bluuebunny/crossref_metadata_2025_split huggingface dataset:
Boronic acid derivative inhibits LexA mediated SOS response in Mycobacteria
Authors: Chatterjee Chitral , Mohan Gokul Raj , Hariharan V.C , Biswas Bhumika , Sundaram Vidya , Srivastava Ashutosh , Matheshwaran Saravanan 
Published: November 2023

AbstractAntimicrobial resistance (AMR) properties of several pathogens pose as one of the major global concerns demanding continuous innovation in order to be controlled. The bacterial “SOS” response, regulated by LexA and RecA, contributes to AMR through advantageous mutations. Therefore, targeting LexA/RecA system with a novel inhibitor could suppress “SOS” response and may reduce AMR. However, RecA presents a challenge as a therapeutic target due to its conservation across species, including humans. Concurrently, LexA, being absent in eukaryotes, can be potentially targeted, in part, due to its association with “SOS” response and developing AMR. Our studies combining bioinformatic, biochemical, biophysical, and cell-based assays present a unique inhibitor of mycobacterial “SOS” response wherein we show that the inhibitor interacts directly with the catalytic site residues of LexA ofMycobacterium tuberculosis (Mtb), consequently hindering its cleavage, resulting in suppression of “SOS” response. We observed important genes under the “SOS” regulon to be down-regulated in the presence of the inhibitor along with a consequent reduction in the rate of mutation frequency of mycobacterial cells. In essence, this study may facilitate further research on potential LexA inhibitors, reducing mutational rates and offering promise in mitigating AMR.
GRA47 and GRA72 areToxoplasma gondiipore-forming proteins that influence small molecule permeability of the parasitophorous vacuole
Authors: Bitew Mebratu A. , Gaete Pablo S. , Swale Christopher , Maru Parag , Contreras Jorge E. , Saeij Jeroen P. J. 
Published: November 2023

AbstractToxoplasma gondii, a medically important intracellular parasite, uses GRA proteins, secreted from dense granule organelles, to mediate nutrient flux across the parasitophorous vacuole membrane (PVM). GRA17 and GRA23 are known pore-forming proteins on the PVM involved in this process, but the roles of additional proteins have remained largely uncharacterized. We recently identifiedGRA72as synthetically lethal withGRA17. DeletingGRA72produced similar phenotypes toΔgra17parasites, and computational predictions suggested it forms a pore. To understand how GRA72 functions we performed immunoprecipitation experiments and identified GRA47 as an interactor of GRA72. Deletion ofGRA47resulted in an aberrant ‘bubble vacuole’ morphology with reduced small molecule permeability, mirroring the phenotype observed inGRA17andGRA72knockouts. Structural predictions indicated that GRA47 and GRA72 form heptameric and hexameric pores, respectively, with conserved histidine residues lining the pore. Mutational analysis highlighted the critical role of these histidines for protein functionality. Validation through electrophysiology confirmed alterations in membrane conductance, corroborating their pore-forming capabilities. Furthermore, Δgra47parasites and parasites expressing GRA47 with a histidine mutation had reducedin vitroproliferation and attenuated virulence in mice. Our findings show the important roles of GRA47 and GRA72 in regulating PVM permeability, thereby expanding the repertoire of potential therapeutic targets againstToxoplasmainfections.IMPORTANCEToxoplasma gondiiis a parasite that poses significant health risks to those with impaired immunity. It replicates inside host cells shielded by the parasitophorous vacuole membrane (PVM), which controls nutrient and waste exchange with the host. GRA72, previously identified as essential in the absence of the GRA17 nutrient channel, is implicated in forming an alternative nutrient channel. Here we found that GRA47 associates with GRA72 and is also important for the PVM’s permeability to small molecules. Removal of GRA47 leads to distorted vacuoles and impairs small molecule transport across the PVM, resembling the effects of GRA17 and GRA72 deletions. Structural models suggest GRA47 and GRA72 form distinct pore structures, with a pore-lining histidine critical to their function.Toxoplasmastrains lacking GRA47, or those with a histidine mutation, have impaired growth and reduced virulence in mice, highlighting these proteins as potential targets for new treatments against Toxoplasmosis.
SUMO chains depolymerization induces slender to stumpy differentiation inT. bruceibloodstream parasites
Authors: Iribarren Paula Ana , Di Marzio Lucía Ayelén , Berazategui María Agustina , Saura Andreu , Coria Lorena , Cassataro Juliana , Rojas Federico , Navarro Miguel , Alvarez Vanina Eder 
Published: November 2023

ABSTRACTTrypanosoma bruceiare extracellular protozoan parasites transmitted by tsetse flies that cause sleeping sickness in humans and nagana in cattle. Inside the mammalian host, differentiation from a bloodstream replicative slender form into a quiescent stumpy form allows the persistence of the parasite and the spread of the infection. SUMOylation is a reversible and dynamic post-translational modification of proteins that regulates diverse nuclear processes, such as DNA replication, repair and transcription. SUMO can be attached to its target proteins either as a single monomer or forming polymeric chains. We found that transgenic cell lines able to conjugate SUMO just as a monomer are attenuatedin vivo. SUMO chain mutant monomorphic parasites display relapsing and remitting waves of parasitemia, at variance with wild-type parasites that cause unremitting parasitemia and mice death. Furthermore, when mice are infected with an analogous SUMO chain mutant generated in a differentiation-competent pleomorphic background, stumpy cells can be observed at unusually low parasitemia values. Our study reveals that SUMO depolymerization could represent a coordinated signal triggered during a quiescence activation program.
USP7 Inhibition Promotes Early Osseointegration in Senile Osteoporotic Mice
Authors: Zhou F , Wang Z , Li H , Wang D , Wu Z , Bai F , Wang Q , Luo W , Zhang G , Xiong Y , Wu Y 
Published: November 2023

AbstractAlthough elderly osteoporotic patients have similar implant survival rates compared to those of normal individuals, they require longer healing periods to achieve proper osseointegration. This may be related to chronic inflammatory responses and impaired stem cell repair functions in the osteoporotic bone microenvironment. Recently, the deubiquitinating enzyme, ubiquitin-specific peptidase 7 (USP7), was found to regulate macrophage immune response and modulate stem cell osteogenic differentiation. The selective inhibitor of USP7, P5091, has also been found to promote bone repair and homeostasis in osteoporotic conditions. However, the roles of USP7 and P5091 in osteoimmunology and dental implant osseointegration under senile osteoporotic conditions remain unclear. In this study, USP7 depletion and P5091 were showed to inhibit inflammation in senescent bone marrow derived macrophages (BMDMs) and promote osteogenic differentiation in aged BMSCs. Furthermore, mRNA-Seq revealed that USP7 depletion could enhance efferocytosis in senescent BMDMs through the EPSIN1/ low-density lipoprotein receptor-related protein 1 (LRP1) pathway and selectively induce apoptosis (senolysis) in aged BMSCs. In senile osteoporotic mice, we found that the osseointegration period was prolonged compared to young mice, and P5091 promoted the early stage of osseointegration, which may be related to macrophage efferocytosis around the implant. Collectively, this study suggests that USP7 inhibition may accelerate the osseointegration process in senile osteoporotic conditions by promoting macrophage efferocytosis and aged BMSCs apoptosis. This has implications for understanding the cellular interactions and signaling mechanisms in the peri-implant bone microenvironment under osteoporotic conditions. It may also provide clinical significance in developing new therapies to enhance osseointegration quality and shorten the edentulous period in elderly osteoporotic patients.
Mitochondria possess a large, non-selective ionic current that is enhanced during cardiac injury
Authors: Balderas Enrique , Lee Sandra H.J. , Shankar Thirupura S. , Yin Xue , Balynas Anthony M. , Kyriakopoulos Christos P. , Selzman Craig H. , Drakos Stavros G. , Chaudhuri Dipayan 
Published: November 2023

ABSTRACTMitochondrial ion channels are essential for energy production and cell survival. To avoid depleting the electrochemical gradient used for ATP synthesis, channels so far described in the mitochondrial inner membrane open only briefly, are highly ion-selective, have restricted tissue distributions, or have small currents. Here, we identify a mitochondrial inner membrane conductance that has strikingly different behavior from previously described channels. It is expressed ubiquitously, and transports cations non-selectively, producing a large, up to nanoampere-level, current. The channel does not lead to inner membrane uncoupling during normal physiology because it only becomes active at depolarized voltages. It is inhibited by external Ca2+, corresponding to the intermembrane space, as well as amiloride. This large, ubiquitous, non-selective, amiloride-sensitive (LUNA) current appears most active when expression of the mitochondrial calcium uniporter is minimal, such as in the heart. In this organ, we find that LUNA current magnitude increases two- to threefold in multiple mouse models of injury, an effect also seen in cardiac mitochondria from human patients with heart failure with reduced ejection fraction. Taken together, these features lead us to speculate that LUNA current may arise from an essential protein that acts as a transporter under physiological conditions, but becomes a channel under conditions of mitochondrial stress and depolarization.
Transcriptional stress induces the generation of DoGs in cancer cells
Authors: Ríos Francisco , Urióstegui-Arcos Maritere , Zurita Mario 
Published: November 2023

AbstractA characteristic of the cellular response to stress, is the production of RNAs generated from readthrough transcription of genes, called downstream-of-gene-(DoG) containing transcripts. Additionally, transcription inhibitor drugs are candidates for fighting cancer. In this work, we report the results of a bioinformatic analysis showing that one of the responses to transcription inhibition is the generation of DoGs in cancer cells. Although some genes that form DoGs were shared between the two cancer lines, there did not appear to be a functional correlation between them. However, our findings show that DoGs are generated as part of the cellular response to transcription inhibition like other types of cellular stress, suggesting that it may be part of the defense against transcriptional stress.
Engineering self-deliverable ribonucleoproteins for genome editing in the brain
Authors: Chen Kai , Stahl Elizabeth C. , Kang Min Hyung , Xu Bryant , Allen Ryan , Trinidad Marena , Doudna Jennifer A. 
Published: November 2023

AbstractThe delivery of CRISPR ribonucleoproteins (RNPs) for genome editingin vitroandin vivohas important advantages over other delivery methods, including reduced off-target and immunogenic effects1. However, effective delivery of RNPs remains challenging in certain cell types due to low efficiency and cell toxicity. To address these issues, we engineered self-deliverable RNPs that can promote efficient cellular uptake and carry out robust genome editing without the need for helper materials or biomolecules. Screening of cell-penetrating peptides (CPPs) fused to CRISPR-Cas9 protein identified potent constructs capable of efficient genome editing of neural progenitor cells. Further engineering of these fusion proteins identified a C-terminal Cas9 fusion with three copies of A22p, a peptide derived from human semaphorin-3a, that exhibited substantially improved editing efficacy compared to other constructs. We found that self-deliverable Cas9 RNPs generated robust genome edits in clinically relevant genes when injected directly into the mouse striatum. Overall, self-deliverable Cas9 proteins provide a facile and effective platform for genome editingin vitroandin vivo.
The new normal: the adoption of food delivery apps
Authors: Madinga Nkosivile Welcome , Blanckensee Jo , Longhurst Lauren , Bundwini Nqobile 
Published: November 2023

PurposeIn the wake of lockdown regulations and limited mobility during the COVID-19 pandemic, dining habits shifted towards usage of food delivery apps to avoid physical interaction. Nonetheless, it is unknown whether the COVID-19 pandemic had an influence on the adoption of food delivery apps. Therefore, this study examined factors influencing the adoption of food delivery apps during the COVID-19 pandemic, as well as the moderating effects of education and age.Design/methodology/approachData were collected from 282 food delivery application users in South Africa using a web-based survey. Partial least square structural equation modelling analysis was used to test the hypotheses, while partial least squares multigroup analysis was used to examine the moderating effect of education level and age.FindingsThe results indicated that perceived ease of use has a significant impact on perceived usefulness and attitudes, perceived usefulness has an impact on attitudes and continuous intention, attitude influences continuous intention and social pressure and convenience influence attitudes. The perceived COVID-19 threat had no impact on attitudes, and education and age had no significant impact on any relationships. The findings are imperative for restaurants and mobile application designers, as they enable more effective strategic management planning.Originality/valueThis study is the first paper to empirically employ technology acceptance model to analyse the adoption of food delivery applications during the COVID-19 pandemic. Its uniqueness is in examining situational influence associated with the pandemic such as social pressure, perceived COVID-19 threat and convenience.
Preparing students for the future workplace: how online teaching and learning during the COVID-19 pandemic hone required transferable skills
Authors: Jacobs Bertha , Taljaard-Swart Hanri , Marx-Pienaar Nadene , Diedericks Lizette , Sonnenberg Nadine , Donoghue Suné , Pretorius Adeline , du Rand Gerrie 
Published: November 2023

PurposeSkilled graduates delivered through vocational programmes are critical to ensure the future growth of emerging economies. This study explored students' reflections and experiences of online teaching and learning (T&L) during the COVID-19 pandemic in South Africa. The study specifically focused on the transferable skills students acquired and their relevance to working in the local retail and hospitality industries.Design/methodology/approachFollowing a case study research design, this study retrospectively delved into the multi-perspectives of students enrolled in vocational programmes. A total of 145 students completed reflective questions via a Qualtrics link regarding the topic in question. Student reflections were grouped and analysed for recurring themes using Atlas.ti. Through thematic analysis, two topical themes emerged related to transferable skills development and the usefulness of skills for future work.FindingsThe findings suggest that although students had to rely on online classes during the COVID-19 pandemic, they still developed vital transferable skills, including communication, teamwork, organisational, self-management, flexibility, technology, metacognition and problem-solving.Practical implicationsThe findings offer valuable input into planning and developing student-centric online courses to facilitate the development of desired transferable skills. Findings could also guide best T&L practices regarding how education and training across digital platforms could be used to ensure that graduates are prepared to navigate the future complexities of working in ever-changing globalised industries.Originality/valueThis study provides new insights into the evolution of T&L and how unexpected situations could provide an opportunity to hone desired skills and prepare students for employment and the 21st century workplace.
Navigating farm waste problems: introducing the Gleaning Innovation Framework
Authors: Mueller Steven M. , Kowalczyk Christine M. , Taillon Brian J. , Rowe William J. 
Published: November 2023

PurposeManaging farm waste is a fundamental problem for farmers with economic, environmental and social impacts throughout the supply chain. Little research has explored innovative product solutions. This paper examines gleaning to reduce farm waste and proposes a resource-based Gleaning Innovation Framework which can lead to differentiated consumer products.Design/methodology/approachA multi-method approach, including descriptive company reviews, practitioner interviews and consumer surveys, evaluated how different participants in the food supply chain view the farm waste problem and the innovation of products through gleaning.FindingsThis research found that practitioners and consumers are cognizant and invested in reducing farm waste, with gleaning as a plausible solution. Future research includes gathering perspectives from retailers and other supply chain members, which may further develop the conceptualization of the gleaning innovation process.Originality/valueUniquely, the authors propose the Gleaning Innovation Framework that provides a platform for innovation across the supply chain to reduce farm waste. The research contributes to the farm waste debate with evidence that gleaning can assist the reduction of farm waste through product innovation. Developing innovations to reduce farm waste in sustainable and environmentally friendly ways would not only benefit the supply chain platform but also society.
Reexamining review variance and movie sales: the inverted-U-shaped relationship and boundary conditions
Authors: Lee Jungwon , Park Cheol 
Published: November 2023

PurposeThis study is based on the heuristic-systematic model (HSM) to dynamically examine the effect of review variance on sales and the boundary conditions that mitigate this effect.Design/methodology/approachBased on the theoretical domain of HSM, a conceptual model is proposed that analyzes the nonlinear relationship between review variance and sales and the interaction and motivation factors that moderate these relationships. Review data from websites targeting the film industry in the USA and South Korea (Korea) were collected to empirically analyze the authors' hypothesis, and panel regression analysis was used for confirmation.FindingsModerated by interactive and motivational factors, review variance exhibits an inverse-U-shaped relationship with review variance. Specifically, as an interaction factor, review valence and owned social media (OSM) resulted in positive interaction effects, and as a motivation factor, the number of alternatives exhibited a positive interaction effect with review variance. The effect of review variance was less pronounced in the USA than in Korea.Originality/valueThe study outcomes reveal a nonlinear relationship between review variance and sales, thus supporting the contradictory findings of previous studies. This study contributes to the literature by using the HSM as a theoretical framework to verify various HSM mechanisms using online review data. This exploratory study also contributes to the international marketing literature by showing that the effects of review variance vary across cultures.
Impact of private and public initiatives on individuals' employment and income during the COVID-19 pandemic: evidence from Peru
Authors: Mongrut Samuel Arturo , Cruz Vivian , Pacussich Daniela 
Published: November 2023

Purpose The purpose of this paper is to determine the impact of private and public initiatives (financial literacy, entrepreneurship, remote work and government aid) on individual job loss and decrease in income during the COVID-19 pandemic in Peru.Design/methodology/approach The authors used an unbalanced panel data analysis with the National Household Survey for 2019–2020. The hypotheses are tested with a probit panel data model since the dependent variables are binary.FindingsThe study findings indicate that financial preparedness reduced the probability of having a decrease in income, but only to informal workers in metropolitan Lima. Furthermore, entrepreneurship helped mainly female informal workers to reduce their probability of becoming unemployed in metropolitan Lima. Besides, the implementation of remote work as a substitute of face-to-face work was not enough to avoid the decrease in income in the case of informal workers and it was only effective to avoid unemployment in the case of formal workers in metropolitan Lima. Finally, public aid proved to be instrumental in mitigating the decrease in income, but only to informal workers in Metropolitan Lima.Research limitations/implications The study results only apply for the first year of the pandemic.Practical implicationsPolicymakers should focus on increasing the financial preparedness of informal workers, especially in provinces.Social implicationsPolicymakers must expand unemployment benefits, and design public aid programs targeting informal workers in provinces.Originality/valueThis is the first study that analyses the impact of private and public initiatives on the decrease in income and unemployment situation of Peruvian individuals during the outbreak of the COVID-19 pandemic.
New Public Governance as a new wave of the public policy: theoretical approach and conceptualization of the trend
Authors: Popęda Piotr , Hadasik Bartłomiej 
Published: November 2023

PurposeThe paper's primary purpose is to define and characterize the innovative concept in public management theory, New Public Governance (NPG), from its theoretical framework and the view of public management institutions. The second objective is to create a logical framework to explain this notion. The broader role of this paper is to expand the understanding of this contemporary public management trend.Design/methodology/approachThe methodological approach of the authors' research is based on a deep understanding of theoretical sources, particularly the scientific precursors in the literature surrounding the NPG theory. The authors used the following methods to achieve the paper's goals: critical thematic literature review and synthetic comparative analysis.FindingsIn regards to scientific analysis, the goals of NPG were achieved, considering that its concept and main characteristics were displayed in definitional terms as a trend in public management, emphasizing institutional cooperation and co-production, having strengths in social inclusion and weaknesses in the lack of participatory experience of the actors. Additionally, the authors created the original 6-CO coherent conceptual framework describing the flows in the NPG operation based on theoretical foundations. The analysis of theoretical sources not only allowed the collection of common and disconnected features of the reasoning behind the definition and depth of the NPG but also insufficient development of the theory in existing sources.Originality/valueThe paper demonstrates critical new scholarship surrounding the NPG theory because it (1) applies one of the latest trends in public management, (2) juxtaposes various academics' understanding of the concept and, most importantly, (3) advances the theory of NPG with the original 6-CO coherent conceptual framework as a practical implication of the theory originator.