bluuebunny/crossref_metadata_2025 huggingface dataset:
DNA Repair Function Scores for 2172 Variants in the BRCA1 Amino-Terminus
Authors: Diabate Mariame , Islam Muhtadi M. , Nagy Gregory , Banerjee Tapahsama , Dhar Shruti , Smith Nahum , Adamovich Aleksandra I. , Starita Lea M. , Parvin Jeffrey D.
Published: April 2023

Single nucleotide variants are the most frequent type of sequence changes detected in the genome and these are frequently variants of uncertain significance (VUS). VUS are changes in DNA for which disease risk association is unknown. Thus, methods that classify the functional impact of a VUS can be used as evidence for variant interpretation. In the case of the breast and ovarian cancer specific tumor suppressor protein, BRCA1, pathogenic missense variants frequently score as loss of function in an assay for homology-directed repair (HDR) of DNA double-strand breaks. We previously published functional results using a multiplexed assay for 1056 amino acid substitutions residues 2-192 in the amino terminus of BRCA1. In this study, we have re-assessed the data from this multiplexed assay using an improved analysis pipeline. These new analysis methods yield functional scores for more variants in the first 192 amino acids of BRCA1, plus we report new results for BRCA1 amino acid residues 193-302. We now present the functional classification of 2172 BRCA1 variants in BRCA1 residues 2-302 using the multiplexed HDR assay. Comparison of the functional determinations of the missense variants with clinically known benign or pathogenic variants indicated 93% sensitivity and 100% specificity for this assay. The results fromBRCA1variants tested in this assay are a resource for clinical geneticists for evidence to evaluate VUS inBRCA1.

AUTHOR SUMMARY

Most missense substitutions inBRCA1are variants of unknown significance (VUS), and individuals with a VUS inBRCA1cannot know from genetic information alone whether this variant predisposes to breast or ovarian cancer. We apply a multiplexed functional assay for homology directed repair of DNA double strand breaks to assess variant impact on this important BRCA1 protein function. We analyzed 2172 variants in the amino-terminus of BRCA1 and demonstrate that variants that are known as pathogenic have a loss of function in the DNA repair assay. Conversely, variants that are known to be benign are functionally normal in the multiplexed assay. We suggest that these functional determinations of BRCA1 variants can be used to augment the information that clinical cancer geneticists provide to patients who have a VUS inBRCA1.
Histone demethylase KDM5 regulates cardiomyocyte maturation by promoting fatty acid oxidation, oxidative phosphorylation, and myofibrillar organization
Authors: Deogharia Manisha , Agrawal Akanksha , Shi Miusi , Jain Abhinav K , McHugh Kevin J. , Altamirano Francisco , Marian A J , Gurha Priyatansh
Published: April 2023

Rationale

Human pluripotent stem cell-derived CMs (iPSC-CMs) are a valuable tool for disease modeling, cell therapy and to reconstruct the CM maturation process and identify, characterize factors that regulate maturation. The transition from immature fetal to adult CM entails coordinated regulation of the mature gene programming, which is characterized by the induction of myofilament and OXPHOS gene expression among others. Recent studies inDrosophila,C. elegans,and C2C12 myoblast cell lines have implicated the histone H3K4me3 demethylase KDM5 and its homologs, as a potential regulator of developmental gene program and mitochondrial function. We speculated that KDM5 may potentiate the maturation of iPSC-CMs by targeting a conserved epigenetic program that encompass mitochondrial OXPHOS and other CM specific maturation genes.

Objectives

The purpose of this study is to determine the role of KDM5 in iPSC-CM maturation.

Methods and Results

Immunoblot analysis revealed that KDM5A, B, and C expression was progressively downregulated in postnatal cardiomyocytes and absent in adult hearts and CMs. Additionally, KDM5 proteins were found to be persistently expressed in iPSC-CMs up to 60 days after the onset of myogenic differentiation, consistent with the immaturity of these cells. Inhibition of KDM5 by KDM5-C70 -a pan-KDM5 inhibitor-resulted in differential regulation of 2,372 genes including upregulation of Fatty acid oxidation (FAO), OXPHOS, and myogenic gene programs in iPSC-CMs. Likewise, genome-wide profiling of H3K4me3 binding sites by the CUT&RUN assay revealed enriched H3K4me3 peaks at the promoter regions of FAO, OXPHOS, and sarcomere genes. Consistent with the chromatin and gene expression data, KDM5 inhibition led to increased expression of multiple sarcomere proteins, enhanced myofibrillar organization and improved calcium handling. Furthermore, inhibition of KDM5 increased H3K4me3 deposits at the promoter region of theESRRAgene, which is known to regulate OXPHOS and cardiomyocyte maturation, and resulted in its increased RNA and protein levels. Finally, KDM5 inhibition increased baseline, peak, and spare oxygen consumption rates in iPSC-CMs.

Conclusions

KDM5 regulates the maturation of iPSC-CMs by epigenetically regulating the expression of ESRRA, OXPHOS, FAO, and sarcomere genes and enhancing myofibril organization and mitochondrial function.
Molecular profiling of high-level athlete skeletal muscle after acute exercise – a systems biology approach
Authors: Reitzner Stefan M , Emanuelsson Eric B , Arif Muhammad , Kaczkowski Bogumil , Kwon Andrew TJ , Mardinoglu Adil , Arner Erik , Chapman Mark A. , Sundberg Carl Johan
Published: April 2023

Life-long high-level exercise training leads to improvements in physical performance and multi-tissue adaptation following changes in molecular pathways. While skeletal muscle baseline differences between exercise-trained and untrained individuals have been previously investigated, it remains unclear how acute exercise multi-omics are influenced by training history. We recruited and extensively characterized 24 individuals categorized as endurance athletes, strength athletes or control subjects. Multi-omics profiling was performed from skeletal muscle before and at three time-points after endurance or resistance exercise sessions. Timeseries multi-omics analysis revealed distinct differences in molecular processes such as fatty- and amino acid metabolism and for transcription factors such as HIF1A and the MYF-family between both exercise history and acute form of exercise. Furthermore, we found a “transcriptional specialization effect” by transcriptional narrowing and intensification. Finally, we performed multi-omics network analysis and clustering, providing a novel resource of skeletal muscle transcriptomic and metabolomic profiling in highly trained and untrained individuals.
Sucrose phosphorylase fromAlteromonas mediterranea: structural insight into the regioselective α-glucosylation of (+)-catechin
Authors: Goux Marine , Demonceaux Marie , Hendrickx Johann , Solleux Claude , Lormeau Emilie , Fredslund Folmer , Tezé David , Offmann Bernard , André-Miral Corinne
Published: April 2023

Sucrose phosphorylases, through transglycosylation reactions, are interesting enzymes that can transfer regioselectively glucose from sucrose, the donor substrate, onto acceptors like flavonoids to form glycoconjugates and hence modulate their solubility and bioactivity. Here, we report for the first time the structure of sucrose phosphorylase from the marine bacteriaAlteromonas mediterranea(AmSP) and its enzymatic properties. Kinetics of sucrose hydrolysis and transglucosylation capacities on (+)-catechin were investigated. Wild-type enzyme (AmSP-WT) displayed high hydrolytic activity on sucrose and was devoid of transglucosylation activity on (+)-catechin. Two variants,AmSP-Q353F andAmSP-P140D catalysed the regiospecific transglucosylation of (+)-catechin: 89% of a novel compound (+)-catechin-4′-O-α-D-glucopyranoside (CAT-4’) for AmSP-P140D and 92% of (+)-catechin-3′-O-α-D-glucopyranoside (CAT-3’) for AmSP-Q353F. The compound CAT-4’ was fully characterized by NMR and mass spectrometry. An explanation for this difference in regiospecificity was provided at atomic level by molecular docking simulations:AmSP-P140D was found to preferentially bind (+)-catechin in a mode that favours glucosylation on its hydroxyl group in position 4’ while the binding mode in AmSP-Q353F favoured glucosylation on its hydroxyl group in position 3’.
A bioorthogonal antibody-based chemically-induced-dimerization switch for therapeutic application
Authors: Martinko Alexander J. , Tran Hai L. , Simonds Erin F. , Cooke Allison L. , Huang Zhong , Raguveer Sruthi , Agullet Judit Pina , Prasad Suchitra , Going Catherine , Marshall Lisa , Park Timothy , Banerjee Sunandan , Macdonald Ramsay , Jian Mike , Ng Kenneth , Palakodaty Akhila , Kaur Manpreet , Ponce Alberto , Tabrizi Mohammad , Hill Zachary B.
Published: April 2023

We present the Indinavir Ligand Induced Transient Engagement switch (IDV LITE Switch), a fully synthetic Chemically Induced Dimerization (CID) system wherein two humanized antibody fragments are heterodimerized by the antiviral drug indinavir. The IDV LITE Switch represents the first CID system made from fully humanized protein components and dimerized by a clinically approved small molecule drug lacking a mammalian target, making it an ideal bioorthogonal molecular switch for application in small-molecule controlled therapeutics.
Cryo-EM structure of the human cardiac myosin filament
Authors: Dutta Debabrata , Nguyen Vu , Campbell Kenneth S. , Padrón Raúl , Craig Roger
Published: April 2023

Abstract

Pumping of the heart is powered by filaments of the motor protein myosin, which pull on actin filaments to generate cardiac contraction. In addition to myosin, the filaments contain cardiac myosin-binding protein C (cMyBP-C), which modulates contractility in response to physiological stimuli, and titin, which functions as a scaffold for filament assembly1. Myosin, cMyBP-C and titin are all subject to mutation, which can lead to heart failure. Despite the central importance of cardiac myosin filaments to life, their molecular structure has remained a mystery for 60 years2. Here, we have solved the structure of the main (cMyBP-C-containing) region of the human cardiac filament to 6 Å resolution by cryo-EM. The reconstruction reveals the architecture of titin and cMyBP-C for the first time, and shows how myosin’s motor domains (heads) form 3 different types of motif (providing functional flexibility), which interact with each other and with specific domains of titin and cMyBP-C to dictate filament architecture and regulate function. A novel packing of myosin tails in the filament backbone is also resolved. The structure suggests how cMyBP-C helps generate the cardiac super-relaxed state3, how titin and cMyBP-C may contribute to length-dependent activation4, and how mutations in myosin and cMyBP-C might disrupt interactions, causing disease5, 6. A similar structure is likely in vertebrate skeletal myosin filaments. The reconstruction resolves past uncertainties, and integrates previous data on cardiac muscle structure and function. It provides a new paradigm for interpreting structural, physiological and clinical observations, and for the design of potential therapeutic drugs.
deMULTIplex2: robust sample demultiplexing for scRNA-seq
Authors: Zhu Qin , Conrad Daniel N. , Gartner Zev J.
Published: April 2023

Single-cell sample multiplexing technologies function by associating sample-specific barcode tags with cell-specific barcode tags, thereby increasing sample throughput, reducing batch effects, and decreasing reagent costs. Computational methods must then correctly associate cell-tags with sample-tags, but their performance deteriorates rapidly when working with datasets that are large, have imbalanced cell numbers across samples, or are noisy due to cross-contamination among sample tags - unavoidable features of many real-world experiments. Here we introduce deMULTIplex2, a mechanism-guided classification algorithm for multiplexed scRNA-seq data that successfully recovers many more cells across a spectrum of challenging datasets compared to existing methods. deMULTIplex2 is built on a statistical model of tag read counts derived from the physical mechanism of tag cross-contamination. Using generalized linear models and expectation-maximization, deMULTIplex2 probabilistically infers the sample identity of each cell and classifies singlets with high accuracy. Using Randomized Quantile Residuals, we show the model fits both simulated and real datasets. Benchmarking analysis suggests that deMULTIplex2 outperforms existing algorithms, especially when handling large and noisy single-cell datasets or those with unbalanced sample compositions.
A system of feed-forward cerebellar circuits that extend and diversify sensory signaling
Authors: Hariani Harsh N. , Algstam A. Brynn , Candler Christian T. , Witteveen Isabelle F. , Sidhu Jasmeen K. , Balmer Timothy S.
Published: April 2023

Sensory signals are processed by the cerebellum to coordinate movements. Numerous cerebellar functions are thought to require the maintenance of a sensory representation that extends beyond the input signal. Granule cells receive sensory input, but they do not prolong the signal and are thus unlikely to maintain a sensory representation for much longer than the inputs themselves. Unipolar brush cells (UBCs) are excitatory interneurons that project to granule cells and transform sensory input into prolonged increases or decreases in firing, depending on their ON or OFF UBC subtype. Further extension and diversification of the input signal could be produced by UBCs that project to one another, but whether this circuitry exists is unclear. Here we test whether UBCs innervate one another and explore how these small networks of UBCs could transform spiking patterns. We characterized two transgenic mouse lines electrophysiologically and immunohistochemically to confirm that they label ON and OFF UBC subtypes and crossed them together, revealing that ON and OFF UBCs innervate one another. A Brainbow reporter was used to label UBCs of the same ON or OFF subtype with different fluorescent proteins, which showed that UBCs innervate their own subtypes as well. Computational models predict that these feed-forward networks of UBCs extend the length of bursts or pauses and introduce delays—transformations that may be necessary for cerebellar functions from modulation of eye movements to adaptive learning across time scales.

SIGNIFICANCE STATEMENT

The cerebellum is essential for the accurate performance of behaviors ranging in complexity from stabilizing an image on the retina to playing a piano or performing a gymnastics routine. Cerebellar dysfunction disrupts the ability to produce smooth movements and leads to a disorder called ataxia. Damage to the vestibular cerebellum occurs in various disorders including medulloblastoma and leads to nystagmus, involuntary movements of the eyes that prevent normal vision. Treating disorders of motor control such as nystagmus, requires a better understanding of how representations of movements are maintained in the firing patterns of neurons in the cerebellar circuit. Here we use transgenic mice to label a type of neuron called the unipolar brush cell and revealed that these cells innervate one another and are likely to increase the length and diversity of spiking patterns in the cerebellum. These transformations may be necessary for numerous functions from controlling eye movements to learning new behaviors.
Cooperative dynamics of DNA grafted magnetic nanoparticles optimize magnetic biosensing and coupling to DNA origami
Authors: Lak Aidin , Wang Yihao , Kolbeck Pauline J. , Pauer Christoph , Chowdhury Mohammad Suman , Cassani Marco , Ludwig Frank , Viereck Thilo , Selbach Florian , Tinnefeld Philip , Schilling Meinhard , Liedl Tim , Tavacoli Joe , Lipfert Jan
Published: April 2023

Magnetic nanoparticles (MNPs) enable unique capabilities for biosensing and actuation via coupling to DNA origami, yet how DNA grafting density affects their dynamics and accessibility remains poorly understood. Here, we demonstrate functionalization of MNPs with single-stranded DNA (ssDNA) via click chemistry conjugation with tunable grafting density. Several complementary methods show that particle translational and rotational dynamics exhibit a sigmoidal dependence on ssDNA grafting density. At low densities ssDNA strands are coiled and cause small changes to particle dynamics, while at high densities they form polymer brushes that cooperatively change particle dynamics. Intermediate ssDNA densities show the highest magnetic biosensing sensitivity for detection of target nucleic acids. Finally, we demonstrate that MNPs with high grafting densities are required to efficiently couple them to DNA origami. These results together establish ssDNA grafting density as a critical parameter for functionalization of MNPs for use in a broad range of applications.
Maturation-Dependent Changes in the Structure and Seeding Capacity of Aβ42 Amyloid Fibrils
Authors: Miller Alyssa , Chia Sean , Klimont Ewa , Knowles Tuomas P.J. , Vendruscolo Michele , Ruggeri Francesco Simone
Published: April 2023

Many proteins self-assemble to form amyloid fibrils, which are highly organized structures stabilized by a characteristic cross-β network of hydrogen bonds. This process underlies a variety of human diseases, and can be exploited to develop versatile functional biomaterials. Thus, amyloid aggregation has been widely studied, shedding light on the properties of fibrils and their intermediates. A question that remains open concerns the microscopic processes that underlie the long-time behaviour of the fibrillar assemblies. Here, we use atomic force microscopy to observe that the fibrils undergo a maturation process, with an increase in both fibril length and thickness, and a change in the cross-β sheet content. These changes affect the ability of the fibrils to catalyse the formation of new aggregates through secondary nucleation. The identification of these changes helps us understand the fibril maturation processes, facilitate the targeting of amyloid fibrils in drug discovery, and offer insight into the development of biocompatible and sustainable protein based materials.
Optogenetic-Induced Muscle Loading Leads to Mechanical Adaptation of the Achilles Tendon Enthesis in Mice
Authors: Ganji Elahe , Lamia Syeda N. , Stepanovich Matthew , Whyte Noelle , Abraham Adam C. , Killian Megan L.
Published: April 2023

The growth of the skeleton depends on the transmission of contractile muscle forces from tendon to bone across the extracellular matrix-rich enthesis. Loss of muscle loading leads to significant impairments in enthesis development. However, little is known about how the enthesis responds to increased loading during postnatal growth. To study the cellular and matrix adaptations of the enthesis in response to increased muscle loading, we used optogenetics to induce skeletal muscle contraction and unilaterally load the Achilles tendon and enthesis in young (i.e., during growth) and adult (i.e., mature) mice. In young mice, daily bouts of unilateral optogenetic loading led to expansion of the calcaneal apophysis and growth plate, as well as increased vascularization of the normally avascular enthesis. Daily loading bouts, delivered for 3 weeks, also led to a mechanically weaker enthesis with increased molecular-level accumulation of collagen damage in young mice. However, adult mice did not exhibit impaired mechanical properties or noticeable structural adaptations to the enthesis. We then focused on the transcriptional response of the young tendon and bone following optogenetic-induced loading. After 1 or 2 weeks of loading, we identified, in tendon, transcriptional activation of canonical pathways related to glucose metabolism (glycolysis) and inhibited pathways associated with cytoskeletal remodeling (e.g., RHOA and CREB signaling). In bone, we identified activation of inflammatory signaling (e.g., NFkB and STAT3 signaling) and inhibition of ERK/MAPK and PTEN signaling. Thus, we have demonstrated the utility of optogenetic-induced skeletal muscle contraction to elicit structural, functional, and molecular adaptation of the enthesisin vivoespecially during growth.
Genome-wide gene birth-death dynamics are associated with diet breadth variation in Lepidoptera
Authors: Dort Hanna , Bijl Wouter van der , Wahlberg Niklas , Nylin Sören , Wheat Christopher W.
Published: April 2023

Comparative analyses of gene birth-death dynamics (GBDD) have the potential to reveal gene families that played an important role in the evolution of morphological, behavioral, or physiological variation. Here, we used whole genomes of 30 species of butterflies and moths to identify GBDD among the Lepidoptera that are associated with specialist or generalist feeding strategies. Our work advances this field by using a uniform set of annotated proteins for all genomes, investigating associations while correcting for phylogeny, and assessing all gene familes rather thana priorisubsets. We discovered that the sizes of several important gene families (e.g., those associated with pesticide resistance, xenobiotic detoxification, and/or protein digestion) are significantly correlated with diet breadth. We also found 12 gene families showing significant shifts in GBDD at the butterfly (Papilionoidea) crown node, the most notable of which was a family of pheromone receptors that underwent a contraction potentially linked with a shift to visual-based mate recognition. Our findings highlight the importance of uniform annotations, phylogenetic corrections and unbiased gene family analyses in generating a list of candidate genes that warrant further exploration.

Significance Statement

Gene duplications and gene deaths are important for the development of novel traits, but their study is often complicated by methodological issues, such as input data coming from different sources with different biases. Here, we address many of these issues in an analysis of gene duplication and death across 30 species of moths by using standardized, genome-wide input data. Importantly, our analysis uses a model that can correlate gene family sizes with any quantitative trait, while also accounting for relatedness between species. Using this model, we provide novel evolutionary insights by showing that the sizes of several important gene families are correlated with increases or decreases in the number of host plant orders that Lepidoptera eat.
Environmental conditions predetermine innate antioxidants pool in sea oat (Uniola paniculataL.) seeds
Authors: Egesa Andrew Ogolla , Pérez Héctor E. , Begcy Kevin
Published: April 2023

Background and Aims

Secondary metabolites such as antioxidants are critical components that protect seeds from stress damage during seed development, desiccation, and ex-situ storage. Antioxidants are essential determinants of seed quality, longevity, and persistence. Understanding the environmental factors that regulate the accumulation, content, and function of antioxidant pools in sea oat seeds is critical for gene banking and understanding the environmental impacts on seed quality.

Methods

Germination, viability, and Trolox Equivalent Antioxidant Capacity (TEAC) were analyzed on seeds from 18 sea oat populations from the US Atlantic and Gulf of Mexico coasts. We first assessed baseline TEAC, followed by TEAC performed on imbibed seeds for 36 hours at 35/25 °C during the day and night, respectively. Then, we analyzed the relationship of the antioxidant pools from these 18 sea oat populations to sampling site environmental classifications.

Key Results

Higher baseline antioxidants were common in regions with extreme environmental conditions corresponding to sea oat populations growing at latitudinal extremes characterized by warmer and colder temperatures. Baseline antioxidants did not correlate with prevailing seed germination. However, higher concentrations of antioxidants following imbibition were associated with poor seed germination in warmer conditions.

Conclusions

Our results indicate that climatic conditions and environmental components associated with temperatures and precipitation may largely influence the innate pool of antioxidants in sea oat seeds. Also, a high amount of antioxidants following sea oat seeds imbibition suggest seed damage or poor viability influenced by environmental stress conditions during seed development.
Dissecting the Determinants of Domain Insertion Tolerance and Allostery in Proteins
Authors: Mathony Jan , Aschenbrenner Sabine , Becker Philipp , Niopek Dominik
Published: April 2023

Domain insertion engineering is a promising approach to recombine the functions of evolutionarily unrelated proteins. Insertion of light-switchable receptor domains into a selected effector protein, for instance, can yield allosteric effectors with light-dependent activity. However, the parameters that determine domain insertion tolerance are poorly understood.

Here, we used an unbiased screen to systematically assess the domain insertion permissibility of several evolutionary unrelated proteins. Training machine learning models on the resulting data allowed us to dissect features informative for domain insertion tolerance and revealed sequence conservation statistics as the strongest indicators of suitable insertion sites. Finally, extending our experimental pipeline towards the identification of switchable hybrids resulted in opto-chemogenetic derivatives of the transcription factor AraC that function as single-protein Boolean logic gates. Our study reveals determinants of domain insertion tolerance and facilitates the engineering of switchable proteins with unique mechanistic properties.
acorn: an R package forde novovariant analysis
Authors: Turner Tychele N.
Published: April 2023

Background

The study ofde novovariation is important for assessing biological characteristics of new variation and for studies related to human phenotypes. Software programs exist to callde novovariants and programs also exist to test the burden of these variants in genomic regions; however, I am unaware of a program that fits in between these two aspects ofde novovariant assessment. This intermediate space is important for assessing the quality ofde novovariants and to understand the characteristics of the callsets. For this reason, I developed the R package acorn.

Results

acorn is an R package that examines various features ofde novovariants including subsetting the data by individual(s), variant type, or genomic region; calculating features including variant change counts, variant lengths, and presence/absence at CpG sites; and characteristics of parental age in relation tode novovariant counts.

Conclusions

acorn is an R package that fills a critical gap in assessingde novovariants and will be of benefit to many investigators studyingde novovariation.
Non-Human Peptides Revealed in Blood Reflect the Composition of Small Intestine Microbiota
Authors: Arapidi Georgij P. , Urban Anatolij S. , Osetrova Maria S. , Shender Victoria O. , Butenko Ivan O. , Bukato Olga N. , Kuznetsov Alexandr A. , Saveleva Tatjana M. , Nos Grigorii A. , Ivanova Olga M. , Lopukhov Leonid V. , Laikov Alexander V. , Sharova Nina I. , Nikonova Margarita F. , Mitin Alexander N. , Martinov Alexander I. , Grigorieva Tatiana V. , Ilina Elena N. , Ivanov Vadim T. , Govorun Vadim M.
Published: April 2023

The previously underestimated effects of commensal gut microbiota on the human body are increasingly being investigated using omics. The discovery of active molecules of interaction between the microbiota and the host may be an important step towards elucidating the mechanisms of symbiosis. Here, we show that in the bloodstream of healthy people, there are over 900 peptides that are fragments of proteins from microorganisms which naturally inhabit human biotopes, including the intestinal microbiota. Absolute quantitation by multiple reaction monitoring has confirmed the presence of bacterial peptides in the blood plasma and serum in the range of approximately 0.1 nM to 1 μM. The abundance of microbiota peptides reaches its maximum about 5h after a meal. Most of the peptides correlate with the bacterial composition of the small intestine and are likely obtained by hydrolysis of membrane proteins with trypsin, chymotrypsin and pepsin — the main proteases of the gastrointestinal tract. The peptides have physicochemical properties allowing them selectively pass the intestinal mucosal barrier and resist fibrinolysis. Proposed approach to the identification of microbiota peptides in the blood may be useful for determining the microbiota composition of hard-to-reach intestinal areas and for monitoring the permeability of the intestinal mucosal barrier.
Design, synthesis, and evaluation of a mitoxantrone probe (MXP) for biological studies
Authors: Wallin Savanna , Singh Sarbjit , Borgstahl Gloria E. O. , Natarajan Amarnath
Published: April 2023

Mitoxantrone (MX) is a robust chemotherapeutic with well-characterized applications in treating certain leukemias and advanced breast and prostate cancers. The canonical mechanism of action associated with MX is its ability to intercalate DNA and inhibit topoisomerase II, giving it the designation of a topoisomerase II poison. Years after FDA approval, investigations have unveiled novel protein-binding partners, such as methyl-CpG-binding domain protein (MBD2), PIM1 serine/threonine kinase, RAD52, and others that may contribute to the therapeutic profile of MX. Moreover, recent proteomic studies have revealed MX’s ability to modulate protein expression, illuminating the complex cellular interactions of MX. Although mechanistically relevant, the differential expression across the proteome does not address the direct interaction with potential binding partners. Identification and characterization of these MX-binding cellular partners will provide the molecular basis for the alternate mechanisms that influence MX’s cytotoxicity. Here, we describe the design and synthesis of a MX-biotin probe (MXP) and negative control (MXP-NC) that can be used to define MX’s cellular targets and expand our understanding of the proteome-wide profile for MX. In proof of concept studies, we used MXP to successfully isolate a recently identified protein-binding partner of MX, RAD52, in a cell lysate pulldown with streptavidin beads and western blotting.

Graphical abstract (Draft)

Highlights

An 8-step synthesis was used to generate a biotinylated-mitoxantrone probe (MXP).

A pulldown of MXP demonstrated selectivity for RAD52, but not Replication Protein A.

Western blot confirmed the identity of the isolated protein, RAD52.
Phosphatase to kinase switch of a critical enzyme contributes to timing of cell differentiation
Authors: Chong Trisha N. , Saurabh Saumya , Panjalingam Mayura , Shapiro Lucy
Published: April 2023

Cell differentiation is an essential biological process that is often subject to strict temporal regulation. The aquatic bacterium,Caulobacter crescentus, undergoes obligate differentiation from a swarmer cell to a stationary, replication-competent stalked cell, with each cell cycle. Here, we report that the switch from phosphatase to kinase activity of the histidine kinase PleC contributes to timing this differentiation event. We show that PleC PAS domain interaction with the polar scaffold protein PodJ localizes PleC to the cell pole and inhibitsin vivokinase activity. Upon PodJ degradation, released PleC switches to its kinase form and phosphorylates the PleD diguanylate cyclase, initiating the signaling pathway responsible for differentiation. While PodJ inhibits PleC kinase activity, it does not impact PleC phosphatase activity on DivK, which is required for pili biogenesis and flagellar rotation. Thus, PleC PAS domain interaction with PodJ regulates PleC subcellular localization, enzymatic activity, and the timing of cell differentiation, revealing that PAS domains affect enzymatic function on diverse substrates by relying on context dependent binding partners.
Gender heterogeneity in the boardroom and corporate sustainability performance of quoted manufacturing firms in Nigeria
Authors: Egbunike Chinedu Francis , Igbinovia Ikponmwosa Michael , Oranefo Chinyere Patricia , Iyoha Agbonrha-Oghoye Imas
Published: April 2023

Purpose

Prior studies have shown that heterogeneity plays a crucial role in addressing soft issues linked to a firm’s corporate social responsibility stance. The purpose of this paper is to extend the prior literature on the effect of gender heterogeneity on environmental, social and economic performance dimensions, specifically, whether the female boardroom presence weakens or strengthens the performance along the three dimensions, commonly referred to as the corporate sustainability.

Design/methodology/approach

The study from a positivist philosophy adopts a quantitative approach, and the final sample consisted of forty-six companies listed on the Nigerian Stock Exchange for the year 2011–2018. The final sample was a balanced panel of 344 firm years. The dependent variables were return on assets (ROA), environmental performance (ENV) and donations made for social causes (SOP). The ENV was measured using a content scoring system, with range of 1 to 5. The data were analysed using the fixed effects and GLM regression models. To further address the issue of endogeneity, a two-stage least squares regression was conducted.

Findings

The findings show a positive relationship between gender heterogeneity and ROA, which was also confirmed for the environmental performance index. However, the sign reversed in the SOP model and showed a negative relationship between gender heterogeneity and donations, the proxy for SOP. The results are in tandem with the stakeholder axioms that argue that commitment to other stakeholder groups strengthens firm performance in the long run.

Research limitations/implications

An implication of this study is the fact that information availability has been rapidly escalating in the country, leading to rising social movements and civic unrest; therefore, corporations that face negative castigations may pay the huge price of product boycott and loss of market value.

Originality/value

The findings of this study provide additional insight into the influence of female boardroom presence on the environmental, social and economic performance of firms. The findings suggest the relevance of the resource dependence theory, especially from a developing country context, to ensure an improved corporate governance structure in Nigerian manufacturing firms.
Hybrid approach for parameter identification of the two-diode model of photovoltaic modules
Authors: Zhang Guoyu , Wang Honghua , Lu Tianhang , Wang Chengliang , Huang Yaopeng
Published: April 2023

Purpose

Parameter identification of photovoltaic (PV) modules plays a vital role in modeling PV systems. This study aims to propose a novel hybrid approach to identify the seven parameters of the two-diode model of PV modules with high accuracy.

Design/methodology/approach

The proposed hybrid approach combines an improved particle swarm optimization (IPSO) algorithm with an analytical approach. Three parameters are optimized using IPSO, whereas the other four are analytically determined. To improve the performance of IPSO, three improvements are adopted, that is, evaluating the particles with two evaluation functions, adaptive evolutionary learning and adaptive mutation.

Findings

The performance of proposed approach is first verified by comparing with several well-established algorithms for two case studies. Then, the proposed method is applied to extract the seven parameters of CSUN340-72M under different operating conditions. The comprehensively experimental results and comparison with other methods verify the effectiveness and precision of the proposed method. Furthermore, the performance of IPSO is evaluated against that of several popular intelligent algorithms. The results indicate that IPSO obtains the best performance in terms of the accuracy and robustness.

Originality/value

An improved hybrid approach for parameter identification of the two-diode model of PV modules is proposed. The proposed approach considers the recombination saturation current of the p–n junction in the depletion region and makes no assumptions or ignores certain parameters, which results in higher precision. The proposed method can be applied to the modeling and simulation for research and development of PV systems.
Young consumers' green marketing orientation: role of customer citizenship behaviour in determining real estate purchase intention in India
Authors: Jacob Jobin , Chully Arun Antony , Godwin Benny J. , George Jossy P.
Published: April 2023

Purpose

The purpose of this paper is to assess green marketing as an influential factor in the purchase of real estate. In this study, the consumer citizenship behaviour of young individuals will be studied with an assessment of real estate purchase intention, strategic green marketing orientation (GMO) and tactical GMO.

Design/methodology/approach

The sample frame consists of young consumers from India’s metropolitan cities. The respondents were in the range of 18 to 35 years of age. These cities provide a high standard of living, more career options and better educational opportunities. Five separate sections of a standardised questionnaire were used, and a structural equation model was used to assess a total of 393 valid replies.

Findings

Green marketing impacts the behaviour that influences the desire of young customer to buy green real estate.

Research limitations/implications

As the focus of this study is primarily on major cities, future research may study similar behaviour in non-metropolitan cities. The study can also be conducted among consumers of other age groups.

Originality/value

The originality, to the best of the author’s knowledge, exists in examining how young consumers’ opinions about green marketing impact their intentions to purchase green houses and real estate in India. This study will be accessible to all parties involved in the housing and real estate industries.
Genealogy of the fair information practice principles
Authors: Stamenkov Gjoko
Published: April 2023

Purpose

The purpose of this general review is to address the evolution and development of the Fair Information Practice Principles (FIPPs).

Design/methodology/approach

This study presents FIPPs from several establishments, compare them and map them to the General Data Protection Regulation (GDPR). Additionally, this study presents and discuss similarities and differences among FIPP sets.

Findings

Although the subject matter of the FIPP sets is very similar, there are differences: their scope differs significantly. The comparison among FIPP sets is presented, and it provides relevant information related to the connectedness between privacy principles.

Originality/value

This study considers the GDPR to be the pinnacle of the efforts to improve personal data protection; it became a role model for other countries to implement similar regulations.
Why do we twitch? Vicarious consumption in video-game livestreaming
Authors: Kohls Harper , Hiler Jacob L. , Cook Laurel Aynne
Published: April 2023

Purpose

This study aims to examine vicarious consumption (VC) via the video-game streaming platform Twitch. The authors posit that watching someone play can offer the same enjoyment (measured through emotional experience, mood and joy) as playing.

Design/methodology/approach

A mixed-methods approach was used. A qualitative phase involving semistructured qualitative interviews, naturalistic inquiry and netnography generated testable hypotheses, which were tested using a two-condition, between-subjects field experiment.

Findings

This research advances the understanding of vicarious and experiential consumption by finding evidence that VC can produce the same levels of emotional experience, mood, attitude toward the product, joy, brand community loyalty and positive word of mouth. It also demonstrates the moderating effect of familiarity on mood change.

Research limitations/implications

This research demonstrates evidence that VC can offer outcomes similar to active consumption (AC). The authors advance research on VC in a new context (video-game livestreaming vs esports and other contexts) and from a new perspective (viewing motivations vs consumer-oriented outcomes). This research thus presents opportunities to explore these and other affective, behavior and cognitive outcomes in other contexts.

Practical implications

To reach Twitch users, marketers must understand how and why media consumers watch. This research provides insight into the community necessary to create effective advertising.

Originality/value

Building upon Sjöblom and Hamari, focusing on motivations for VC of esports and other related works, the authors expand the context to video-game livestreaming as a whole and examine affective, behavioral and cognitive outcomes compared with AC. Though VC has been researched and conceptualized theoretically, empirical testing is rare. This research offers empirical evidence that VC can offer the same levels of enjoyment as AC.
Auditor choice and audit fees through the lens of agency theory: evidence from Chinese family firms
Authors: Rahman Md Jahidur , Zhu Hongtao , Hossain Md Moazzem
Published: April 2023

Purpose

From an agency perspective, the authors investigate whether family ownership and control configurations are systematically associated with a firm's choice of auditor and audit fees. Agency theory is an economic theory that purposes the existence of a contract between two parties, principals and agents. Auditor choice and audit fees by family firms provide interesting insights given the unique nature of the agency problems faced by such firms.

Design/methodology/approach

The authors employ Big-4 auditors (PWC, KPMG, E&Y and Deloitte) as a proxy for high quality auditor (Big N) for the auditor choice model. For the audit fee model, the dependent variable is the natural logarithm of audit fees (LnAF). The authors use two measures for family firm as explanatory variables: (1) a dummy variable (FAM_Control), which equals one if the firm is classified as a family firm and (2) FAM_Ownership, which is an indicator variable with a value of one if a firm has family members who hold CEO position, occupy board seats, or hold at least 10% of the firm's equity. Data of Chinese listed firms from 2011 to 2021 are used. The authors adopt the Heckman (1979) two-stage model to mitigate the potential endogeneity issue involved in the selection of Big-N auditors.

Findings

The findings suggest that compared with non-family firms, Chinese family firms have a less tendency to employ Big-4 auditors due to less severe agency problems between owners and managers. Additionally, Chinese family firms sustain higher audit fees than non-family firms. Similar to the prior literature, however, Chinese family firms audited by Big-4 auditors incur lower audit fees than family firms audited by non-Big-4 auditors in this study. In contrast to young-family firms, old-family firms are less likely to pick top-tier auditors and sustain lower audit fees. Consistent and robust results are found from endogeneity tests and sensitivity analyses.

Originality/value

The empirical evidence provides a unique insight, for accounting practitioners, policymakers, family owners and other capital market participants concerning the diverse effects of various family ownership and control features on selecting high-quality auditors and audit fees. This study advances the understanding, showing that a lower demand for audit quality occurs in Chinese family firms as they encounter less severe Type I agency problems. However, the more severe Type II agency problems in Chinese family firms sustain higher audit fees due to higher audit risk and greater audit effort.
The role of virtue ethics in enhancing reputation through combatting financial crimes
Authors: AlKhouri Ritab , Halteh Pashaar , Halteh Khaled , Tiwari Milind
Published: April 2023

Purpose

This paper aims to outline how certain lessons from ethical systems can be relevant and applicable to tackling unethical behavior, including financial crime, within the finance profession.

Design/methodology/approach

This paper adopts a pragmatic perspective while acknowledging that there is a myriad of reasons managers act unethically, including the reality that many do so knowingly and deliberately. The matter is further complicated by human nature, given an individual’s behavior (ethical or unethical) is not easily discernable from their psychological, sociological, theological or cultural attributes.

Findings

Although such systems may not solve the problem of corrupt behavior, research suggests that industry professionals can learn to act in a more responsible and ethical manner. Given the wounded reputation of the financial sector, owing to their role in committing financial crimes such as money laundering, advances in ethical conduct would elevate both the effectiveness of the sector, as well as its reputation.

Originality/value

It is impractical to think we can completely resolve the problem of unethical behavior. Improvement, however, seems possible through promoting virtuous character traits and ethical behavior in individuals and organizations. Virtue ethics can play a significant role in combating financial crime and supporting anti-money laundering initiatives.
Unlocking supply chain product and process innovation through the development of supply chain learning capabilities under technological turbulence: Evidence from Egyptian SMEs
Authors: Abdelaziz Mahmoud Abdelaziz Ahmed , Wu Jiani , Yuan Changwei , Ghonim Mohamed Ahmed
Published: April 2023

Purpose

In light of the current challenges in the business environment, firms, particularly those involved in supply chains, must foster innovation. In this context, the current study employs the theory of dynamic organizational capabilities (DOCs) to track supply chain learning capabilities (SCLCs) and independently uncover their relationship to innovation at both the product and process levels. Similarly, the study intends to investigate the influence of technological turbulence (TT) on these relationships as a moderating variable.

Design/methodology/approach

The data were gathered using in-person interviews with 189 CEOs with some supply chain management proficiency from small and medium-sized enterprises (SMEs) in the industrial zones of eastern Egypt. The study used a survey approach to collect data, and the SEM-PLS technique was utilized to analyze the data.

Findings

Study findings revealed that SCLCs positively affect product and process innovation. In addition, TT positively moderates the relationship between SCLCs and product and process innovation, except for risk-taking capability. Further theoretical and practical implications are derived from the study findings.

Originality/value

This research adds to the knowledge of the dynamic capabilities theory (DCT), which affects how firms interact with their external environment. Studying learning capabilities are employed as essential competencies to counterbalance high levels of TT in the external environment in terms of innovative performance and vice versa if firms do not attempt to strengthen their dynamic learning capabilities in supply chains. In addition, this study contributes to the literature by studying learning capabilities from the external perspective, where SCLCs are being developed as a new variable to improve innovation.