bluuebunny/crossref_metadata_2025 huggingface dataset:
IndepthPathway: an integrated tool for in-depth pathway enrichment analysis based on bulk and single cell sequencing data
Authors: Lee Sanghoon , Deng Letian , Wang Yue , Wang Kai , Sartor Maureen A. , Wang Xiaosong
Published: August 2022

Single-cell sequencing (SCS) enables exploring the pathways and processes of cells, and cell populations. However, there is a paucity of pathway enrichment methods designed to tolerate the high noise and low gene coverage of this technology. When gene expression data are noisy and signals are sparse, testing pathway enrichment based on the genes expression may not yield statistically significant results which is particularly problematic when detecting the pathways enriched in less abundant cells that are vulnerable to disturbances. In this project, we developed a Weighted Concept Signature Enrichment Analysis (WCSEA) algorithm specialized for pathway enrichment analysis from single cell transcriptomics (scRNA-seq). WCSEA took a broader approach for assessing the functional relations of pathway gene sets to differentially expressed genes, and leverage the cumulative signature of molecular concepts characteristic of the highly differentially expressed genes, which we termed as the universal concept signature, to tolerate the high noise and low coverage of this technology. We then incorporated WCSEA into a R package called “IndepthPathway” for biologists to broadly leverage this method for pathway analysis based on bulk and single cell sequencing data. Through simulating technical variability and dropouts in gene expression characteristic of scRNA-seq as well as benchmarking on a real dataset of matched single cell and bulk RNAseq data, we demonstrate that IndepthPathway presents outstanding stability and depth in pathway enrichment results under stochasticity of the data, thus will substantially improve the scientific rigor of the pathway analysis for single cell sequencing data. The IndepthPathway package is available through:https://github.com/wangxlab/IndepthPathway.
Super-resolution vibrational imaging based on photoswitchable Raman probe
Authors: Shou Jingwen , Komazawa Ayumi , Wachi Yuusaku , Kawatani Minoru , Fujioka Hiroyoshi , Spratt Spencer John , Mizuguchi Takaha , Oguchi Kenichi , Obata Fumiaki , Tachibana Ryo , Misawa Yoshihiro , Kojima Ryosuke , Urano Yasuteru , Kamiya Mako , Ozeki Yasuyuki
Published: August 2022

Super-resolution vibrational microscopy is a promising tool to increase the degree of multiplexing of nanometer-scale biological imaging, because the spectral linewidth of molecular vibration is about 50 times narrower than that of fluorescence. However, current techniques of super-resolution vibrational microscopy still suffer from various limitations including the need for cell fixation, high power loading or complicated frequency-modulated detection schemes. Herein we utilize photoswitchable stimulated Raman scattering (SRS) to develop a method that we call reversible saturable optical Raman transitions (RESORT) microscopy, which overcomes these limitations. We first describe a new kind of photoswitchable Raman probe designated DAE620 and then we employ a standard SRS detection scheme to validate its signal activation and depletion characteristics when exposed to low-power (microwatt level) continuous-wave laser light. By harnessing the SRS signal depletion of DAE620 through a donut-shaped beam, we demonstrate super-resolution vibrational imaging of mammalian cells with excellent chemical specificity and spatial resolution beyond the optical diffraction limit. Our results indicate RESORT microscopy to be an effective tool with high potential for multiplexed super-resolution imaging of live cells.
Predicting anti-cancer drug synergy using extended drug similarity profiles
Authors: Hosseini Sayed-Rzgar , Zhou Xiaobo
Published: August 2022

Combination therapy is a promising strategy for confronting the complexity of cancer. However, experimental exploration of the vast space of potential drug combinations is costly and unfeasible. Therefore, computational methods for predicting drug synergy are much-needed for narrowing down this space, especially when examining new cellular contexts. Here, we thus introduce CCSynergy, a flexible, context-aware and integrative deep learning framework that we have established to unleash the potential of the Chemical Checker extended drug similarity profiles for the purpose of drug synergy prediction. We have shown that CCSynergy enables predictions of superior accuracy, remarkable robustness and improved context-generalizability as compared to the state-of-the-art methods in the field. Having established the potential of CCSynergy for generating experimentally validated predictions, we exhaustively explored the untested drug combination space. This resulted in a compendium of potentially synergistic drug combinations on hundreds of cancer cell lines, which can guide future experimental screens.
FAVOR: Functional Annotation of Variants Online Resource and Annotator for Variation across the Human Genome
Authors: Zhou Hufeng , Arapoglou Theodore , Li Xihao , Li Zilin , Zheng Xiuwen , Moore Jill , Asok Abhijith , Kumar Sushant , Blue Elizabeth E. , Buyske Steven , Cox Nancy , Felsenfeld Adam , Gerstein Mark , Kenny Eimear , Li Bingshan , Matise Tara , Philippakis Anthony , Rehm Heidi , Sofia Heidi J. , Snyder Grace ,   NHGRI Genome Sequencing Program Variant Functional Annotation Working Group, Weng Zhiping , Neale Benjamin , Sunyaev Shamil R. , Lin Xihong
Published: August 2022

Large-scale whole genome sequencing (WGS) studies and biobanks are rapidly generating a multitude of coding and non-coding variants. They provide an unprecedented resource for illuminating the genetic basis of human diseases. Variant functional annotations play a critical role in WGS analysis, result interpretation, and prioritization of disease- or trait-associated causal variants. Existing functional annotation databases have limited scope to perform online queries or are unable to functionally annotate the genotype data of large WGS studies and biobanks for downstream analysis. We develop the Functional Annotation of Variants Online Resources (FAVOR) to meet these pressing needs. FAVOR provides a comprehensive online multi-faceted portal with summarization and visualization of all possible 9 billion single nucleotide variants (SNVs) across the genome, and allows for rapid variant-, gene-, and region-level online queries. It integrates variant functional information from multiple sources to describe the functional characteristics of variants and facilitates prioritizing plausible causal variants influencing human phenotypes. Furthermore, a scalable annotation tool, FAVORannotator, is provided for functionally annotating and efficiently storing the genotype and variant functional annotation data of a large-scale sequencing study in an annotated GDS file format to facilitate downstream analysis. FAVOR and FAVORannotator are available at https://favor.genohub.org.
A CRISPR-Cas9-mediated F0 screen to identify pro-regenerative genes in the zebrafish retinal pigment epithelium
Authors: Lu Fangfang , Leach Lyndsay L. , Gross Jeffrey M.
Published: August 2022

Ocular diseases resulting in death of the retinal pigment epithelium (RPE) lead to vision loss and blindness. There are currently no FDA-approved strategies to restore damaged RPE cells. Stimulating intrinsic regenerative responses within damaged tissues has gained traction as a possible mechanism for tissue repair. Zebrafish possess remarkable regenerative abilities, including within the RPE; however, our understanding of the underlying mechanisms remains limited. Here, we conducted an F0 in vivo CRISPR-Cas9-mediated screen of 27 candidate RPE regeneration genes. The screen involved injection of a ribonucleoprotein complex containing three highly mutagenic guide RNAs per target gene followed by PCR-based genotyping to identify large intragenic deletions and MATLAB-based automated quantification of RPE regeneration. Through this F0 screening pipeline, eight positive and seven negative regulators of RPE regeneration were identified. Further characterization of one candidate, cldn7b, revealed novel roles in regulating macrophage/microglia infiltration after RPE injury and in clearing RPE/pigment debris during late-phase RPE regeneration. Taken together, these data support the utility of targeted F0 screens for validating pro-regenerative factors and reveal novel factors that could regulate regenerative responses within the zebrafish RPE.

Summary statement

We present a rapid CRISPR-Cas9-mediated F0 screen, which revealed novel regulators of retinal pigment epithelium (RPE) regeneration in zebrafish. This screen and identified factors will greatly facilitate discovery of underlying RPE regenerative mechanisms.
Plumage colouration differs between offspring raised in natural cavities and nestboxes
Authors: Janas Katarzyna , Lecce Irene Di , Szulkin Marta , Sudyka Joanna
Published: August 2022

Most of our knowledge on hole-nesting birds, including plumage colouration (an important component of visual signalling), comes from studies on populations breeding in human-provided nestboxes. However, as demonstrated in comparative studies, multiple parameters, such as cavity dimensions and microclimatic conditions, differ between natural and artificial cavities. Despite this, no study so far examined the impact of cavity type on plumage colouration to verify whether extrapolation of results from birds growing in nestboxes is justified. Here, we examined the impact of cavity type – natural cavities vs. nestboxes - on the carotenoid-based colouration of blue tit (Cyanistes caeruleus) and great tit (Parus major) nestlings. We found clear differences in plumage colouration depending on the type of cavity in which the birds developed. Our study adds to the growing body of evidence confirming that varying properties of natural cavities and nestboxes might influence nestling physiology, leading to phenotypic differences in the long-term.
Controlling for false discoveries subsequently to large scale one-way ANOVA testing in proteomics: practical considerations
Authors: Burger Thomas
Published: August 2022

In discovery proteomics, as well as many other “omic” approaches, the possibility to test for the differential abundance of hundreds (or of thousands) of features simultaneously is appealing, despite requiring specific statistical safeguards, among which controlling for the False Discovery Rate (FDR) has become standard. Moreover, when more than two biological conditions or group treatments are considered, it has become customary to rely on the one-way Analysis of Variance (ANOVA) framework, where a first global differential abundance landscape provided by an omnibus test can be subsequently refined using various post-hoc tests. However, the interactions between the FDR control procedures and the post-hoc tests are complex, because both correspond to different types of multiple test corrections. This article surveys various ways to orchestrate them in a data processing workflow and discusses their pros and cons.
The Immunological Proteome Resource
Authors: Brenes Alejandro J. , Hukelmann Jens L. , Spinelli Laura , Howden Andrew J.M. , Marchingo Julia M. , Sinclair Linda V. , Rollings Christina , James Olivia J. , Phair Iain R , Matthews Stephen P. , Ross Sarah H. , Arthur J. Simon C. , Swamy Mahima , Finlay David K. , Lamond Angus I. , Cantrell Doreen A.
Published: August 2022

The Immunological Proteome Resource (ImmPRes;http://immpres.co.uk/) is an open access public resource integrating proteomic data generated by large-scale mass-spectrometry analysis of murine hematopoietic populations. The initial focus is T lymphocytes and how their proteomes are shaped by immune activation, environment, and intracellular signalling pathways with an aim to expand it to B cells and innate immune cells. It is a multidisciplinary effort between immunology and mass spectrometry-based labs with the objective to help define an in-depth high-quality map of immune cell proteomes. Maintaining data reproducibility and integrity are a priority within the resource, thus there is an in-depth protocols section explaining in detail the sample processing and the mass spectrometry-based analysis. ImmPRes provides open access to proteomic datasets covering a wide range of murine leukocyte populations with analysis of copy numbers per cell of > 10,000 proteins, enabling new understanding of lymphocyte phenotypes. All data is accessible via a simple graphical interface that supports easy interrogation of the data and options to download data summaries and raw data files.
Locus Coeruleus firing patterns selectively modulate brain activity and dynamics
Authors: Grimm Christina , Duss Sian N. , Privitera Mattia , Munn Brandon R. , Frässle Stefan , Chernysheva Maria , Patriarchi Tommaso , Razansky Daniel , Wenderoth Nicole , Shine James M. , Bohacek Johannes , Zerbi Valerio
Published: August 2022

Noradrenaline (NA) release from the brainstem nucleus locus coeruleus (LC) changes activity and connectivity in neuronal networks across the brain, thus modulating multiple behavioural states. NA release is mediated by both tonic and burst-like neuronal LC activity. However, it remains unknown whether the functional changes in downstream projection areas depend on these firing patterns. Using optogenetics, pupillometry, photometry, and functional MRI in mice, we show that tonic and burst LC firing patterns elicit brain responses that are specific to the activation frequency and temporal pattern. Tonic activation of the LC evokes nonlinear responses in prefrontal, limbic, and cerebellar regions, in line with the proposed inverted-U relationship between LC activity and behaviour. We further demonstrate that LC activity enhances network integration and acts as a facilitator of brain state transitions, hence increasing brain flexibility. Together, these findings reveal how the LC-NA system achieves a nuanced regulation of global circuit operations.
AcaFinder: genome mining for anti-CRISPR associated genes
Authors: Yang Bowen , Zheng Jinfang , Yin Yanbin
Published: August 2022

Anti-CRISPR (Acr) proteins are encoded by (pro)viruses to inhibit their host’s CRISPR-Cas systems. Genes encoding Acr and Aca (Acr associated) proteins often co-localize to form acr-aca operons. Here, we present AcaFinder as the first Aca genome mining tool. AcaFinder can: (i) predict Acas and their associated acr-aca operons using guilt-by-association (GBA); (ii) identify homologs of known Acas using an HMM (Hidden Markov model) database; (iii) take input genomes for potential prophages, CRISPR-Cas systems, and self-targeting spacers (STSs); and (iv) provide a standalone program (https://github.com/boweny920/AcaFinder) and a web server (http://aca.unl.edu/Aca). AcaFinder was applied to mining over 16,000 prokaryotic and 142,000 gut phage genomes. After a multi-step filtering, 36 high-confident new Aca families were identified, which is three times of the 12 known Aca families. Seven new Aca families were from major human gut bacteria (Bacteroidota, Actinobacteria, Fusobacteria) and their phages, while most known Aca families were from Proteobacteria and Firmicutes. A complex association network between Acrs and Acas was revealed by analyzing their operonic co-localizations. It appears very common in evolution that the same aca genes can recombine with different acr genes and vice versa to form diverse acr-aca operon combinations.

Importance

At least four bioinformatics programs have been published for genome mining of Acrs since 2020. In contrast, no bioinformatics tools are available for automated Aca discovery. As the self-transcriptional repressor of acr-aca operons, Aca can be viewed as anti-anti-CRISPRs, with a great potential in the improvement of CRISPR-Cas technology. Although all the 12 known Aca proteins contain a conserved Helix-Turn-Helix (HTH) domain, not all HTH-containing proteins are Acas. However, HTH-containing proteins with an adjacent Acr homologs encoded in the same genetic operon are likely Aca proteins. AcaFinder implements this guilt-by-association (GBA) idea and the idea of using HMMs of known Acas for homologs into one software package. Applying AcaFinder in screening prokaryotic and gut phage genomes reveals a complex acr-aca operonic co-localization network between different families of Acrs and Acas.
Depth-resolved Laue microdiffraction with coded apertures
Authors: Gürsoy Doğa , Sheyfer Dina , Wojcik Michael , Liu Wenjun , Tischler Jonathan Z.
Published: August 2022

A rapid data acquisition and reconstruction method is introduced to image the crystalline structure of materials and the associated strain and orientations at micrometre resolution using Laue diffraction. The method relies on scanning a coded aperture across the diffracted X-ray beam from broadband illumination and a reconstruction algorithm to resolve Laue microdiffraction patterns as a function of depth along the incident illumination path. It provides rapid access to full diffraction information for sub-micrometre volume elements in bulk materials. Both the theory and the experimental validation of this imaging approach are presented.
High-resolution 3D X-ray diffraction microscopy: 3D mapping of deformed metal microstructures
Authors: Kutsal Mustafacan , Poulsen Henning Friis , Winther Grethe , Sørensen Henning Osholm , Detlefs Carsten
Published: August 2022

Three-dimensional X-ray diffraction microscopy, 3DXRD, has become an established tool for orientation and strain mapping of bulk polycrystals. However, it is limited to a finite spatial resolution of ∼1.5–3 µm. Presented here is a high-resolution modality of the technique, HR-3DXRD, for 3D mapping of submicrometre-sized crystallites or subgrains with high spatial and angular resolution. Specifically, the method is targeted to visualization of metal microstructures at industrially relevant degrees of plastic deformation. Exploiting intrinsic crystallographic properties of such microstructures, the high resolution is obtained by placing a high-resolution imaging detector in between the near-field and far-field regimes. This configuration enables 3D mapping of deformation microstructure by determining the centre of mass and volume of the subgrains and generating maps by tessellation. The setup is presented, together with a data analysis approach. Full-scale simulations are used to determine limitations and to demonstrate HR-3DXRD on realistic phantoms. Misalignments in the setup are shown to cause negligible shifts in the position and orientation of the subgrains. Decreasing the signal-to-noise ratio is observed to lead primarily to a loss in the number of determined diffraction spots. Simulations of an α-Fe sample deformed to a strain of ε
vM
= 0.3 and comprising 828 subgrains show that, despite the high degree of local texture, 772 of the subgrains are retrieved with a spatial accuracy of 0.1 µm and an orientation accuracy of 0.0005°.
How does contract flexibility affect the sustainability performance of public–private partnership projects? A serial multiple mediator model
Authors: Tian Bo , Fu Jiaxin , Xu Yongshun , Sun Longshan
Published: August 2022

Purpose

The risks and uncertainties of public–private partnership (PPP) projects threaten their sustainability. Contract flexibility, which is based on the theory of incomplete contract and transaction cost, may be a viable solution to this issue. The purpose of this study is to investigate the relationship between contract flexibility and the sustainability performance of PPP projects. The multiple mediating roles of justice perception and cooperation efficiency are assessed, thereby allowing the pathways and conditions to be understood more comprehensively for improving the sustainability performance of PPP projects.

Design/methodology/approach

Nine hypotheses in the proposed research model are tested via structural equation modeling using data acquired from 218 Chinese PPP professionals.

Findings

Results show that contract flexibility positively affects PPP project sustainability performance. Justice perception and cooperation efficiency play direct and sequential mediating roles in this effect.

Originality/value

This study validates that contract flexibility positively impacts the sustainability performance of PPP projects, where justice perception and cooperation efficiency serve direct and sequential mediating roles. The findings of this study contribute to an improved understanding of the effect of contract flexibility on the sustainability performance of PPP projects. Furthermore, they provide important theoretical and practical insights into contract management as well as beneficial information and valuable initiatives for improving the sustainability of PPP projects.
India Post: its 21st-century avatar
Authors: Subramanian R. Bala , Thakur Munish
Published: August 2022

Learning outcomes

The case has the following learning objectives: to assess the importance of the business environment, its impact on the organization and how the organization responds to the changes in the business environment; to apply the resource-based view of the organization and resource dependence theory; and to apply and analyze the organization’s strategic initiatives within the framework of the political, economic, social and technological analysis model, Porter’s five forces of business analysis and to make recommendations based on the above analysis.

Case overview/synopsis

The paradigm shift in technology has an impact on business. With 155,015 Post Offices, India Post has the most widely distributed postal network in the world. This case captures the journey of India Post from inception to its current form. Over its life, the organization has evolved because of multiple changes. But the recent changes have threatened to disrupt the organization. These changes have been induced by three major forces: technology, the rise of competition, especially foreign players, and social changes in urban and rural India because of changing consumption patterns as incomes rise and online retail grows. The organization has reacted to this threat by leveraging its resources to offer new products according to customer tastes by entering more unique industries and product categories. They have started logistics services in association with Indian railways and started offering retail services such as bill collection and college application forms. Also, they have created a financial division, “Payment Bank.” Thus, they have evolved from being a single entity of postal-related services to various services. The case poses a dilemma if these product diversifications are thriving as the organization’s product portfolio has diversified, given its existing capabilities and ability to create newer capabilities, particularly the payment bank.

Complexity academic level

The case is ideally suited for the discussion of resource-based view of the firm in the subject strategic management and organizational theory. The case can be used to discuss resource dependence theory as well. It is equally well suited to discuss the impact of environment in business in the subject organization theory and the impact of technology on change in the subject organizational change. The case is meant for MBA. The case can be used for executive audience as well.

Supplementary materials

Teaching notes are available for educators only.

Subject code

CSS 11: Strategy.
Crowdsourced product returns in C2B e-commerce: a post-pandemic no-contact consumer incentive-based model
Authors: Kumar Chitresh , Ganguly Anirban
Published: August 2022

Purpose

This study aims to investigate the conditions for the financial feasibility of an incentive-based model for self-drop or crowdsourced drop of the product to be returned at designated drop boxes (thereby ensuring a contactless process).

Design/methodology/approach

Constraint-based non-linear mathematical modeling was done for cost differential with and without crowdsourcing. This was analyzed against returns on investment for the installed infrastructure. Scenarios were looked into from the linear, iso-elastic and logarithmic demand functions to identify the optimal incentive policy. The results were further evaluated using “willingness to return” for customer willingness for product returns via drop boxes.

Findings

Crowdsourcing is viable when product returns are no more than 15%–20% of the overall products, with a logistics cost differential of 15%–25%. These were only viable when the product return incentive was within the range of 15%–20% of the product cost, as well as the penalty was in the range of 25 to 40% for wrong returns.

Research limitations/implications

The findings are expected to aid the organizations in successfully designing product return policies while adhering to the post-COVID-19 norms, including contactless transactions and social distancing.

Originality/value

The study provides a look into the viability sensitivity of effective gains/profitability against the required level of service for returns, wrong returns, penalties and incentives for crowdsourcing in a developing country like India.
Structural performance of single-skin glass façade systems exposed to fire
Authors: Badr Mohamed , Youssef Maged A. , El-Fitiany Salah , Vedrtnam Ajitanshu
Published: August 2022

Purpose

Understanding the structural performance of external glass curtain walls (façades) during fire exposure is critical for the safety of the occupants as their failure can lead to fire spread throughout the entire building. This concern is magnified by the recent increase in fire incidents and wildfires. This paper presents the first simplified technique to model single-skin façades during fire exposure and then utilizes it to examine the structural behaviour of vertical, inclined and oversized façade panels.

Design/methodology/approach

The proposed technique is based on conducting simplified heat transfer calculations and then utilizing a widely used structural analysis software program to analyze the façade. Validation for the proposed technique with reference to available experimental and numerical studies by others is presented. A parametric study is then conducted to assess the structural performance of different glass façade systems during exposure to fire.

Findings

The proposed technique was found to provide accurate predictions of the structural performance of glass façades during fire exposure. The structural performance of inclined façade systems during fire exposure was found to be superior to vertical and oversized façade systems.

Originality/value

This research paper is the first to provide a simplified technique that can be utilized to model single-skin facades under fire. The presented technique along with the conducted parametric study will improve the understanding of the fire behaviour of single-skin glass facades, which will lead to safer applications.
CRITICAL URBAN PEDAGOGY: Convites as Sites of Southern Urbanism, Solidarity Construction and Urban Learning
Authors: Ortiz Catalina , Millan Gynna
Published: August 2022

Learning from the pedagogical potentials of Southern city‐making practices is imperative to foster emancipatory urban learning settings. However, the ways in which urban learning spaces beyond professional settings operate and how Southern urbanism practices constitute new critical pedagogies are poorly understood. We draw on research about urban learning on ‘slum upgrading’ in the city of Medellín (Colombia), a benchmark in dealing in tandem with informality and urban violence, to analyze the pedagogical potentials of convites. Convites are an essential sociospatial mechanism of self‐build settlements rooted in solidarity networks that initiate collective action and celebration through public cooking. This practice of makeshift community kitchens led by women became the backbone of the response to the scarcities caused by the pandemic in self‐built neighborhoods in Latin America. In this article we ask what Southern urbanism and critical pedagogy can learn from convites. We then analyze the ways in which convites combine community kitchens as learning environments, the use of collective storytelling as a learning device, and collective action through networked solidarities. We argue that critical urban pedagogy is a situated pedagogy derived from everyday relations of place, body and materiality infused by memory and articulated by storytelling.
Penile size in term newborns in Addis Ababa, Ethiopia
Authors: Meskele Kisu , Meseret Fikir , Yesuf Aman , Fantahun Bereket
Published: August 2022

Aim

To determine the normative value of stretched penile length (SPL) for Ethiopian newborns and to set a cut‐off point for micropenis.

Methods

A total of 221 term newborns were included in the study. Stretched penile length was measured in the first 72 h of postnatal age in neonates with a gestational age of 37–42 completed weeks. SPL < −2 SD was taken as micropenis in this study.

Results

The minimum and maximum penile length were 2.5 cm and 5 cm, respectively, with a mean ± SD of 3.28 ± 0.42. SPL at −2 SD and +2 SD were 2.43 and 4.12 cm respectively. A significant correlation was observed between penile length and body length (p = 0.005). Neonates born via instrumental delivery had larger SPL compared to those who were delivered by caesarean section (p = 0.01) or by vaginal delivery (p = 0.006).

Conclusion

The mean stretched penile length in our study mirrors findings from other African studies. SPL < 2.43 cm can be considered as micropenis in our setting. Therefore, routine genital examination and interpretation at birth is crucial to identify micropenis which might herald a serious underlying condition that needs further investigation.
Comparative assessment of viral dynamic models for SARS‐CoV‐2 for pharmacodynamic assessment in early treatment trials
Authors: Agyeman Akosua A. , You Tao , Chan Phylinda L. S. , Lonsdale Dagan O. , Hadjichrysanthou Christoforos , Mahungu Tabitha , Wey Emmanuel Q. , Lowe David M. , Lipman Marc C. I. , Breuer Judy , Kloprogge Frank , Standing Joseph F.
Published: August 2022

Pharmacometric analyses of time series viral load data may detect drug effects with greater power than approaches using single time points. Because SARS‐CoV‐2 viral load rapidly rises and then falls, viral dynamic models have been used. We compared different modelling approaches when analysing Phase II‐type viral dynamic data. Using two SARS‐CoV‐2 datasets of viral load starting within 7 days of symptoms, we fitted the slope‐intercept exponential decay (SI), reduced target cell limited (rTCL), target cell limited (TCL) and TCL with eclipse phase (TCLE) models using nlmixr. Model performance was assessed via Bayesian information criterion (BIC), visual predictive checks (VPCs), goodness‐of‐fit plots, and parameter precision. The most complex (TCLE) model had the highest BIC for both datasets. The estimated viral decline rate was similar for all models except the TCL model for dataset A with a higher rate (median [range] day−1: dataset A; 0.63 [0.56–1.84]; dataset B: 0.81 [0.74–0.85]). Our findings suggest simple models should be considered during pharmacodynamic model development.
Chicken‐derived CD20 antibodies with potent B‐cell depletion activity
Authors: Chockalingam Karuppiah , Kumar Anil , Song Jianxun , Chen Zhilei
Published: August 2022

We report four novel anti‐human CD20 (hCD20) monoclonal antibodies (mAbs) discovered from a phylogenetically distant species—chickens. The chicken–human chimaeric antibodies exhibit at least 10‐fold enhanced antibody‐dependent cellular cytotoxicity (ADCC) and 4–8‐fold stronger complement‐dependent cytotoxicity (CDC) relative to the clinically used mouse–human chimaeric anti‐hCD20 antibody rituximab (RTX). Thus, to our knowledge these mAbs are the first to significantly outperform RTX in both Fc‐mediated mechanisms of action. The antibodies show 20–100‐fold superior depletion of B cells in whole blood from healthy humans relative to RTX and retain efficacy in vivo. One of the mAbs, AC1, can bind mouse CD20, indicating specificity for a novel hCD20 epitope inaccessible to current (mouse‐derived) anti‐hCD20 mAbs. A humanized version of one antibody, hAC11‐10, was created by complementarity‐determining region (CDR) grafting into a human variable region framework and this molecule retained the ADCC, in vitro human whole‐blood B‐cell depletion, and in vivo lymphoma cell depletion activities of the parent. These mAbs represent promising monotherapy candidates for improving upon current less‐than‐ideal clinical outcomes in lymphoid malignancies and provide an arsenal of biologically relevant molecules for the development of next‐generation CD20‐mediated immunotherapies including bispecific T‐cell engagers (BiTE), antibody–drug conjugates (ADC) and chimaeric antigen receptor‐engineered T (CAR‐T) cells.
Existing indicators do not adequately monitor progress toward meeting invasive alien species targets
Authors: Vicente Joana R. , Vaz A. Sofia , Roige Mariona , Winter Marten , Lenzner Bernd , Clarke David A. , McGeoch Melodie A.
Published: August 2022

Monitoring the progress parties have made toward meeting global biodiversity targets requires appropriate indicators. The recognition of invasive alien species (IAS) as a biodiversity threat has led to the development of specific targets aiming at reducing their prevalence and impact. However, indicators for adequately monitoring and reporting on the status of biological invasions have been slow to emerge, with those that exist being arguably insufficient. We performed a systematic review of the peer‐reviewed literature to assess the adequacy of existing IAS indicators against a range of policy‐relevant and scientifically valid properties. We found that very few indicators have most of the desirable properties and that existing indicators are unevenly spread across the components of the Driver‐Pressure‐State‐Response and Theory of Change frameworks. We provide three possible reasons for this: (i) inadequate attention paid to the requirements of an effective IAS indicator, (ii) insufficient data required to populate and inform policy‐relevant, scientifically robust indicators, or (iii) deficient investment in the development and maintenance of IAS indicators. This review includes an analysis of where current inadequacies in IAS indicators exist and provides a roadmap for the future development of indicators capable of measuring progress made toward mitigating and halting biological invasions.
Land's Constraints and Possibilities–High‐Altitude Farmers in the Eastern Alps
Authors: Schneider Almut
Published: August 2022

High‐altitude farmers in South Tyrol (Italy) live and work in the mountain belt of the Eastern Alps and are the focus of an ongoing research project on which first results are presented here. Located between 1200 and 1900 m above sea level, some of their farmsteads are among the highest in Western Europe. This historico‐political development of the region accounts for the relatively favorable situation of these farmers. Since the 1970s, the regional government has regularly subsidized these smallholdings, to ensure that the farmers can remain on their land and market their produce. Keeping the mountain sites cultivated is crucial for ecological reasons but also for the tourist industry on which the region and its people depend heavily. How do farmers approach the apparent contradiction between self‐sufficiency that lies at the core of their work, and, the resources that they need and receive from external agencies?
Findings of collagenous colitis with minimal endoscopic changes using texture and color enhancement imaging
Authors: Koyama Yohei , Uchida Kumiko , Fukuzawa Masakatsu
Published: August 2022

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Multimodal testing reveals subclinical neurovascular dysfunction in prediabetes, challenging the diagnostic threshold of diabetes
Authors: Kirthi Varo , Reed Kate I. , Alattar Komeil , Zuckerman Benjamin P. , Bunce Catey , Nderitu Paul , Alam Uazman , Clarke Bronagh , Hau Scott , Al‐Shibani Fatima , Petropoulos Ioannis N. , Malik Rayaz A. , Pissas Theodoros , Bergeles Christos , Vas Prashanth , Hopkins David , Jackson Timothy L.
Published: August 2022

Aim

To explore if novel non‐invasive diagnostic technologies identify early small nerve fibre and retinal neurovascular pathology in prediabetes.

Methods

Participants with normoglycaemia, prediabetes or type 2 diabetes underwent an exploratory cross‐sectional analysis with optical coherence tomography angiography (OCT‐A), handheld electroretinography (ERG), corneal confocal microscopy (CCM) and evaluation of electrochemical skin conductance (ESC).

Results

Seventy‐five participants with normoglycaemia (n = 20), prediabetes (n = 29) and type 2 diabetes (n = 26) were studied. Compared with normoglycaemia, mean peak ERG amplitudes of retinal responses at low (16‐Td·s: 4.05 μV, 95% confidence interval [95% CI] 0.96–7.13) and high (32‐Td·s: 5·20 μV, 95% CI 1.54–8.86) retinal illuminance were lower in prediabetes, as were OCT‐A parafoveal vessel densities in superficial (0.051 pixels/mm2, 95% CI 0.005–0.095) and deep (0.048 pixels/mm2, 95% CI 0.003–0.093) retinal layers. There were no differences in CCM or ESC measurements between these two groups. Correlations between HbA1c and peak ERG amplitude at 32‐Td·s (r = −0.256, p = 0.028), implicit time at 32‐Td·s (r = 0.422, p < 0.001) and 16‐Td·s (r = 0.327, p = 0.005), OCT parafoveal vessel density in the superficial (r = −0.238, p = 0.049) and deep (r = −0.3, p = 0.017) retinal layers, corneal nerve fibre length (CNFL) (r = −0.293, p = 0.017), and ESC‐hands (r = −0.244, p = 0.035) were observed. HOMA‐IR was a predictor of CNFD (β = −0.94, 95% CI −1.66 to −0.21, p = 0.012) and CNBD (β = −5.02, 95% CI −10.01 to −0.05, p = 0.048).

Conclusions

The glucose threshold for the diagnosis of diabetes is based on emergent retinopathy on fundus examination. We show that both abnormal retinal neurovascular structure (OCT‐A) and function (ERG) may precede retinopathy in prediabetes, which require confirmation in larger, adequately powered studies.
Understanding and Designing Experiences with the 77 Human Needs System (Part 1: Human Experience and Human Needs)
Authors: Beier Guido
Published: August 2022

It is important to understand that we are always experiencing, continuously, without pause.

Take a deep dive into understanding “experience” and how conventional methods of defining it have been inadequate for truly addressing and meeting customer needs.
Effect of PCSK9 inhibitors on remnant cholesterol and lipid residual risk: The LIPID‐REAL registry
Authors: Cordero Alberto , Fernández Olmo Mª. Rosa , Cortez Quiroga Gustavo A. , Romero‐Menor Cesar , Fácila Lorenzo , Seijas‐Amigo José , Rondán Murillo Juan , Sandin Miriam , Rodríguez‐Mañero Moisés , Bello Mora María C. , Valle Alfonso , Fornovi Aisa , Freixa Pamias Roman , Bañeras Jordi , Blanch García Pedro , Clemente Lorenzo María Milagros , Sánchez‐Álvarez Sergio , López‐Rodríguez Luis , González‐Juanatey José R.
Published: August 2022

Background

Monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low‐density lipoprotein cholesterol (LDLc) by 55%, regardless of baseline treatments. Nonetheless, the effect of other lipid parameters, such as cholesterol remnants or, the so‐called lipid residual risk, is unknown.

Methods

Multicenter and retrospective registry of patients treated with PCSK9 inhibitors from 14 different hospitals in Spain. Before and on‐treatment lipid parameters were recorded. Residual lipid risk was estimated by (1) cholesterol remnants, (2) triglycerides/HDLc ratio (TG/HDL), (3) total cholesterol/HDLc (TC/HDL) and (4) the triglycerides‐to‐glucose index (TGGi).

Results

Six hundred fifty‐two patients were analysed, mean age of 60.2 (9.63) years, 24.69% women and mean LDLc before treatment 149.24 (49.86) mg/dl. Median time to second blood determination was 187.5 days. On‐treatment LDLc was 67.46 (45.78) mg/dl, which represented a 55% reduction. Significant reductions were observed for TG/HDL ratio, cholesterol remnants, TC/HDL ratio and TGGi. As consequence, 34.61% patients had LDLc <55 mg/dl and cholesterol remnants <30 mg/dl; additionally, 31.95% had cholesterol remnants <30 mg/dl but LDLc >55 mg/dl. Patients who had levels of cholesterol remnants >30 mg/dl before initiating the treatment with PCSK9 had higher reductions in cholesterol remnants, TG/HDL ratio, TC/HDL and TGGi. By contrast, no reduction differences were observed according to baseline LDLc (< or > the mean), age, gender or obesity.

Conclusions

This multicenter and retrospective registry of real‐world patients treated with PCSK9 inhibitors demonstrates a positive effect on cholesterol remnants and lipid residual risk beyond LDLc reductions.
Conservative management of a horizontal root fracture in a primary maxillary central incisor: Case report
Authors: Sancas Mariana Coutinho , Pires Paula Maciel , Primo Laura Guimarães
Published: August 2022

Dental trauma occurs frequently in toddlers and the treatment protocols vary depending on each case. Thus, clinicians must not only plan the treatment but also consider any possible sequelae and characteristics related to the child and the family. The aim of this paper was to report a case of a three‐year‐old boy who had a horizontal root fracture in the middle third of the primary maxillary right incisor root (tooth 51) and crown discoloration of the primary maxillary left incisor (tooth 61) which were successfully treated with conservative management. The management was established in agreement with the family and was based on active surveillance. The clinical and radiographic follow‐ups showed no changes besides pulp canal calcification of the left incisor throughout the eight years of follow‐up. The pulps remained normal with no pathological signs throughout their life cycle and the permanent successors erupted normally, presenting an excellent result of the non‐invasive approach adopted.
Caregiving roles of female guardians, older siblings, and time spent on child activities
Authors: Hapunda Given
Published: August 2022

Objective

This pilot study investigated the different roles Zambian guardians and older siblings play in stimulating children and how time spent engaging in child stimulating activities was associated with child stimulation. In this study, guardians were women who are primary caregivers of the children.

Background

A lot of research has been done on child stimulation but little is known of different roles caregivers, especially older siblings, play in child stimulation.

Method

Questionnaires were administered to caregivers (both older siblings and guardians) of children between 3 and 5 years of age and their older siblings above 7 years old.

Results

Results showed that despite the female guardians spending more time taking care of their children, older siblings were significantly more involved in child stimulating activities than the female guardians. Further data showed that guardians with more education were associated with increased child stimulation. However, socioeconomic status, age of guardians, and family size were not associated with child stimulation.

Conclusion

In poor communities, older siblings engage more in child stimulating activities than their guardians. Child stimulation interventions have often focused on parents (guardians) leaving out older siblings who may play a more critical role, especially in circumstance were parental care and availability are absent. Therefore, for child cognitive and socioemotional stimulation interventions to be more effective in poor communities, they should include siblings. More research is needed to understand the role of male guardians and the degree to which sibling stimulation predicts cognitive and socioemotional development.
The corona blues according to daily life changes by COVID‐19: A partial least squares regression model
Authors: Gim Tae‐Hyoung Tommy
Published: August 2022

This study identifies determinants of the variation in depression resulting from COVID‐19, specifies in detail the changes to daily life, and then compares the determinants' magnitude. The determinants were combined into three groups: first, the unpredictability of the disease and side effects by its response measures (specifically, restrictions on the freedom of movement and strain on social relationships); second, (mis)information through social media, public authorities, and mass media; and third, income reductions and other sociodemographic factors. Daily life changes were divided into four categories: travel/mobility, time at home (alone and with family), domestic activities (remote work, online shopping, food deliveries, reading, and online networking), and conflicts (with family and neighbors). We measured the total 29 predictors using data from the 2020 Seoul Survey, which is based on face‐to‐face interviews with a probability sample of adult residents. We made our estimations using partial least squares regression, which can analyze all original variables regardless of collinearity. The regression model found that major stressors include declines in out‐of‐home offline networking and the rise of domestic activities—and subsequent conflicts with family—restrictions on mobility (specifically, those of leisure travel), and income reductions. In contrast, changes to working and shopping (to remote work and online shopping) rather than leisure increased uses of private transportation modes. Moreover, we found influences of all forms of communications and media to be insignificant. We shall also provide a discussion on policy and academic implications of the findings.
Hierarchical microstructure growth in a precursor‐derived SiOC thin film prepared on silicon substrate
Authors: Ricohermoso Emmanuel III , Heripre Eva , Solano‐Arana Susana , Riedel Ralf , Ionescu Emanuel
Published: August 2022

Silicon oxycarbide film deposited on a silicon substrate has shown superior electrical conductivity relative to its monolithic counterpart. In this work, the evolution of different microstructures detected on the SiOC film reveals its hierarchical microstructure. The existence of sp2‐hybridized carbon domains has been unambiguously confirmed by means of Raman spectroscopy and transmission electron microscopy corroborated with electron energy loss spectroscopy. The diffusion coefficient of carbon in silica and its dependence on temperature were studied by assessing energy‐dispersive X‐ray spectroscopy profiles taken from the cross‐sections of samples annealed at temperatures in the range from 1100°C to 1400°C. The activation energy for diffusion of carbon in silica was determined to be approximately 3.05 eV, which is significantly lower than the values related to the self‐diffusion of silicon and oxygen. The microstructural evolution of precursor to SiCnO4‐n and SiC serves as migration path of sp2‐hybridized carbon to the SiOx layer. With increasing temperature, the formation of microscale carbon‐rich segregation is promoted while the SiOC film becomes thinner.
Effect of a YIG nanoparticle additive on the magnetic properties of MnZn ferrites for MHz frequency applications
Authors: Ying Yao , Feng Jiawei , Li Zhaocheng , Zheng Jingwu , Yu Jing , Li Wangchang , Qiao Liang , Cai Wei , Li Juan , Huang Hui , Zhao Tiejun , Che Shenglei
Published: August 2022

In this study, MnZn ferrites with added YIG nanoparticles were developed for MHz frequency applications. The effect of the magnetic YIG additive on the power loss, initial permeability, and cutoff frequency of MnZn ferrites was investigated. A small quantity of added YIG effectively reduces the power loss and concurrently increases the initial permeability. Compared to the results for the MnZn ferrite with no added YIG, the optimal MnZn ferrite with 600 ppm added YIG exhibits a reduction in the power loss at 25°C of 56.4% and 36.6% at 1 MHz/50 mT and 3 MHz/10 mT, respectively, and a 13.9% increase in the initial permeability. This sample also exhibits a good stability of the power loss against temperature. The power loss remains below 205 kW/m3 over temperatures ranging from 25 to 140°C. The effect mechanism of YIG addition on the magnetic properties of MnZn ferrites was studied. An analysis based on the equivalent circuit model showed that the reduction in the eddy current loss and power loss mainly results from the increase in the grain boundary resistance caused by the addition of highly resistive YIG.