bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of Gαsand Gαolfactivation by catechol and non-catechol dopamine D1 receptor agonists
Authors: Nguyen Anh Minh , Semeano Ana , Quach Vianna , Inoue Asuka , Nichols David E. , Yano Hideaki
Published: October 2023

The dopamine D1 receptor (D1R) couples to Gαsand Gαolfand plays a crucial role in regulating voluntary movement and other cognitive functions, making it a potential therapeutic target for several neurological and neuropsychiatric disorders, such as Parkinson’s disease and schizophrenia. In the central nervous system, Gαsis widely expressed in the cortex and Gαolfis predominantly found in the striatum. We used two different configurations of bioluminescence resonance energy transfer (BRET) assays and a fluorescence-based cyclic AMP (cAMP) production functional assay to test a series of tetracyclic catechol (dihydrexidine, methyl-dihydrexidine, doxanthrine) and non-catechol (tavapadon, PF-8294, PF-6142) D1R agonists for their activity at these G proteins. We discovered that these tetracyclic catechol compounds, PF-8294 and PF-6142 exerted full agonism when D1R coupled to Gαsbut partial agonism when D1R coupled to Gαolf. In contrast, tavapadon acted as a full agonist at Gαolfand a partial agonist at Gαs. The effects of these compounds on the cortical and nigral electrophysiological events agree with their selectivity profiles. This suggests the possibility of achieving region-specific pharmacology and opens new directions for developing D1R drugs to treat relevant neurological and neuropsychiatric disorders.
Intraoperative Bioprinting of Human Adipose-derived Stem cells and Extra-cellular Matrix Induces Hair Follicle-Like Downgrowths and Adipose Tissue Formation during Full-thickness Craniomaxillofacial Skin Reconstruction
Authors: Kang Youngnam , Yeo Miji , Derman Irem Deniz , Ravnic Dino J. , Singh Yogendra Pratap , Alioglu Mecit Altan , Wu Yang , Makkar Jasson , Driskell Ryan R. , Ozbolat Ibrahim T.
Published: October 2023

Craniomaxillofacial (CMF) reconstruction is a challenging clinical dilemma. It often necessitates skin replacement in the form of autologous graft or flap surgery, which differ from one another based on hypodermal/dermal content. Unfortunately, both approaches are plagued by scarring, poor cosmesis, inadequate restoration of native anatomy and hair, alopecia, donor site morbidity, and potential for failure. Therefore, new reconstructive approaches are warranted, and tissue engineered skin represents an exciting alternative. In this study, we demonstrated the reconstruction of CMF full-thickness skin defects using intraoperative bioprinting (IOB), which enabled the repair of defects via direct bioprinting of multiple layers of skin on immunodeficient rats in a surgical setting. Using a newly formulated patient-sourced allogenic bioink consisting of both human adipose-derived extracellular matrix (adECM) and stem cells (ADSCs), skin loss was reconstructed by precise deposition of the hypodermal and dermal components under three different sets of animal studies. adECM, even at a very low concentration such as 2% or less, has shown to be bioprintable via droplet-based bioprinting and exhibitedde novoadipogenic capabilities bothin vitroandin vivo. Our findings demonstrate that the combinatorial delivery of adECM and ADSCs facilitated the reconstruction of three full-thickness skin defects, accomplishing near-complete wound closure within two weeks. More importantly, both hypodermal adipogenesis and downgrowth of hair follicle-like structures were achieved in this two-week time frame. Our approach illustrates the translational potential of using human-derived materials and IOB technologies for full-thickness skin loss.
High diversity, abundance and expression of hydrogenases in groundwater
Authors: Li Shengjie , Mosier Damon , Kouris Angela , Humez Pauline , Mayer Bernhard , Strous Marc , Diao Muhe
Published: October 2023

Hydrogen may be the most important electron donor available in the subsurface. Here we analyze the diversity, abundance and expression of hydrogenases in 5 proteomes, 25 metagenomes and 265 amplicon datasets of groundwaters with diverse geochemistry. A total of 1,772 new [NiFe]-hydrogenase gene sequences were recovered, which almost doubled the number of sequences in a widely used database. [NiFe]-hydrogenases were highly abundant, almost as abundant as the DNA-directed RNA polymerase. The abundance of hydrogenase genes increased with depth from 0 to 129 m. Hydrogenases were present in 502 out of 1,245 metagenome-assembled-genomes. The populations with hydrogenases accounted for ∼50% of all populations. Hydrogenases were actively expressed, making up as much as 5.9% of methanogen proteomes. Most of the newly discovered diversity of hydrogenases was in “Group 3b”, which was linked to sulfur metabolism. “Group 3d” was the most abundant, which was previously linked to fermentation, but we observed this group mainly in methanotrophs and chemoautotrophs. “Group 3a”, associated with methanogenesis, was the most active in proteomes. Two newly discovered groups of [NiFe]-hydrogenases further expanded the biodiversity. Our results highlight the vast diversity, abundance and expression of hydrogenases in the sampled groundwaters, suggesting a high potential for hydrogen oxidation in subsurface habitats.
Complex priors and flexible inference in recurrent circuits with dendritic nonlinearities
Authors: Lyo Benjamin S. H. , Savin Cristina
Published: October 2023

Despite many successful examples in which probabilistic inference can account for perception, we have little understanding of how the brain represents and uses structured priors that capture the complexity of natural input statistics. Here we construct a recurrent circuit model that can implicitly represent priors over latent variables, and combine them with sensory and contextual sources of information to encode task-specific posteriors. Inspired by the recent success of diffusion models as means of learning and using priors over images, our model uses dendritic nonlinearities optimized for denoising, and stochastic somatic integration with the degree of noise modulated by an oscillating global signal. Combining these elements into a recurrent network yields a dynamical system that samples from the prior at a rate prescribed by the period of the global oscillator. Additional inputs reflecting sensory or top-down contextual information alter these dynamics to generate samples from the corresponding posterior, with different input gating patterns selecting different inference tasks. We demonstrate that this architecture can sample from low dimensional nonlinear manifolds and multimodal posteriors. Overall, the model provides a new framework for circuit-level representation of probabilistic information, in a format that facilitates flexible inference.
GTDB-based packages enhance GraftM performance
Authors: Korzhenkov Aleksei A.
Published: October 2023

In this short note I present a way to enhance GraftM performance and incorporate novel genome-based prokaryotic taxonomy to sequencing data classification.
A cautionary tale about properly vetting datasets used in supervised learning predicting metabolic pathway involvement
Authors: Huckvale Erik D. , Moseley Hunter N.B.
Published: October 2023

The mapping of metabolite-specific data to pathways within cellular metabolism is a major data analysis step needed for biochemical interpretation. A variety of machine learning approaches, particularly deep learning approaches, have been used to predict these metabolite-to-pathway mappings, utilizing a training dataset of known metabolite-to-pathway mappings. A few such training datasets have been derived from the Kyoto Encyclopedia of Gene and Genomes (KEGG). However, several prior published machine learning approaches utilized an erroneous KEGG-derived training dataset that used SMILES molecular representations strings (KEGG-SMILES dataset) and contained a sizable proportion (∼26%) duplicate entries. The presence of so many duplicates taint the training and testing sets generated from k-fold cross-validation of the KEGG-SMILES dataset. Therefore, the k-fold cross-validation performance of the resulting machine learning models was grossly inflated by the erroneous presence of these duplicate entries. Here we describe and evaluate the KEGG-SMILES dataset so that others may avoid using it. We also identify the prior publications that utilized this erroneous KEGG-SMILES dataset so their machine learning results can be properly and critically evaluated. In addition, we demonstrate the reduction of model k-fold cross-validation performance after de-duplicating the KEGG-SMILES dataset. This is a cautionary tale about properly vetting prior published benchmark datasets before using them in machine learning approaches. We hope others will avoid similar mistakes.
Peptidoglycan-Chi3l1 interaction shapes gut microbiota in intestinal mucus layer
Authors: Chen Yan , Yang Ruizhi , Qi Bin , Shan Zhao
Published: October 2023

The balanced gut microbiota in intestinal mucus layer plays an instrumental role in the health of the host. However, the mechanisms by which the host regulates microbial communities in the mucus layer remain largely unknown. Here, we discovered that the host regulates bacterial colonization in the gut mucus layer by producing a protein called Chitinase 3-like protein 1 (Chi3l1). Intestinal epithelial cells are stimulated by the gut microbiota to express Chi3l1. Once expressed, Chi3l1 is secreted into the mucus layer where it interacts with the gut microbiota, specifically through a component of bacterial cell walls called peptidoglycan. This interaction between Chi3l1 and bacteria is beneficial for the colonization of bacteria in the mucus, particularly for gram-positive bacteria likeLactobacillus. Moreover, a deficiency of Chi3l1 leads to an imbalance in the gut microbiota, which exacerbates colitis induced by dextran sodium sulfate (DSS). By performing fecal microbiota transplantation from Villin-cre mice or replenishingLactobacillusin IECΔChil1mice, we were able to restore their colitis to the same level as that of Villin-cre mice. In summary, this study shows a “scaffold model” for microbiota homeostasis by interaction between intestinal Chi3l1 and bacteria cell wall interaction, and it also highlights that an unbalanced gut microbiota in the intestinal mucus contributes to the development of colitis.
YlaN is an iron(II) binding protein that functions to relieve Fur-mediated repression of gene expression inStaphylococcus aureus
Authors: Boyd Jeffrey M. , Esquilín-Lebrón Karla , Campbell Courtney J. , Kaler Kylie Ryan , Norambuena Javiera , Foley Mary E. , Stephens Timothy G. , Rios Gustavo , Mereddy Gautam , Zheng Vincent , Bovermann Hannah , Kim Jisun , Kulczyk Arkadiusz W. , Yang Jason H. , Greco Todd M. , Cristea Ileana M. , Carabetta Valerie J. , Beavers William N. , Bhattacharya Debashish , Skaar Eric P. , Parker Dane , Carroll Ronan K. , Stemmler Timothy L.
Published: October 2023

Iron (Fe) is a trace nutrient required by nearly all organisms. As a result of the demand for Fe and the toxicity of non-chelated cytosolic ionic Fe, regulatory systems have evolved to tightly balance Fe acquisition and usage while limiting overload. In most bacteria, including the mammalian pathogenStaphylococcus aureus, the ferric uptake regulator (Fur) is the primary transcriptional regulator that controls the transcription of genes that code for Fe uptake and utilization proteins. YlaN was demonstrated to be essential inBacillus subtilisunless excess Fe is added to the growth medium, suggesting a role in Fe homeostasis. Here, we demonstrate that YlaN is expendable inS. aureus; however, YlaN became essential upon Fe deprivation. A nullfurallele bypassed the essentiality of YlaN. The transcriptional response of Fur derepression resulted in a reprogramming of metabolism to prioritize fermentative growth over respiratory growth. The absence of YlaN diminished the derepression of Fur-dependent transcription during Fe limitation. Bioinformatic analyses suggest thatylaNwas recruited to Gram positive bacteria and once acquired was maintained in the genome as it co-evolved with Fur. Consistent with a role for YlaN in influencing Fur-dependent regulation, YlaN and Fur interactedin vivo. YlaN bound Fe(II)in vitrousing oxygen or nitrogen ligands with an association constant that is consistent with a physiological role in Fe sensing and/or buffering. These findings have led to a model wherein YlaN is an Fe(II) binding protein that influences Fur-dependent regulation through direct interaction.

Importance

Iron (Fe) is an essential nutrient for nearly all organisms. If Fe homeostasis is not maintained, Fe can accumulate in the cytosol where it is toxic. Questions remain about how cells efficiently balance Fe uptake and usage to prevent imbalance. Iron uptake and proper metalation of proteins are essential processes in the mammalian bacterial pathogenStaphylococcus aureus. Understanding the gene products involved in Fe ion regulation, uptake, and usage, as well as the physiological adaptations thatS. aureususes to survive in Fe-depleted conditions, will provide insight into the role that Fe has in pathogenesis. These data will also provide insight into the selective pressures imparted by the mammalian host.
A polarized cell system amenable to subcellular resolution imaging of influenza virus infection
Authors: Jean-Baptiste Brault , Catherine Thouvenot , Magda Cannata Serio , Sylvain Paisant , Julien Fernandes , David Gény , Lydia Danglot , Adeline Mallet , Nadia Naffakh
Published: October 2023

The life cycle of influenza A viruses (IAV), and notably intracellular trafficking of the viral genome, depend on multiple interactions with the cellular cytoskeleton and endomembrane system. A limitation of the conventional cellular models used for mechanistic study and subcellular imaging of IAV infection is that they are cultured in two dimensions (2D) under non-polarizing conditions, and therefore they do not recapitulate the intracellular organization of the polarized respiratory epithelial cells naturally targeted by IAVs. To overcome this limitation, we developed an IAV-infection assay in a 3D cell culture system which allows imaging along the baso-lateral axis of polarized cells, with subcellular resolution. Here we describe a protocol to grow polarized monolayers of Caco2-TC7 cells on static Cytodex-3 microcarrier beads, infect them with IAV, and subsequently perform immunostaining and confocal imaging, or electron microscopy, on polarized IAV-infected cells. This method can be extended to other pathogens that infect human polarized epithelial cells.
Reassessing Fragility: A Comparative Analysis of the Fragility Index With the Relative Risk Index
Authors: Heston Thomas F.
Published: October 2023

Background

In biostatistics, assessing the fragility of research findings is crucial for understanding their clinical significance. This study focuses on the fragility index, unit fragility index, and relative risk index as measures to evaluate statistical fragility. The relative risk index quantifies the deviation of observed findings from therapeutic equivalence. In contrast, the fragility indices assess the susceptibility of p-values to change significance with minor alterations in outcomes within a 2×2 contingency table. While the fragility indices have intuitive appeal and have been widely applied, their behavior across a wide range of contingency tables has not been rigorously evaluated.

Methods

Using a Python software program, a simulation approach was employed to generate random 2×2 contingency tables. All tables under consideration exhibited p-values < 0.05 according to Fisher’s exact test. Subsequently, the fragility indices and the relative risk index were calculated. To account for sample size variations, fragility, and risk quotients were also calculated. A correlation matrix assessed the collinearity between each metric and the p-value.

Results

The analysis included 2,000 contingency tables with cell counts ranging from 20 to 480. Notably, the formulas for calculating the fragility indices encountered limitations when cell counts approached zero or duplicate cell counts hindered standardized application. The correlation coefficients with p-values were as follows: unit fragility index (-0.806), fragility index (-0.802), fragility quotient (-0.715), unit fragility quotient (-0.695), relative risk index (-0.403), and relative risk quotient (-0.261).

Conclusion

Compared with the relative risk index and quotient, in the context of p-values < 0.05, the fragility indices and their quotients exhibited stronger correlations. This implies that the fragility indices offer limited additional information beyond the p-value alone. In contrast, the relative risk index displays relative independence, suggesting that it provides meaningful insights into statistical fragility by assessing how far observed findings deviate from therapeutic equivalence, regardless of the p-value.
Axonopathy and altered synaptic development in early hippocampal epileptogenesis of Dravet syndrome
Authors: Layer Nikolas , Müller Peter , Ayash Maya , Pfeiffer Friederike , Saile Meret , Klopfer Fabian , Iavarone Stefano , Santuy Andrea , Fallier-Becker Petra , Hedrich Ulrike B. S. , Lerche Holger , Koch Henner , Wuttke Thomas V.
Published: October 2023

Dravet syndrome caused bySCN1Avariants is a severe developmental epileptic encephalopathy (DEE) characterized by pharmaco-resistant epileptic seizures and progressive neurodevelopmental decline with cognitive impairment and autism-spectrum-traits. Numerous preceding studies indicate that the initial pathophysiology due to impaired NaV1.1 function mainly derives from reduced interneuron firing leading to a network hyperexcitability (Bender et al. 2012). However, little is known how epileptogenesis and generally disease pathogenesis progress from the inborn molecular defect to infantile seizure onset. We address this question in a Dravet mouse model by comprehensive single-cell RNA sequencing and selected downstream analysis via single-cell electrophysiology, histology, live cell imaging and electron microscopy. Our data reveal a continuum of early primary (preseizure) and secondary (post-seizure onset) transcriptomic changes in various cell populations in the hippocampus. Focusing oncornu ammonis, we find a number of transcriptional pathways that are dysregulated including synaptic transmembrane adhesion molecules of the neurexin superfamily and voltage-gated ion channels. Further investigations support an ultrastructural and functional axonopathy and synaptopathy of parvalbumin interneurons. These processes precede somatic firing impairment and seizures suggesting they underlie fundamental early-phase disease mechanisms. Taken together we provide a cellularly resolved transcriptomic resource of early disease phases of Dravet syndrome and demonstrate epileptogenesis beyond NaV1.1 loss-of-function during an early developmental time window of CNS maturation. Altogether these data establish proof-of principle that the concept of epileptogenesis, originally devised for acquired forms of epilepsy, similarly applies to genetic epilepsies and DEEs.
Compact Programmable Control of Protein Secretion in Mammalian Cells
Authors: Vlahos Alexander E. , Call Connor C. , Kadaba Samarth E. , Guo Siqi , Gao Xiaojing J.
Published: October 2023

Synthetic biology currently holds immense potential to engineer the spatiotemporal control of intercellular signals for biomedicine. Programming behaviors using protein-based circuits has advantages over traditional gene circuits such as compact delivery and direct interactions with signaling proteins. Previously, we described a generalizable platform called RELEASE to enable the control of intercellular signaling through the proteolytic removal of ER-retention motifs compatible with pre-existing protease-based circuits. However, these tools lacked the ability to reliably program complex expression profiles and required numerous proteases, limiting delivery options. Here, we harness the recruitment and antagonistic behavior of endogenous 14-3-3 proteins to create RELEASE-NOT to turn off protein secretion in response to protease activity. By combining RELEASE and RELEASE-NOT, we establish a suite of protein-level processing and output modules called Compact RELEASE (compRELEASE). This innovation enables functions such as logic processing and analog signal filtering using a single input protease. Furthermore, we demonstrate the compactness of the post-translational design by using polycistronic single transcripts to engineer cells to control protein secretion via lentiviral integration and leverage mRNA delivery to selectively express cell surface proteins only in engineered cells harboring inducible proteases. CompRELEASE enables complex control of protein secretion and enhances the potential of synthetic protein circuits for therapeutic applications, while minimizing the overall genetic payload.
The ABCF proteins inEscherichia coliindividually alleviate nascent peptide-induced noncanonical translations
Authors: Chadani Yuhei , Uemura Eri , Yamazaki Kohei , Kurihara Miku , Taguchi Hideki
Published: October 2023

Organisms possess a wide variety of proteins with a diverse repertoire of amino acid sequences, and their synthesis relies on the ribosome. Empirical observations have led to the misconception that ribosomes are robust protein factories, but in reality, they have several weaknesses. For instance, ribosomes stall during the translation of the proline-rich sequences, but the translation elongation factor EF-P assists in synthesizing proteins containing the poly-proline sequences. Thus, living organisms have evolved to expand the translation capability of ribosomes through the acquisition of translation elongation factors, enabling the synthesis of diverse proteins.

In this study, we have revealed thatEscherichia coliATP-Binding Cassette family-F (ABCF) proteins, YheS, YbiT, EttA and Uup, individually cope with various noncanonical translations induced by nascent peptide sequences within the exit tunnel of the ribosome. The correspondence between noncanonical translations and ABCFs was YheS for the translational arrest by nascent SecM, YbiT for poly-basic sequence-dependent ribosome stalling and poly-acidic sequence-dependent intrinsic ribosome destabilization (IRD), EttA for IRD at the early stage of elongation, and Uup for poly-proline-dependent stalling. Our results suggest that the ATP hydrolysis-coupled structural rearrangement and interdomain linker sequence between the two nucleotide-binding domains play crucial roles in alleviating the noncanonical translations. Our study highlights a new aspect of ABCF proteins to reduce the potential risks that are encoded within the nascent peptide sequences.

Significance statement

Proteins, that constitute living organisms, exhibit a diverse range of amino acid sequences. However, it has become evident that ribosomes have difficulties in synthesizing certain amino acid sequences, including the poly-basic, poly-acidic, and poly-proline sequences. The mechanisms underlying the expression of proteins with such challenging sequences remain largely elusive. In this study, we have unveiled that translation factor ABCF proteins inEscherichia colipromote various kinds of problematic amino acid sequences that inhibit efficient translation. Through the actions of translation elongation factors including the ABCF proteins, the translation system acquires robustness in synthesizing a vast repertoire of amino acid sequences.
7,8-Dihydroxyflavone is a direct inhibitor of pyridoxal phosphatase
Authors: Brenner Marian , Zink Christoph , Witzinger Linda , Keller Angelika , Hadamek Kerstin , Bothe Sebastian , Neuenschwander Martin , Villmann Carmen , von Kries Jens Peter , Schindelin Hermann , Jeanclos Elisabeth , Gohla Antje
Published: October 2023

Vitamin B6 deficiency has been linked to cognitive impairment in human brain disorders for decades. Still, the molecular mechanisms linking vitamin B6 to these pathologies remain poorly understood, and whether vitamin B6 supplementation improves cognition is unclear as well. Pyridoxal phosphatase (PDXP), an enzyme that controls levels of pyridoxal 5’-phosphate (PLP), the co-enzymatically active form of vitamin B6, may represent an alternative therapeutic entry point into vitamin B6-associated pathologies. However, pharmacological PDXP inhibitors to test this concept are lacking. We now identify a PDXP and age-dependent decline of PLP levels in the murine hippocampus that provides a rationale for the development of PDXP inhibitors. Using a combination of small molecule screening, protein crystallography and biolayer interferometry, we discover, visualize and analyze 7,8-dihydroxyflavone (7,8-DHF) as a direct and potent PDXP inhibitor. 7,8-DHF binds and reversibly inhibits PDXP with low micromolar affinity and sub-micromolar potency. In mouse hippocampal neurons, 7,8-DHF increases PLP in a PDXP-dependent manner. These findings validate PDXP as a druggable target. Of note, 7,8-DHF is a well-studied molecule in brain disorder models, although its mechanism of action is actively debated. Our discovery of 7,8-DHF as a PDXP inhibitor offers novel mechanistic insights into the controversy surrounding 7,8-DHF-mediated effects in the brain.
Investigations on Antarctic fish IgM drives the generation of an engineered mAb by CRISPR/Cas9
Authors: Ametrano Alessia , Miranda Bruno , Moretta Rosalba , Dardano Principia , De Stefano Luca , Oreste Umberto , Coscia Maria Rosaria
Published: October 2023

IgM is the major circulating Ig isotype in teleost fish, showing in Antarctic fish unique features such as an extraordinary long hinge region, which plays a crucial role in antibody structure and function. In this work, we describe the replacement of the hinge region of a murine monoclonal antibody (mAb) with the peculiar hinge from Antarctic fish IgM. We use the CRISPR/Cas9 system as a powerful tool for generating the engineered mAb. Then, we assessed its functionality by using an innovative plasmonic substrate based on bimetallic nanoislands (AgAuNIs). The affinity constant of the modified mAb was 2.5-fold higher than the one obtained from wild-type mAb against the specific antigen. Here, we show the suitability of the CRISPR/Cas9 method for modifying a precise region in immunoglobulin gene loci. The overall results could open a frontier in further structural modifications of mAbs for biomedical and diagnostic purposes.
Fyn-mediated phosphorylation of Menin disrupts telomere maintenance in stem cells
Authors: Paul Souren , McCourt Preston M. , Le Le Thi My , Ryu Joohyun , Czaja Wioletta , Bode Ann M. , Contreras-Galindo Rafael , Dong Zigang
Published: October 2023

Telomeres protect chromosome ends and determine the replication potential of dividing cells. The canonical telomere sequence TTAGGG is synthesized by telomerase holoenzyme, which maintains telomere length in proliferative stem cells. Although the core components of telomerase are well-defined, mechanisms of telomerase regulation are still under investigation. We report a novel role for the Src family kinase Fyn, which disrupts telomere maintenance in stem cells by phosphorylating the scaffold protein Menin. We found that Fyn knockdown prevented telomere erosion in human and mouse stem cells, validating the results with four telomere measurement techniques. We show that Fyn phosphorylates Menin at tyrosine 603 (Y603), which increases Menin’s SUMO1 modification, C-terminal stability, and importantly, its association with the telomerase RNA component (TR). Using mass spectrometry, immunoprecipitation, and immunofluorescence experiments we found that SUMO1-Menin decreases TR’s association with telomerase subunit Dyskerin, suggesting that Fyn’s phosphorylation of Menin induces telomerase subunit mislocalization and may compromise telomerase function at telomeres. Importantly, we find that Fyn inhibition reduces accelerated telomere shortening in human iPSCs harboring mutations for dyskeratosis congenita.
PAPγ associates with PAXT nuclear exosome to control the abundance of PROMPT ncRNAs
Authors: Contreras Xavier , Depierre David , Akkawi Charbel , Srbic Marina , Helsmoortel Marion , Cuvier Olivier , Kiernan Rosemary
Published: October 2023

Pervasive transcription of the human genome generates an abundance of RNAs that must be processed and degraded. The nuclear RNA exosome is the main RNA degradation machinery in the nucleus. However, nuclear exosome must be recruited to its substrates by targeting complexes, such as NEXT or PAXT. By proteomic analysis, we have identified additional subunits of PAXT, including many orthologs of MTREC found inS. pombe. In particular, we show that polyA polymerase gamma (PAPγ) was associated with PAXT. Genome-wide mapping of the binding sites of ZFC3H1, RBM27 and PAPγ, showed that PAXT is recruited to the TSS of hundreds of genes. Loss of ZFC3H1 abolished recruitment of PAXT subunits including PAPγ to TSSs and concomitantly increased the abundance of PROMPTs at the same sites. Moreover, PAPγ, as well as MTR4 and ZFC3H1, was implicated in the polyadenylation of PROMPTs. Our results thus provide key insights into the direct targeting of PROMPT ncRNAs by PAXT at their genomic sites.
A human-specific microRNA controls the timing of excitatory synaptogenesis
Authors: Soutschek Michael , Bianco Alessandra Lo , Galkin Simon , Wüst Tatjana , Colameo David , Germade Tomas , Gross Fridolin , von Ziegler Lukas , Bohacek Johannes , Germain Pierre-Luc , Winterer Jochen , Kleele Tatjana , Schratt Gerhard
Published: October 2023

Neural circuit development in the human cortex is considerably prolonged in comparison to non-human primates, a trait that contributes to the remarkable cognitive capacity of modern humans. Here, we explore the regulatory role of non-coding RNAs, which dramatically expanded during brain evolution, in synapse development of human-induced pluripotent stem-cell derived neurons. Inhibition of a human-specific microRNA, miR-1229-3p, results in accelerated formation of excitatory synapses and enhanced synaptic transmission. Mechanistically, miR-1229-3p controls mitochondrial homeostasis by targeting important regulators of mitochondrial autophagy and fission, such as Pink1. Stimulation of mitochondrial metabolism rescues decreased calcium buffering in miR-1229-3p depleted neurons. Our findings reveal an important function of human-specific miR-1229-3p in developmental timing of human synaptogenesis and generally implicate non-coding RNAs in the control of human connectivity and cognition.

One-Sentence Summary

A human-specific microRNA slows down the formation and maturation of neuronal synapses by reducing mitochondrial metabolism and renewal.
Targeted Protein Relocalization via Protein Transport Coupling
Authors: Ng Christine S. C. , Liu Aofei , Cui Bianxiao , Banik Steven M.
Published: October 2023

Subcellular protein localization regulates protein function and can be corrupted in cancers1and neurodegenerative diseases2–4. The localization of numerous proteins has been annotated5–7, and pharmacologically relevant approaches for precise rewiring of localization to address disease-driving phenotypes would be an attractive targeted therapeutic approach. Molecules which harness the trafficking of a shuttle protein to control the subcellular localization of a target protein could provide an avenue for targeted protein relocalization for interactome-rewiring therapeutics. To realize this concept, we deploy a quantitative approach to identify features which govern the ability to hijack protein trafficking, develop a collection of shuttle proteins and ligands, and demonstrate relocalization of proteins bearing endogenous localization signals. Using a custom imaging analysis pipeline, we show that endogenous localization signals can be overcome through molecular coupling of target proteins to shuttle proteins containing sufficiently strong native localization sequences expressed in the necessary abundance. We develop nuclear hormone receptors as viable shuttles which can be harnessed with Targeted Relocalization Activating Molecules (TRAMs) to redistribute disease-driving mutant proteins such as SMARCB1Q318X, TDP43ΔNLS, and FUSR495X. Small molecule-mediated relocalization of FUSR495Xto the nucleus from the cytoplasm reduced the number of cellular stress granules in a model of cellular stress. Using Cas9-mediated knock-in tagging, we demonstrate nuclear enrichment of both low abundance (FOXO3a) and high abundance (FKBP12) endogenous proteins via molecular coupling to nuclear hormone receptor trafficking. Finally, small molecule-mediated redistribution of NMNAT1 from nuclei to axons in primary neurons was able to slow axonal degeneration and pharmacologically mimic the WldS gain-of-function phenotype from mice resistant to certain types of neurodegeneration8. The concept of targeted protein relocalization could therefore nucleate approaches for treating disease through interactome rewiring.
OptoProfilin: A Single Component Biosensor of Applied Cellular Stress
Authors: Mann Noah , Hill Jahiem , Wang Kenneth , Hughes Robert M.
Published: October 2023

The actin cytoskeleton is a biosensor of cellular stress and a potential prognosticator of human disease. In particular, aberrant cytoskeletal structures such as cofilin-actin rods and stress granules formed in response to energetic and oxidative stress are closely linked to neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and ALS. Whether these cytoskeletal phenomena can be harnessed for the development of biosensors for cytoskeletal dysfunction and, by extension, neurodegenerative disease progression, remains an open question. In this work, we describe the design and development of an optogenetic iteration of profilin, an actin monomer binding protein with critical functions in cytoskeletal dynamics. We demonstrate that this optically activated profilin (‘OptoProfilin’) can act as an optically triggered biosensor of applied cellular stress in select immortalized cell lines. Notably, OptoProfilin is a single component biosensor, likely increasing its utility for experimentalists. While a large body of preexisting work closely links profilin activity with cellular stress and neurodegenerative disease, this, to our knowledge, is the first example of profilin as an optogenetic biosensor of stress-induced changes in the cytoskeleton.
Powder shampoo formulation with antioxidant activity: in vitro perspectives
Authors: Madhavan Aishwariya , Unnati Meher , Rachana K. , Jain Prateek , Bhashasaraswathi K. , Joshi Apurva Kumar
Published: October 2023

Purpose

The purpose of the study was to develop a powder shampoo with antioxidant attributes.

Design/methodology/approach

Dry shampoo compositions were formulated containing alpha olefin sulfonate (AOS), sodium cocoyl isethionate (SCI), microcrystalline cellulose, mannitol, carboxymethyl cellulose, maltodextrin and sodium benzoate with or without extract of Cinnamomum zeylanicum bark. Cinnamon extract was chosen for this study owing to its ubiquitously known antioxidant attributes. The formulations were tested for detergency action and antioxidant potential in vitro.

Findings

Cinnamomum zeylanicum extract exhibited noticeable antioxidant activity in vitro. The authors observed that addition of the bark extract to the shampoo formulation was associated with remarkable increase in total phenolic content, total antioxidant activity and radical scavenging activity without any effect on detergency action.

Research limitations/implications

This preliminary study provides a powder shampoo formulation which exhibits antioxidant attributes as a result of incorporation of cinnamon bark extract. Clinical efficacy of the formulation remains to be tested.

Practical implications

Owing to the powder format of the shampoo, the formulation can be manufactured with ease and economically. Functionalizing the formulation with enhancement of antioxidant activity by incorporation of cinnamon bark extract may be associated with beneficial clinical outcomes, which remains to be tested.

Social implications

The proposed formulation may be stored and sold in eco-friendly packing material, thus could pave the way for reducing the burden of plastic consumption by the shampoo industry.

Originality/value

The present work demonstrates that incorporation of cinnamon bark extract to a powder shampoo formulation, containing AOS and SCI as principle surfactants, significantly enhances its antioxidant attributes.
All by myself: examining social media’s effect on social withdrawal and the mediating roles of moral disengagement and cyberaggression
Authors: Tan Caroline S.L.
Published: October 2023

Purpose

The purpose of this study is to examine how the constructs of false self, preference for online social interaction (POSI), compulsive internet use (CIU), and online disinhibition affect social withdrawal in a social media context. The mediating effects of moral disengagement and cyber aggression are also tested.

Design/methodology/approach

Data were collected using an online survey (n = 533) from consumers in Japan. This study used structural equation modeling and PROCESS to examine the proposed relationships.

Findings

The study revealed that false self positively affects moral disengagement while online disinhibition positively affects cyber aggression and moral disengagement. Preference for online social interaction and compulsive internet use both positively impacts social withdrawal. Cyber aggression and moral disengagement were established mediators between false self/ Preference for online social interaction/ compulsive internet use/ online disinhibition and social withdrawal.

Research limitations/implications

Although restricted to cyberaggression, owing to the reciprocal relationship between cyber victimization and cyberaggression, cyber victimization can be included for further study. This study expands the understanding of social withdrawal within the context of social media.

Practical implications

Based on the findings, policies and programs that address mental health that build self-esteem, self-confidence and reduce anxiety ought to be undertaken. Managing and formulating guidelines on anonymity should also be taken into consideration.

Originality/value

This research demonstrates the crucial constructs that affect social media users negatively from the aspects of cyberaggression, moral disengagement and social withdrawal. It also establishes the importance of mental health in reducing adverse effects from social media.
The lip motion trajectory of eccentric oil seal considering material viscoelasticity
Authors: Zhai Fugang , Li Shengnan , Xing Yangtao
Published: October 2023

Purpose

This paper aims to study the motion trajectory of the oil seal for shaft in eccentric state and derive equation of lip motion trajectory.

Design/methodology/approach

This paper analyzes the force during the motion of the eccentric lip by considering the material viscoelasticity, and a cam-plate mechanism is established as an equivalent model for the motion between the shaft and the lip; according to this, the equation of lip motion trajectory is derived.

Findings

The trajectory of the lip lags that of the shaft in the eccentric state because the viscoelasticity-affected lip recovery velocity is lower than the shaft recovery speed. The lip trajectory enters the lag phase earlier and the lag phase’s duration is longer with the increase of the eccentricity and rotational speed, because the deviation of the recovery velocities between the lip and the shaft will be exacerbated.

Originality/value

Innovatively, by considering the viscoelasticity of the material, the cam-plate mechanism is used to equivalent the motion of the shaft-lip to derive the equation for the radial motion trajectory of the eccentric lip. The regularity of lip motion is the key to determining the performance of oil seals, and the eccentric lip trajectory research method revealed in this paper provides a research basis for the performance research and optimization of eccentric oil seals.

Peer review

The peer review history for this article is available at: https://publons.com/publon/10.1108/ILT-06-2023-0161/
Earnings management: a three-decade analysis and future prospects
Authors: Bansal Manish
Published: October 2023

Purpose

This paper undertakes an extensive and systematic review of the literature on earnings management (EM) over the past three decades (1992–2022). Furthermore, the study identifies emerging research themes and proposes future avenues for further investigation in the realm of EM.

Design/methodology/approach

For this study, a comprehensive collection of 2,775 articles on EM published between 1992 and 2022 was extracted from the Scopus database. The author employed various tools, including Microsoft Excel, R studio, Gephi and visualization of similarities viewer, to conduct bibliometric, content, thematic and cluster analyses. Additionally, the study examined the literature across three distinct periods: prior to the enactment of the Sarbanes-Oxley Act (1992–2001), subsequent to the implementation of the Sarbanes-Oxley Act (2002–2012), and after the adoption of International Financial Reporting Standards (2013–2022) to draw more inferences and insights on EM research.

Findings

The study identifies three major themes, namely the operationalization of EM constructs, the trade-off between EM tools (accrual EM, real EM and classification shifting) and the role of corporate governance in mitigating EM in emerging markets. Existing literature in these areas presents mixed and inconclusive findings, suggesting the need for further theoretical development. Further, the study findings observe a shift in research focus over time: initially, understanding manipulation techniques, then evaluating regulatory measures, and more recently, investigating the impact of global accounting standards. Several emerging research themes (technology advancements, cross-cultural and cross-national studies, sustainability, behavioral aspects and non-financial indicators of EM) have been identified. This study subsequent analysis reveals an evolving EM landscape, with researchers from disciplines like data science, computer science and engineering applying their analytical expertise to detect EM anomalies. Furthermore, this study offers significant insights into sophisticated EM techniques such as neural networks, machine learning techniques and hidden Markov models, among others, as well as relevant theories including dynamic capabilities theory, learning curve theory, psychological contract theory and normative institutional theory. These techniques and theories demonstrate the need for further advancement in the field of EM. Lastly, the findings shed light on prominent EM journals, authors and countries.

Originality/value

This study conducts quantitative bibliometric and thematic analyses of the existing literature on EM while identifying areas that require further development to advance EM research.
Prediction of traditional Chinese medicine prescriptions based on multi-label resampling
Authors: Jiang Xiaomei , Wang Shuo , Liu Wenjian , Yang Yun
Published: October 2023

Purpose

Traditional Chinese medicine (TCM) prescriptions have always relied on the experience of TCM doctors, and machine learning(ML) provides a technical means for learning these experiences and intelligently assists in prescribing. However, in TCM prescription, there are the main (Jun) herb and the auxiliary (Chen, Zuo and Shi) herb collocations. In a prescription, the types of auxiliary herbs are often more than the main herb and the auxiliary herbs often appear in other prescriptions. This leads to different frequencies of different herbs in prescriptions, namely, imbalanced labels (herbs). As a result, the existing ML algorithms are biased, and it is difficult to predict the main herb with less frequency in the actual prediction and poor performance. In order to solve the impact of this problem, this paper proposes a framework for multi-label traditional Chinese medicine (ML-TCM) based on multi-label resampling.

Design/methodology/approach

In this work, a multi-label learning framework is proposed that adopts and compares the multi-label random resampling (MLROS), multi-label synthesized resampling (MLSMOTE) and multi-label synthesized resampling based on local label imbalance (MLSOL), three multi-label oversampling techniques to rebalance the TCM data.

Findings

The experimental results show that after resampling, the less frequent but important herbs can be predicted more accurately. The MLSOL method is shown to be the best with over 10% improvements on average because it balances the data by considering both features and labels when resampling.

Originality/value

The authors first systematically analyzed the label imbalance problem of different sampling methods in the field of TCM and provide a solution. And through the experimental results analysis, the authors proved the feasibility of this method, which can improve the performance by 10%−30% compared with the state-of-the-art methods.
The state of family business research in the Visegrád countries
Authors: Csákné Filep Judit , Martyniuk Olga Anna , Wojtyra-Perlejewska Marta
Published: October 2023

Purpose

The institutional context in which family firms operate influences their behaviour and performance, yet literature reviews seldom analyse family firms on a regional basis. To fill this gap, this review aims to present research on family entrepreneurship in the transition economies of the Visegrád countries (V4). In this particular group of European economies, the current formal institutions have largely evolved along Western European lines. However, the transformation of informal institutions appears to be still in its infancy.

Design/methodology/approach

In order to identify the most representative authors, the methodologies used, the main research topics and to establish a future research agenda, the authors selected, through a systematic process, 112 papers from the Web of Science up to the year 2022. The authors performed a bibliographic analysis using clustering algorithms, complemented by a traditional literature review.

Findings

The performance of family firms in transition economies has been the subject of very little research. The results allowed the authors to identify four main areas of research: governance, innovation, sustainability, competitive advantage and considering the influence of the region's characteristics on family business behaviour.

Originality/value

Studies from transition economies can contribute to a broader understanding of family firms in terms of the impact of the institutional environment (especially the influence of sociological changes and specific historical experiences of family members) on their long-term planning, socioemotional wealth (SEW) protection and ethics. In light of recent events, research from the region may also contribute to the understanding of how and to what extent “familiness” influences crisis management or socially responsible behaviour in family firms.
The dangerous use of genetic information
Authors: Johnson David Eugene , Shaw Debora Jane
Published: October 2023

Purpose

The purpose of this paper is to inform or alert readers to the extensive use and ready availability of genetic information that poses varying degrees of social and legal danger. The eugenics movement of the 1920s and the general acceptance of genetic essentialism provide context for considering contemporary examples of the problem.

Design/methodology/approach

This paper takes an argumentative approach, supporting proposals with ideas from historical and current research literature.

Findings

The limits of data protection, extensive use of direct-to-consumer genetic testing and use of genetic information in white nationalist circles portend a resurgence of eugenic beliefs from a century ago.

Social implications

Research-based recommendations may help to avoid extreme consequences by encouraging people to make informed decisions about the use of genetic information.

Originality/value

The paper counterposes contemporary understanding of genetic testing and data accessibility with the much older ideology of eugenics, leading to concerns about how white nationalists might further their aims with 21st century technology.