bluuebunny/crossref_metadata_2025 huggingface dataset:
Dissecting the Impact of Maternal Androgen Exposure on Offspring Health through Targeting the Androgen Receptor in Developmental Programming
Authors: Lu Haojiang , Jiang Hong , Li Congru , Derisoud Emilie , Zhao Allan , Eriksson Gustaw , Lindgren Eva , Pui Han-Pin , Risal Sanjiv , Pei Yu , Maxian Theresa , Ohlsson Claes , Benrick Anna , Haider Sandra , Stener-Victorin Elisabet , Deng Qiaolin
Published: December 2023

Women with polycystic ovary syndrome (PCOS) exhibit sustained elevation in circulating androgens during pregnancy, an independent risk factor linked to pregnancy complications and adverse neonatal outcomes. Yet, further investigation is required to understand the precise mechanisms and the impact on cell-type specific placental dysfunction. To explore these dynamics, a PCOS-like mice model was induced with continuous androgen exposure throughout pregnancy, mimicking the human-PCOS. This resulted in impaired placental and embryonic development, leading to mid-gestation lethality. Co-treatment with the androgen receptor blocker, flutamide, prevented this lethality. Comprehensive analysis using whole-genome bisulfite and RNA sequencing revealed the diminished proportion of trophoblast precursors by downregulation ofCdx2. The absence ofGcm1,Synb,andPrl3b1further resulted in decreased numbers of syncytiotrophoblasts and sinusoidal trophoblast giant cells, leading to observed compromised placenta labyrinth formation. Importantly, human trophoblast organoids exposed to androgens exhibited analogous alterations, highlighting impaired trophoblast differentiation as a key feature in PCOS-related pregnancy complications. Remarkably, all effects were mediated through the androgen receptor pathways, as demonstrated by comparable offspring phenotypes to controls when treated with flutamide. These findings provide novel insight into the PCOS-related pregnancy complications, and potential cellular targets for future treatment.
Molecular signature of primate astrocytes reveals pathways and regulatory changes contributing to the human brain evolution
Authors: Ciuba K. , Piotrowska A. , Chaudhury D. , Dehingia B. , Duński E. , Behr R. , Soroczyńska K. , Czystowska-Kuźmicz M. , Abbas M. , Figiel I. , Włodarczyk J. , Verkhratsky A. , Niedbała M. , Kaspera W. , Wilczyński B. , Pękowska A.
Published: December 2023

Astrocytes contribute to the development and regulation of the higher-level functions of the brain, the critical targets of evolution. However, the molecular signature of foetal astrocyte evolution in primates is unknown. Here, to address this question, we use human, chimpanzee, and macaque induced pluripotent stem cell-derived foetal astrocytes (iAstrocytes). Human iAstrocytes are bigger and more complex than the non-human primate iAstrocytes. We find loci related to the regulation of cell size with increased expression in the human lineage. Likewise, we uncover that genes and mechanisms implicated in long-range intercellular signalling are activated in the human iAstrocytes. Strikingly, loci downregulated in the human lineage frequently relate to intellectual disability raising new questions on the trade-offs associated with the evolution of the human mind. Using our system, through a multilevel regulome analysis and machine learning, we uncover that functional activation of enhancers coincides with a previously unappreciated, pervasive gain of binding sites of ‘stripe’ transcription factors. In summary, we shed new light on a mechanism driving the acquisition of the regulatory potential of enhancers.
Using feedback in pooled experiments augmented with imputation for high genotyping accuracy at reduced cost
Authors: Clouard Camille , Nettelblad Carl
Published: December 2023

Conducting genomic selection in plant breeding programs can substantially speed up the development of new varieties. Genomic selection provides more reliable insights when it is based on dense marker data, in which the rare variants can be particularly informative while they are delicate to capture with sufficient statistical power. Despite the release of new performing technologies, the cost of large-scale genotyping remains a major limitation to the implementation of genomic selection. We suggest to combine pooled genotyping with population-based imputation as a cost-effective computational strategy for genotyping SNPs. Pooling saves genotyping tests and has proven to accurately capture the rare variants that are usually missed by imputation. In this study, we investigate an extension to our joint model of pooling and imputation via iterative coupling. In each iteration, the imputed genotype probabilities serve as feedback input for rectifying the decoded data, before running a new imputation in these adjusted data. Such flexible set up indirectly imposes consistency between the imputed genotypes and the pooled observations. We demonstrate that repeated cycles of feedback can take full advantage of the strengths in both pooling and imputation. The iterations improve greatly upon the initial genotype predictions, achieving very high genotype accuracy for both low and high frequency variants. We enhance the average concordance from 94.5% to 98.4% at a very limited computational cost and without requiring any additional genotype testing. We believe that these results could be of interest for plant breeders and crop scientists.

Author summary

In applications such as large-scale population surveys or plant breeding, the cost of genetic testing can limit the number of samples that are genotyped, or force the reduction to more cost-effective low-density marker panels. A reduction in the number of samples or the number of variants surveyed can reduce the power to detect important genetic correlations. We propose a scheme of pooled genotype testing, which would allow for using half the number of test assays for the same number of individuals surveyed. The data from overlapping pool tests is augmented with genotype imputation. We have previously shown that this approach was competitive, but with some drawbacks. Most strikingly, the error rate for common variants could be in the range of 10%. Now, we propose a new computational method for reconstructing SNP genotypes with pooling and imputation, adding an iterative coupled model connecting the two. This model allows us to exploit the advantages of both methods and achieves consistently high genotype reconstruction accuracy. We demonstrate the performance of our approach on a hypothetical plant breeding application based on a public genetic dataset from wheat samples. However, main aspects of the methodology would translate to many other settings.
Diversity in recombination hotspot characteristics and gene structure shape fine-scale recombination patterns in plant genomes
Authors: Brazier Thomas , Glémin Sylvain
Published: December 2023

During the meiosis of many eukaryote species, crossovers tend to occur within narrow regions called recombination hotspots. In plants, it is generally thought that gene regulatory sequences, especially promoters and 5’-3’ untranslated regions, are enriched in hotspots, but this has been characterized in a handful of species only. We also lack a clear description of fine-scale variation in recombination rates within genic regions and little is known about hotspot position and intensity in plants. To address this question we constructed fine-scale recombination maps from genetic polymorphism data and inferred recombination hotspots in eleven plant species. We detected gradients of recombination both in 5’ and 3’ of genic regions in most species, yet gradients varied in intensity and shape depending on specific hotspot locations and gene structure. To further characterize recombination gradients, we decomposed them according to gene structure by rank and number of exons. We generalized the previously observed pattern that recombination hotspots are organized around the boundaries of coding sequences, especially 5’ promoters. However, our results also provided new insight into the relative importance of the 3’ end of genes in some species and the possible location of hotspots away from genic regions in some species. Variation among species seemed driven more by hotspot location among and within genes than by differences in size or intensity among species. Our results shed light on the variation in recombination rates at a very fine scale, more detailed than whole genome averaged estimates used so far, revealing the diversity and complexity of genic recombination gradients emerging from the interaction between hotspot location and gene structure.
Age-dependent heterogeneity in the antigenic effects of mutations to influenza hemagglutinin
Authors: Welsh Frances C. , Eguia Rachel T. , Lee Juhye M. , Haddox Hugh K. , Galloway Jared , Chau Nguyen Van Vinh , Loes Andrea N. , Huddleston John , Yu Timothy C. , Le Mai Quynh , Nhat Nguyen T.D. , Thanh Nguyen Thi Le , Greninger Alexander L. , Chu Helen Y. , Englund Janet A. , Bedford Trevor , Matsen Frederick A. , Boni Maciej F. , Bloom Jesse D.
Published: December 2023

ABSTRACT

Human influenza virus evolves to escape neutralization by polyclonal antibodies. However, we have a limited understanding of how the antigenic effects of viral mutations vary across the human population, and how this heterogeneity affects virus evolution. Here we use deep mutational scanning to map how mutations to the hemagglutinin (HA) proteins of the A/Hong Kong/45/2019 (H3N2) and A/Perth/16/2009 (H3N2) strains affect neutralization by serum from individuals of a variety of ages. The effects of HA mutations on serum neutralization differ across age groups in ways that can be partially rationalized in terms of exposure histories. Mutations that fixed in influenza variants after 2020 cause the greatest escape from sera from younger individuals. Overall, these results demonstrate that influenza faces distinct antigenic selection regimes from different age groups, and suggest approaches to understand how this heterogeneous selection shapes viral evolution.
Catalytically inactive dKbCas12d guided by sgRNA and new insights into its binding through a single-molecule approach
Authors: Alekseev Aleksandr , Klimko Valerii , Abramova Marina , Franzusova Irina , Vinnik Victor , Vasileva Aleksandra , Selkova Polina , Khodorkovskii Mikhail , Arseniev Anatolii
Published: December 2023

CRISPR-Cas12d is a distinct V-D type system discovered in the metagenomes of Candidate Phyla Radiation bacteria. It stands out from most closely related systems due to its 17-19 nucleotide short spacer region and specialized stabilizing scoutRNAs. We made significant improvements to this system by modifying its scoutRNA to create sgRNA, which greatly simplifies its use. We found mutations in the RuvC domain of the effector protein KbCas12d that resulted in loss of nuclease activity. We obtained two catalytically inactive dKbCas12d variants: D827A and E913A. Using the optical tweezers technique, we demonstrated the high specificity of dKbCas12d in binding targets on individual DNA molecules. Engineered sgRNA and catalytically inactive dKbCas12d variants have promising applications in biotechnology for the precise regulation of gene expression and molecular diagnostics.
Inhibition of the UFD-1-NPL-4 complex triggers an inflammation-like response inCaenorhabditis elegans
Authors: Rao Rajneesh , Aballay Alejandro , Singh Jogender
Published: December 2023

The UFD-1 (ubiquitin fusion degradation 1)-NPL-4 (nuclear protein localization homolog 4) heterodimer is involved in extracting ubiquitinated proteins from several plasma membrane locations, including the endoplasmic reticulum. This heterodimer complex helps in the degradation of ubiquitinated proteins via proteasome with the help of AAA+ ATPase CDC-48. While the ubiquitin-proteasome system is known to have important roles in maintaining innate immune responses, the role of the UFD-1-NPL-4 complex in regulating immunity remains elusive. In this study, we investigate the role of the UFD-1-NPL-4 complex in maintainingCaenorhabditis elegansinnate immune responses. Inhibition of the UFD-1-NPL-4 complex activates an inflammation-like response that reduces the survival of the wild-type worms on the pathogenic bacteriumPseudomonas aeruginosadespite diminishing colonization of the gut with the bacterium. This inflammation-like response improves the survival of severely immunocompromised worms on pathogenic bacteria but is detrimental on nonpathogenic bacteria. Transcriptomics studies reveal that the GATA transcription factor ELT-2 mediates the inflammation-like response upon inhibition of the UFD-1-NPL-4 complex. Our studies uncover important roles of the UFD-1-NPL-4 complex in innate immunity and reveal the existence of inflammation-like responses inC. elegans.
The 3D ultrastructural morphology of a marine ammonia-oxidizing archaeon
Authors: Zhou Yangkai , Yan An , Yang Jiawen , He Wei , Guo Shuai , Li Yifan , Dai Yanchao , Pan Xijiang , Cui Dongyu , Pereira Olivier , Teng Wenkai , Bi Ran , Chen Songze , Fan Lu , Wang Peiyi , Liao Yan , Qin Wei , Sui Sen-Fang , Zhu Yuanqing , Zhang Chuanlun , Liu Zheng
Published: December 2023

Nitrososphaerota, formerly known asThaumarchaeota, constitute a diverse and widespread group of ammonia-oxidizing archaea (AOA) inhabiting ubiquitously in marine and terrestrial environments, playing a pivotal role in global nitrogen cycling. Despite their significance in Earth’s ecosystems, the cellular organization of AOA remains largely unexplored, leading to a significant question unanswered of how the machinery of these organisms underpins metabolic functions. In this study, we combined chromatic-aberration-corrected cryo-electron tomography (cryo-ET), scanning transmission electron microscopy (STEM), and energy dispersive X-ray spectroscopy (EDS) to unveil the cellular organization and elemental composition ofNitrosopumilus maritimusSCM1, a representative member of marineNitrososphaerota. Our tomograms show the native ultrastructural morphology of SCM1 and one to several dense storage granules in the cytoplasm. STEM-EDS analysis identifies two types of storage granules in which one type is possibly composed of polyphosphate, while the other type is polyhydroxyalkanoate. Collectively, these findings provide visual evidence for the resilience of AOA in the vast oligotrophic marine environment.
Membrane protein sequence features direct post-translational insertion
Authors: Kalinin Ilya A. , Peled-Zehavi Hadas , Barshap Alon B.D. , Tamari Shai A. , Weiss Yarden , Nevo Reinat , Fluman Nir
Published: December 2023

The proper folding of multispanning membrane proteins (MPs) hinges on the accurate insertion of their transmembrane helices (TMs) into the membrane. Predominantly, TMs are inserted during protein translation, via a conserved mechanism centered around the Sec translocon. Our study reveals that the C-terminal TMs (cTMs) of numerous MPs across various organisms bypass this cotranslational route, necessitating an alternative posttranslational insertion strategy. We demonstrate that evolution has refined the hydrophilicity and length of these proteins’ C-terminal tails to optimize cTM insertion. Alterations in the C-tail sequence disrupt cTM insertion in bothE. coliand human, leading to protein defects, loss of function, and genetic diseases. InE. coli, we identify YidC, a member of the widespread Oxa1 family, as the insertase facilitating cTMs insertion, with C-tail mutations disrupting the productive interaction of cTMs with YidC. Thus, MP sequences are fine-tuned for effective collaboration with the cellular biogenesis machinery, ensuring proper membrane protein folding.
Targeting plasmid-encoded proteins that contain immunoglobulin-like domains to combat antimicrobial resistance
Authors: Prieto Alejandro , Miró Lluïsa , Margolles Yago , Bernabeu Manuel , Salguero David , Merino Susana , Tomás Joan , Corbera Juan Alberto , Pérez-Bosque Anna , Hüttener Mário , Fernández Luis Ángel , Juárez Antonio
Published: December 2023

Antimicrobial resistance (AMR) poses a significant threat to human health. Although vaccines have been developed to combat AMR, it has proven challenging to associate specific vaccine antigens with AMR. Bacterial plasmids play a crucial role in the transmission of AMR. Our recent research has identified a group of bacterial plasmids (specifically, IncHI plasmids) that encode large molecular mass proteins containing bacterial immunoglobulin-like domains. These proteins are found on the external surface of the bacterial cells, such as in the flagella or conjugative pili. In this study, we show that these proteins are antigenic and can protect mice from infection caused by an AMRSalmonellastrain harboring one of these plasmids. Furthermore, we successfully generated nanobodies targeting these proteins, that were shown to interfere with the conjugative transfer of IncHI plasmids. Considering that these proteins are also encoded in other groups of plasmids, such as IncA/C and IncP2, targeting them could be a valuable strategy in combating AMR infections caused by bacteria harboring different groups of AMR plasmids. Since the selected antigens are directly linked to AMR itself, the protective effect extends beyond specific microorganisms to include all those carrying the corresponding resistance plasmids.
ESM-Scan - a tool to guide amino acid substitutions
Authors: Totaro Massimo G. , Vide Uršula , Zausinger Regina , Winkler Andreas , Oberdorfer Gustav
Published: December 2023

Protein structure prediction and (re)design have gone through a revolution in the last three years. The tremendous progress in these fields has been almost exclusively driven by readily available machine-learning algorithms applied to protein folding and sequence design problems. Despite these advancements, predicting site-specific mutational effects on protein stability and function remains an unsolved problem. This is a persistent challenge mainly because the free energy of large systems is very difficult to compute with absolute accuracy and subtle changes to protein structures are also hard to capture with computational models. Here, we describe the implementation and use of ESM-Scan, which uses the ESM zero-shot predictor to scan entire protein sequences for preferential amino acid changes, thus enabling in-silico deep mutational scanning experiments. We benchmark ESM-Scan on its predictive capabilities for stability and functionality of sequence changes using three publicly available datasets and proceed by experimentally evaluating the tool’s performance on a challenging test case of a blue-light-activated diguanylate cyclase from Methylotenera species (MsLadC). We used ESM-Scan to predict conservative sequence changes in a highly conserved region of this enzyme responsible for allosteric product inhibition. Our experimental results show that the ESM-zero shot model emerges as a robust method for inferring the impact of amino acid substitutions, especially when evolutionary and functional insights are intertwined. ESM-Scan is publicly available athttps://huggingface.co/spaces/thaidaev/zsp
Numerous independent gains of torpor and hibernation across endotherms, linked with adaptation to diverse environments
Authors: Kontopoulos Dimitrios - Georgios , Levesque Danielle L. , Hiller Michael
Published: December 2023

Many endotherms from diverse taxonomic groups can respond to environmental changes through dormancy, i.e., by greatly reducing their energy expenditure for up to 24 hours (daily torpor) or longer (hibernation). We currently have a poor understanding of how dormancy evolved across endotherms and its associations with physiological traits and ecological factors. To fill this gap, we thoroughly examine the evolutionary patterns of dormancy and its links with 21 key ecophysiological variables across 1,338 extant endotherms. We find that daily torpor and hibernation are parts of a dormancy continuum, and that there are several, albeit weak, associations between dormancy and species’ physiological or environmental characteristics. Furthermore, we show that early endotherm ancestors likely did not hibernate and that this trait evolved multiple times in independent lineages. Overall, our results provide an explanation for the remarkable variation in dormancy patterns, even among species occupying highly similar niches.
Paleocene origin of a streamlined digestive symbiosis in leaf beetles
Authors: García-Lozano Marleny , Henzler Christine , Porras Miguel Ángel González , Pons Inès , Berasategui Aileen , Lanz Christa , Budde Heike , Oguchi Kohei , Matsuura Yu , Pauchet Yannick , Goffredi Shana , Fukatsu Takema , Windsor Donald , Salem Hassan
Published: December 2023

Timing the acquisition of a beneficial microbe relative to the evolutionary history of its host can shed light on the adaptive impact of a partnership. Here, we investigated the onset and molecular evolution of an obligate symbiosis between Cassidinae leaf beetles andCandidatusStammera capleta, a γ-proteobacterium. Residing extracellularly within foregut symbiotic organs,Stammeraupgrades the digestive physiology of its host by supplementing plant cell wall-degrading enzymes. We observe thatStammerais a shared symbiont across tortoise and hispine beetles that collectively comprise the Cassidinae subfamily, despite differences in their folivorous habits. In contrast to its transcriptional profile during vertical transmission,Stammeraelevates the expression of genes encoding digestive enzymes while in the foregut symbiotic organs, matching the nutritional requirements of its host. Symbiont acquisition during the Paleocene (∼62 Mya) did not coincide with the origin of Cassidinae beetles, despite the widespread distribution ofStammeraacross the subfamily. Early-diverging lineages lack the symbiont and the specialized organs that house it. Reconstructing the ancestral state of host-beneficial factors revealed thatStammeraencoded three digestive enzymes at the onset of symbiosis, including polygalacturonase – a pectinase that is universally shared. While non-symbiotic cassidines encode polygalacturonase endogenously, their repertoire of plant cell wall-degrading enzymes is more limited compared to symbiotic beetles supplemented with digestive enzymes fromStammera. Highlighting the potential impact of a symbiotic condition and an upgraded metabolic potential,Stammera-harboring beetles exploit a greater variety of plants and are more speciose compared to non-symbiotic members of the Cassidinae.
ERK1/2 inhibition disrupts alcohol memory reconsolidation and prevents relapse
Authors: Rahamim Nofar , Liran Mirit , Aronovici Coral , Flumin Hila , Gordon Tamar , Urshansky Nataly , Barak Segev
Published: December 2023

Relapse to alcohol abuse after periods of abstinence, often caused by cue-induced alcohol craving, is a major challenge in the treatment of alcohol addiction. Therefore, disruption of the cue-alcohol associative memories can diminish the risk of relapse. Upon retrieval, memories become temporarily labile before they reconsolidate in a process that requires protein synthesis. Accumulating evidence suggests that the mammalian target of rapamycin complex 1 (mTORC1), which is responsible for the translation of a subset of dendritic proteins, is crucial for memory reconsolidation. Here, we explored the involvement of two regulatory pathways of mTORC1, namely phosphoinositide 3-kinase (PI3K)-AKT and extracellular regulated kinase1/2 (ERK1/2), in the reconsolidation process in a rat model of non-operant alcohol self-administration. We found that retrieval of alcohol memories using an odor-taste cue increased ERK1/2 activation in the amygdala, but did not affect the PI3K-AKT pathway. Importantly, inhibition of ERK1/2 shortly after alcohol memory retrieval impaired reconsolidation and led to long-lasting suppression of relapse to alcohol drinking. Additionally, we show that attenuation of alcohol memories and relapse was also induced by post-retrieval administration of lacosamide, an inhibitor of collapsin response mediator protein-2 (CRMP2) – a translational product of mTORC1 that is functionally regulated by PI3K-AKT signaling. Together, our findings provide evidence for the crucial role of ERK1/2 and CRMP2 in the reconsolidation of alcohol memories, and mark the FDA-approved drug, lacosamide, as a potential treatment for alcohol use disorder.
Lsr2, a pleiotropic regulator at the core of the infectious strategy ofMycobacterium abscessus
Authors: Gerges Elias , del Pilar Rodríguez-Ordoñez María , Durand Nicolas , Herrmann Jean-Louis , Crémazy Frédéric
Published: December 2023

Mycobacterium abscessusis a non-tuberculous mycobacterium, causing lung infections in cystic fibrosis patients. During pulmonary infection,M. abscessusswitches from smooth (Mabs-S) to rough (Mabs-R) morphotypes, the latter being hyper-virulent. Previously, we isolated thelsr2gene as differentially expressed during S-to-R transition.lsr2encodes a pleiotropic transcription factor that falls under the superfamily of nucleoid-associated proteins (NAPs). Here, we used two functional genomics methods, RNA-seq and ChIP-seq, to elucidate the molecular role of Lsr2 in the pathobiology ofM. abscessus. Transcriptomic analysis shows that Lsr2 differentially regulates gene expression across both morphotypes, most of which are involved in several key cellular processes ofM. abscessus, including host adaptation and antibiotic resistance. These results were confirmed through RT-qPCR, as well as by minimum inhibitory concentration (MIC) tests and infection tests on macrophages in the presence of antibiotics. ChIP-seq analysis revealed that Lsr2 extensively binds theM. abscessusgenome at AT-rich sequences and appears to form long domains that participate in the repression of its target genes. Unexpectedly, the genomic distribution of Lsr2 revealed no distinctions between Mabs-S and Mabs-R, implying more intricate mechanisms at play for achieving target selectivity.

IMPORTANCE

Lsr2 is a crucial transcription factor and chromosome organizer involved in intracellular growth and virulence in the smooth and rough morphotypes ofMycobacterium abscessus(Mabs). Using RNA-seq and ChIP-seq, we investigated the molecular role of Lsr2 in gene expression regulation along with its distribution on Mabs genome. Our study demonstrates the pleiotropic regulatory role of Lsr2, regulating the expression of many genes coordinating essential cellular and molecular processes in both morphotypes. In addition, we have elucidated the role of Lsr2 in antibiotic resistance bothin vitroandin vivo, wherelsr2mutant strains display heightened sensitivity to antibiotics. Through ChIP-seq, we reported the widespread distribution of Lsr2 on Mabs genome, revealing a direct repressive effect due to its extensive binding on promoters or coding sequences of its targets. This study unveils the significant regulatory role of Lsr2, intricately intertwined with its function in shaping the organization of the Mabs genome.
A heptavalent O-antigen bioconjugate vaccine exhibits differential functional antibody responses against diverseKlebsiella pneumoniaeisolates
Authors: Wantuch Paeton L. , Knoot Cory J. , Robinson Lloyd S. , Vinogradov Evgeny , Scott Nichollas E. , Harding Christian M. , Rosen David A.
Published: December 2023

Klebsiella pneumoniaeis a concerning pathogen that is now the leading cause of neonatal sepsis and is increasingly difficult to treat due to heightened antibiotic resistance. Thus, there is an urgent need for preventive and effective immunotherapies targetingK. pneumoniae. Vaccination represents a tractable approach to combat this resistant bacterium in some settings; however, there is currently not a licensedK. pneumoniaevaccine available.K. pneumoniaesurface polysaccharides, including the terminal O-antigen polysaccharides of lipopolysaccharide, have long been attractive candidates for vaccine inclusion. Herein we describe the generation of a bioconjugate vaccine targeting seven of the predominant O-antigen subtypes inK. pneumoniae. Each of the seven bioconjugates were immunogenic in isolation, with limited cross-reactivity among subtypes. Vaccine-induced antibodies demonstrated varying degrees of binding to a wide variety ofK. pneumoniaestrains, including suspected hypervirulent strains, all expressing different O-antigen and capsular polysaccharide combinations. Further, sera from vaccinated mice induced complement-mediated killing of many of theseK. pneumoniaestrains. Finally, we found that increased quantity of capsule interferes with O-antigen antibodies’ ability to bind and mediate killing of someK. pneumoniaestrains, including those carrying hypervirulence-associated genes. Taken together, these data indicate that this novel heptavalent O-antigen bioconjugate vaccine formulation exhibits promising efficacy against some, but not all,K. pneumoniaeisolates.
Impact of CRISPR/HDR-editing versus lentiviral transduction on long-term engraftment and clonal dynamics of HSPCs in rhesus macaques
Authors: Lee Byung-Chul , Gin Ashley , Wu Chuanfeng , Singh Komudi , Grice Max , Mortlock Ryland , Abraham Diana , Fan Xing , Zhou Yifan , AlJanahi Aisha , Choi Uimook , de Ravin Suk See , Shin Taehoon , Hong Sogun , Dunbar Cynthia E.
Published: December 2023

For precise genome editing via CRISPR/homology-directed repair (HDR), effective and safe editing of long-term engrafting hematopoietic stem cells (LT-HSCs) requires both sufficient HDR efficiency and protection of LT-HSC function and number. The impact of HDR on true LT-HSCs clonal dynamics in a relevant large animal model has not previously been studied. To track the HDR-edited cells, autologous rhesus macaque (RM) CD34+cells were electroporated with the gRNA/Cas9 ribonucleoprotein (RNP) and HDR cassette barcode library structure and reinfused into RMs following myeloablation. For competitive model animals, fractionated CD34+cells were transduced with a barcoded GFP-expressing lentiviral vector (LV) and electroporated via HDR machinery, respectively.CD33knockout (KO) neutrophils were prevalent early following engraftment and then rapidly decreased, resulting in less than 1% total editing efficiency. Interestingly, in competitive animals, a higher concentration of i53 mRNA result in a less steep reduction inCD33KO cells, presented a modest decrease in HDR rate (0.1-0.2%) and total indels (1.5-6.5%). In contrast, the drop off of LV-transduced GFP+cells stabilized at 20% after 2 months. We next retrieved embedded barcodes and revealed that various clones contributed to early hematopoietic reconstitution, then after dominant clones appeared at steady state throughout the animals. In conclusion, CRISPR/HDR edited cells disappeared rapidly after the autologous transplantation in RM despite substantial gene editing outcome, whereas LV-transduced cells were relatively well maintained. Clonality of HDR-edited cells drastically shrank at early stage and then relied on several dominant clones, which can be mildly mitigated by the introduction of i53 mRNA.
Restrictor synergizes with Symplekin and PNUTS to terminate extragenic transcription
Authors: Russo Marta , Piccolo Viviana , Polizzese Danilo , Prosperini Elena , Borriero Carolina , Polletti Sara , Bedin Fabio , Marenda Mattia , Michieletto Davide , Mandana Gaurav Madappa , Rodighiero Simona , Cuomo Alessandro , Natoli Gioacchino
Published: December 2023

Transcription termination pathways mitigate the detrimental consequences of unscheduled promiscuous initiation occurring at hundreds of thousands of genomiccis-regulatory elements. The Restrictor complex, composed of the Pol II-interacting protein WDR82 and the RNA-binding protein ZC3H4, suppresses processive transcription at thousands of extragenic sites in mammalian genomes. Restrictor-driven termination does not involve nascent RNA cleavage, and its interplay with other termination machineries is unclear. Here we show that efficient termination at Restrictor-controlled extragenic transcription units involves the recruitment of the protein phosphatase 1 (PP1) regulatory subunit PNUTS, a negative regulator of the SPT5 elongation factor, and Symplekin, a protein associated with RNA cleavage complexes but also involved in cleavage-independent and phosphatase-dependent termination of noncoding RNAs in yeast. PNUTS and Symplekin act synergistically with, but independently from, Restrictor to dampen processive extragenic transcription. Moreover, the presence of limiting nuclear levels of Symplekin imposes a competition for its recruitment among multiple transcription termination machineries, resulting in mutual regulatory interactions. Hence, by synergizing with Restrictor, Symplekin and PNUTS enable efficient termination of processive, long-range extragenic transcription.
The effects of situational and dispositional factors on audit quality threatening behaviour: exploring the moderating influence of religiosity
Authors: Liu Shilin , Sulaiman Noor Adwa , Shahimi Suhaily
Published: December 2023

Purpose

Using attribution theory, this study examined the effects of situational factors [time budget pressure (TBP), organisational ethical culture (OEC) and quality control procedures (QCPs)] and dispositional factors [auditor professional commitment (APC) and internal locus of control (ILOC)] on audit quality threatening behaviour (AQTB). In addition, it observed the moderating role of religiosity in the relationship between situational and dispositional factors and AQTB.

Design/methodology/approach

A total of 189 external auditors responded to the survey questionnaire. This study employed structural equation modelling via SmartPLS to analyse the proposed model.

Findings

The results documented that the OEC and QCPs situational factors were negatively related to the incidence of AQTB, whilst TBP was positively linked to the incidence of AQTB. Dispositional factors APC and ILOC were negatively connected to AQTB. Furthermore, the findings recorded the moderating effect of religiosity on most of the situational and dispositional factors related to AQTB.

Practical implications

Regulators and accounting firms' efforts to promote high audit quality (AQ) may consider the theological/religious lens and reinforce ethical culture and quality control to reduce AQTB.

Originality/value

The findings provide further insights into situational and dispositional factors that may cause or impede the incidence of AQTB in auditing practices, as well as the moderating role of religiosity in curbing AQTB.
Developing and validating a positive mental health scale for the global south construction industry: the construction industry positive mental health inventory (CI-PMHI)
Authors: Frimpong Samuel , Sunindijo Riza Yosia , Wang Cynthia Changxin , Hon Carol K. H. , Boadu Elijah Frimpong , Dansoh Ayirebi , Yiu (Kenneth) Tak Wing
Published: December 2023

Purpose

Promoting positive mental health is increasingly being encouraged as the focus of research and policies on the mental health of construction personnel. Most measures of mental health, however, typically use negative indicators such as depression and anxiety and are not specifically developed for the construction workforce, especially those with a Global South background. These limitations have made it challenging to measure construction personnel’s positive mental health. The purpose of this study was, therefore, to develop a scale for measuring the positive mental health of construction personnel with a Global South background.

Design/methodology/approach

Guided by Keyes’ two-continua model of mental health, the study objectives were addressed through a mixed-methods study using the case of Ghana. Qualitative data collected from eight key stakeholder groups using 16 interviews and two rounds of focus group discussions were analysed thematically. Quantitative data were obtained through a survey of 425 construction personnel and analysed using confirmatory factor analysis and correlation analysis.

Findings

Thematic analysis revealed a four-dimensional structure of positive mental health, namely, emotional, psychological, social and spiritual. Confirmatory factor analysis and correlation analysis of the results indicated good instrument validity and reliability.

Originality/value

Existing measures of positive mental health are based on a three-dimensional model, i.e. emotional, social and psychological well-being. By including spiritual well-being, this study proposes a four-dimensional measurement model as a more comprehensive and promising measure to use in surveys of positive mental health among the construction workforce, especially those with a Global South background, and to develop suitable interventions for them.
Examining the role of digital leadership and organisational resilience on the performance of SMEs during the COVID-19 pandemic
Authors: Lathabhavan Remya , Kuppusamy Thenmozhi
Published: December 2023

Purpose

The coronavirus disease 2019 (COVID-19) pandemic adversely affected small and medium-sized enterprises (SMEs) in India. Amongst the challenges faced were the adjustments required in leadership skills to address pandemic-induced technological changes and the necessity for employee skill upgrading. This study examined the factors that influenced organisational performance in Indian SMEs, particularly in the context of the digital transformations that were brought about by the pandemic.

Design/methodology/approach

The study employed a cross-sectional design to investigate a set of hypotheses that were formulated to understand the relationships amongst digital leadership, digital training, empowerment and organisational performance. The data were collected during the pandemic from 487 employees who were working in various SMEs in India. Questionnaires were distributed through email and social media platforms, and electronic consent was obtained from each participant.

Findings

The study's findings indicated positive associations amongst digital leadership, digital training, empowerment and organisational performance. They also highlighted the mediating role of empowerment in these relationships. Furthermore, organisational resilience was found to positively moderate the relationship between empowerment and performance.

Originality/value

The study stands amongst the pioneers in exploring the role of digital leadership and digital training during the pandemic and their impact on employee empowerment amongst SMEs in a developing country.
Linkages between high-performance work practices and family-centered goals: implications for financial performance in family firms
Authors: Sánchez-Marín Gregorio , Lozano-Reina Gabriel , Beglaryan Mane
Published: December 2023

Purpose

This study explores what impact high-performance work practices (HPWP) – from the ability-motivation-opportunity (AMO) framework – might have on financial performance among family firms and examines the mediating role played by family-centered goals (FCGs).

Design/methodology/approach

The empirical approach is based on data collected from a sample of 339 Spanish small and medium-sized family enterprises operating in the industry and service sectors. To test the hypotheses, this paper applies a path analysis modeling tool to estimate both indirect and direct effects in mediator models.

Findings

The results indicate that the AMO framework has a significant impact on financial performance through the lens of FCGs. In addition, family businesses' keen concern to preserve family wealth influences the effectiveness of HPWPs, making firms more socioemotionally oriented at the expense of economic impact.

Research limitations/implications

This paper underscores the importance of integrating family aspirations into strategic human resource management (HRM) design, emphasizing the significance of socioemotional wealth (SEW) preservation.

Practical implications

The findings offer practical insights for family managers, family owners and human resource (HR) practitioners, suggesting the need to align HR practices with family goals and to strategically balance socioemotional and financial wealth considerations. Family owners in key management positions must skillfully manage HR strategies in order to harmonize family and firm goals.

Originality/value

By examining the mediating effect of FCGs, this paper advances and extends SEW theory in the context of HRM by considering the relationships between HR practices and firm performance as a mixed gamble approach.
SDG commentary: services that sustainably manage resources for all humans-the regenerative service economy framework
Authors: Russell-Bennett Rebekah , Polonsky Michael Jay , Fisk Raymond P.
Published: December 2023

Purpose

The purpose of this paper is to propose a new service framework for managing nature and physical resources that balances the needs of people and planet.

Design/methodology/approach

The process used in this paper was a rapid literature review and content analysis of 202 articles in service journals and learned that there are limited papers on Sustainable Development Goal (SDG) #6 (clean water and sanitation) or SDG #7 (affordable and clean energy) and very few articles on SDG #12 (responsible production and consumption) that focused on environmental components of services. This highlighted the need to conceptualise a service framework for managing these resources sustainably.

Findings

The proposed regenerative service economy framework for managing natural and physical resources for all humans (without harming the planet) reflects insights from analysing the available service articles. The framework draws on the circular economy, an Indigenous wholistic framework and service thinking to conceptualise how service research can manage natural and physical resources in ways that serve both people and the planet.

Originality/value

This paper introduces the regenerative service economy framework to the service literature as an approach for guiding service researchers and managers in sustainably managing natural and physical resources in a sustainable way.
The role of artificial intelligence for management decision: a structured literature review
Authors: Oppioli Michele , Sousa Maria José , Sousa Miguel , de Nuccio Elbano
Published: December 2023

Purpose

The topic of artificial intelligence (AI) has been expanding rapidly in recent years, gaining the attention of academics and practitioners. This study provides a structured literature review (SLR) on AI and management decisions (MDs) by analysing the scientific output and defining new research topics.

Design/methodology/approach

The study uses a rigorous methodological approach to summarise the state of the art of the past literature. The authors used Scopus as the database for data collection and utilised the Bibliometrix R package. In total, 204 peer-reviewed English articles were collected and analysed.

Findings

The results showed that literature in this field is emerging. Studies are focused on using AI as forecasting and classification for management decision-making, AI as a tool to improve knowledge management in organisations and extract information. The cluster analysis revealed the presence of five thematic clusters of studies on the topic.

Originality/value

The study’s originality lies in providing a new perspective on AI for MDs. In particular, the analysis reveals a new classification of research streams and provides fruitful research questions to continue research on the topic.
Optimization design of a two-stage multidirectional vibration isolation system for large airborne equipment
Authors: Zhu Hongyan , Wu Xiaochong , Lv Pengzhen , Wang Yuansheng , Lin Huagang , Liu Wei , Yue Zhufeng
Published: December 2023

Purpose

Improvement and optimization design of a two-stage vibration isolation system proposed in this paper are conducted to ensure the device of electronic work effective.

Design/methodology/approach

The proposed two-stage vibration isolation system of airborne equipment is optimized and parameterized based on multi-objective genetic algorithm.

Findings

The results show that compared with initial two-stage vibration isolation system, the angular vibration of the two-stage vibration isolation system becomes 3.55 × 10-4 rad, which decreases by 89%. The linear isolation effect is improved by at least 67.7%.

Originality/value

The optimized two-stage vibration isolation system effectively improves the vibration reduction effect, the resonance peak is obviously improved and the reliability of the mounting bracket and the shock absorber is highly improved, which provides an analysis method for two-stage airborne equipment isolation design under complex dynamic environment.
A reflection on the intergenerational maps project as pedagogical performance
Authors: Khatoon Iffat
Published: December 2023

Purpose

The paper aims to explore the intergenerational maps project that set out to map the Brimbank and Moonee Valley residents' awareness of their favourite aspects of their local community. In reflecting on the way this project enabled local knowledge exchanges between different age groups, the paper examines the way intergenerational interactions become pedagogical and make public and public pedagogy visible.

Design/methodology/approach

This research paper employs the theoretical and methodological framework of performance (Charman and Dixon, 2021) to read the author's experience with the intergenerational maps project. Insights gained from performance framework are shared to illuminate the complexity of public pedagogy and its entanglement with place, public and knowledge.

Findings

The critical reflection on the author's encounter with a pedagogical event points to the importance of using a new theorisation of public pedagogy (Charman and Dixon, 2021) as a useful generative method to guide the reading, learning and research within the fields of public pedagogy and intergenerational relations.

Practical implications

The practical implications of this paper centres on its deployment of a new theorisation of public pedagogy as a useful framework for studying intergenerational interactions. This places these intergenerational interactional dynamics in the field of public pedagogy and can be practically applied to further develop desirable public pedagogical practices within the arena of public pedagogy.

Originality/value

The paper offers a subjective interpretation of the author's experience with an intergenerational interaction project and presents an application of a theoretical framework to read events as pedagogical performances that brings insights into the pedagogical potential of these public performances.