bluuebunny/crossref_metadata_2025 huggingface dataset:
Up‐Regulated Interleukin‐10 Induced by E2F Transcription Factor 2–MicroRNA‐17‐5p Circuitry in Extrafollicular Effector B Cells Contributes to Autoantibody Production in Systemic Lupus Erythematosus
Authors: Xu Lingxiao , Wang Lei , Shi Yumeng , Deng Yun , Oates Jim C. , Kamen Diane L. , Gilkeson Gary S. , Wang Fang , Zhang Miaojia , Tan Wenfeng , Tsao Betty P.
Published: September 2021

Objective

Elevated interleukin‐10 (IL‐10) levels in patients with systemic lupus erythematosus (SLE) have B cell–promoting effects, contributing to autoantibody production and tissue damage. We aimed to characterize up‐regulated IL‐10+ B cell subsets and dysregulated IL10 expression in SLE B cells for new therapeutic options.

Methods

Proportions of Th10 and IL‐10+ B cell subsets in peripheral blood mononuclear cells (PBMCs) were assessed using flow cytometry. The IL10 3′‐untranslated region (3′‐UTR) dual‐luciferase vector was constructed and cotransfected with small interfering RNA (siRNA), microRNA (miRNA) mimics, or miRNA inhibitors into Raji cells. Transcript levels were quantified using TaqMan assays.

Results

Culture conditions that induced IL‐10+ Breg cells in healthy controls resulted in expansion of IL‐10+ double‐negative 2 (DN2; IgD−CD27−CD21−CD11c+) B cells in SLE PBMCs. Proportions of IL‐10+ DN2, but not those of IL‐10− DN2, correlated with disease activity and levels of antibodies to double‐stranded DNA (dsDNA) (r = 0.60, P = 0.03 for cohort 1; r = 0.38, P = 0.03 for cohort 2), and were associated with high levels or seropositivity of anti‐Sm (P = 0.03 for cohort 1; P = 0.01 for cohort 2) and IgG anticardiolipin (P < 0.01 for cohort 1; P = 0.02 for cohort 2) in SLE patients from 2 cohorts, of mainly African American subjects (cohort 1) and of Asian subjects (cohort 2). Proportions of Th10 (CD45RA−CXCR5−CXCR3+PD‐1highCD4+) cells correlated with IL‐10+ DN2 frequencies (r = 0.60, P < 0.01 for cohort 2), antinuclear antibody titers (r = 0.52, P = 0.01 for cohort 2), and proteinuria levels (r = 0.72, P < 0.01 for cohort 2) in SLE patients. Screening of predicted IL10 3′‐UTR–targeting miRNAs in SLE B cells identified miRNA‐17‐5p (miR‐17‐5p) and miR‐20a‐5p, with their levels inversely correlated with IL10 (r = −0.47, P < 0.01 for miR‐17‐5p; r = −0.37, P = 0.03 for miR‐20‐5p) and transcription factor E2F2 (r = −0.48, P = 0.04 for miR‐17‐5p; r = −0.45, P = 0.05 for miR‐20‐5p). In Raji cells, knockdown of E2F2 expression resulted in increased levels of miR‐17‐5p and miR‐20a‐5p and decreased IL10 messenger RNA (mRNA) and protein levels, and overexpression and inhibition of miR‐17‐5p down‐regulated and up‐regulated, respectively, IL10 mRNA levels, suggesting regulation of IL10 expression by an E2F2‐miR‐17‐5p loop.

Conclusion

IL‐10 promotes extrafollicular autoimmune responses in patients with active SLE, which might be dampened by targeting the E2F2–miR‐17‐5p circuitry.
2D MOFs‐based Materials for the Application of Water Pollutants Removing: Fundamentals and Prospects
Authors: Liu Jiadi , Li Qingqing , Mao Feifei , Wang Kuaibing , Wu Hua
Published: September 2021

Water quality can have serious impacts on human health. One crucial issue of water pollution seriously affects our safety due to the continually emerging of discovered anthropogenic pollutants. The water treatment technologies are persistent improvement to adapt such new contaminants, which accelerates the evolution of materials science to explore solving the problems. Metal‐organic Frameworks (MOFs) as the significant porous and multi‐dimensional networks has been concerned for toxic pollutant elimination, especially probed the applications of outstanding layered 2D skeletons MOFs‐based materials. The emphases of this review highlight the 2D MOFs‐based materials used in water remediation and treatment strategies including adsorption and catalysis methods. Further, the prospects and challenges of 2D MOFs‐based materials for water treatments applications would be surveyed meticulously for the future research and development.
Hydroxy‐Porphyrin as an Effective, Endogenous Molecular Clamp during Early Stages of Amyloid Fibrillization
Authors: Nath Soumav , Roy Priti , Mandal Raki , Roy Rajat , Buell Alexander K. , Sengupta Neelanjana , Tarafdar Pradip K.
Published: September 2021

Amyloid fibril formation of proteins is of great concern in neurodegenerative disease and can be detrimental to the storage and stability of biologics. Recent evidence suggests that insulin fibril formation reduces the efficacy of type II diabetes management and may lead to several complications. To develop anti‐amyloidogenic compounds of endogenous origin, we have utilized the hydrogen bond anchoring, π stacking ability of porphyrin, and investigated its role on the inhibition of insulin amyloid formation. We report that hydroxylation and metal removal from the heme moiety yields an excellent inhibitor of insulin fibril formation. Thioflavin T, tyrosine fluorescence, Circular Dichorism (CD) spectroscopy, Field emission scanning electron microscopy (FESEM) and molecular dynamics (MD) simulation studies suggest that hematoporphyrin (HP) having hydrogen bonding ability on both sides is a superior inhibitor compared to hemin and protoporphyrin (PP). Experiments with hen egg white lysozyme (HEWL) amyloid fibril formation also validated the efficacy of endogenous porphyrin based small molecules. Our results will help to decipher a general therapeutic strategy to counter amyloidogenesis.
Social disparities in health behaviours: The role of class‐related behavioural norms and social class identification
Authors: Blondé Jérôme , Easterbrook Matthew J. , Kulich Clara , Chipeaux Marion , Lorenzi‐Cioldi Fabio
Published: September 2021

Inequalities in health behaviours (i.e., the tendency of socially disadvantaged people, compared to more advantaged people, to engage in fewer healthy behaviours) have been mostly accounted for by individual and environmental factors. The present research proposed to consider a social identity perspective by examining the combined impact of class‐related norms and social class identification on intentions to engage in healthy behaviours. Based on a correlational study (N = 407), our results showed that healthy behaviours were perceived to be more normative of the upper‐middle class than the lower‐middle class, regardless of participants' class membership. We also found that intentions to perform healthy behaviours increased among those who highly identified with the upper‐middle class, when they perceived healthy behaviours as highly normative of that class. Moreover, those who highly identified with the lower‐middle class (vs. the upper‐middle class) reported lower intentions when healthy behaviours were viewed as normative of the upper‐middle class. This suggests that a stronger prevalence of healthy behaviours among socially privileged people is driven by in‐group conformity, whereas the tendency to act less healthily among those disadvantaged would be underpinned by out‐group rejection. More generally, these findings underscore the importance of social identity factors in providing novel insights for research on health disparities.
Structural Studies Provide New Insights into the Role of Lysine Acetylation on Substrate Recognition by CARM1 and Inform the Design of Potent Peptidomimetic Inhibitors
Authors: Zhang Yurui , Marechal Nils , van Haren Matthijs J. , Troffer‐Charlier Nathalie , Cura Vincent , Cavarelli Jean , Martin Nathaniel I.
Published: September 2021

The dynamic interplay of post‐translational modifications (PTMs) in chromatin provides a communication system for the regulation of gene expression. An increasing number of studies have highlighted the role that such crosstalk between PTMs plays in chromatin recognition. In this study, (bio)chemical and structural approaches were applied to specifically probe the impact of acetylation of Lys18 in the histone H3 tail peptide on peptide recognition by the protein methyltransferase coactivator‐associated arginine methyltransferase 1 (CARM1). Peptidomimetics that recapitulate the transition state of protein arginine N‐methyltransferases, were designed based on the H3 peptide wherein the target Arg17 was flanked by either a free or an acetylated lysine. Structural studies with these peptidomimetics and the catalytic domain of CARM1 provide new insights into the binding of the H3 peptide within the enzyme active site. While the co‐crystal structures reveal that lysine acetylation results in minor conformational differences for both CARM1 and the H3 peptide, acetylation of Lys18 does lead to additional interactions (Van der Waals and hydrogen bonding) and likely reduces the cost of desolvation upon binding, resulting in increased affinity. Informed by these findings a series of smaller peptidomimetics were also prepared and found to maintain potent and selective CARM1 inhibition. These findings provide new insights both into the mechanism of crosstalk between arginine methylation and lysine acetylation as well as towards the development of peptidomimetic CARM1 inhibitors.
Design, Synthesis and Structural Analysis of Glucocerebrosidase Imaging Agents
Authors: Rowland Rhianna J. , Chen Yurong , Breen Imogen , Wu Liang , Offen Wendy A. , Beenakker Thomas J. , Su Qin , van den Nieuwendijk Adrianus M. C. H. , Aerts Johannes M. F. G. , Artola Marta , Overkleeft Herman S. , Davies Gideon J.
Published: September 2021

Gaucher disease (GD) is a lysosomal storage disorder caused by inherited deficiencies in β‐glucocerebrosidase (GBA). Current treatments require rapid disease diagnosis and a means of monitoring therapeutic efficacy, both of which may be supported by the use of GBA‐targeting activity‐based probes (ABPs). Here, we report the synthesis and structural analysis of a range of cyclophellitol epoxide and aziridine inhibitors and ABPs for GBA. We demonstrate their covalent mechanism‐based mode of action and uncover binding of the new N‐functionalised aziridines to the ligand binding cleft. These inhibitors became scaffolds for the development of ABPs; the O6‐fluorescent tags of which bind in an allosteric site at the dimer interface. Considering GBA's preference for O6‐ and N‐functionalised reagents, a bi‐functional aziridine ABP was synthesized as a potentially more powerful imaging agent. Whilst this ABP binds to two unique active site clefts of GBA, no further benefit in potency was achieved over our first generation ABPs. Nevertheless, such ABPs should serve useful in the study of GBA in relation to GD and inform the design of future probes.
Inherent Reactivity of Spiro‐Activated Electrophilic Cyclopropanes
Authors: Jüstel Patrick M. , Stan Alexandra , Pignot Cedric D. , Ofial Armin R.
Published: September 2021

The kinetics of the ring‐opening reactions of thiophenolates with geminal bis(acceptor)‐substituted cyclopropanes in DMSO at 20 °C was monitored by photometric methods. The determined second‐order rate constants of the SN2 reactions followed linear relationships with Mayr nucleophilicity parameters (N/sN) and Brønsted basicities (pKaH) of the thiophenolates as well as with Hammett substituent parameters (σ) for groups attached to the thiophenolates. Phenyl‐substituted cyclopropanes reacted by up to a factor of 15 faster than their unsubstituted analogues, in accord with the known activating effect of adjacent π‐systems in SN2 reactions. Variation of the electronic properties of substituents at the phenyl groups of the cyclopropanes gave rise to parabolic Hammett relationships. Thus, the inherent SN2 reactivity of electrophilic cyclopropanes is activated by electron‐rich π‐systems because of the more advanced C1−C2 bond polarization in the transition state. On the other hand, electron‐poor π‐systems also lower the energetic barriers for the attack of anionic nucleophiles owing to attractive electrostatic interactions.
Sophoridine Derivatives Induce Apoptosis and Autophagy to Suppress the Growth of Triple‐Negative Breast Cancer through Inhibition of mTOR Signaling
Authors: Dai Linlin , Wang Luyao , Tan Cheng , Cai Jun , Shen Hongsheng , Zhang Ting , Zhi Shuang , Yang Zibo , Hu Yunhui , Zhao Xiumei , Li Dongdong
Published: September 2021

In order to improve the antitumor potency and therapeutic margins of natural product sophoridine, its novel nitrogen mustard carbamate derivatives were designed and synthesized. In screening their in vitro activity, we found all the tested compounds were more potent against the highly aggressive triple‐negative breast cancer cell line MDA‐MB‐231. Cellular functional assays showed that representative compounds could induce G1‐phase arrest and trigger apoptosis, evidenced by the alteration of Bax, Bcl‐2, caspase‐3 and PARP levels. Furthermore, these compounds significantly enhanced the autophagic flux with increased expression of LC3‐II and Beclin‐1, as well as decreased level of p62, which may attribute to simultaneously inhibition of the phosphorylation of p70S6K, 4E‐BP1 and AKT, the key substrates of the mTOR signaling pathway. In vivo, two compounds revealed potent antitumor activity in mice bearing MDA‐MB‐231. Altogether, our work describes novel leads to yield more potent chemotherapeutics against triple‐negative breast cancers, possibly mesenchymal stem‐like subtype.
Critical Conditions for Studying Interleukin‐11 Signaling In Vitro and Avoiding Experimental Artefacts
Authors: Viswanathan Sivakumar , Ng Benjamin , Widjaja Anissa A. , Pua Chee Jian , Tham Nevin , Tan Jessie , Cook Stuart A. , Schafer Sebastian
Published: September 2021

Interleukin (IL) 11 is a member of the IL6 family of cytokines which require the ubiquitous gp130 receptor to activate canonical (JAK/STAT) and non‐canonical (e.g., ERK) signaling pathways. The IL11 cytokine is upregulated in a number of fibro‐inflammatory diseases and cancer, where it binds the cognate IL11 receptor alpha subunit (IL11RA) to form a hexameric IL11:IL11RA:gp130 signaling complex. The specific IL11RA receptor is highly expressed on cells of the stromal and parenchymal niche but expressed at low levels on immune cells, highly passaged cells, or transformed cell lines. Consequently, primary cells such as hepatic stellate cells, fibroblasts, and hepatocytes are ideal experimental systems to study IL11 signaling in vitro. In contrast to immortalized cell lines, primary cells better display relevant cellular physiology and pathobiology. This collection of protocols details experimental and culturing conditions for primary cells that preserve meaningful cellular states and physiological responses ex vivo in conventional 2D cell culture systems. Readouts of cellular activity are chosen carefully to capture the non‐canonical, post‐transcriptional activity of IL11 signaling. Our data suggest that cell type, cell culture conditions, passage number, concentrations of stimuli, timing, and other factors have major implications for studies of IL11 signaling. In vitro experiments with primary cell material need to be planned and executed with great caution. Otherwise, physiologically relevant mechanisms may become dysfunctional and reproducible experimental artefacts can obscure our view of true cytokine biology. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC.

Basic Protocol 1: Expansion of primary human hepatic stellate cells (HSCs) and human renal proximal tubular epithelial cells (HRPTEpiCs)

Basic Protocol 2: Expansion of primary human lung fibroblasts (HLFs)

Alternate Protocol 1: Isolation and expansion of primary mouse lung fibroblasts

Support Protocol 1: Freezing and thawing of primary cells

Support Protocol 2: Operetta high‐content imaging‐based phenotyping

Support Protocol 3: Colorimetric assay of solubilized collagen

Support Protocol 4: Quantification of fibrosis marker secretion

Support Protocol 5: Western blotting studies of IL11 signaling in HSCs, HLFs, and HRPTEpiCs

Basic Protocol 3: IL11 stimulation of primary human hepatocytes

Alternate Protocol 2: IL11 stimulation of primary mouse hepatocytes

Support Protocol 6: Alanine transaminase (ALT) secretion by human and mouse hepatocytes
Immuno‐Spin Trapping Method for the Analysis of S‐Nitrosylated Proteins
Authors: Sircar Esha , Stoyanovsky Detcho A. , Billiar Timothy R. , Sengupta Rajib
Published: September 2021

The dynamic and unstable nature of protein nitrosothiols (PSNOs) derived from complex biological matrices (like cell lysates) make them unsuitable for proteomic/biochemical analysis in vitro. In an attempt to increase the stability of cell‐derived PSNOs, scientists have devised methods to derivatize thiols undergoing nitrosylation, with a suitable molecule, to yield a stable adduct that could easily be detected using appropriate antibodies. The Biotin Switch Assay (BTSA) is currently the most widely used method for tagging PSNOs; however, the error‐prone and cumbersome nature of the BTSA protocol prompted the development of alternative mechanisms of tagging cell‐derived PSNOs. One such method is the immuno‐spin trapping method using 5,5‐dimethyl‐1‐pyrroline N‐oxide (DMPO), which effectively overcomes the shortcomings of the BTSA and proves to be a promising alternative. Here we describe the protocol for DMPO‐based PSNO labeling and subsequent proteomic analysis by western blotting with an anti‐DMPO antibody. © 2021 Wiley Periodicals LLC.

Basic Protocol: Labeling of cell‐derived PSNOs by DMPO‐based immuno‐spin trapping and their subsequent analysis by immunostaining
MXene/Carbon Nanotube Hybrids: Synthesis, Structures, Properties, and Applications
Authors: Yu Le Ping , Zhou Xiao Hong , Lu Lu , Xu Lyu , Wang Feng Jun
Published: September 2021

Since the successful preparation of few‐layer transition metal carbides from three‐dimensional MAX phases in 2011, MXenes (known as a family of layered transition metal carbides, nitrides, and carbonitrides) have been intensively studied. Though MXenes have been adopted as active materials in many applications, issues including aggregation and restacking are likely to hamper their potential applications. In order to address these prevailing challenges, the concept of MXene/carbon nanotube (CNT) hybrids was proposed initially in 2015, where CNTs were incorporated as the spacers and conductive additives. Ever since, MXene/CNT hybrids with different architectures have been synthesized by a number of methods and applied in numerous fields. Herein, after the discussion about general synthesis approaches, architectures, and properties of the hybrids, this Review summarized the recent advances in the application of MXene/CNT hybrids in energy storage devices, sensors, electrocatalysis, electromagnetic interference shielding, and water treatment, in which the function of individual components was clarified. In the end, the current research trend in this field were discussed and several technical issues were highlighted along with some suggestions on future research directions.
How can urban environments support dementia risk reduction? A qualitative study
Authors: Röhr Susanne , Rodriguez Francisca S. , Siemensmeyer Rosa , Müller Felix , Romero‐Ortuno Roman , Riedel‐Heller Steffi G.
Published: September 2021

Objective

Interventions to reduce the risk of cognitive decline and dementia largely focus on individual‐level strategies. To maximize risk reduction, it is also necessary to consider the environment. With the majority of older people living in cities, we explored how urban environments could support risk reduction.

Materials and Methods

In our qualitative study, we conducted semi‐structured interviews with community members aged ≥65 years and stakeholders, all living in Leipzig, Germany. Interview guides were informed by the framework on modifiable risk factors for dementia of the Lancet Commission on Dementia Prevention, Intervention, and Care. Interviews were audio‐recorded, verbatim‐transcribed, and thematically analysed.

Results

Community members (n = 10) were M = 73.7 (SD = 6.0) years old and 50% were women. Stakeholders (n = 10) were aged 39–72 years, and 70% were women. Stakeholders' fields included architecture, cultural/arts education, environmental sciences, geriatrics, health policy, information and technology, philosophy, psychology, public health, and urban sociology. Across interviews with both older individuals and stakeholders, three main themes were identified: (i) social participation and inclusion (emphasizing social contacts, social housing, intergenerationality, neighbourhood assistance, information and orientation, digital and technological literacy, lifelong learning, co‐creation/co‐design), (ii) proximity and accessibility (emphasizing proximity and reachability, mobility, affordability, access to health care, access to cultural events, public toilets), (iii) local recreation and wellbeing (emphasizing safety in traffic, security, cleanliness and environmental protection, urban greenery, climate change and heat waves, outdoor physical activity).

Discussion

The design of urban environments holds large potential to create favourable conditions for community‐dwelling individuals to practice lifestyles that promote brain health. Public policy should involve community members in co‐creating such environments.
Extending the Ecological Interface Design process—Integrated EID
Authors: Kant Vivek , Sudakaran Jayasurya Salem
Published: September 2021

This article aims to extend the traditional Ecological Interface Design (EID) process. With the rapid pace of digitalization in technological systems, there is a need for a design process that can handle the systemic design goals and the experiential basis of interaction. Currently, the traditional EID is well‐positioned to address these challenges. However, methodologically, it needs to be substantiated to make it accessible for designers, designing for novel arenas, such as Industry 4.0. Further, substantiating the design process will help designers, engineers, and human factors researchers with an accessible pathway that links the design brief to the final interface form. Therefore, this article delves into the “design” basis in the work of the Risø group and other prominent EID researchers and practitioners. In addition, it draws from a variety of themes in the discipline of design that addresses methodology. In particular, key insights are drawn from the design methods movement (1960s—); design, communication, and complexity from the Ulm school of design, 1953–1968; cognitive research conducted on designers and design activities; and finally, interaction design and communication design processes and models. All of these insights have been used syncretically to create the new integrated EID (iEID) process. This new design process consists of nine stages divided into three phases of divergence, transformation, and convergence, converting the initial design brief to the final interface. The steps of iEID are demonstrated using the example of interface design for a “digital twin” in the manufacturing sector.
Viscoelastic hydromagnetic oscillatory flow in a channel in the presence of sinusoidal pressure gradient and linear motion of the plate
Authors: Ojha Kanaka Lata , Swain Kharabela , Dash Pratikshya
Published: September 2021

The surge of interest to explain the effect of sinusoidal pressure gradient on an unsteady two‐dimensional viscoelastic hydromagnetic flow in a channel backed with porous material is the focus of discussion in the present problem. The channel walls are subjected to constant motion. The presence of a transverse magnetic field at a distance acts as an additional body force, a controlling device, as well an input of the system. The elasticity of the liquid in motion and porosity of the medium characterize the flow field. The analytical solution ends in an important conclusion: the degree of the elastic property of the liquid (addition of polymeric substance) acts to accelerate the flow, and the magnetic intensity of the transversal magnetic field acts as an input to decelerate the motion as well as regulate the oscillatory time to avoid flow reversal.
Paid and unpaid productivity losses due to premature mortality from cancer in Europe in 2018
Authors: Ortega‐Ortega Marta , Hanly Paul , Pearce Alison , Soerjomataram Isabelle , Sharp Linda
Published: September 2021

When someone dies prematurely from cancer this represents a loss of productivity for society. This loss can be valued and provides a measure of the cancer burden. We estimated paid and unpaid productivity lost due to cancer‐related premature mortality in 31 European countries in 2018. Lost productivity was estimated for all cancers combined and 23 cancer sites, overall, by region and country. Deaths aged 15 to 64 were abstracted from GLOBOCAN 2018. Unpaid time lost (housework, caring, volunteering) was derived from Eurostat. Paid and unpaid productivity losses were valued using the human capital approach. In total, 347,149 premature cancer deaths occurred (60% male). The total value of cancer‐related lost productivity was €104.6 billion. Of this, €52.9 billion (50.6%) was due to lost paid work, and €51.7 billion (49.4%) to unpaid work. Females accounted for 36.7% of paid work costs but half (51.1%) of the unpaid work costs. Costs were highest in Western Europe (€52.0 billion). The most costly cancer was lung (€21.7 billion), followed by breast (€10.6 billion). The average loss per premature death was highest for Hodgkin's lymphoma (€506 345), melanoma (€450 694), brain cancer (€428 449) and leukaemia (€378 750). Cancer‐related lost productivity costs are significant. Almost half are due to unpaid work losses, indicating the importance of considering both paid and unpaid labour in assessing the cancer economic burden. The high cost per premature death of some less common cancers illustrates the potential benefits that could accrue from investment in prevention and control of these cancers.
Molecular profiles and urinary biomarkers of upper tract urothelial carcinomas associated with aristolochic acid exposure
Authors: Karanović Sandra , Ardin Maude , Tang Zuojian , Tomić Karla , Villar Stephanie , Renard Claire , Venturini Elisa , Lorch Adam H. , Lee Daniel S. , Stipančić Želimir , Slade Neda , Vuković Brinar Ivana , Dittrich Damir , Karlović Krešimir , Borovečki Fran , Dickman Kathleen G. , Olivier Magali , Grollman Arthur P. , Jelaković Bojan , Zavadil Jiri
Published: September 2021

Recurrent upper tract urothelial carcinomas (UTUCs) arise in the context of nephropathy linked to exposure to the herbal carcinogen aristolochic acid (AA). Here we delineated the molecular programs underlying UTUC tumorigenesis in patients from endemic aristolochic acid nephropathy (AAN) regions in Southern Europe. We applied an integrative multiomics analysis of UTUCs, corresponding unaffected tissues and of patient urines. Quantitative microRNA (miRNA) and messenger ribonucleic acid (mRNA) expression profiling, immunohistochemical analysis by tissue microarrays and exome and transcriptome sequencing were performed in UTUC and nontumor tissues. Urinary miRNAs of cases undergoing surgery were profiled before and after tumor resection. Ribonucleic acid (RNA) and protein levels were analyzed using appropriate statistical tests and trend assessment. Dedicated bioinformatic tools were used for analysis of pathways, mutational signatures and result visualization. The results delineate UTUC‐specific miRNA:mRNA networks comprising 89 miRNAs associated with 1,862 target mRNAs, involving deregulation of cell cycle, deoxyribonucleic acid (DNA) damage response, DNA repair, bladder cancer, oncogenes, tumor suppressors, chromatin structure regulators and developmental signaling pathways. Key UTUC‐specific transcripts were confirmed at the protein level. Exome and transcriptome sequencing of UTUCs revealed AA‐specific mutational signature SBS22, with 68% to 76% AA‐specific, deleterious mutations propagated at the transcript level, a possible basis for neoantigen formation and immunotherapy targeting. We next identified a signature of UTUC‐specific miRNAs consistently more abundant in the patients' urine prior to tumor resection, thereby defining biomarkers of tumor presence. The complex gene regulation programs of AAN‐associated UTUC tumors involve regulatory miRNAs prospectively applicable to noninvasive urine‐based screening of AAN patients for cancer presence and recurrence.
Management of amended variant classification laboratory reports by genetic counselors in the United States and Canada: An exploratory study
Authors: Richardson Brooke , Fitzgerald‐Butt Sara M. , Spoonamore Katherine G. , Wetherill Leah , Helm Benjamin M. , Breman Amy M.
Published: September 2021

For the past two decades, the guidelines put forth by the American College of Medical Genetics and Genomics (ACMG) detailing providers’ clinical responsibility to recontact patients have remained mostly unchanged, despite evolving variant interpretation practices which have yielded substantial rates of reclassification and amended reports. In fact, there is little information regarding genetic counselors’ roles in informing patients of reclassified variants, or the process by which these amended reports are currently being handled. In this study, we developed a survey to measure current experiences with amended variant reports and preferences for ideal management, which was completed by 96 genetic counselors from the United States and Canada. All respondents indicated they were the individuals responsible for disclosing initial positive genetic testing results and any clinically actionable reclassified variant reports, and over half (56%) received at least a few amended variant reports each year. Nearly a quarter (20/87) of respondents reported having a standard operating procedure (SOP) for managing amended reports and all were very satisfied (12/20) or satisfied (8/20) with the SOP. Of those without a protocol, 76% (51/67) would prefer to have an SOP implemented. Respondents reported a preference for (1) laboratories to send amended variant reports directly to the genetic counselor or ordering physician through email or an online portal, and (2) notification to patients ideally occurring through a phone call. In the event that the original genetic counselor is inaccessible, respondents reported a preference for reports to be sent directly to another genetic counselor (36%) on the team or the clinic in general (27%). Information from this study provides insight into the current practices of genetic counselors as applied to amended reports and what improvements may increase the efficiency of the reporting process. Moreover, these results suggest a need for an updated statement addressing duty to recontact, specifically as it applies to amended variant reports.
Late‐onset argininosuccinic aciduria in a 72‐year‐old man presenting with fatal hyperammonemia
Authors: Leuger Laurent , Dieu Xavier , Chao de la Barca Juan Manuel , Moriconi Mikael , Halley Guillaume , Donin de Rosière Xavier , Reynier Pascal , Mirebeau‐Prunier Delphine , Homedan Chadi
Published: September 2021

Argininosuccinate lyase deficiency (ASLD, MIM #207900) is an inherited urea cycle disorder. There are mainly two clinical forms, an acute neonatal form which manifests as life‐threatening hyperammonemia, and a late‐onset form characterised by polymorphic neuro‐cognitive or psychiatric presentation with transient hyperammonemia episodes. Here, we report a late‐onset case of ASLD in a 72‐year‐old man carrying a homozygous pathogenic variant in the exon 16 of the ASL gene, presenting for the first time with fatal hyperammonemic coma. This case report shows the need to systematically carry out an ammonia assay when faced with an unexplained coma.
The link between avian brachial index, flight capability and the neornithine evolutionary radiation
Authors: Karoullas Carolina , Nudds Robert L.
Published: September 2021

In dictating the relative distances between the elbow, shoulder and wrist, avian brachial index (BI = humerus/radius‐ulna length) likely influences wing kinematics and, therefore, might predict extinct avian flight capability. This underpins the hypothesis that non‐neornithine Mesozoic avialans with relatively low BIs (associated with improved flight capabilities) restricted neornithine diversification until after the Cretaceous–Paleogene boundary. Here, correlations between flight metrics (wingbeat frequency (f), stroke angle (θ), wing loading (Q) and aspect ratio) and BI were investigated and vice versa. Additionally, the evolutionary model best describing the phylogenetic distribution of BI, and the temporal patterns in BI, flight metrics, body mass (Mb), and size‐corrected humerus (Lh) and radius‐ulna (Lru) length were determined. BI was best described by Ornstein–Uhlenbeck processes, with lowαvalues indicating a gradual shift towards a future theoretical optimum. BI also decreased overall through evolutionary time with the flight metrics mirroring temporal patterns of change in BI.Mb,LhandLruoverall decreased apart from increases inLhandLrufollowing the middle‐late Miocene (also leading to BI increasing) due to diversifications of the Anatinae and Sphenisciformes.Lhoverall decreased further thanLru.Consequently, decreasingLhmainly contributed to decreasing BI through evolutionary time, implying flight performance increased through neornithine evolution. However, the timings of radiations in these variables implies an Eocene radiation of neornthine flight ecology rather than a rapid expansion into niches vacated by non‐neornithine Mesozoic avialians following the Cretaceous–Paleogene boundary. Multiple regressions showedf,θandQexplained 60% of variation in BI. However, unequivocally evaluating whether BI is related to wing movement (and flight capability) requires direct measures of wing movement for many species, which are currently unavailable. Finally, the findings here and previously observed clade‐specificity in BI, suggest flight ecology may also be clade‐specific. Hence, the utility of phylogeny in predicting flight ecology requires exploration.
On boundary exact controllability of one‐dimensional wave equations with weak and strong interior degeneration
Authors: Kogut Peter I. , Kupenko Olga P. , Leugering Günter
Published: September 2021

In this paper, we study exact boundary controllability for a linear wave equation with strong and weak interior degeneration of the coefficient in the principle part of the elliptic operator. The objective is to provide a well‐posedness analysis of the corresponding system and derive conditions for its controllability through boundary actions. Passing to a relaxed version of the original problem, we discuss existence and uniqueness of solutions, and using the HUM method we derive conditions on the rate of degeneracy for both exact boundary controllability and the lack thereof.
Modified homotopy perturbation approach for the system of fractional partial differential equations: A utility of fractional Wronskian
Authors: Kumar Rakesh , Koundal Reena , Ali Shehzad Sabir
Published: September 2021

In this paper, generalized aspects of least square homotopy perturbation are presented to treat the system of nonlinear fractional partial differential equations (FPDEs), and the method is called as generalization of least square homotopy perturbation (GLSHP). The concept of fractional partial Wronskian is introduced to detect the linear independence of functions depending on more than one variable through Caputo fractional calculus. Definition of fractional partial Wronskian is provided along with linear independence theorem. It is found that solutions converge more rapidly through GLSHP in comparison to classical fractional homotopy perturbation method (FHPM). Outcomes of this generalization are validated by taking examples from nonlinear fractional wave equations.
A monostatic laser polarization isolation system for light pollution and velocity combined laser heterodyne detection
Authors: Qu Yang , Jia Xue , Chen Zhongbiao
Published: September 2021

In order to solve the signal aliasing problem when tracking and detecting mobile laser pollution sources, a monostatic laser polarization isolation system is designed and built. Through the polarization state and received power detection experiments, the results of the prototype show that this system can effectively separate different signal echoes and has excellent signal receiving ability.
Screening Design of Experiments of AGET ATRP of Butyl Methacrylate in a Stirred Emulsion Reactor
Authors: Awad Mohammed , Dhib Ramdhane , Duever Thomas
Published: September 2021

This study investigates the ab initio atom transfer radical polymerization of butyl methacrylate using activator generated by electron transfer in a well‐mixed 2 L emulsion reactor. A first time reported polymerization system initiates by a catalyst complex with hexamethylenetetramine as a ligand and in presence of sodium dodecyl sulfate as an anionic surfactant. The system shows a relatively low monomer conversion rate of 14% and a controlled number average molecular weight (Mn) of 8 kg mol−1with a polydispersity index (Ð) of 1.24 for 2 h reaction time. A statistical design of experiments is followed to study the effects of reaction temperature, surfactant amount, stirring speed, and ligand amount to assess their impact on the monomer conversion,Mn, andÐ. A fractional factorial with a resolution IV design is adopted and an empirical regression model is developed from eight experimental trials. The results tell that the reaction temperature has the greatest influential on the process outputs. Also, the surfactant amount and stirring speed strongly affect the conversion rate, while the ligand amount strongly affects theMnandÐ. The results also show that the temperature–surfactant interaction is the most significant on the conversion rate andMn.
A bioarchaeological approach for the examination of two Lithuanian clergymen: Juozapas Arnulfas Giedraitis and Simonas Mykolas Giedraitis (18th–19th centuries AD)
Authors: Piombino‐Mascali Dario , Brindzaitė Rūta , Jankauskas Rimantas , Girčius Rokas , Tamošiūnas Algirdas , Motuzaitė Matuzevičiūtė Giedrė , Kozakaitė Justina
Published: September 2021

In the summer of 2019, members of the Faculty of Medicine of Vilnius University were summoned by the diocese of Telšiai to carry out an investigation of the mortal remains of Juozapas Arnulfas Giedraitis and Simonas Mykolas Giedraitis, two high religious dignitaries entombed in the crypt of the parish of St Peter and St Paul, Apostles, at Varniai (Samogitia, Lithuania). The aim of the study was to confirm their identity, to obtain data for compiling an osteo‐biographic profile, and to assess any manipulation of the bodies that resulted in their preservation. The remains concerned underwent anthropological, paleopathological, and archaeobotanical investigations, supplemented by a radiological analysis for the individual who displayed tissue mummification. There was evidence of bodily processing after death, which included internal organ removal, the use of specific plant species known to have antiseptic and disinfectant properties, as well as chemical preservatives. In combination with the available historic sources, this study aimed to provide a detailed bioarchaeological assessment to enrich our understanding of previously undocumented postmortem bodily treatments and preservation practices among these high‐ranked Lithuanian clergymen.
Nano fibrillated cellulose‐based foam by Pickering emulsion: Preparation, characterizations, and application as dye adsorbent
Authors: Purkayastha Srijita , Ghosh Anup K. , Saha Sampa
Published: September 2021

An ecofriendly and biodegradable porous structure was prepared from drying aqueous foams based on nano fibrillated cellulose (NFC), extracted from softwood pulp by subcritical water/CO2 treatment (SC‐NFC). The primary aim of this work was to use the modified SC‐NFC as stabilizer for a water‐based Pickering emulsion which upon drying, yielded porous cellulosic materials, a good dye adsorbent. In order to exploit the carboxymethylated SC‐NFC (CMSC‐NFC, with a degree of substitution of 0.35 and a charge density of 649 μeqv/g) as a stabilizer for water‐based Pickering emulsion in subsequent step, an optimized quantity of octyl amine (30 mg/g of SC‐NFC) was added to make them partially hydrophobic. A series of dry foam structures were prepared by varying the concentrations of treated CMSC‐NFCs and 4 wt% was found to be the optimum concentration to yield foam with high porosity (99%) and low density (0.038 g/cc) along with high compression strength (0.24 MPa), superior to the conventionally extracted NFC. The foams were applied to capture as high as 98% of methylene blue dyes, making them a potential green candidate for treating industrial effluent. In addition, the dye adsorption kinetics and isotherms were found to be well suited with second order kinetics and Langmuir isotherm models.
Registration of ‘S13‐3851C’ soybean as a high‐yielding conventional cultivar with high oil content and broad disease resistance and adaptation
Authors: Chen P. , Shannon G. , Scaboo A. , Crisel M. , Smothers S. , Clubb M. , Selves S. , Vieira C. C. , Ali M. L. , Lee D. , Nguyen H. T. , Li Z. , Mitchum M. G. , Bond J. , Meinhardt C. , Usovsky M. , Li S. , Mengistu A. , Robbins R. T.
Published: September 2021

‘S13‐3851C’ (Reg. no. CV‐541, PI 698653) is an early maturity group IV (relative maturity 4.4) conventional soybean [Glycine max (L.) Merr.] cultivar released by the University of Missouri–Fisher Delta Research Center Soybean Breeding Program. It was developed from a conventional breeding scheme focusing on parental traits including high oil content, multiple disease resistance, and high yielding potential. S13‐3851C has purple flowers, light tawny pubescence, tan pod wall, and indeterminate growth habit. Seeds of S13‐3851C have a black hilum and intermediate seed luster, with 230.8 g kg−1 of oil and 404.1 g kg−1 of protein content on a dry‐weight basis. S13‐3851C is resistant to stem canker, sudden death syndrome, charcoal rot, and Phytophthora root rot. S13‐3851C showed high yield potential and broad adaptability in 113 environments across 12 states, yielding 102% of the check average and 103% of the test average in Missouri and other southern states during the testing period (2014–2018).
Automation of single‐cell proteomic sample preparation
Authors: Alexovič Michal , Sabo Ján , Longuespée Rémi
Published: September 2021

Molecular heterogeneity exists at different spatial scales in biological samples and is an important parameter in the development of pathologies and resistances to therapies. When aiming to reach molecular heterogeneity of cells at extremely low spatial scales, single‐cell analysis can be the ultimate choice. Proteomics performed in bulk population of cells (macroproteomics) is prone to mask molecular heterogeneity. Mass spectrometry‐based single cell proteomics (SCP‐MS) is the right solution to overcome this issue. Three main problems can be identified using SCP‐MS: (i) analytical loss during sample preparation, (ii) inefficient microinjection/delivery of proteins/peptides from samples to MS and (iii) low analytical throughput. Technologies for automation of SCP have recently gained attention to improve methods accuracy, sensitivity, throughput and in‐depth and low‐biased proteome analysis. In this minireview, we therefore overview the state‐of‐the‐art of automation of SCP‐MS sample preparation approaches.
Is the modified shuttle test a maximal effort test in children and adolescents with asthma?
Authors: Reimberg Mariana M. , Ritti‐Dias Raphael , Selman Jessyca P. , Scalco Rebeca S. , Wandalsen Gustavo F. , Solé Dirceu , Hulzebos Erik J. , Takken Tim , Dal Corso Simone , Lanza Fernanda C.
Published: September 2021

Purpose

Whether the modified shuttle test (MST) achieves maximal effort in children and adolescents with asthma is unclear. The aim was to compare the physiological responses of MST to the cardiopulmonary exercise test (CPET) in pediatric patients with asthma, to observe its convergent validity.

Patients and Methods

A cross‐sectional study with volunteers with asthma (6–17 years of age) under regular treatment. The MST is an external‐paced test, and the participants were allowed to walk/run. CPET was performed on a cycle ergometer to compare with MST. Gas exchange (VO2, VCO2, and VE) and heart rate (HR) were the outcomes and were continuously assessed in both tests.

Results

Forty‐seven volunteers were included, normal lung function expiratory forced volume at 1st second/forced vital capacity (FEV1/FVC) 88.6 (7.7). VO2peak was higher at MST (2.0 ± 0.6 L/min) compared to CPET (1.6 ± 0.5 L/min), p < 0.001. Similar results was observed to VE at MST (50 ± 16 L/min) versus VE at CPET (40 ± 13 L/min), and to VCO2 at MST (2.1 ± 0.8 L/min) versus VCO2 at CPET (1.7 ± 0.6 L/min), p < 0.001. HR was also higher at MST (94 ± 6%pred) versus CPET (87 ± 8%pred), p = 0.002. VO2peak in MST correlated to the CPET (r = 0.78, p < 0.001). The ICC of VO2peak between tests was 0.73 (0.06–0.89), p < 0.001, and VO2peak Bland–Altman analysis showed a bias of 0.46 L/min.

Conclusion

The MST showed a maximal physiologic response in children and adolescents with asthma. It is a valid test and can be used as an alternative to evaluating exercise capacity.
Year‐round sub‐seasonal forecast skill for Atlantic–European weather regimes
Authors: Büeler Dominik , Ferranti Laura , Magnusson Linus , Quinting Julian F. , Grams Christian M.
Published: September 2021

Weather regime forecasts are a prominent use case of sub‐seasonal prediction in the midlatitudes. A systematic evaluation and understanding of year‐round sub‐seasonal regime forecast performance is still missing, however. Here we evaluate the representation of and forecast skill for seven year‐round Atlantic–European weather regimes in sub‐seasonal reforecasts from the European Centre for Medium‐Range Weather Forecasts. Forecast calibration improves regime frequency biases and forecast skill most strongly in summer, but scarcely in winter, due to considerable large‐scale flow biases in summer. The average regime skill horizon in winter is about 5 days longer than in summer and spring, and 3 days longer than in autumn. The Zonal Regime and Greenland Blocking tend to have the longest year‐round skill horizon, which is driven by their high persistence in winter. The year‐round skill is lowest for the European Blocking, which is common for all seasons but most pronounced in winter and spring. For the related, more northern Scandinavian Blocking, the skill is similarly low in winter and spring but higher in summer and autumn. We further show that the winter average regime skill horizon tends to be enhanced following a strong stratospheric polar vortex (SPV), but reduced following a weak SPV. Likewise, the year‐round average regime skill horizon tends to be enhanced following phases 4 and 7 of the Madden–Julian Oscillation (MJO) but reduced following phase 2, driven by winter but also autumn and spring. Our study thus reveals promising potential for year‐round sub‐seasonal regime predictions. Further model improvements can be achieved by reduction of the considerable large‐scale flow biases in summer, better understanding and modeling of blocking in the European region, and better exploitation of the potential predictability provided by weak SPV states and specific MJO phases in winter and the transition seasons.
On moving average control charts and their conditional average run lengths
Authors: Maghsoodloo Saeed , Barnes Dilcu
Published: September 2021

Moving average control charts have been presented in the Quality Control literature in the past 75 years; however, their conditional average run lengths have not been obtained. The objective of this article is to derive the autocorrelation function between two moving averages, and then make application of the bivariate normal distribution to compute the conditional type II error probability at the future time, t +1, given that a manufacturing process is in statistical control at the present time t. Our Tables 3 through 8 show that the values of Shewhart's average run length and the corresponding conditional first‐order moving average run lengths are almost the same after one standard deviation shift from the target of a normal process mean. Our conclusion section 6 describes that the comparisons of the two average run lengths are not on a valid statistical basis.