bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigenetic anti-cancer treatment with a stabilized carbocyclic Decitabine analogue
Authors: Traube Franziska R. , Brás Natércia F. , Roos Wynand P. , Sommermann Corinna C. , Diehl Tamara , Mayer Robert J. , Ofial Armin R. , Müller Markus , Zipse Hendrik , Carell Thomas
Published: January 2022

5-Aza-2’-deoxycytidine (Decitabine, AzadC) is a nucleoside analogue, which is in clinical use to treat patients with myelodysplastic syndrome or acute myeloid leukemia. Its mode of action is unusual because the compound is one of the few drugs that act at the epigenetic level of the genetic code. AzadC is incorporated as an antimetabolite into the genome and creates covalent, inhibitory links to DNA methyltransferases (DNMTs) that methylate 2’-deoxycytidine (dC) to 5-methyl-dC (mdC). Consequently, AzadC treatment leads to a global loss of mdC, which presumably results in a reactivation of silenced genes, among them tumor suppressor and DNA damage response genes. Because AzadC suffers from severe instability, which limits its use in the clinic, a more sophisticated AzadC derivative would be highly valuable. Here, we report that a recently developed carbocyclic AzadC analogue (cAzadC) blocks DNMT1 in the AML cell line MOLM-13 as efficient as AzadC. Moreover, cAzadC has a surprisingly strong anti-proliferative effect and leads to a significantly higher number of double strand breaks compared to AzadC, while showing less off-target toxicity. These results show that cAzadC triggers more deleterious repair and apoptotic pathways in cancer cells than AzadC, which makes cAzadC a promising next generation epigenetic drug.
Mosquito odorant receptor sensitive to natural spatial repellents and inhibitory compounds
Authors: Xu Pingxi , Choo Young-Moo , An Sunny , Leal Gabriel M. , Leal Walter S.
Published: January 2022

Previously, we have identified an odorant receptor (OR) from the southern house mosquito Culex quinquefasciatus, CquiOR32, which responded to both odorants (agonists) and inhibitory compounds (antagonists). CquiOR32/CquiOrco-expressing oocytes responded to methyl salicylate and other odorants with inward (regular) currents but gave currents in the reverse direction when challenged with eucalyptol and other inhibitors. To determine whether hitherto unknown ORs show this intrareceptor inhibition, we have now examined two other receptors in the same cluster, CquiOR27 and CquiOR28. We cloned and tested four variants of CquiOR28, but none of the 250 compounds in our panel of odorants, including an Orco ligand candidate (OCL12), elicited inward or outward currents. By contrast, CquiOR27/CquiOrco-expressing oocytes gave robust, dose-dependent inward currents when challenged with γ-octalactone and other odorants. On the other hand, octylamine and other phenolic compounds elicited dose-dependent currents in the reverse direction. When stimulatory and inhibitory compounds were presented in binary mixtures, γ-octalactone-elicited inward currents were attenuated in a dose-dependent manner according to the concentration of octylamine. As part of our chemical ecology approach, we tested the repellency activity of the best ligands in the surface landing and feeding assay and a newly reported hand-in cage assay. Protection elicited by γ-octalactone did not differ significantly from that of DEET at the same dose. In the hand-in cage assay, a cream formulation of γ-octalactone showed 97.0 ± 1.3% protection, with 47.6 ± 8.3% and 1.4 ± 0.7% landings per trial in the hands covered with a control and γ-octalactone cream, respectively (N=8, p=0.0078, Wilcoxon matched-pairs signed-rank test).
Meta-analysis of Microbiome Association Networks Reveal Patterns of Dysbiosis in Diseased Microbiomes
Authors: Lam Tony J. , Ye Yuzhen
Published: January 2022

The human gut microbiome is composed of a diverse and dynamic population of microbial species which play key roles in modulating host health and physiology. While individual microbial species have been found to be associated with certain disease states, increasing evidence suggests that higher-order microbial interactions may have an equal or greater contribution to host fitness. To better understand microbial community dynamics, we utilize complex networks to study interactions through a meta-analysis of microbial association networks between healthy and disease gut microbiomes. Taking advantage of the large number of metagenomes derived from healthy individuals and patients with various diseases, together with recent advances in network inference that can deal with sparse compositional data, we inferred microbial association networks based on co-occurrence of gut microbial species and made the networks publicly available as a resource (github repository named GutNet). Through our meta-analysis of inferred networks, we were able to identify network-associated features that help stratify between healthy and disease states such as the differentiation of various bacterial phyla and enrichment of Proteobacteria interactions in diseased networks. Additionally, our findings show that the contributions of taxa in microbial associations are disproportionate to their abundances and that rarer taxa of microbial species play an integral part in shaping dynamics of microbial community interactions. Overall, this meta-analysis revealed valuable insights into microbial community dynamics between healthy and disease phenotypes.
Longitudinal Morphological and Functional Characterization of Human Heart Organoids Using Optical Coherence Tomography
Authors: Ming Yixuan , Hao Senyue , Xu Zhiyao , Goestenkors Anna , Lewis-Israeli Yonatan R. , Volmert Brett D. , Aguirre Aitor , Zhou Chao
Published: January 2022

Organoids play an increasingly important role asin vitromodels for studying organ development, disease mechanisms, and drug discovery. Organoids are self-organizing, organ-like three-dimensional (3D) cell cultures developing organ-specific cell types and functions. Recently, three groups independently developed self-assembling human heart organoids (hHOs) from human pluripotent stem cells (hPSCs). In this study, we utilized a customized spectral-domain optical coherence tomography (SD-OCT) system to characterize the growth of hHOs. Development of chamber structures and beating patterns of the hHOs were observed via OCT and calcium imaging. We demonstrated the capability of OCT to produce 3D images in a fast, label-free, and non-destructive manner. The hHOs formed cavities of various sizes, and complex interconnections were observed as early as on day 4 of differentiation. The hHOs models and the OCT imaging system showed promising insights as anin vitroplatform for investigating heart development and disease mechanisms.
ATLIGATOR: Editing protein interactions with an atlas-based approach
Authors: Kynast Josef Paul , Schwägerl Felix , Höcker Birte
Published: January 2022

Motivation

Recognition of specific molecules by proteins is a fundamental cellular mechanism and relevant for many applications. Being able to modify binding is a key interest and can be achieved by repurposing established interaction motifs. We were specifically interested in a methodology for the design of peptide binding modules. By leveraging interaction data from known protein structures, we plan to accelerate the design of novel protein or peptide binders.

Results

We developed ATLIGATOR – a computational method to support the analysis and design of a protein’s interaction with a single side chain. Our program enables the building of interaction atlases based on structures from the PDB. From these atlases pocket definitions are extracted that can be searched for frequent interactions. These searches can reveal similarities in unrelated proteins as we show here for one example. Such frequent interactions can then be grafted onto a new protein scaffold as a starting point of the design process. The ATLIGATOR tool is made accessible through a python API as well as a CLI with python scripts.

Availability and Implementation

Source code can be downloaded at github (https://www.github.com/Hoecker-Lab/atligator), installed from PyPI (“atligator”) and is implemented in Python 3.
A natural fungal gene drive enacts killing through targeting DNA
Authors: Urquhart Andrew S. , Gardiner Donald M.
Published: January 2022

Fungal spore-killers are a class of selfish genetic elements that positively bias their own inheritance by killing non-inheriting gametes following meiosis. As killing takes place specifically within the developing fungal ascus, a tissue which is experimentally difficult to isolate, our understanding of the mechanisms underlying spore killers are limited. In particular, how these loci kill other spores within the fungal ascus is largely unknown. Here we overcome these experimental barriers by developing model systems in two evolutionary distant organisms, Escherichia coli (bacterium) and Saccharomyces cerevisiae (yeast). Using these systems, we show that the Podospora anserina spore killer protein Spok1 enacts killing through targeting DNA.

Significance Statement

Natural gene drives have shaped the genomes of many eukaryotes and recently have been considered for applications to control undesirable species. In fungi these loci are called spore-killers. Despite their importance in evolutionary processes and possible applications our understanding of how they enact killing is limited. We show that the spore killer protein Spok1, which has homologues throughout the fungal tree of life, acts via DNA disruption. Spok1 is only the second spore killer locus in which the cellular target of killing has been identified and is the first known to target DNA. We also show that the DNA disrupting activity of Spok1 is functional in both bacteria and yeast suggesting a highly conserved mode of action.
Human Parainfluenza 2 & 4: clinical and genetic epidemiology in the UK, 2013-2017, reveals distinct disease features and co-circulating genomic subtypes
Authors: Chellapuri Akhil , Smitheman Matthew , Chappell Joseph G. , Clark Gemma , Howson-Wells Hannah C. , Berry Louise , Ball Jonathan K. , Irving William L. , Tarr Alexander W. , McClure C. Patrick
Published: January 2022

Human Parainfluenza viruses (HPIV) are constituted by four members of the genetically distinct genera of Respirovirus (type 1 and 3) and Orthorubulavirus (type 2 and 4), causing significant upper and lower respiratory tract infections in both children and adults worldwide. However, despite frequent molecular diagnosis, they are frequently considered collectively or with HPIV4 overlooked entirely. We therefore investigated clinical and viral epidemiological distinctions of the relatively less prevalent Orthorubulaviruses HPIV2 & 4 at a regional UK hospital across four winter epidemic seasons. HPIV2 & 4 infection was observed across all age groups, but predominantly in children under 9 and adults over 40, with almost twice as many HPIV4 as HPIV2 cases. Fever, abnormal haematology, elevated C-reactive protein and hospital admission were more frequently seen in HPIV2 than HPIV4 infection. Each of the four seasonal peaks of either HPIV2, HPIV4 or both, closely matched that of RSV, occurring in November and December and preceding that of Influenza A. A subset of viruses were partially sequenced, indicating co-circulation of multiple subtypes of both HPIV2 & 4, but with little variation between each epidemic season or from limited global reference sequences.
Analysis of clinical trial registry entry histories using the novel R package cthist
Authors: Carlisle Benjamin Gregory
Published: January 2022

Historical clinical trial registry data can only be retrieved by manually accessing individual clinical trials through registry websites. This limits the feasibility, accuracy and reproducibility of certain kinds of research on clinical trial activity and presents challenges to the transparency of the enterprise of human research. This paper presentscthist, a novel, free and open sourceRpackage that enables mass downloading of clinical trial registry entry histories and returns structured data for analysis.

Documentation of the implementation of the packagecthistis provided, as well as 3 brief case studies with example code.
Hypnosis and music interventions for pain, anxiety, sleep, and well-being in palliative care: a systematic review and meta-analysis
Authors: Bissonnette Josiane , Dumont Emilie , Pinard Anne-Marie , Landry Mathieu , Rainville Pierre , Ogez David
Published: January 2022

Abstract
Background
Maintaining quality of life is a primary goal of palliative care (PC). Complementary interventions can help meet the needs of patients at the end of life.
Objectives
This meta-analysis aims to 1) evaluate the feasibility, acceptability, and fidelity of music and hypnosis interventions designed for patients in PC; 2) evaluate the impact of these interventions on pain, anxiety, sleep, and well-being.
Methods
Relevant studies were sourced from major databases. We selected both randomised controlled trials (RCT) and studies relying on pre-post design with details of the intervention(s).
Results
Four RCT and seven non-randomised pre-post studies met the inclusion criteria. Overall, the feasibility and acceptability of the interventions reached an adequate level of satisfaction. However, only three studies reported using a written protocol. The meta-analysis of RCT indicated a significant decrease in pain with an effect size of -0.42, p = .003. The small number of RCT studies did not allow us to quantify the effects for other variables. Analyses of data from pre-post designs indicated a favourable outcome for pain, anxiety, sleep, and well-being.
Conclusion
Despite the limited number of studies included in our meta-analysis, hypnosis and music intervention in the context of PC shows promising results in terms of feasibility and acceptability, as well as improvements on pain, anxiety, sleep and well-being. The available studies are insufficient to compare the efficacy across interventions and assess the potential benefits of their combinations. These results underscore the importance of further research on well-described complementary interventions relying on hypnosis and music.
Immunogenicity of a third dose of BNT162b2 to ancestral SARS-CoV-2 & Omicron variant in adults who received two doses of inactivated vaccine
Authors: Leung Nancy H. L. , Cheng Samuel M. S. , Martín-Sánchez Mario , Au Niki Y. M. , Ng Yvonne Y. , Luk Leo L. H. , Chan Karl C. K. , Li John K. C. , Leung Yonna W. Y. , Tsang Leo C. H. , Chaothai Sara , Kwan Kelvin K. H. , Ip Dennis K. M. , Poon Leo L. M. , Leung Gabriel M. , Malik Peiris J. S. , Cowling Benjamin J.
Published: January 2022

Background

Limited data exist on antibody responses to mixed vaccination strategies involving inactivated COVID-19 vaccines, particularly in the context of emerging variants.

Methods

We conducted an open label trial of a third vaccine dose of an mRNA vaccine (BNT162b2, Fosun Pharma/BioNTech) in adults aged ≥30 years who had previously received two doses of inactivated COVID-19 vaccine. We collected blood samples before administering the third dose and 28 days later, and tested for antibodies to the ancestral virus using a binding assay (ELISA), a surrogate virus neutralization test (sVNT) and a live virus plaque reduction neutralization test (PRNT). We also tested for antibodies against the Omicron variant using live-virus PRNT.

Results

In 315 participants, a third dose of BNT162b2 substantially increased antibody titers on each assay. Mean ELISA levels increased from an optical density (OD) of 0.3 to 2.2 (p<0. 001), and mean sVNT levels increased from an inhibition of 17% to 96% (p<0.001). In a random subset of 20 participants, the geometric mean PRNT50 titers rose very substantially by at least 24 fold from Day 0 to Day 28 against the ancestral virus (p<0.001) and rose by at least 11 fold against the Omicron variant (p<0.001). In daily monitoring, post-vaccination reactions subsided within 7 days for over 99% of participants.

Conclusions

A third dose of COVID-19 vaccination with an mRNA vaccine substantially improved antibody levels against the ancestral virus and the Omicron variant with well-tolerated safety profile, in adults who had received two doses of inactivated vaccine 6 months earlier.

In this open label trial of Chinese adults aged ≥30 years who received two doses of inactivated COVID-19 vaccine 6 months earlier, third-dose mRNA vaccine substantially improved antibody levels against the ancestral virus and Omicron variant with well-tolerated safety profile.
Tonic GluD1 channel current is independent of G protein activity in the dorsal raphe nucleus
Authors: Copeland Daniel S. , Gantz Stephanie C.
Published: January 2022

Abstract

Previously, using electrophysiological recordings from adult male and female mouse brain slices containing the dorsal raphe nucleus, we showed that GluD1R channels carry ionic current and are modulated via activation of Gαq-coupled α1-adrenergic receptors (α1-AR) in a GTP-dependent manner (Gantz et al., 2020). GluD1R channels also carry a tonic cation current, generally ~−20 pA at subthreshold membrane potentials (Gantz et al., 2020). The origin of tonic GluD1R channel current is unknown. Here, using the same preparation, we show there is no role of on-going G protein-coupled receptor activity in generating or sustaining tonic GluD1R channel current. Neither augmentation nor disruption of G protein activity had an effect on tonic GluD1R current. These results reveal that tonic GluD1R current arises from a mechanism separate from on-going activity of G protein-coupled receptors. Under current clamp, block of GluD1R channels hyperpolarized the membrane by ~10 mV at subthreshold potentials leading to reduced excitability. Thus, GluD1R channels carry a G protein-independent tonic current that contributes to subthreshold drive of action potential firing in the dorsal raphe nucleus.
Insights into the Human Gut Virome by Sampling a Population from the Indian Subcontinent
Authors: Bhardwaj Kanchan , Garg Anjali , Pandey Abhay Deep , Sharma Himani , Kumar Manish , Vrati Sudhanshu
Published: January 2022

Gut virome plays an important role in human physiology but remains poorly understood. This study reports an investigation of the human gut DNA-virome of a previously unexplored ethnic population through metagenomics of faecal samples collected from individuals residing in Northern India. Analysis shows that, similar to the populations investigated earlier, majority of the identified virome belongs to bacteriophages and a smaller fraction (< 20%) consists of viruses that infect animals, archaea, protists, multiple domains or plants. However, crAss-like phages, in this population, are dominated by the genera VII, VIII and VI. Interestingly, it also reveals the presence of a virus family, Sphaerolipoviridae, which has not been detected in the human gut earlier. Viral families, Siphoviridae, Myoviridae, Podoviridae, Microviridae, Herelleviridae and Phycodnaviridae are detected in all of the analyzed individuals, which supports the existence of a core virome. Lysogeny-associated genes were found in less than 10% of the assembled genomes and a negative correlation was observed in the richness of bacterial and free-viral species, suggesting that the dominant lifestyle of gut phage is not lysogenic. This is in contrast to some of the earlier studies. Further, several hundred high-quality viral genomes were recovered. Detailed characterization of these genomes would be useful for understanding the biology of these viruses and their significance in human physiology.

Importance

Viruses are important constituents of the human gut microbiome but it remains poorly understood. The Indian subcontinent is a unique biogeographic region and the Indian population is known to harbour a distinct bacterial microbiome. However, the gut virome in this population has not been investigated earlier. Therefore, in this study, we investigated fecal samples of 12 healthy individuals to analyze their gut virome, through metagenomics.
Improving the Identification Coverage of Protein Interactome by Enhancing the Click Chemistry-based Cross-linking Enrichment Efficiency
Authors: Zhao Lili , Zhao Qun , An Yuxin , Gao Hang , Zhang Xiaodan , Liang Zhen , Zhang Lihua , Zhang Yukui
Published: January 2022

Chemical cross-linking coupled with mass spectrometry has emerged as a powerful strategy which enables global profiling of protein interactome with direct interaction interfaces in complex biological systems. The alkyne-tagged enrichable cross-linkers are preferred to improve the coverage of low-abundance cross-linked peptides, combined with click chemistry for biotin conjugation to allow the cross-linked peptides enrichment. However, a systematic evaluation on the efficiency of click approaches (protein-based or peptide-based) and diverse cleavable click chemistry ligands (acid, reduction, photo) for cross-linked peptides enrichment and release is lacking. Herein, together with in vivo chemical cross-linking by alkyne-tagged cross-linker, we explored the click chemistry-based enrichment approaches on protein and peptide level with three cleavable click chemistry ligands, respectively. By comparison, the approach of protein-based click chemistry conjugation with acid-cleavable tag was demonstrated to permit the most cross-linked peptides identification. The advancement of this strategy enhanced the proteome-wide cross-linking analysis, permitting a detection of 5,017 protein-protein interactions among 1,909 proteins across all subcellular compartments with wide abundance distribution in cell. Therefore, all these results demonstrated a guideline value of our work for efficient cross-linked peptides enrichment, thus facilitated the in-depth profiling of protein interactome for functional analysis.

GRAPHICAL ABSTRACT
Global analysis of biosynthetic gene clusters reveals conserved and unique natural products in entomopathogenic nematode-symbiotic bacteria
Authors: Shi Yi-Ming , Hirschmann Merle , Shi Yan-Ni , Ahmed Shabbir , Abebew Desalegne , Tobias Nicholas J. , Grün Peter , Crames Jan J. , Pöschel Laura , Kuttenlochner Wolfgang , Richter Christian , Herrmann Jennifer , Müller Rolf , Thanwisai Aunchalee , Pidot Sacha J. , Stinear Timothy P. , Groll Michael , Kim Yonggyun , Bode Helge B.
Published: January 2022

Microorganisms contribute to the biology and physiology of eukaryotic hosts and affect other organisms through natural products. Xenorhabdus and Photorhabdus (XP) living in mutualistic symbiosis with entomopathogenic nematodes produce a myriad of natural products to mediate bacteria–nematode–insect interactions. However, a lack of systematic analysis of the biosynthetic gene clusters (BGCs) has limited the understanding of how natural products justify the bacterial niche specificity. Here we combine pangenome and sequence similarity networks to analyze BGCs from 45 XP species. The identified 1,000 BGCs belong to 176 families, over half of which are unknown. Eleven BGCs represent the most conserved families. We then homologously express the ubiquitous and unique BGCs and identify compounds featuring unusual architectures. The bioactivity evaluation demonstrates that the prevalent compounds are eukaryotic proteasome inhibitors, insect virulence factors, or insect immune suppressors. These findings account for the functional basis of bacterial natural products in this tripartite relationship.
Promoting Fc-Fc interactions between anti-capsular antibodies provides strong immune protection against Streptococcus pneumoniae
Authors: Aguinagalde Leire , den Boer Maurits A. , Castenmiller Suzanne M. , Zwarthoff Seline A. , Gosselaar-de Haas Carla J.C , Aerts Piet C. , Beurskens Frank J. , Schuurman Janine , Heck Albert J.R. , van Kessel Kok P.M. , Rooijakkers Suzan H.M.
Published: January 2022

Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and an important cause of childhood mortality. Despite the introduction of successful vaccines, the global spread of both non-vaccine serotypes and antibiotic-resistant strains reinforce the development of alternative therapies against this pathogen. One possible route is the development of monoclonal antibodies (mAbs) that induce killing of bacteria via the immune system. Here we investigate whether mAbs can be used to induce killing of pneumococcal serotypes for which the current vaccines show unsuccessful protection. Our study demonstrates that when human mAbs against pneumococcal capsule polysaccharides (CPS) have a poor capacity to induce complement activation, a critical process for immune protection against pneumococci, their activity can be strongly improved by hexamerization-enhancing mutations. Our data indicate that anti-capsular antibodies may have a low capacity to form higher-order oligomers (IgG hexamers) that are needed to recruit complement component C1. Indeed, specific point mutations in the IgG-Fc domain that strengthen hexamerization strongly enhance C1 recruitment and downstream complement activation on encapsulated pneumococci. Specifically, hexamerization-enhancing mutations E430G or E345K in CPS6-IgG strongly potentiate complement activation on S. pneumoniae strains that express capsular serotype 6 (CPS6), and the highly invasive serotype 19A strain. Furthermore, these mutations improve complement activation via mAbs recognizing CPS3 and CPS8 strains. Importantly, hexamer-enhancing mutations enable mAbs to induce strong phagocytosis and intracellular killing by human neutrophils. Finally, passive immunization with CPS6-IgG1-E345K protected mice from developing severe pneumonia. Altogether, this work provides an important proof-of-concept for future optimization of antibody therapies against encapsulated bacteria.
Anin vitroneurogenetics platform for precision disease modeling in the mouse
Authors: Cortes Daniel E. , Escudero Mélanie , Korgan Austin C. , Edwards Alyssa , Aydin Selcan C. , Munger Steven C. , Charland Kevin , Zhang Zhong-Wei , O’Connell Kristen M.S. , Reinholdt Laura G. , Pera Martin F.
Published: January 2022

The power and scope of disease modeling can be markedly enhanced through the incorporation of broad genetic diversity. In the the mouse, the introduction of pathogenic mutations into a single inbred strain sometimes fails to mimic human disease. We describe a cross-species precision disease modeling platform that exploits mouse genetic diversity to bridge cell-based modeling with whole organism analysis. We developed a universal protocol that permitted robust and reproducible neural differentiation of genetically diverse human and mouse pluripotent stem cell lines, then carried out a proof of concept study of the neurodevelopmental geneDYRK1A. The resultsin vitroreliably predicted the effects of genetic background onDYRK1Aloss of function phenotypes and identified optimal mouse strains forin vivodisease modeling. Transcriptomic comparison of responsive and unresponsive strains identified novel molecular pathways conferring sensitivity or resilience toDYRK1Aloss, and highlighted differential mRNA isoform usage as an important genetic determinant of response This cross-species strategy will be an powerful tool in the functional analysis of candidate disease variants identified through human genetic studies.

Teaser: Genetically diverse mouse embryonic stem cells provide a rapid approach to precision modeling of human disease.
Immune response to COVID‐19 vaccination is attenuated by poor disease control and antimyeloma therapy with vaccine driven divergent T‐cell response
Authors: Ramasamy Karthik , Sadler Ross , Jeans Sally , Weeden Paul , Varghese Sherin , Turner Alison , Larham Jemma , Gray Nathanael , Carty Oluremi , Barrett Joe , Bowcock Stella , Oppermann Udo , Cook Gordon , Kyriakou Chara , Drayson Mark , Basu Supratik , Moore Sally , McDonald Sarah , Gooding Sarah , Javaid Muhammad K.
Published: January 2022

Myeloma patients frequently respond poorly to bacterial and viral vaccination. A few studies have reported poor humoral immune responses in myeloma patients to COVID‐19 vaccination. Using a prospective study of myeloma patients in the UK Rudy study cohort, we assessed humoral and interferon gamma release assay (IGRA) cellular immune responses to COVID‐19 vaccination post second COVID‐19 vaccine administration. We report data from 214 adults with myeloma (n = 204) or smouldering myeloma (n = 10) who provided blood samples at least three weeks after second vaccine dose. Positive Anti‐spike antibody levels (> 50 iu/ml) were detected in 189/203 (92.7%), positive IGRA responses were seen in 97/158 (61.4%) myeloma patients. Only 10/158 (6.3%) patients were identified to have both a negative IGRA and negative anti‐spike protein antibody response. In all, 95/158 (60.1%) patients produced positive results for both anti‐spike protein serology and IGRA. After adjusting for disease severity and myeloma therapy, poor humoral immune response was predicted by male gender. Predictors of poor IGRA included anti‐CD38/anti‐BCMA (B‐cell maturation antigen) therapy and Pfizer‐BioNTech vaccination. Further work is required to understand the clinical significance of divergent cellular response to vaccination.
The dominant p.Thr274Pro mutation in the von Willebrand factor propeptide causes the von Willebrand disease type 1 phenotype in two unrelated patients
Authors: Pagliari Maria Teresa , Baronciani Luciano , Cordiglieri Chiara , Colpani Paola , Cozzi Giovanna , Siboni Simona M. , Peyvandi Flora
Published: January 2022

Background

von Willebrand factor propeptide (VWFpp) plays an important role in VWF multimerization and storage. VWFpp mutations have been previously associated with types 1, 3 and 2A/IIC von Willebrand disease (VWD).

Aims

To characterize the novel p.Thr274Pro variant identified in two unrelated type 1 VWD patients.

Methods

Phenotype tests were performed to evaluate patients’ plasma and platelets following the current ISTH‐SSC guidelines. Molecular analysis was performed using next‐generation sequencing. The pcDNA3.1‐VWF‐WT and mutant pcDNA3.1‐VWF‐Thr274Pro expression vectors were transiently transfected into HEK293 cells to evaluate recombinant (r)VWF constitutive and regulated secretion. For the latter, the transfected cells were stimulated with phorbol‐12‐myristate‐13‐acetate. Immunofluorescence staining was performed to assess the localization of WT‐rVWF and Thr274Pro‐rVWF in endoplasmic reticulum, lysosomes, cis‐/trans‐Golgi and pseudo‐Weibel Palade bodies.

Results

Biochemical characterization of patients’ plasma samples indicated a type 1 VWD diagnosis. Both patients were heterozygous for the p.Thr274Pro variant. Hybrid Thr274Pro/WT‐rVWF showed a secretion reduction of 36±4% according to patients’ plasma VWF:Ag levels, whereas Thr274Pro‐rVWF secretion was strongly impaired (21±2%). The amount of rVWF in cell lysates was nearly normal for both Thr274P (62±17%) and Thr274Pro/WT‐rVWF (72±23%). The regulated secretion was impaired for Thr274Pro/WT‐rVWF, whereas Thr274Pro‐rVWF was not released at all. Immunofluorescence staining revealed no particular differences between WT and Thr274Pro‐rVWF, although Thr274Pro‐rVWF showed less pseudo‐Weibel Palade bodies with a rounder shape than WT‐rVWF.

Conclusions

The novel p.Thr274Pro mutation has a dominant effect and it is responsible of patients’ type 1 VWD phenotype through a combined mechanism of reduced synthesis, impaired secretion and multimerization.
Role of speaker gender in toddler lexical processing
Authors: Bacon Desia , Saffran Jenny
Published: January 2022

Adults and children utilize social category information during incremental language processing. Gender is a particularly salient social category that is often marked both in speakers' voices and the visual world. However, it is unknown whether toddlers exploit gender cues to draw connections between language and other aspects of their environment. The current study investigates whether toddlers use gender cues available in voices and objects during real‐time language processing. 22‐ to 24‐month‐old toddlers (N = 38) were tested in a looking‐while‐listening paradigm. On each trial, toddlers viewed two highly familiar objects designed to be prototypically masculine and feminine (via color and patterns) and heard either a male or female speaker label the target object. Lexical processing was facilitated when the vocal gender matched the gender of the target object. This work demonstrates that toddlers consider both object‐feature information and inferred speaker gender (based on speaker' voice) during online language processing.
The structure of tropical bat–plant interaction networks during an extreme El Niño‐Southern Oscillation event
Authors: Oliveira Hernani F. M. , Pinheiro Rafael Barros Pereira , Varassin Isabela Galarda , Rodríguez‐Herrera Bernal , Kuzmina Maria , Rossiter Stephen J. , Clare Elizabeth L.
Published: January 2022

Interaction network structure reflects the ecological mechanisms acting within biological communities, which are affected by environmental conditions. In tropical forests, higher precipitation usually increases fruit production, which may lead frugivores to increase specialization, resulting in more modular and less nested animal–plant networks. In these ecosystems, El Niño is a major driver of precipitation, but we still lack knowledge of how species interactions change under this influence. To understand bat–plant network structure during an extreme El Niño‐Southern Oscillation event, we determined the links between plantivorous bat species and the plants they consume by DNA barcoding seeds and pulp in bat faeces. These interactions were recorded in the dry forest and rainforest of Costa Rica, during the dry and the wet seasons of an extreme El Niño year. From these we constructed seasonal and whole‐year bat–plant networks and analysed their structures and dissimilarities. In general, networks had low nestedness, had high modularity, and were dominated by one large compartment which included most species and interactions. Contrary to our expectations, networks were less nested and more modular in drier conditions, both in the comparison between forest types and between seasons. We suggest that increased competition, when resources are scarce during drier seasons and habitats, lead to higher resource partitioning among bats and thus higher modularity. Moreover, we have found similar network structures between dry and rainforests during El Niño and non‐El Niño years. Finally, most interaction dissimilarity among networks occurred due to interaction rewiring among species, potentially driven by seasonal changes in resource availability.
Brexit and multilingualism in the European Union
Authors: Ginsburgh Victor , Moreno‐Ternero Juan D.
Published: January 2022

The European Union (EU) spends more than one billion euros per year ensuring translation and interpretation of 24 languages to preserve multilingualism. We examine how this budget should be fairly allocated, taking into account linguistic and economic realities of each member country. Our analysis tries to estimate the value of keeping English as a procedural language (in fact, almost a lingua franca) in the post‐Brexit EU, where, today, just about one percent of the population speaks it as native language.
Philosophy in relation to other disciplines exploring human nature
Authors: Haldane John
Published: January 2022

This paper explores philosophy in its relation to other disciplines and practices that also seek to understand the distinctive nature of human persons. It begins with a consideration of the nature of philosophy, arguing for a pluralistic conception reflecting different ends, and relating these to art, politics, religion, and science. It illustrates this via connections between the thought and work of Andy Warhol and Arthur Danto, Wagner and Nietzsche, and Roger Scruton and James MacMillan. It then shifts to a fifth methodological conception of philosophy as the discipline of disciplines, specifically in clarifying concepts and presuppositions, and relates this to marking the boundaries of personhood. Finally, it explores a particular example of philosophy in relation to another practice, art, this time giving priority to art itself.
HnRNP K mislocalisation in neurons of the dentate nucleus is a novel neuropathological feature of neurodegenerative disease and ageing
Authors: Sidhu Rahul , Gatt Ariana , Fratta Pietro , Lashley Tammaryn , Bampton Alexander
Published: January 2022

Nuclear depletion and cytoplasmic mislocalisation of the RNA‐binding protein heterogeneous ribonucleoprotein K (hnRNP K) within pyramidal neurons of the frontal cortex have been shown to be a common neuropathological feature in frontotemporal lobar degeneration (FTLD) and elderly control brain. Here, we describe a second neuronal subtype vulnerable to mislocalisation within the dentate nucleus of the cerebellum. In contrast to neurons within the cerebellar cortex that typically exhibited normal, nuclear staining, many neurons of the dentate nucleus exhibited striking mislocalisation of hnRNP K to the cytoplasm within neurodegenerative disease brain. Mislocalisation frequency in this region was found to be significantly higher in both FTLD‐TDP A and Alzheimer's disease (AD) brain than in age‐matched controls. However, within control (but not disease) subjects, mislocalisation frequency was significantly associated with age‐at‐death with more elderly controls typically exhibiting greater levels of the pathology. This study provides further evidence for hnRNP K mislocalisation being a more anatomically diverse pathology than previously thought and suggests that potential dysfunction of the protein may be more broadly relevant to the fields of neurodegeneration and ageing.
Experimental evidence of quint points and non-quantum chirality in a minimalist autonomous electronic oscillator
Authors: Volos Christos K. , Gallas Jason A. C.
Published: January 2022

Recent intensive simulations have uncovered remarkable phenomena in stability diagrams of classical oscillators, for instance, quint points, parameter rings, and chiral structures of non-quantum origin. So far, their experimental observation has remained elusive. Here, using a simple electronic circuit, we report the experimental detection of five phases of oscillation spread around a quint point, an exceptional point where five oscillatory modes meet. This finding corroborates predictions of non-quantum chirality in the control parameter space of nonlinear oscillators governed by rate equations.
Modeling and analysis of target influence in social networks
Authors: Deng Jinsheng , Li Pei , Qiao Fengcai , Zhao Tao
Published: January 2022

Nowadays, research on social networks has attracted a large amount of attention from both academic and industrial societies. To understand the diffusion process and guide viral marketing, it is of importance to model and then estimate the influence of a seed user on a target user, which is defined as target influence in this paper. In famous diffusion models like independent cascade model and linear threshold model, tremendous computational costs are usually required in estimating influence probability through simulation. In this paper, we adopt duplicate forwarding model, and propose two measurements for the target influence, which can be analyzed theoretically. The former is the average number of duplicates the target user receives, and the latter is the probability of the target user receiving at least one duplicate. We further find the former will approach infinity if the spread intensity exceeds some threshold, but the latter can be adopted without this constraint. We also seek to use the latter to estimate the influence probability in the independent cascade model, and find it achieves much better accuracy than other heuristic metrics. All results are verified through simulations in real-world social networks, and we believe approach proposed here can provide insights to solve the problems like target influence maximization and influence maximization.
Lift Enhancement of Tiltrotor Wing Using a Gurney Flap
Authors: Chen Hao , Chen Bo
Published: January 2022

A numerical investigation was undertaken to explore the lift-enhancing characteristics of the Gurney flap on a tiltrotor wing. The heights of Gurney flaps range from 1 to 4% wing chord lengths. The Navier-Stokes equations with the Spalart-Allmaras turbulence model were solved to simulate the flow structure around the Gurney flap. The computational results show that the presence of the Gurney flap can dramatically improve the tiltrotor wing lift coefficient. Compared with the baseline configuration, the maximum lift coefficient is increased by 10.67, 15.33, and 20.67% for the 1, 2, and 4% height Gurney flaps. On the other hand, the Gurney flap also results in a drag penalty, and the overall effect on the wing lift-to-drag is detrimental. In particular, at an angle of attack of 2°, use of a 4% chord length Gurney flap decreases the lift-to-drag ratio by 31.47%. Further studies demonstrate that the wing lift increments are proportional to the square root of the Gurney flap height.
The Impact of Self-Efficacy and Perceived Value on Customer Engagement under Live Streaming Commerce Environment
Authors: Cao Jihua , Li Jie , Wang Yunfeng , Ai Mengqi
Published: January 2022

Live streaming commerce, which has led to the emergence of new forms of social commerce called live streaming, has already improved the performance of many social commerce streamers. Live streaming commerce is an emerging business model that has blended the functions of e-commerce and live webcasting. The total sales volume will increase when the streamers and the customers communicate in the real-time interaction platform. In live streaming commerce, customer engagement behavior has been beneficial for realizing the value of live streaming commerce, which scholars have studied and valued. However, internal and external factors often affect customer engagement behavior, and most of the existing research focuses on only one aspect. This article will analyze internal and external influencing factors (internal influencing factors are based on self-efficacy theory, and external influencing factors are based on value-based adoption models) and their interactions to get a broad conclusion. To understand customer engagement behavior in the live streaming commerce with comprehensive research, the article constructs a customer engagement model in the live streaming commerce environment and uses structural equations for empirical testing. In applying self-efficacy theory, it is committed to distinguishing the functional logic between general self-efficacy and special self-efficacy and understanding the mechanism of special self-efficacy, namely, the influence mechanism of live streaming self-efficacy on perceived value and customer engagement in specific situations. The research results show that general self-efficacy positively influences perceived usefulness, perceived entertainment, and live streaming commerce self-efficacy, while perceived usefulness, perceived entertainment, and live streaming commerce self-efficacy positively affect perceived value, live streaming commerce self-efficacy, and self-efficacy. Perceived value has a positive and significant impact on customer engagement behavior. This research explains the influencing factors and mechanism of customer engagement in the live streaming commerce environment from the internal and external perspectives, enriches the theoretical research on customer engagement, and provides practical guidance for customer engagement behavior in the live streaming commerce environment.
Three Potential Tumor Markers Promote Metastasis and Recurrence of Colorectal Cancer by Regulating the Inflammatory Response: ADAM8, LYN, and S100A9
Authors: Liu Jiawei , Li Jing , Du Haolin , Xu Liming , Yang Zhenbang , Yuan Mengjiao , Zhang Kaiyue , Li Jialei , Xing Wenjun , Wang Shoujie , Hu Tingting , Wang Jinjin , Wang Jin , Gong Qian
Published: January 2022

Metastasis and recurrence are major causes of colorectal cancer (CRC) death, but their molecular mechanisms are unclear. In this study, genes associated with CRC metastasis and recurrence were identified by weighted gene coexpression network analysis, selecting the top 25% most variant genes in the dataset GSE33113. By average linkage hierarchical clustering, a total of 21 modules were generated. One key module was identified as the most relevant to the prognosis of CRC. Gene Ontology analysis indicated that genes associated with tumor metastasis and recurrence in this module were significantly enriched in inflammatory biological functions. Functional analysis was performed on the key module, and candidate hub genes (ADAM8, LYN, and S100A9) were screened out by expression and survival analysis. In summary, the three core genes identified in this study could greatly improve our understanding of CRC metastasis and recurrence. The results also provide a theoretical basis for the use of three core genes (ADAM8, LYN, and S100A9) as a combined marker for early diagnosis, which could benefit CRC patients.
Investigate the Process Parameter on the Friction Stir Welding of Dissimilar Aluminium Alloys
Authors: Raja R. , Parthiban A. , Nandha Gopan S. , Degefa Derese
Published: January 2022

The welding of different materials with an acceptable quality range is an emerging study area; engineers and scientists worldwide have long been concerned with dissimilar welding materials. This study focuses on determining the friction stir welding of different aluminuim alloys; an experimental investigation was conducted (AA7475-T651 and AA2219-O). It also describes the FSW process parameters and response measurement for defining weld quality and the procedure for measuring them. Taguchi L27, orthogonal array method, is preferred for optimizing FSW parameters such as shoulder diameter, tool rotational speed, and traverse speed. The effect of welding parameters is investigated through the ANOVA table and graphs. The SEM analysis investigates the fracture and micrographic analysis in the heat-affected zone and thermo-mechanically affected zone.
Nursing Progress of Hypertonic Saline Inhalation in the Treatment of Infantile Bronchitis Based on Image Enhancement
Authors: Li Haiyan , Song Yangang , Chen Xue , Sun Hesheng
Published: January 2022

The onset of bronchiolitis is closely related to the anatomical characteristics of the bronchi in children of this age. This kind of injury is caused by epithelial necrosis, nasal mucosa, and mucosal edema caused by narrowing and blockage of the trachea. Children with this serious phenomenon will have respiratory and heart failure, which threatens the life of children to a large extent. In this paper, based on image enhancement technology, hypertonic saline aerosol inhalation treatment of pediatric bronchiolitis nursing care, through related cases, the application of image enhancement technology in hypertonic saline aerosol inhalation therapy and pediatric bronchiolitis is analyzed, and the tone mapping function is used. Tone mapping functions, hereditary arithmetics, and slope regimes for experimental field capture and detection were used for the objective of therapeutic approaches for the treatment of pediatric capillary pneumonia by hypertonic inhalation. Experimental results show that imaging technology hypertonic inhalation can control the main symptoms of bronchiolitis in infants and young children. Inhalation of 3% saline can shorten the course of moderately chronic children to half a year and can reduce the length of hospital stay by a quarter of the original requires hospitalization time, and the cure rate of pediatric bronchiolitis is increased to 93.7%.