bluuebunny/crossref_metadata_2025 huggingface dataset:
GOLDEN2-like1is sufficient but not necessary for chloroplast biogenesis in mesophyll cells of C4grasses
Authors: Lambret-Frotte Julia , Smith Georgia , Langdale Jane A.
Published: February 2023

Chloroplasts are the site of photosynthesis. In land plants, chloroplast biogenesis is regulated by a family of transcription factors namedGOLDEN2-like(GLK). In C4grasses, it has been hypothesized that genome duplication events led to the sub-functionalization ofGLKparalogs (GLK1andGLK2) to control chloroplast biogenesis in two distinct cell types: mesophyll and bundle sheath cells. Although previous characterization ofgolden2(g2) mutants in maize has demonstrated a role forGLK2paralogs in regulating chloroplast biogenesis in bundle sheath cells, the function ofGLK1has remained elusive. Here we show that, contrary to expectations,GLK1is not required for chloroplast biogenesis in mesophyll cells of maize. Comparisons between maize andSetaria viridis, which represent two independent C4origins within the Poales, further show that the role ofGLKparalogs in controlling chloroplast biogenesis in mesophyll and bundle sheath cells differs between species. Despite these differences, complementation analysis revealed thatGLK1andGLK2genes from maize are both sufficient to restore functional chloroplast development in mesophyll and bundle sheath cells ofSetaria viridismutants. Collectively our results suggest an evolutionary trajectory in C4grasses whereby both orthologs retained the ability to induce chloroplast biogenesis butGLK2adopted a more prominent developmental role, particularly in relation to chloroplast activation in bundle sheath cells.
Light-Responsive MicroRNAs in Human Retinal Tissue are Differentially Regulated by Distinct Wavelengths of Light
Authors: Celiker Canan , Weissová Kamila , Černá Kateřina Amruz , Oppelt Jan , Šebestíková Jana , Lišková Petra , Bárta Tomáš
Published: February 2023

Retinal microRNA (miRNA) molecules play critical roles in a wide range of processes including cell proliferation, cell death, and synaptic plasticity. Recently they have been shown to regulate crucial processes that are associated with perception of light including visual function, light adaptation, and control of genes regulating circadian light entrainment. Despite extensive work on retinal miRNAs in different model organisms, light-regulated miRNAs in human retina are not known. Here, we aim to characterize these miRNAs. We generated light responsive human retinal organoids that express miRNA families and clusters typically found in the retina. Using in-house-developed photostimulation device, we found that 51 miRNAs are up- or downregulated upon brief photostimulation periods. Clustering analysis revealed that only two miRNA families and three clusters are upregulated, while eight families and ten cluster are downregulated upon photostimulation. Additionally, we found that the light-regulated miRNAs have rapid turnover, and their expression is differentially regulated by distinct wavelengths of light. This study demonstrates that only a small subset of miRNAs is light-responsive in human retinal tissue and the generated human retinal organoids are a valuable model for studying the molecular mechanisms of light perception in the retina.
Sulcal variability in anterior lateral prefrontal cortex contributes to variability in reasoning performance among young adults
Authors: Willbrand Ethan H. , Jackson Samantha , Chen Szeshuen , Hathaway Catherine B. , Voorhies Willa I. , Bunge Silvia A. , Weiner Kevin S.
Published: February 2023

Identifying structure-function correspondences is a major goal among biologists, cognitive neuroscientists, and brain mappers. Recent studies have identified relationships between performance on cognitive tasks and the presence or absence of small, shallow indentations, or sulci, of the human brain. Building on the previous finding that the presence of one such sulcus in the left anterior lateral prefrontal cortex (aLPFC) was related to reasoning task performance in children and adolescents, we tested whether this relationship extended to a different sample, age group, and reasoning task. As predicted, the presence of this aLPFC sulcus—the ventral para-intermediate frontal sulcus—was also associated with higher reasoning scores in young adults (ages 22-36). These findings have not only direct developmental, but also evolutionary relevance—as recent work shows that the pimfs-v is exceedingly rare in chimpanzees. Thus, the pimfs-v is a novel developmental, cognitive, and evolutionarily relevant feature that should be considered in future studies examining how the complex relationships among multiscale anatomical and functional features of the brain give rise to abstract thought.
STAT3 protects HSCs from intrinsic interferon signaling and loss of long-term blood-forming activity
Authors: Patel Bhakti , Zhou Yifan , Babcock Rachel L. , Ma Feiyang , Zal Malgorzata A. , Kumar Dhiraj , Medik Yusra B. , Kahn Laura M. , Pineda Josué E. , Park Elizabeth M. , Tang Ximing , Raso Maria Gabriela , Zal Tomasz , Clise-Dwyer Karen , Giancotti Filippo G. , Colla Simona , Watowich Stephanie S.
Published: February 2023

STAT3 function in hematopoietic stem and progenitor cells (HSPCs) has been difficult to discern asStat3deficiency in the hematopoietic system induces systemic inflammation, which can impact HSPC activity. To address this, we established mixed bone marrow (BM) chimeric mice with CreER-mediatedStat3deletion in 20% of the hematopoietic compartment.Stat3-deficient HSPCs had impaired hematopoietic activity and failed to undergo expansion in BM in contrast toStat3-sufficient (CreER) controls. Single-cell RNA sequencing of Lin−ckit+Sca1+BM cells revealed altered transcriptional responses inStat3-deficient hematopoietic stem cells (HSCs) and multipotent progenitors, including intrinsic activation of cell cycle, stress response, and interferon signaling pathways. Consistent with their deregulation,Stat3-deficient Lin−ckit+Sca1+cells accumulated γH2AX over time. Following secondary BM transplantation,Stat3-deficient HSPCs failed to reconstitute peripheral blood effectively, indicating a severe functional defect in the HSC compartment. Our results reveal essential roles for STAT3 in HSCs and suggest the potential for using targeted synthetic lethal approaches with STAT3 inhibition to remove defective or diseased HSPCs.

Key Points

STAT3 is critical for hematopoietic activity and hematopoietic stem cell maintenance in non-inflammatory conditions

STAT3 has a cell-intrinsic role in the suppression of interferon signaling and myeloid-skewed transcription in hematopoietic stem cells
The balance of acidic and hydrophobic residues predicts acidic transcriptional activation domains from protein sequence
Authors: Kotha Sanjana R. , Staller Max Valentín
Published: February 2023

Transcription factors activate gene expression in development, homeostasis, and stress with DNA binding domains and activation domains. Although there exist excellent computational models for predicting DNA binding domains from protein sequence (Stormo, 2013), models for predicting activation domains from protein sequence have lagged behind (Erijman et al., 2020; Ravarani et al., 2018; Sanborn et al., 2021), particularly in metazoans. We recently developed a simple and accurate predictor of acidic activation domains on human transcription factors (Staller et al., 2022). Here, we show how the accuracy of this human predictor arises from the balance between hydrophobic and acidic residues, which together are necessary for acidic activation domain function. When we combine our predictor with the predictions of neural network models trained in yeast, the intersection is more predictive than individual models, emphasizing that each approach carries orthogonal information. We synthesize these findings into a new set of activation domain predictions on human transcription factors.
Emergence of High-Order Functional Hubs in the Human Brain
Authors: Santos Fernando A.N. , Tewarie Prejaas K.B. , Baudot Pierre , Luchicchi Antonio , Barros de Souza Danillo , Girier Guillaume , Milan Ana P. , Broeders Tommy , Centeno Eduarda G.Z. , Cofre Rodrigo , Rosas Fernando E , Carone Davide , Kennedy James , Stam Cornelis J. , Hillebrand Arjan , Desroches Mathieu , Rodrigues Serafim , Schoonheim Menno , Douw Linda , Quax Rick
Published: February 2023

Network theory is often based on pairwise relationships between nodes, which is not necessarily realistic for modeling complex systems. Importantly, it does not accurately capture non-pairwise interactions in the human brain, often considered one of the most complex systems. In this work, we develop a multivariate signal processing pipeline to build high-order networks from time series and apply it to resting-state functional magnetic resonance imaging (fMRI) signals to characterize high-order communication between brain regions. We also propose connectivity and signal processing rules for building uniform hypergraphs and argue that each multivariate interdependence metric could define weights in a hypergraph. As a proof of concept, we investigate the most relevant three-point interactions in the human brain by searching for high-order “hubs” in a cohort of 100 individuals from the Human Connectome Project. We find that, for each choice of multivariate interdependence, the high-order hubs are compatible with distinct systems in the brain. Additionally, the high-order functional brain networks exhibit simultaneous integration and segregation patterns qualitatively observable from their high-order hubs. Our work hereby introduces a promising heuristic route for hypergraph representation of brain activity and opens up exciting avenues for further research in high-order network neuroscience and complex systems.
Inferring a directed acyclic graph of phenotypes from GWAS summary statistics
Authors: Zilinskas Rachel , Li Chunlin , Shen Xiaotong , Pan Wei , Yang Tianzhong
Published: February 2023

Summary

Estimating phenotype networks is a growing field in computational biology. It deepens the understanding of disease etiology and is useful in many applications. In this study, we present a method that constructs a phenotype network by assuming a Gaussian linear structure model embedding a directed acyclic graph (DAG). We utilize genetic variants as instrumental variables and show how our method only requires access to summary statistics from a genome-wide association study (GWAS) and a reference panel of genotype data. Besides estimation, a distinct feature of the method is its summary statistics-based likelihood ratio test on directed edges. We applied our method to estimate a causal network of 29 cardiovascular-related proteins and linked the estimated network to Alzheimer’s disease (AD). A simulation study was conducted to demonstrate the effectiveness of this method. An R package sumdag implementing the proposed method, all relevant code, and a Shiny application are available athttps://github.com/chunlinli/sumdag.
Defining the structure, signals, and cellular elements of the gastric mesenchymal niche
Authors: Manieri Elisa , Tie Guodong , Seruggia Davide , Madha Shariq , Maglieri Adrianna , Huang Kun , Fujiwara Yuko , Zhang Kevin , Orkin Stuart H. , He Ruiyang , McCarthy Neil , Shivdasani Ramesh A.
Published: February 2023

PDGFRA-expressing mesenchyme provides a niche for intestinal stem cells. Corresponding compartments are unknown in the stomach, where corpus and antral glandular epithelia have similar niche dependencies but are structurally distinct from the intestine and from each other. Previous studies considered antrum and corpus as a whole and did not assess niche functions. Using high-resolution imaging and sequencing, we identify regional subpopulations and niche properties of purified mouse corpus and antral PDGFRA+cells. PDGFRAHisub-epithelial myofibroblasts are principal sources of BMP ligands in both gastric segments; two molecularly distinct groups distribute asymmetrically along antral glands but together fail to support epithelial organoidsin vitro. In contrast, strategically positioned PDGFRALocells that express CD55 enable corpus and antral organoid growth in the absence of other cellular or soluble factors. Our study provides detailed insights into spatial, molecular, and functional organization of gastric mesenchyme and the spectrum of signaling sources for stem cell support.
Unique Amphipathicα-helix Drives Membrane Insertion and Enzymatic Activity of ATG3
Authors: Nishimura Taki , Lazzeri Gianmarco , Mizushima Noboru , Covino Roberto , Tooze Sharon A.
Published: February 2023

Abstract

Autophagosome biogenesis requires a localized perturbation of lipid membrane dynamics and a unique protein-lipid conjugate. Autophagy-related (ATG) proteins catalyze this biogenesis on cellular membranes, but the underlying molecular mechanism remains unclear. Focusing on the final step of the protein-lipid conjugation reaction, ATG8/LC3 lipidation, we show how membrane association of the conjugation machinery is organized and fine-tuned at the atomistic level. Amphipathicα-helices in ATG3 proteins (AHATG3) are found to have low hydrophobicity and to be less bulky. Molecular dynamics simulations reveal that AHATG3regulates the dynamics and accessibility of the thioester bond of the ATG3∼LC3 conjugate to lipids, allowing covalent lipidation of LC3. Live cell imaging shows that the transient membrane association of ATG3 with autophagic membranes is governed by the less bulky- hydrophobic feature of AHATG3. Collectively, the unique properties of AHATG3facilitate protein- lipid bilayer association leading to the remodeling of the lipid bilayer required for the formation of autophagosomes.

Teaser

We uncover the unique biophysical property of amphipathicα-helix essential for autophagy
Thrombin activation of the factor XI dimer is a multi-staged process for each subunit
Authors: Barroeta Awital Bar , Albanese Pascal , Marquart J. Arnoud , Meijers Joost C.M. , Scheltema Richard A.
Published: February 2023

Factor XI (FXI), a protein in the intrinsic coagulation pathway, can be activated by two enzymes. In hemostasis, FXI is activated by thrombin, while FXIIa-mediated activation is prothrombotic. The interactions between FXI and its activating enzymes are poorly understood due to their transient nature. Here, we applied structural proteomics, molecular dynamics simulations and binding assays to investigate the interface between thrombin and FXI including the dynamics underlying FXI activation. We demonstrate that activation of FXI is a multi-staged process, where thrombin first binds to Pro520 on FXI, after which it migrates towards the activation site by engaging the apple 1 domain and finally Arg378. We validated with known mutation sites and additionally found that Pro520 is conserved in prekallikrein (PK). This enables binding of thrombin even though it cannot activate PK. Understanding the exact binding of thrombin to FXI points a way for future interventions for bleeding or thrombosis.
Cooperation and cheating orchestrateVibrioassemblages and polymicrobial synergy in oysters infected with OsHV-1 virus
Authors: Oyanedel Daniel , Lagorce Arnaud , Bruto Maxime , Haffner Philippe , Morot Amandine , Dorant Yann , de La Forest Divonne Sébastien , Delavat François , Inguimbert Nicolas , Montagnani Caroline , Morga Benjamin , Toulza Eve , Chaparro Cristian , Escoubas Jean-Michel , Labreuche Yannick , Gueguen Yannick , Vidal-Dupiol Jeremie , de Lorgeril Julien , Petton Bruno , Degremont Lionel , Tourbiez Delphine , Pimparé Léa-Lou , Leroy Marc , Romatif Océane , Pouzadoux Juliette , Mitta Guillaume , Roux Frédérique Le , Charrière Guillaume M. , Travers Marie-Agnès , Destoumieux-Garzón Delphine
Published: February 2023

Polymicrobial diseases significantly impact the health of humans and animals but remain understudied in natural systems. We recently described the Pacific Oyster Mortality Syndrome (POMS), a polymicrobial disease that impacts oyster production and is prevalent worldwide. Analysis of POMS-infected oysters on the French North Atlantic coast revealed that the disease involves co-infection with the endemic ostreid herpesvirus 1 (OsHV-1) and virulent bacterial species such asVibrio crassostreae. However, it is unknown whether consistentVibriopopulations are associated with POMS in different regions, howVibriocontribute to POMS, and how they interact with the OsHV-1 virus during pathogenesis.

We resolved theVibriopopulation structure in oysters from a Mediterranean ecosystem and investigated their functions in POMS development. We find thatVibrio harveyiandVibrio rotiferianusare the predominant species found in OsHV-1-diseased oysters and show that OsHV-1 is necessary to reproduce the partition of theVibriocommunity observed in the field. By characterizing the interspecific interactions between OsHV-1,V. harveyiandV. rotiferianus, we find that onlyV. harveyisynergizes with OsHV-1. When co-infected, OsHV-1 andV. harveyibehave cooperatively by promoting mutual growth and accelerating oyster death.V. harveyishowed high virulence potential in oysters and dampened host cellular defenses, making oysters a more favorable niche for microbe colonization. We next investigated the interactions underlying the co-occurrence of diverseVibriospecies in diseased oysters. We found thatV. harveyiharbors genes responsible for the biosynthesis and uptake of a key siderophore called vibrioferrin. This important resource promotes the growth ofV. rotiferianus, a cheater that efficiently colonizes oysters during POMS without costly investment in host manipulation nor metabolite sharing.

By connecting field-based approaches, laboratory infection assays and functional genomics, we have uncovered a web of interdependencies that shape the structure and function of the POMS pathobiota. We showed that cooperative behaviors contribute to synergy between bacterial and viral co-infecting partners. Additional cheating behaviors further shape the polymicrobial consortium. Controlling such behaviors or countering their effects opens new avenues for mitigating polymicrobial diseases.
RNA-Seq reveals thatPseudomonas aeruginosamounts growth medium-dependent competitive responses when sensing diffusible cues fromBurkholderia cenocepacia
Authors: Leinweber Anne , Laffont Clémentine , Lardi Martina , Eberl Leo , Pessi Gabriella , Kümmerli Rolf
Published: February 2023

Most habitats host diverse bacterial communities, offering opportunities for inter-species interactions. While competition might often dominate such interactions, little is known about whether bacteria can sense competitors and mount adequate responses. The competition-sensing hypothesis proposes that bacteria can use cues such as nutrient stress and cell damage to prepare for battle. Here, we tested this hypothesis by measuring transcriptome changes inPseudomonas aeruginosaexposed to the supernatant of its competitorBurkholderia cenocepacia. We found thatP. aeruginosaexhibited significant and growth-medium-dependent transcriptome changes in response to competition. In iron-rich medium,P. aeruginosaup-regulated genes encoding the type-VI secretion system and the siderophore pyoverdine, whereas genes encoding phenazine toxins and hydrogen cyanide were upregulated under iron-limited conditions. Moreover, general stress response and quorum-sensing regulators were upregulated upon supernatant exposure. Altogether, our results reveal nuanced competitive responses ofP. aeruginosawhen confronted withB. cenocepaciasupernatant, integrating both environmental and social cues.
Genome-wide screens for mitonuclear co-regulators uncover links between compartmentalized metabolism and mitochondrial gene expression
Authors: Kramer Nicholas J. , Prakash Gyan , Choquet Karine , Soto Iliana , Petrova Boryana , Merens Hope E. , Kanarek Naama , Churchman L. Stirling
Published: February 2023

Mitochondrial oxidative phosphorylation (OXPHOS) complexes are assembled from proteins encoded by both nuclear and mitochondrial DNA. These dual-origin enzymes pose a complex gene regulatory challenge for cells, in which gene expression must be coordinated across organelles using distinct pools of ribosomes. How cells produce and maintain the accurate subunit stoichiometries for these OXPHOS complexes remains largely unknown. To identify genes involved in dual-origin protein complex synthesis, we performed FACS-based genome-wide screens analyzing mutant cells with unbalanced levels of mitochondrial- and nuclear-encoded subunits of cytochromecoxidase (Complex IV). We identified novel genes involved in OXPHOS biogenesis, including two uncharacterized genes:PREPLandNME6. We found that PREPL specifically regulates Complex IV biogenesis by interacting with mitochondrial protein synthesis machinery, while NME6, an uncharacterized nucleoside diphosphate kinase (NDPK), controls OXPHOS complex biogenesis through multiple mechanisms reliant on its NDPK domain. First, NME6 maintains local mitochondrial pyrimidine triphosphate levels essential for mitochondrial RNA abundance. Second, through stabilizing interactions with RCC1L, NME6 modulates the activity of mitoribosome regulatory complexes, leading to disruptions in mitoribosome assembly and mitochondrial RNA pseudouridylation. Taken together, we propose that NME6 acts as a link between compartmentalized mitochondrial metabolites and mitochondrial gene expression. Finally, we present these screens as a resource, providing a catalog of genes involved in mitonuclear gene regulation and OXPHOS biogenesis.
RNPS1 stabilizes NAT10 protein to facilitate translation in cancer via tRNA ac4C modification
Authors: Wang Xiaochen , Li Kang , Cheng Maosheng , Xu Hao , Chen Jie , Peng Xin , Ling Rongsong , Chen Jianwen , Wan Yuehan , Ke Lixin , Zhang Caihua , Zhang Qitong , Zou Yutong , Chen Fangfang , Chen Zhi , Chen Shuang , Li Jingting , Peng Liang , Chen Qianming , Wang Cheng , Liu Qi , Chen Demeng
Published: February 2023

NAT10 is dysregulated and plays an essential role in various types of cancers. However, the exact machenism of how NAT10 regulates cancer progression remains debatable. In this report, we show that NAT10 affects tumorigeneis mainly based on its acetylation function on tRNA. In addition, we found NAT10 regulate the ac4C of tRNA in cancer via interaction with RNPS1, which in turn protect NAT10 from degradation by E3 ubiquitin ligase ZSWIM6. We developed TRMC-seq method to compreshensively profile tRNA ac4C sites and uncovered the presence of ac4C in a broader range of tRNA isoacceptors than previous studies. Multi-omics analysis identified AP-1 signaling pathway as a major downstream mediator of NAT10. Mechanistically, we found NAT10 is responsible for the translation efficiency genes which contain higher ac4C-tRNA codon. Importantly, our genetic mouse model validated our in vitro findings of NAT10 in cancer. Our study highlights a role of NAT10 in mediating tRNA ac4C to regulate the translation and tumorigenesis of cancer.
Changes in social behaviour with alterations of MAPK3 and KCTD13/CUL3 pathways in two new outbred rat models for the 16p11.2 syndromes with autism spectrum disorders
Authors: Lorenzo Sandra Martin , Muniz Moreno Maria Del Mar , Atas Helin , Pellen Marion , Nalesso Valérie , Raffelsberger Wolfgang , Prevost Geraldine , Lindner Loic , Birling Marie-Christine , Menoret Séverine , Tesson Laurent , Negroni Luc , Concordet Jean-Paul , Anegon Ignacio , Herault Yann
Published: February 2023

Copy number variations (CNVs) of the human 16p11.2 locus are associated with several developmental/neurocognitive syndromes. Particularly, deletion and duplication of this genetic interval are found in patients with autism spectrum disorders, intellectual disability and other psychiatric traits. The high gene density associated with the region and the strong phenotypic variability of incomplete penetrance, make the study of the 16p11.2 syndromes extremely complex. To systematically study the effect of 16p11.2 CNVs and identify candidate genes and molecular mechanisms involved in the pathophysiology, mouse models were generated previously and showed learning and memory, and to some extent social deficits. To go further in understanding the social deficits caused by 16p11.2 syndromes, we engineered deletion and duplication of the homologous region to the human 16p11.2 genetic interval in two rat outbred strains, Sprague Dawley (SD) and Long Evans (LE). The 16p11.2 rat models displayed convergent defects in social behaviour and only a few cognitive defects. Interestingly major pathways affecting MAPK3 and CUL3 were found altered in the rat 16p11.2 models with additional changes in males compared to females. Altogether, the consequences of the 16p11.2 genetic region dosage on social behaviour are now found in three different species: humans, mice and rats. In addition, the rat models pointed to sexual dimorphism, with lower severity of phenotypes in rat females compared to male mutants. This phenomenon is also observed in humans. We are convinced that the two rat models will be key to further investigating social behaviour and understanding the brain mechanisms and specific brain regions that are key to controlling social behaviour.
Ormdl3 regulation of specific ceramides is dispensable for β-cell function and glucose homeostasis under obesogenic conditions
Authors: Hurley Liam D , Lee Hugo , Wade Gina , Simcox Judith , Engin Feyza
Published: February 2023

Chronic elevation of sphingolipids contributes to β-cell failure. ORMDL3 has been identified as a key regulator of sphingolipid homeostasis, however, its function in pancreatic β-cell pathophysiology remains unclear. Here, we generated a mouse model lackingOrmdl3within pancreatic β-cells (Ormdl3β-/-). We show that loss of β-cellOrmdl3does not alter glucose tolerance, insulin sensitivity, insulin secretion, islet morphology, or cellular ceramide levels on standard chow diet. When challenged with a high fat diet, whileOrmdl3β-/-mice did not exhibit any alteration in metabolic parameters or islet architecture, lipidomics analysis revealed significantly higher levels of very long chain ceramides in their islets. Taken together, our results reveal that loss ofOrmdl3alone is not sufficient to impinge upon β-cell function or whole-body glucose and insulin homeostasis, but loss ofOrmdl3does alter specific sphingolipid levels.
Crystal structures reveal the framework ofcis-acyltransferase modular polyketide synthases
Authors: Keatinge-Clay Adrian T. , Miyazawa Takeshi , Zhang Jie , Ray Katherine A. , Lutgens Joshua D. , Bista Ramesh , Lin Sally N.
Published: February 2023

Although the domains ofcis-acyltransferase (cis-AT) modular polyketide synthases (PKS’s) have been understood at atomic resolution for over a decade, the domain-domain interactions responsible for the architectures and activities of these giant molecular assembly lines remain largely uncharacterized. The multimeric structure of the α6β6fungal fatty acid synthase (FAS) provides 6 equivalent reaction chambers for its acyl carrier protein (ACP) domains to shuttle carbon building blocks and the growing acyl chain between surrounding, oriented enzymatic domains. The presumed homodimeric oligomerization ofcis-AT assembly lines is insufficient to provide similar reaction chambers; however, the crystal structure of a ketosynthase (KS)+AT didomain presented here and three already reported show an interaction between the AT domains appropriate for lateral multimerization. This interaction was used to construct a framework for the pikromycin PKS from its KS, AT, and docking domains that contains highly-ordered reaction chambers. Its AT domains also mediate vertical interactions, both with upstream KS domains and downstream docking domains.
Chemoproteomic Profiling Reveals that Anti-Cancer Natural Product Dankastatin B Covalently Targets Mitochondrial VDAC3
Authors: Belcher Bridget P. , Machicao Paulo A. , Tong Binqi , Ho Emily , Friedli Julia , So Brian , Bui Helen , Isobe Yosuke , Maimone Thomas J. , Nomura Daniel K.
Published: February 2023

Chlorinated gymnastatin and dankastatin alkaloids derived from the fungal strainGymnascella dankaliensishave been reported to possess significant anti-cancer activity but their mode of action is unknown. These members possess electrophilic functional groups that may undergo covalent bond formation with specific proteins to exert their biological activity. To better understand the mechanism of action of this class of natural products, we mapped the proteome-wide cysteine-reactivity of the most potent of these alkaloids, dankastatin B, using activitybased protein profiling chemoproteomic approaches. We identified a primary target of dankastatin B in breast cancer cells as cysteine C65 of the voltage-dependent anion selective channel on the outer mitochondrial membrane VDAC3. We demonstrated direct and covalent interaction of dankastatin B with VDAC3. VDAC3 knockdown conferred hyper-sensitivity to dankastatin B-mediated anti-proliferative effects in breast cancer cells indicating that VDAC3 was at least partially involved in the anti-cancer effects of this natural product. Our study reveals a potential mode of action of dankastatin B through covalent targeting of VDAC3 and highlight the utility of chemoproteomic approaches in gaining mechanistic understanding of electrophilic natural products.
Deep learning-based codon optimization with large-scale synonymous variant datasets enables generalized tunable protein expression
Authors: Constant David A. , Gutierrez Jahir M. , Sastry Anand V. , Viazzo Rebecca , Smith Nicholas R. , Hossain Jubair , Spencer David A. , Carter Hayley , Ventura Abigail B. , Louie Michael T. M. , Kohnert Christa , Consbruck Rebecca , Bennett Joshua , Crawford Kenneth A. , Sutton John M. , Morrison Anneliese , Steiger Andrea K. , Jackson Kerianne A. , Stanton Jennifer T. , Abdulhaqq Shaheed , Hannum Gregory , Meier Joshua , Weinstock Matthew , Gander Miles
Published: February 2023

Increasing recombinant protein expression is of broad interest in industrial biotechnology, synthetic biology, and basic research. Codon optimization is an important step in heterologous gene expression that can have dramatic effects on protein expression level. Several codon optimization strategies have been developed to enhance expression, but these are largely based on bulk usage of highly frequent codons in the host genome, and can produce unreliable results. Here, we develop deep contextual language models that learn the codon usage rules from natural protein coding sequences across members of theEnterobacteralesorder. We then fine-tune these models with over 150,000 functional expression measurements of synonymous coding sequences from three proteins to predict expression inE. coli. We find that our models recapitulate natural context-specific patterns of codon usage and can accurately predict expression levels across synonymous sequences. Finally, we show that expression predictions can generalize across proteins unseen during training, allowing forin silicodesign of gene sequences for optimal expression. Our approach provides a novel and reliable method for tuning gene expression with many potential applications in biotechnology and biomanufacturing.
Molecular architecture and platelet-activating properties of small immune complexes assembled on intact heparin and their possible involvement in heparin-induced thrombocytopenia
Authors: Yang Yang , Du Yi , Ivanov Daniil , Niu Chendi , Clare Rumi , Smith James W. , Nazy Ishac , Kaltashov Igor A.
Published: February 2023

Heparin-induced thrombocytopenia (HIT) is an adverse reaction to heparin leading to a reduction in circulating platelets with an increased risk of thrombosis. It is precipitated by polymerized immune complexes consisting of pathogenic antibodies that recognize a small chemokine platelet factor 4 (PF4) bound to heparin, which trigger platelet activation and a hypercoagulable state. Characterization of these immune complexes is extremely challenging due to the enormous structural heterogeneity of such macromolecular assemblies and their constituents (especially heparin). We use native mass spectrometry to characterize small immune complexes formed by PF4, heparin and monoclonal HIT-specific antibodies. Up to three PF4 tetramers can be assembled on a heparin chain, consistent with the results of molecular modeling studies showing facile polyanion wrapping along the polycationic belt on the PF4 surface. Although these assemblies can accommodate a maximum of only two antibodies, the resulting immune complexes are capable of platelet activation despite their modest size. Taken together, these studies provide further insight into molecular mechanisms of HIT and other immune disorders where anti-PF4 antibodies play a central role.
Effect of geomagnetic activity on investors and managers: evidence from the pricing and timing of disclosure of earnings news
Authors: Asthana Sharad , Kalelkar Rachana
Published: February 2023

Purpose

This paper's purpose was to examine the impact of geomagnetic activity (GMA) on the timing and valuation of earnings information disclosed by firms every quarter.

Design/methodology/approach

The authors start the analyses with a sample of 112,669 client firms from 1989 to 2018. To analyze the impact of GMA on the earnings response coefficient (ERC), the authors use the three-day cumulative abnormal returns and cumulative abnormal returns for the extended post-earnings announcement window [2, 75] as the dependent variables. The authors interact unexpected earnings (UE) with the C9 Index, an index commonly used to measure GMA and study how GMA affects the pricing of new public information. To examine the effect of GMA on the timing of disclosure of earnings news, the authors regress a variant of the GMA index on the propensity to disclose bad earnings news.

Findings

The authors find significantly lower earnings response coefficients during periods of high GMA. This effect is permanent and stock prices do not correctly incorporate the implications of earnings information over time. The authors also show that managerial behavior is affected by GMA as well and the managers are more (less) likely to release bad (good) news during periods of higher activity. Finally, the authors also find that in situations where stakeholders are likely to rely on modern technology that depends minimally on humans, the adverse impact of GMA on the pricing of earnings information is mitigated.

Originality/value

The literature on the effect of GMA on the capital market is very limited and focuses primarily on stock returns, while the behavioral finance literature focuses on circumstances like weather, temperature and sporting outcome to study how the investors' mood affects their capital market behavior. The authors add to both the literature by investigating how GMA influences investors' and managers' behaviors in the capital market.
A supply chain perspective of prefabricated housebuilding diffusion in New Zealand
Authors: Masood Rehan , Roy Krishanu , González Vicente A. , Lim James B.P. , Nasir Abdur Rehman
Published: February 2023

Purpose

Globally, prefabrication in housebuilding has evolved as an innovative approach to attain sustainability and affordability. However, the SC, including non-producers and producers, of prefabricated housebuilding projects is still not perceptually aligned, hindering innovation diffusion. This paper investigates the contemporary industry perspective on PHB for conceptualisation, market share and growth, innovation diffusion and the producer's role in the context of New Zealand.

Design/methodology/approach

An exploratory qualitative research design was chosen to learn the perceptual stance of the industry. A semi-structured survey was conducted, followed by interviews with selected supply chain participants, who were producers and non-producers and had relevant experience in the PHB industry.

Findings

This study reports the common terminologies used by supply chain members, with justification and explanation. Further, the perceived market share and growth of the PHB industry are obtained and compared with subsequent studies to determine the capability and capacity. The perception of the diffusion of PHB by type is reported to portray the overall trend of the industry. In the last, the role of producers as the suppliers of PHB projects is investigated to establish the stakeholder positional criticality.

Practical implications

This study can help researchers and practitioners gain insight into the PHB industry from a multi-dimensional perspective. This study is a potential first step to formalise the policy, programme, strategies and action plan for the uptake of the PHB in the New Zealand.

Originality/value

PHB diffusion in the supply chain perspective, considering multi-dimensional aspects, has not been considered in previous studies as government agencies produce most of the literature. This academic research establishes the theoretical linkage towards PHB diffusion and reports the current status.
Trends in financing of basic education in Ghana – a political economy analysis
Authors: Adamba Clement
Published: February 2023

Purpose

Using a political economy framework, this paper examines the financing trend, by investigating three systematic spikes occurring between 2004 and 2016. The study aims to provide a useful review of the interaction of politics, financial decisions and educational outcomes. Additionally it provides a useful guide, especially to academics, to identify political and economic conceptualizations that will predict expenditure decision-making of political actors and to be able to provide policy advice on the future effect of such decisions on availability and accessibility of public goods.

Design/methodology/approach

The paper adopts a secondary data analysis approach, drawing upon secondary data sources such as from the Ministry of Education, budget statements from the Ministry of Finance, as well as relevant policy documents. Additional information for the study was also extracted from the manifestos of the two leading political parties in Ghana – the New Patriotic Party and the National Democratic Congress and their viewpoints on financing of education in Ghana.

Findings

Using two epochal years when financing of education peaked (2008 and 2012), which coincided with election years, the trend lends itself to being interpreted as opportunistic spending. It appears to give credence to a conclusion that the increases in spending are more politically directed and nonneutral.

Originality/value

This paper fulfills an identified need to study the trend of basic education financing in Ghana, which will help policy actors make better-informed decisions with the introduction of the novel “adaptive opportunism” framework analysis tool.
Designing circular supply chains in start-up companies: evidence from Italian fashion and construction start-ups
Authors: Ciccullo Federica , Pero Margherita , Patrucco Andrea S.
Published: February 2023

Purpose

The theory of complex adaptive systems (CASs) represents an interesting perspective to study the characteristics of circular supply chains (CSCs). In this regard, the current literature lacks evidence regarding coordination and integration mechanisms, characteristics of the environment and emerging system properties of CSCs. This paper aims to fill this gap and focuses on how and why companies design (i.e. configure and coordinate) their CSCs and what value these design choices help to create across different industries.

Design/methodology/approach

The authors use a multiple case study approach and analyze data collected from a sample of five sustainable start-ups operating in the fashion and construction industries in Italy to better understand how these companies design (i.e. configure and coordinate) their CSCs.

Findings

Results reveal that in the two industries under investigation, the design of CSCs built around open and closed–loop logic is triggered by the intention to solve a negative sustainability impact. The sustainability impact determines whether the value is restored within the same supply chain, in another, or inside or outside the same industry. Interestingly, start-ups appear to coordinate other CSC actors with three leading roles: (1) orchestrator, (2) integrated orchestrator and (3) circular manufacturer. The coordination role of the start-ups differs in each supply chain configuration based on the level of vertical integration of manufacturing activities.

Originality/value

From a theoretical perspective, the authors' results expand previous supply chain management (SCM) literature by presenting an empirical analysis of the configuration and coordination of CSCs, and discussing the drivers for creating such circularity from a CAS perspective. From a managerial perspective, the authors offer a practical experience to entrepreneurs on how to transform circular and sustainable business model aspirations into CSC practices.
An analysis of barriers for successful implementation of municipal solid waste management in Beijing: an integrated DEMATEL-MMDE-ISM approach
Authors: Wang Chao , Sun Yongkang , Lim Ming K. , Ghadimi Pezhman , Azadnia Amir Hossein
Published: February 2023

Purpose

With rapid industrialization and urbanization, municipal solid waste (MSW) management has become a serious challenge worldwide, especially in developing countries. The Beijing Municipality is a representative example of many local governments in China that are facing MSW management issues. Although there have been studies in the area of MSW management in the literature, less attention has been devoted to developing a structured framework that identifies and interprets the barriers to MSW management in megacities, especially in Beijing. Therefore, this study focuses on identifying a comprehensive list of barriers affecting the successful implementation of MSW management in Beijing.

Design/methodology/approach

Through an extensive review of related literature, 12 barriers are identified and classified into five categories: government, waste, knowledge dissemination, MSW management process and market. Using an integrated approach including the decision-making trial and evaluation laboratory (DEMATEL), maximum mean de-entropy algorithm (MMDE) and interpretive structural modeling (ISM), a conceptual structural model of MSW implementation barriers is constructed to provide insights for industrial decision-makers and policymakers.

Findings

The results show that a lack of economic support from the government, imperfect MSW-related laws and regulations, the low education of residents and the lack of publicity of waste recycling knowledge are the main barriers to MSW management in Beijing. Combined with expert opinions, the paper provides suggestions and guidance to municipal authorities and industry practitioners to guide the successful implementation of MSW management.

Practical implications

The findings of this study can provide a reference for MSW management in other metropolises in China and other developing countries.

Originality/value

This study proposes a hybrid DEMATEL-MMDE-ISM approach to resolve the subjectivity issues of the traditional ISM approach and it analyzes the barriers that hinder MSW management practices in Beijing.
Prognosis of entrepreneurial traits among agricultural undergraduate students in India using machine learning
Authors: Jarial Sapna , Verma Jayant
Published: February 2023

Purpose

This study aimed to understand the agri-entrepreneurial traits of undergraduate university students using machine learning (ML) algorithms.

Design/methodology/approach

This study used a conceptual framework of individual-level determinants of entrepreneurship and ML. The Google Survey instrument was prepared on a 5-point scale and administered to 656 students in different sections of the same class during regular virtual classrooms in 2021. The datasets were analyzed and compared using ML.

Findings

Entrepreneurial traits existed among students before attending undergraduate entrepreneurship courses. Establishing strong partnerships (0.359), learning (0.347) and people-organizing ability (0.341) were promising correlated entrepreneurial traits. Female students exhibited fewer entrepreneurial traits than male students. The random forest model exhibited 60% accuracy in trait prediction against gradient boosting (58.4%), linear regression (56.8%), ridge (56.7%) and lasso regression (56.0%). Thus, the ML model appeared to be unsuitable to predict entrepreneurial traits. Quality data are important for accurate trait predictions.

Research limitations/implications

Further studies can validate K-nearest neighbors (KNN) and support vector machine (SVM) models against random forest to support the statement that the ML model cannot be used for entrepreneurial trait prediction.

Originality/value

This research is unique because ML models, such as random forest, gradient boosting and lasso regression, are used for entrepreneurial trait prediction by agricultural domain students.
Sociocultural discrepancy in archaeological sites of Mexico: an overview of the situation in the state of Morelos
Authors: Gonzalez Armenta Emmanuel David
Published: February 2023

Purpose

The aim is to expose the lack of recognition of archaeological sites as a symbolic identity and cultural integrator, showcasing how a deconstructed ideal of public policies and social practices resulted from mismanagement in the processes of safeguarding the historical culture of the sites. It is intended to highlight this discrepancy as to raise awareness on the equivocal direction these complications are heading to and to stress the advocacy for knowledge dissemination government sectors should aim on promoting.

Design/methodology/approach

The article draws substantively on the analysis of case studies at state and national level. The archaeological cultural value interpretation is supported by the analysis of historical records such as exploration logs, government organizations’ workbooks, norms and regulations of archaeological conservation and literature review. The current deconstructed cultural value of archaeological sites is interpreted given trends of promotion of archaeological heritage, which ultimately resulted in a misconception of origins.

Findings

The subsequent analysis shows that present-day political and social activities on archaeological sites are predisposed by a mismanagement of cultural promotion. The preference for activities that differ from indigenous traditions, commercialization of culture and urban growth have diverged the ideal of culture integration and knowledge dissemination these sites were rescued for, leading to the ignorance of the population towards their cultural value. This phenomenon demonstrates that archaeology in Morelos is currently submerged in a misconception of origins.

Originality/value

The article aims to expose an array of references to issues of the usefulness of archaeological heritage for political and economic purposes as a referent for future studies.