorubicin (Dox) release profiles in the different vesicle systems, which displayed delayed release in every case. After 24 h, the Dox release percentages ranged between 43–53%. The prepared vesicles show not only excellent stability but also a good response to an external magnetic field, which makes them good candidates to be used in field‐assisted therapies, thus trying to improve therapeutic efficacy and avoiding possible adverse effects.
Nature‐inspired virtual machine placement mechanisms: A systematic review
Authors: Kong Yuqiang , He Yaoping , Abnoosian Karlo
Published: March 2022

Cloud data centers do not completely use their resources, resulting in resource underutilization. Cloud computing companies primarily leverage virtualization technologies to supply cost‐effective service provision. In order to optimize cloud performance, virtual machines (VMs) must be placed among physical machines (PMs). When it comes to concentrating on the issues in the cloud computing environment, effective VM placement (VMP) is one of the primary difficulties that might cost suppliers money. VMP may be applied in a variety of ways in cloud computing. In terms of lowering related processing overhead, consolidating the cloud environment to become a highly on‐demand method, balancing the load among PMs, power usage, and refining performance, VMP techniques still require improvement in the computing environment. This study aims to provide a comprehensive overview of VMP approaches. This article provides an up‐to‐date survey of the most related VMP literature to highlight study possibilities in cloud settings utilizing nature‐inspired metaheuristic algorithms. The findings suggest that placing VMs in the most efficient place saves power usage substantially. The key problem is to minimize data center energy usage without compromising performance or breaking service level agreements. Finally, we will discuss and look at what further may be accomplished in this line of science.
A multi‐agent based mechanism for collaboratively detecting distributed denial of service attacks in internet of vehicles
Authors: Dong Tingting , Chen Lei , Zhou Li , Xue Fei , Qin Huilin
Published: March 2022

Distributed denial of service (DDoS) attacks have become a hidden danger in the development of the internet of vehicles (IoV). DDoS attacks for TCP protocol are studied to improve the information security environment of IoV. For the distribution characteristics of DDoS attacks, an information sharing and collaborative detection mechanism based on multi‐agent is proposed. Considering the relationship between the features of adjacent moments in the TCP communication, the DDoS detection model based on hidden Markov model is built, and the Viterbi algorithm is improved for the problem of the false alarm in the observation sequence. The optimal communication strategy among agents is determined by deep reinforcement learning, and fusion algorithm is designed to improve the current strategy of agents. Three groups of comparative experiments are designed and analyzed. The simulation results show that proposed algorithms are effective.
Identifying Antidepressants Less Likely to Cause Hyponatremia: Triangulation of Retrospective Cohort, Disproportionality, and Pharmacodynamic Studies
Authors: Nagashima Takuya , Hayakawa Takashi , Akimoto Hayato , Minagawa Kimino , Takahashi Yasuo , Asai Satoshi
Published: March 2022

Antidepressants are known to cause hyponatremia, but conflicting evidence exists regarding specific antidepressants. To identify antidepressants less likely to cause hyponatremia, we conducted a triangulation study integrating retrospective cohort, disproportionality, and pharmacodynamic studies. In the retrospective cohort study of patients (≥ 60 years) in Nihon University School of Medicine’s Clinical Data Warehouse (2004–2020), a significant decrease in serum sodium levels was observed within 30 days after initiation of a selective serotonin reuptake inhibitor (SSRI; mean change −1.00 ± 0.23 mmol/L, P < 0.001) or serotonin‐noradrenaline reuptake inhibitor (SNRI; −1.01 ± 0.31 mmol/L, P = 0.0013), whereas no decrease was found for a noradrenergic and specific serotonergic antidepressant (mirtazapine; +0.55 ± 0.47 mmol/L, P = 0.24). Within‐class comparison revealed no decrease in serum sodium levels for fluvoxamine (+0.74 ± 0.75 mmol/L, P = 0.33) among SSRIs and milnacipran (+0.08 ± 0.87 mmol/L, P = 0.93) among SNRIs. In the disproportionality analysis of patients (≥ 60 years) in the Japanese Adverse Drug Event Report database (2004–2020), a significant increase in hyponatremia reports was observed for SSRIs (reporting odds ratio 4.41, 95% confidence interval 3.58–5.45) and SNRIs (5.66, 4.38–7.31), but not for mirtazapine (1.08, 0.74–1.58), fluvoxamine (1.48, 0.94–2.32), and milnacipran (0.85, 0.45–1.62). Finally, pharmacoepidemiological–pharmacodynamic analysis revealed a significant correlation between the decrease in serum sodium levels and binding affinity for serotonin transporter (SERT; r = −0.84, P = 0.02), suggesting that lower binding affinity of mirtazapine, fluvoxamine, and milnacipran against SERT is responsible for the above difference. Although further research is needed, our data suggest that mirtazapine, fluvoxamine, and milnacipran are less likely to cause hyponatremia.
Vericiguat in Combination with Short‐Acting Nitroglycerin in Patients With Chronic Coronary Syndromes: The Randomized, Phase Ib, VENICE Study
Authors: Boettcher Michael , Düngen Hans‐Dirk , Donath Frank , Mikus Gerd , Werner Nikos , Thuermann Petra A. , Karakas Mahir , Besche Nina , Koch Tanja , Gurniak Matthias , Becker Corina
Published: March 2022

Vericiguat is a soluble guanylate cyclase stimulator indicated to reduce the risk of cardiovascular death and heart failure (HF) hospitalization in adults with symptomatic chronic HF and ejection fraction less than 45%. Guidelines recommend short‐acting nitrates, such as sublingual nitroglycerin, for the treatment of acute angina pectoris in patients with chronic coronary syndromes (CCSs), common comorbidities in HF. We evaluated safety, tolerability, and the pharmacodynamic interaction between vericiguat and nitroglycerin, coadministered in patients with CCSs. In this phase Ib, double‐blind, randomized, multicenter study, 36 patients with CCSs received either vericiguat 2.5 mg (up‐titrated every 2 weeks to 5 mg and 10 mg) or placebo. Patients also received nitroglycerin (0.4 mg sublingual). In total, 31 patients completed the study (vericiguat + nitroglycerin, n = 21; placebo + nitroglycerin, n = 10). There was no increase in treatment‐emergent adverse events (TEAEs) with vericiguat + nitroglycerin vs. placebo + nitroglycerin; three patients discontinued due to TEAEs (vericiguat + nitroglycerin, n = 1; placebo + nitroglycerin, n = 2). Decreases in mean blood pressure (BP; 6–10 mmHg systolic BP (SBP); 4–6 mmHg diastolic BP (DBP)) were independent of vericiguat exposure and occurred to a similar extent at trough and peak concentrations with all vericiguat doses and placebo. Coadministration of vericiguat with nitroglycerin in patients with CCSs was well tolerated, and the combination is unlikely to cause significant adverse effects beyond those known for nitroglycerin.
Measurable Residual Disease Detection in B‐Acute Lymphoblastic Leukemia: The Children's Oncology Group (COG) Method
Authors: Borowitz Michael J. , Wood Brent L. , Keeney Michael , Hedley Benjamin D.
Published: March 2022

Measurable (minimal) residual disease (MRD) in B‐acute lymphoblastic leukemia (B‐ALL), as assessed by flow cytometry, is an established prognostic factor used to adjust treatment in most pediatric therapeutic protocols. MRD in B‐ALL has been standardized by the Children's Oncology Group in North America and more recently in a multicenter Foundation for the National Institutes of Health–funded study. This article outlines the reagents, instrument setup, and analysis protocols required for the reproducible detection of residual leukemic cells in patients following induction therapy for B‐ALL. © 2022 Wiley Periodicals LLC.

Basic Protocol 1: Staining and flow cytometry for B‐acute lymphoblastic leukemia (B‐ALL) measurable residual disease detection

Support Protocol: Specimen collection, handling, storage, and shipping

Basic Protocol 2: Analysis and interpretation of data for B‐ALL measurable residual disease detection

Basic Protocol 3: Analysis of samples lacking sufficient CD19+ events
Preparation and Use of Cellular Reagents: A Low‐resource Molecular Biology Reagent Platform
Authors: Bhadra Sanchita , Paik Inyup , Torres Jose‐Angel , Fadanka Stéphane , Gandini Chiara , Akligoh Harry , Molloy Jenny , Ellington Andrew D.
Published: March 2022

Protein reagents are indispensable for most molecular and synthetic biology procedures. Most conventional protocols rely on highly purified protein reagents that require considerable expertise, time, and infrastructure to produce. In consequence, most proteins are acquired from commercial sources, reagent expense is often high, and accessibility may be hampered by shipping delays, customs barriers, geopolitical constraints, and the need for a constant cold chain. Such limitations to the widespread availability of protein reagents, in turn, limit the expansion and adoption of molecular biology methods in research, education, and technology development and application. Here, we describe protocols for producing a low‐resource and locally sustainable reagent delivery system, termed “cellular reagents,” in which bacteria engineered to overexpress proteins of interest are dried and can then be used directly as reagent packets in numerous molecular biology reactions, without the need for protein purification or a constant cold chain. As an example of their application, we describe the execution of polymerase chain reaction (PCR) and loop‐mediated isothermal amplification (LAMP) using cellular reagents, detailing how to replace pure protein reagents with optimal amounts of rehydrated cellular reagents. We additionally describe a do‐it‐yourself fluorescence visualization device for using these cellular reagents in common molecular biology applications. The methods presented in this article can be used for low‐cost, on‐site production of commonly used molecular biology reagents (including DNA and RNA polymerases, reverse transcriptases, and ligases) with minimal instrumentation and expertise, and without the need for protein purification. Consequently, these methods should generally make molecular biology reagents more affordable and accessible. © 2022 Wiley Periodicals LLC.

Basic Protocol 1: Preparation of cellular reagents

Alternate Protocol 1: Preparation of lyophilized cellular reagents

Alternate Protocol 2: Evaluation of bacterial culture growth via comparison to McFarland turbidity standards

Support Protocol 1: SDS‐PAGE for protein expression analysis of cellular reagents

Basic Protocol 2: Using Taq DNA polymerase cellular reagents for PCR

Basic Protocol 3: Using Br512 DNA polymerase cellular reagents for loop‐mediated isothermal amplification (LAMP)

Support Protocol 2: Building a fluorescence visualization device
Generation of Complex Syngeneic Liver Organoids from Induced Pluripotent Stem Cells to Model Human Liver Pathophysiology
Authors: Raggi Claudia , Selleri Silvia , M'Callum Marie‐Agnes , Paganelli Massimiliano
Published: March 2022

The study of human liver pathophysiology has been hampered for decades by the lack of easily accessible, robust, and representative in vitro models. The discovery of induced pluripotent stem cells (iPSCs)—which can be generated from patients’ somatic cells, engineered to harbor specific mutations, and differentiated into hepatocyte‐like cells—opened the way to more meaningful modeling of liver development and disease. Nevertheless, representative modeling of many complex liver conditions requires the recreation of the interplay between hepatocytes and nonparenchymal liver cells. Here we describe protocols we developed to generate and characterize complex human liver organoids composed of iPSC‐derived hepatic, endothelial, and mesenchymal cells. With all cell types derived from the same iPSC population, such organoids reproduce the liver niche, allowing for the study of liver development and the modeling of complex inflammatory and fibrotic conditions. © 2022 Wiley Periodicals LLC.

Basic Protocol 1: Differentiation of human iPSCs into hepatic progenitor cells (hepatoblasts)

Basic Protocol 2: Differentiation of human iPSCs into endothelial progenitor cells

Support Protocol 1: Characterization of iPSC‐derived endothelial progenitor cells

Basic Protocol 3: Differentiation of human iPSCs into mesenchymal progenitor cells

Support Protocol 2: Characterization of iPSC‐derived mesenchymal progenitor cells

Basic Protocol 4: Generation of complex syngeneic liver organoids
Specialist supportive clinical management for anorexia nervosa: Analysis of therapy content and relation to outcome
Authors: McIntosh Virginia Violet Williams , Carter Janet Deborah , Jordan Jennifer , Loughlin Alex
Published: March 2022

Objective

Psychotherapy for anorexia nervosa (AN) is complex and multifaceted, with little known about likely effective components of treatments. The current study explored the spoken content of specialist supportive clinical management (SSCM) for AN, a treatment with evidence of effectiveness in several randomized clinical trials.

Method

One hundred seventy‐eight therapy sessions constituting all ten therapist–patient dyads of those who completed SSCM treatment in the original clinical trial of SSCM, were transcribed verbatim. Themes were developed and content analyzed using qualitative content analysis of complete therapy sessions by four analysts, with 10% of sessions cocoded for interrater agreement.

Results

Over three quarters of session content was within the clinical management theme, the largest subtheme relating to normalizing eating, followed by weight, mechanics of SSCM, and encouragement of self‐care. Approximately 20% of total content was in the supportive psychotherapy theme, half about relationships. The relative proportion of clinical management content remained high, decreasing during the last five sessions. Those achieving good outcome did not have a lower ratio of clinical management to supportive psychotherapy content.

Discussion

The current study revealed strong clinical management focus on core symptoms of AN—normalization of eating and weight gain—throughout SSCM for AN.

Public Significance

Six clinical trials have found SSCM to be effective in treating AN. Content of SSCM sessions in the original trial was classified using qualitative content analysis. Study findings revealed strong clinical management focus on core AN symptoms—normalization of eating and weight gain—throughout SSCM, with the ratio of clinical management to supportive psychotherapy greater for those with a good outcome.
Simultaneously estimating food web connectance and structure with uncertainty
Authors: Gupta Anubhav , Furrer Reinhard , Petchey Owen L.
Published: March 2022

Food web models explain and predict the trophic interactions in a food web, and they can infer missing interactions among the organisms. The allometric diet breadth model (ADBM) is a food web model based on the foraging theory. In the ADBM, the foraging parameters are allometrically scaled to body sizes of predators and prey. In Petchey et al. (Proceedings of the National Academy of Sciences, 2008; 105: 4191), the parameterization of the ADBM had two limitations: (a) the model parameters were point estimates and (b) food web connectance was not estimated.

The novelty of our current approach is: (a) We consider multiple predictions from the ADBM by parameterizing it with approximate Bayesian computation, to estimate parameter distributions and not point estimates. (b) Connectance emerges from the parameterization, by measuring model fit using the true skill statistic, which takes into account prediction of both the presences and absences of links.

We fit the ADBM using approximate Bayesian computation to 12 observed food webs from a wide variety of ecosystems. Estimated connectance was consistently greater than previously found. In some of the food webs, considerable variation in estimated parameter distributions occurred and resulted in considerable variation (i.e., uncertainty) in predicted food web structure.

These results lend weight to the possibility that the observed food web data is missing some trophic links that do actually occur. It also seems likely that the ADBM likely predicts some links that do not exist. The latter could be addressed by accounting in the ADBM for additional traits other than body size. Further work could also address the significance of uncertainty in parameter estimates for predicted food web responses to environmental change.
Social associations in common carp (Cyprinus carpio): Insights from induced feeding aggregations for targeted management strategies
Authors: Hundt Peter J. , White Lauren A. , Craft Meggan E. , Bajer Przemyslaw G.
Published: March 2022

Heterogeneity in social interactions can have important consequences for the spread of information and diseases and consequently conservation and invasive species management. Common carp (Cyprinus carpio) are a highly social, ubiquitous, and invasive freshwater fish. Management strategies targeting foraging carp may be ideal because laboratory studies have suggested that carp can learn, have individual personalities, a unique diet, and often form large social groups. To examine social feeding behaviors of wild carp, we injected 344 carp with passive integrated transponder (PIT) tags and continuously monitored their feeding behaviors at multiple sites in a natural lake in Minnesota, USA. The high‐resolution, spatio‐temporal data were analyzed using a Gaussian mixture model (GMM). Based on these associations, we analyzed group size, feeding bout duration, and the heterogeneity and connectivity of carp social networks at foraging sites. Wild carp responded quickly to bait, forming aggregations most active from dusk to dawn. During the 2020 baiting period (20 days), 133 unique carp were detected 616,593 times. There was some evidence that feeding at multiple sites was constrained by basin geography, but not distance alone. GMM results suggested that feeding bouts were short, with frequent turnover of small groups. Individual foraging behavior was highly heterogeneous with Gini coefficients of 0.79 in 2020 and 0.66 in 2019. “Superfeeders”—those contributing to 80% of total cumulative detections (top 18% and top 29% of foragers in 2020 and 2019 respectively)—were more likely to be detected earlier at feeding stations, had larger body sizes, and had higher network measures of degree, weighted degree, and betweenness than non‐superfeeders. Overall, our results indicate that wild carp foraging is social, easily induced by bait, dominated by large‐bodied individuals, and potentially predictable, which suggests social behaviors could be leveraged in management of carp, one of the world's most recognizable and invasive fish.
Interspecific differences in the responses of root phosphatase activities and morphology to nitrogen and phosphorus fertilization in Bornean tropical rain forests
Authors: Hirano Yu , Kitayama Kanehiro , Imai Nobuo
Published: March 2022

Soil organic phosphorus (P) compounds can be the main P source for plants in P‐limited tropical rainforests. Phosphorus occurs in diverse chemical forms, including monoester P, diester P, and phytate, which require enzymatic hydrolysis by phosphatase into inorganic P before assimilation by plants. The interactions between plant interspecific differences in organic P acquisition strategies via phosphatase activities with root morphological traits would lead to P resource partitioning, but they have not been rigorously evaluated. We measured the activities of three classes of phosphatases (phosphomonoesterase, PME; phosphodiesterase, PDE; and phytase, PhT), specific root length (SRL), root diameter, and root tissue density in mature tree species with different mycorrhizal associations (ectomycorrhizal [ECM] or arbuscular mycorrhizal [AM]) and different successional status (climax or pioneer species) in Sabah, Malaysia. We studied nitrogen (N)‐ and P‐fertilized plots to evaluate the acquisition strategies for organic P under P‐limited conditions 7 years after fertilization was initiated. P fertilization reduced the PME activity in all studied species and reduced PhT and PDE activities more in climax species than in the two pioneer species, irrespective of the mycorrhizal type. PDE activity increased in some climax species after N fertilization, suggesting that these species allocate excess N to the synthesis of PDE. Moreover, PME and PhT activities, but not PDE activity, correlated positively with SRL. We suggest that climax species tend to be more strongly dependent on recalcitrant organic P (i.e., phytate and/or diester P) than pioneer species, regardless of the mycorrhizal type. We also suggest that trees in which root PME or PhT activity is enhanced can increase their SRL to acquire P efficiently. Resource partitioning of soil organic P would occur among species through differences in their phosphatase activities, which plays potentially ecologically important role in reducing the competition among coexisting tree species in lowland tropical rainforests.
Wind and fire: Rapid shifts in tree community composition following multiple disturbances in the southern boreal forest
Authors: Anoszko Elias , Frelich Lee E. , Rich Roy L. , Reich Peter B.
Published: March 2022

Under a warming climate, the southern boreal forest of North America is expected to see a doubling in fire frequency and potential for increased wind disturbance over the next century. Although boreal forests are often considered fire‐adapted, projected increases in disturbance frequency will likely result in novel combinations of disturbances with severities and impacts on community composition outside historic norms. Using a network of repeatedly measured vegetation monitoring plots, we followed changes in tree community composition in areas of the Boundary Waters Canoe Area Wilderness (BWCAW), in Minnesota, USA, experiencing disturbances ranging from severe windstorms or wildfires to areas affected by wind followed by fire or multiple fires within a short period of time. Using nonmetric multidimensional scaling ordination, hierarchical cluster analysis, and permutational analysis of variance, we compared successional pathways across different disturbance types and combinations to test whether multiple disturbances had altered successional pathways or caused greater convergence relative to single disturbances. We found that multiple disturbances often resulted in strong shifts toward wind‐dispersed early‐successional tree species, while single disturbances tended to have multiple successional pathways that favored both late‐ and early‐successional species. All disturbances in our study resulted in significant shifts in composition, but we generally failed to find statistical evidence of changes in community dispersion. Although boreal forests appear to be somewhat resilient to multiple disturbance events, multiple disturbances resulted in post‐disturbance tree communities that were heavily dominated by disturbance‐adapted deciduous trees at the expense of conifers. Our results demonstrate that multiple disturbances are capable of altering successional pathways relative to single disturbance events and that increasingly frequent disturbances are likely to alter boreal forest structure and composition, perhaps leading to a forest region strikingly unlike that of today.
Development and Characterisation of Highly Conjugated Functionalised Ferrocenylene Macrocycles
Authors: Sheppard Stephanie A. , Bennett Troy L. R. , Long Nicholas J.
Published: March 2022

Multiple synthetic pathways were explored for the preparation of ethynylarene‐containing ferrocenylene macrocyles. Accordingly, the synthesis of novel bis‐ and tris‐ferrocenylene macrocycles, containing a diethynylpyridine bridging group was achieved, and evidence is also provided for a number of linear‐analogues formed as by‐products. The electrochemical properties of the macrocycles were examined, and it was shown that the number of observable redox processes does not necessarily correlate with the number of redox active centres. Additionally, examination of the comproportionation constants of the tris‐ferrocenylene macrocycle demonstrated that the monocationic and dicationic species could be assigned to class II and I/II borderline of the Robin‐Day classification, respectively. The synthesis of these molecules presents an opportunity towards the development of conjugated ferrocenylene macrocycles for electronic applications.
Chronotypes and disabling musculoskeletal pain: A Finnish birth cohort study
Authors: Heikkala Eveliina , Oura Petteri , Korpela Tuukka , Karppinen Jaro , Paananen Markus
Published: March 2022

Background

It has been suggested that chronotype, the individual preference for 24‐h circadian rhythms, influences health. Sleep problems and mental distress are amongst the greatest risk factors for musculoskeletal (MS) pain. The aims of this study were first, to explore the associations between chronotypes and MS pain, with special reference to disabling MS pain and second, to test whether mental distress and insomnia have a modifying role in the associations between chronotypes and MS pain.

Methods

The dataset of 4961 individuals was composed of Northern Finns surveyed on MS pain, chronotypes and confounding factors (sex, insomnia, sleep duration, smoking, mental distress, occupational status, education level and number of coexisting diseases) at 46 years. The relationships between chronotypes (evening [E], intermediate [I] and morning [M]) and MS pain were evaluated using multinomial logistic regression. To address the second aim, we included an interaction term (chronotype*mental distress, chronotype*insomnia) in the logistic model.

Results

Compared to the M‐types, both the E‐ and I‐types had increased odds of suffering ‘disabling pain’ in the unadjusted model (odds ratio [OR] 1.79, 95% confidence interval [CI] 1.37–2.33; OR 1.54, 95% CI 1.29–1.84, respectively). However, the association remained statistically significant only after adjusting for all covariates amongst the I‐types (OR 1.39, 95% CI 1.15–1.67). Neither mental distress nor insomnia was found to modify the chronotype–MS pain association.

Conclusions

The results highlight the importance of chronotypes for individuals’ MS health but suggest the presence of confounding factors in the interplay between these factors.

Significance

This study shows that evening and intermediate chronotypes are associated with disabling MS pain, but that mental distress, insomnia and coexisting diseases also play a role in these associations.
Seismic demands of steel moment resisting frames with inelastic beam‐to‐column web panel zones
Authors: Skiadopoulos Andronikos , Lignos Dimitrios G.
Published: March 2022

This paper intends to provide quantitative seismic response characteristics of steel moment resisting frames (MRFs) with inelastic beam‐to‐column panel zone joints. Two modeling approaches are proposed for this purpose along with a methodology to consider the fracture potential at the bottom beam flange in steel MRFs due to panel zone kinking. Both approaches, which are validated with available experiments, preserve the behavioral insights of inelastic panel zones. Nonlinear static and dynamic analyses are then conducted to quantify the seismic demands of 32 prototype steel MRFs while their panel zones exhibit various levels of inelastic deformations. Engineering demand parameter hazard curves are developed to interpret the results for a risk‐targeted seismic performance. The results demonstrate that steel MRFs with panel zone shear distortions of 10 to 15 times the shear distortion at yield, , have a mean annual frequency of collapse ranging from to , which is up to two times lower than corresponding results with code‐compliant steel MRFs (i.e., It is shown that steel MRFs with inelastic deformations of 10 in their panel zones, (a) enjoy up to 50% reduction in residual story drift ratios at a design basis earthquake; (b) their beam‐to‐column connections do not experience fractures due to panel zone kinking; and (c) local buckling in steel beams is very limited even at low probability of occurrence earthquakes. The above hold true when the current detailing and fabrication practice is employed. The findings have implications on seismic design and the post‐seismic repairability of steel MRFs.