bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of novel toxin domains and characterization of a broadly distributed family of lipid-targeting NlpC/P60
Authors: Nicastro Gianlucca G. , Sibinelli-Sousa Stephanie , Hespanhol Julia Takuno , Santos Thomas W. C. , Munoz Joseph P. , Santos Rosangela S. , Perez-Sepulveda Blanca M. , Miyamoto Sayuri , Aravind L. , de Souza Robson F. , Bayer-Santos Ethel
Published: September 2024

Bacterial warfare is a common and ancient phenomenon in nature, where bacterial species use strategies to inhibit the growth or kill competitors. This involves the production and deployment of antibacterial toxins that disrupt essential cellular processes in target cells. Polymorphic toxins comprise a group of offensive systems with a modular structure featuring a conserved N-terminal translocation domain fused to diverse C-terminal toxin domains. The continuous arms race in which bacteria acquire new toxin and immunity proteins to promote increased adaptation to their environment is responsible for the diversification of this toxin repertoire. Here, we deployedin-silicostrategies to analyze 10,000 genomes and identify toxin domains secreted via the type VI secretion system ofSalmonella. We identified and manually curated 128 candidates, which are widespread polymorphic toxins detected in a vast array of species and linked to diverse secretion systems. In addition, 45 previously uncharacterized toxin domains were identified. STox15 was among the most frequent candidates found in the dataset and was selected for in-depth characterization. STox15 is an antibacterial effector belonging to the NlpC/P60 papain-like fold superfamily with a permuted catalytic core typical of lipid-targeting versions rather than peptidases or amidases. Biochemical analysis with recombinant protein and lipidomics of intoxicatedEscherichia colirevealed that STox15 displays phospholipase activity cleaving off acyl groups from phosphatidylglycerol and phosphatidylethanolamine.

Importance

This work broadens our understanding of polymorphic toxin domains and provides the first direct characterization of a lipid-targeting NlpC/P60 domain in biological conflicts.
Megabase-scale loss of heterozygosity provoked by CRISPR-Cas9 DNA double-strand breaks
Authors: Regan Samantha B. , Medhi Darpan , White Travis B. , Jiang Yi-Zhen , Jia Su , Deng Qichen , Jasin Maria
Published: September 2024

Harnessing DNA double-strand breaks (DSBs) is a powerful approach for gene editing, but it may provoke loss of heterozygosity (LOH), which predisposes to tumorigenesis. To interrogate this risk, we developed a two- color flow cytometry-based system (Flo-LOH), detecting LOH in ∼5% of cells following a DSB. After this initial increase, cells with LOH decrease due to a competitive disadvantage with parental cells, but if isolated, they stably propagate. Segmental loss from terminal deletions with de novo telomere addition and nonreciprocal translocations is observed as well as whole chromosome loss, especially following a centromeric DSB. LOH spans megabases distal from the DSB, but also frequently tens of megabases centromere-proximal. Inhibition of microhomology-mediated end joining massively increases LOH, which is synergistically increased with concomitant inhibition of canonical nonhomologous end joining. The capacity for large-scale LOH must therefore be considered when using DSB-based gene editing, especially in conjunction with end joining inhibition.
Accurate quantitation of 16S gene copies in low biomass samples post-antibiotic treatment through deep sequencing with a balanced nucleotide synthetic spike-in approach
Authors: Chang Chia-Chi , Huang Licai , Jin Yimei , Jamal Mohamed A. , Hayase Eiko , Halsey Taylor , Ortega Miriam R. , Pham Dung , Glover Israel , Flores Ivonne , McDaniel Lauren , Prasad Rishika , Peterson Christine , Jenq Robert R.
Published: September 2024

The microbiota significantly impacts health and treatment outcomes. While 16S rRNA gene sequencing reveals relative bacterial abundances, it does not provide absolute quantification. We developed a cost-effective solution incorporating synthetic DNA standards designed to ensure balanced nucleotide representation at each position. These standards are spiked into samples before DNA extraction, enabling simultaneous quantification of both relative and absolute bacterial abundances. We applied this method to samples collected from mice and patients, both before and after antibiotic treatment. Our approach showed a reduction in total bacterial density in mice and patients post-antibiotic treatment. This spike-in standard method can be adapted to samples with varying bacterial densities, allowing quantification of absolute taxonomical abundances without the need for an additional quantitative PCR assessment. Our approach also improves sequencing quality scores for low biomass samples.
Identification of the drug/metabolite transporter 1 as a marker of quinine resistance in a NF54×Cam3.IIP. falciparumgenetic cross
Authors: Kanai Mariko , Mok Sachel , Yeo Tomas , Shears Melanie J. , Ross Leila S. , Jeon Jin H. , Narwal Sunil , Haile Meseret T. , Tripathi Abhai K. , Mlambo Godfree , Kim Jonathan , Gil-Iturbe Eva , Okombo John , Fairhurst Kate J. , Bloxham Talia , Bridgford Jessica L. , Sheth Tanaya , Ward Kurt E. , Park Heekuk , Rozenberg Felix D. , Quick Matthias , Mancia Filippo , Lee Marcus C.S. , Small-Saunders Jennifer L. , Uhlemann Anne-Catrin , Sinnis Photini , Fidock David A.
Published: September 2024

The genetic basis ofPlasmodium falciparumresistance to quinine (QN), a drug used to treat severe malaria, has long been enigmatic. To gain further insight, we used FRG-NOD human liver-chimeric mice to conduct aP. falciparumgenetic cross between QN-sensitive and QN-resistant parasites, which also differ in their susceptibility to chloroquine (CQ). By applying different selective conditions to progeny pools prior to cloning, we recovered 120 unique recombinant progeny. These progeny were subjected to drug profiling and QTL analyses with QN, CQ, and monodesethyl-CQ (md-CQ, the active metabolite of CQ), which revealed predominant peaks on chromosomes 7 and 12, consistent with a multifactorial mechanism of resistance. A shared chromosome 12 region mapped to resistance to all three antimalarials and was preferentially co-inherited withpfcrt. We identified an ATP-dependent zinc metalloprotease (FtsH1) as one of the top candidates and observed using CRISPR/Cas9 SNP-edited lines thatftsh1is a potential mediator of QN resistance and a modulator of md-CQ resistance. As expected, CQ and md-CQ resistance mapped to a chromosome 7 region harboringpfcrt. However, for QN, high-grade resistance mapped to a chromosome 7 peak centered 295kb downstream ofpfcrt. We identified the drug/metabolite transporter 1 (DMT1) as the top candidate due to its structural similarity to PfCRT and proximity to the peak. Deleting DMT1 in QN-resistant Cam3.II parasites significantly sensitized the parasite to QN but not to the other drugs tested, suggesting that DMT1 mediates QN response specifically. We localized DMT1 to structures associated with vesicular trafficking, as well as the parasitophorous vacuolar membrane, lipid bodies, and the digestive vacuole. We also observed that mutant DMT1 transports more QN than the wild-type isoformin vitro. Our study demonstrates that DMT1 is a novel marker of QN resistance and a new chromosome 12 locus associates with CQ and QN response, withftsh1is a potential candidate, suggesting these genes should be genotyped in surveillance and clinical settings.
Zebrafish Polymerase Theta and human Polymerase Theta: orthologues with homologous function
Authors: Thomas Corey , Green Sydney , Kimball Lily , Schmidtke Isaiah R , Griffin Makayla , Rothwell Lauren , Par Ivy , Schobel Sophia , Palacio Yayleene , Towle-Weicksel Jamie B , Weicksel Steven E
Published: September 2024

DNA Polymerase Theta (Pol θ) is a conserved an A-family polymerase that plays an essential role in repairing double strand breaks, through micro-homology end joining, and bypassing DNA lesions, through translesion synthesis, to protect genome integrity. Despite its essential role in DNA repair, Pol θ is inherently error-prone. Recently, key loop regions were identified to play an important role in key functions of Pol θ.

Here we present a comparative structure-function study of the polymerase domain of zebrafish and human Pol θ. We show that these two proteins share a large amount of sequence and structural homology. However, we identify differences in the amino acid composition within the key loop areas shown to drive characteristic Pol θ functions. Despite these differences zebrafish Pol θ still displays characteristics identify in human Pol θ, including DNA template extension in the presence of different divalent metals, microhomology-mediated end joining, and translesion synthesis. These results will support future studies looking to gain insight into Pol θ function on the basis of evolutionarily conserved features.
Homeodomain protein codes specify neuronal diversity in the first ganglion of theDrosophilavisual system
Authors: Xu Chundi , Newstein Peter , Sastry Rishi G. , Doe Chris Q.
Published: September 2024

Recent advances in single-cell transcriptional profiling have enabled us to map diverse neuron types acrossDrosophila, mice, and even human brains, yet we still lack a mechanistic understanding of how these neuron types arise in the brain and expand during evolution. We identified homeodomain transcription factor (HDTF) codes in newborn neurons that specify the five neuron types (L1-L5) in theDrosophilalamina, the first ganglion of the visual system. Specifically, we discovered that the pan-lamina HDTF Scro is required for lamina progenitors to exit proliferation and differentiate into lamina neurons. Furthermore, we showed that specific HDTFs are expressed in distinct newborn neurons and specify different lamina neuron types: Zfh1 for L1 and L3, Dve for L2, and Bsh for L4 and L5. Intriguingly, we found that the loss of both Dve and Bsh causes L2, L4, and L5 neurons to revert to L1 and L3 neuron types, potentially representing ancestral lamina neuron types. HDTFs are evolutionarily conserved and broadly expressed in brains across species. Based on these findings, we propose a model in which distinct HDTFs in newborn neurons specify different neuron types in the brain and have been utilized to expand neuron diversity during evolution.
Remote cognitive tests predict neurodegenerative biomarkers in the Insight 46 cohort
Authors: Del Giovane Martina , Giunchiglia Valentina , Cai Ziyuan , Leoni Marguerite , Street Rebecca , Lu Kirsty , Wong Andrew , Popham Maria , Nicholas Jennifer M. , Trender William , Helleyer Peter J. , Parker Thomas D. , Murray-Smith Heidi , Malhotra Paresh A. , Crutch Sebastian J. , Richards Marcus , Hampshire Adam , Schott Jonathan M.
Published: September 2024

BACKGROUND

Alzheimer’s disease-related biomarkers detect pathology years before symptoms emerge, when disease-modifying therapies might be most beneficial. Remote cognitive testing provides a means of assessing early changes. We explored the relationship between neurodegenerative biomarkers and cognition in cognitively normal individuals.

METHODS

We remotely deployed 13 computerised Cognitron tasks in 255 Insight 46 participants. We generated whole brain, hippocampal, and white matter hyperintensity volumes at ages 69-71, rates of change over two-years, amyloid load and positivity. We examined the relationship between Cognitron, biomarkers, and standard neuropsychological tests.

RESULTS

Slower response time on a delayed recognition task predicted amyloid positivity (OR=1.79,CI:1.15, 2.95). Brain and hippocampal atrophy rates correlated with poorer visuospatial performance (b=-0.42, CI:-0.80, -0.05) and accuracy on immediate recognition (b=-0.01, CI:-0.01, -0.001), respectively. Standard tests correlated with Cognitron composites (rho=0.43, p<0.001).

DISCUSSION

Remote computerised testing correlates with standard supervised assessments and holds potential for studying early cognitive changes associated with neurodegeneration.
Socioeconomic inequalities and diabetes complications: An analysis of administrative data from Hungary
Authors: Elek Péter , Mayer Balázs , Varga Orsolya
Published: September 2024

Background

Diabetes complications are associated with increased healthcare costs and worsened patient outcomes. In this paper we analyze how individual-level demographic and territorial-level socioeconomic and healthcare variables influence the presence and severity of diabetes complications and their relationship with mortality.

Methods

Our study utilizes anonymized administrative data from Hungary, containing outpatient and inpatient records of all diabetes patients between 2010 to 2017. We construct settlement-year level and individual-year level panel datasets to analyze diabetes prevalence, incidence and complications, employing Poisson and logit models to explore associations between complications and the explanatory variables. The adapted Diabetes Complications Severity Index (aDCSI) is employed to quantitatively evaluate the severity of complications by aggregating individual complication scores from ICD-10 diagnosis codes.

Results

Diabetes prevalence and incidence are higher in settlements with above-median unemployment rates, where patients exhibit more severe complications, as shown by higher average aDCSI scores. Among socioeconomic factors, unemployment rate is particularly associated with increased aDCSI scores, while better healthcare access is associated with lower aDCSI scores in unadjusted but with higher scores in adjusted models. The presence and severity of complications, especially renal, cardio-vascular and peripheral vascular ones, substantially increase five-year inpatient mortality. Most of the mortality difference by settlement-level unemployment rate disappears when complications are accounted for.

Conclusions

Territorial-level socioeconomic disparities, especially elevated unemployment rates, significantly exacerbate the severity of diabetes complications, which subsequently heightens the mortality risk among diabetic patients. Enhancing health-care access in lower socioeconomic regions may alleviate these disparities and lessen the impact of complications.
Assessment of Health-Related Quality of Life (HRQoL) of Type 2 Diabetic Patients in Ghana
Authors: Ahiale Christine , Kumah Augustine
Published: September 2024

Background

Over the last decades, non-communicable diseases such as diabetes have remarkably increased due to rapid urbanization, unhealthy lifestyles, and ageing. The World Health Organization (WHO) indicates that the “diabetes epidemic” will continue in the coming decades, yielding enormous human and economic costs around the world. This study aims at accessing the health-related Quality of Life (QoL) of Type 2 Diabetic Patients in Ghana.

Method

This was a hospital-based cross-sectional descriptive study conducted in the 3 regions in Ghana among 1194 patients with type 2 diabetes who were seeking healthcare at the regional hospitals of the selected regions for at least 12 months. A multi-stage sampling technique was used in recruiting the participants. The WHOQOL-BREF tool was adopted to assess the health-related QoL of diabetic patients. Data was analyzed using STATA version 16.1, and the findings were presented in the tables. Statistical significance was set at (P < 0.05).

Results

Out of the 1194 participants, 90% (1079) reported a satisfactory quality of life. The majority (60.3%) of participants were above 50 years of age. The overall mean score of the QoL was 6.25 (±1.28) for all four domains: psychological, physical, social, relationship, and environmental health. Marital status, occupational status, and self-reported health status predicted overall QOL. Males have a better quality of life than females, and those below 50 also have a better quality of life than those above 50. Similarly, those employed had a better quality of life than the unemployed; however, those who were married, unmarried, educated, and non-educated had no significant differences in their quality of life. Sex was associated with all the domains. Marital status was associated with the environmental, social, and psychological domains. Age was associated with psychological and physical domains. On predictors of quality of life, all demographic variables (age, sex, educational status, marital status, and employment status) predicted quality of life across all domains.

Conclusion

This study provided valuable insights on predictors of health-related QoL among type 2 diabetic patients in Ghana, which would guide policymakers, healthcare providers, and stakeholders in improving diabetes management and ultimately enhancing the quality of life for individuals living with diabetes in Ghana. Evidence-based interventions should be implemented to address the factors influencing the QoL of diabetic patients in Ghana.
BLTP3A is associated with membranes of the late endocytic pathway and is an effector of CASM
Authors: Hanna Michael G , Rodriguez Cruz Hely O , Fujise Kenshiro , Wu Yumei , Xu C Shan , Pang Song , Zhuoning Li , Monetti Mara , De Camilli Pietro
Published: September 2024

Recent studies have identified a family of rod-shaped proteins thought to mediate lipid transfer at intracellular membrane contacts by a bridge-like mechanism. We show one such protein, BLTP3A/UHRF1BP1 binds VAMP7 vesicles via its C-terminal region and anchors them to lysosomes via the binding of its chorein domain containing N-terminal region to Rab7. Upon lysosome damage and resulting mATG8 recruitment to their surface by CASM, BLTP3A first dissociates from lysosomes but then reassociates with them via an interaction of its LIR motif with mATG8. Such interaction is mutually exclusive to the binding of BLTP3A to vesicles and leaves its N-terminal chorein domain, i.e. the proposed entry site of lipids into this family of proteins, available for binding to another membrane, possibly the ER. Loss of BLTP3A increases the lysis of lysosomes in response to damage. Our findings reveal that BLTP3A is an effector of CASM, potentially as part of a mechanism to help repair or minimize lysosome damage by delivering lipids.
Mapping and engineering RNA-controlled architecture of the multiphase nucleolus
Authors: Quinodoz SA , Jiang L , Abu-Alfa AA , Comi TJ , Zhao H , Yu Q , Wiesner LW , Botello JF , Donlic A , Soehalim E , Zorbas C , Wacheul L , Košmrlj A , Lafontaine DLJ , Klinge S , Brangwynne CP
Published: September 2024

Biomolecular condensates are key features of intracellular compartmentalization. As the most prominent nuclear condensate in eukaryotes, the nucleolus is a layered multiphase liquid-like structure and the site of ribosome biogenesis. In the nucleolus, ribosomal RNAs (rRNAs) are transcribed and processed, undergoing multiple maturation steps that ultimately result in formation of the ribosomal small subunit (SSU) and large subunit (LSU). However, how rRNA processing is coupled to the layered nucleolar organization is poorly understood due to a lack of tools to precisely monitor and perturb nucleolar rRNA processing dynamics. Here, we developed two complementary approaches to spatiotemporally map rRNA processing and engineerde novonucleoli. Using sequencing in parallel with imaging, we found that rRNA processing steps are spatially segregated, with sequential maturation of rRNA required for its outward movement through nucleolar phases. Furthermore, by generating syntheticde novonucleoli through an engineered rDNA plasmid system in cells, we show that defects in SSU processing can alter the ordering of nucleolar phases, resulting in inside-out nucleoli and preventing rRNA outflux, while LSU precursors are necessary to build the outermost layer of the nucleolus. These findings demonstrate how rRNA is both a scaffold and substrate for the nucleolus, with rRNA acting as a programmable blueprint for the multiphase architecture that facilitates assembly of an essential molecular machine.
Motility-dependent processes inToxoplasma gondiitachyzoites and bradyzoites: same same but different
Authors: Kent Robyn S. , Ward Gary E.
Published: September 2024

The tachyzoite stage of the apicomplexan parasiteToxoplasma gondiiutilizes motility for multiple purposes during its lytic cycle, including host cell invasion, egress from infected cells, and migration to new uninfected host cells to repeat the process. Bradyzoite stage parasites, which establish a new infection in a naïve host, must also use motility to escape from the cysts that are ingested by the new host and then migrate to the gut wall, where they either invade cells of the intestinal epithelium or squeeze between these cells to infect the underlying connective tissue. We know very little about the motility of bradyzoites, which we analyze in detail here and compare to the well-characterized motility and motility-dependent processes of tachyzoites. Unexpectedly, bradyzoites were found to be as motile as tachyzoites in a 3D model extracellular matrix, and they showed increased invasion into and transmigration across certain cell types, consistent with their need to establish the infection in the gut. The motility of the two stages was inhibited to the same extent by cytochalasin D and KNX-002, compounds known to target the parasite’s actomyosin-based motor. In contrast, other compounds that impact tachyzoite motility (tachyplegin and enhancer 5) have less of an effect on bradyzoites, and rapid bradyzoite egress from infected cells is not triggered by treatment with calcium ionophores, as it is with tachyzoites. The similarities and differences between these two life cycle stages highlight the need to characterize both tachyzoites and bradyzoites for a more complete understanding of the role of motility in the parasite life cycle and the effect that potential therapeutics targeting parasite motility will have on disease establishment and progression.
Shape transformation of vesicles induced by orientational arrangement of membrane proteins
Authors: Feng Menglong , Dong Kunhao , Cao Yuansheng , Ma Rui
Published: September 2024

Vesicles of lipid bilayer can adopt a variety of shapes due to different coating proteins. The ability of proteins to reshape membrane is typically characterized by inducing spontaneous curvature of the membrane at the coated area. BAR family proteins are known to have a crescent shape and can induce membrane curvature along its concaved body axis but not in the perpendicular direction. We model this type of proteins as a rod-shaped molecule with an orientation and induce normal curvature along its orientation in the tangential plane of the membrane surface. We show how a ring of these proteins reshape an axisymmetric vesicle when the protein curvature or orientation is varied. A discontinuous shape transformation from a protrusion shape without a neck to a one with a neck is found. Increasing the rigidity of the protein ring is able to smooth out the transition. Furthermore, we show that varying the protein orientation is able to induce an hourglass-shaped neck, which is significantly narrower than the reciprocal of the protein curvature. Our results offer a new angle to rationalize the helical structure formed by many proteins that carry out membrane fission functions.
Enzyme Activity Regulates Substrate Diffusion by Modulating Viscosity in Crowded Milieu
Authors: Bevilacqua Alessandro , Maciel Mauricio Rios , Pascarelli Stefano , Dindo Mirco , Shen Amy Q. , Laurino Paola
Published: September 2024

Enzymatic activity and its tight regulation are fundamental for cellular metabolism and life. While classical models of enzyme kinetics explain the behaviour of enzymes in buffer solutions, there are elusive properties that emerge from enzymes in their native, crowded environment. In this study, we harness liquid-liquid phase separation (LLPS) to createin vitrodroplets that mimic cytosolic protein crowding, offering a unique window to understand enzyme kinetics within well controlled microenvironments. We discover that the enzyme self-regulates its activity by modifying the shear viscosity of both the protein-rich droplets and the surrounding bulk solution. Through microscopy and rheology techniques, we discovered a significant correlation between enzyme activity and the shear viscosity of the droplets and bulk solution, influencing substrate diffusion. Our findings suggest that enzymes control their activity, influencing the organization and dynamics of macromolecular crowding within droplets. These results provide new insights into how enzymes regulate both their physical environment and metabolic processes in cell.
Tris inhibits a GH1 β-glucosidase by a linear mixed inhibition mechanism
Authors: Chagas Rafael S. , Marana Sandro R.
Published: September 2024

Here we demonstrate that Tris (2-amino-2-(hydroxymethyl)-1,3-propanediol), largely used as buffering agent, is a linear mixed inhibitor (Ki= 12 ± 2 mM and α = 3 ± 1) of the GH1 β-glucosidase from the insectSpodoptera frugiperda(Sfβgly). Such inhibition mechanism implies in the formation of a non-productive ESI complex involving Sfβgly, substrate and Tris. In addition, Tris binding reduces by 3 fold the enzyme affinity for the substrate. Hence, at concentrations higher than theKi, Tris can completely abolish Sfβgly activity, whereas even at lower concentrations the presence of Tris causes underestimation of β-glucosidase kinetic parameters (Kmandkcat). In agreement to the inhibition mechanism, computational docking showed that Tris could bind to a pocket placed at the lateral of the active site opening in the Sfβgly-substrate complex, hence leading to the formation of a ESI complex. Computational docking also showed that Tris may find binding spots in the interior of the active site of the Sfβgly and several GH1 β-glucosidases. Moreover, the variety of their active site shapes results in a multiplicity of binding profiles, foreseeing different inhibition mechanism. Thus, Tris inhibition is probably common among GH1 β-glucosidases. This remark should be taken into account in their study, highlighting the importance of the appropriate buffer for accurate enzyme characterization.
Impact of social isolation stress on safety learning and the structure of defensive behavior during a spatial-based learning task involving thermal threat
Authors: Villalon Stephanie A. , Felix-Ortiz Ada C. , Lozano-Ortiz Kelly , McCarrey John R. , Burgos-Robles Anthony
Published: September 2024

Safety learning during threat and adversity is critical for behavioral adaptation, resiliency, and survival. Using a novel mouse paradigm involving thermal threat, we recently demonstrated that safety learning is highly susceptible to stress. Yet, our previous study primarily considered male mice and did not thoroughly scrutinize the relative impacts of stress on potentially distinct defensive mechanisms implemented by males and females during the thermal task. The present study assessed these issues while analyzing a variety of defensive behaviors related to safety-seeking, escape, coping, protection, ambivalence, and risk-taking. After a two-week social isolation stress period, mice were required to explore a box arena that had thermal threat and safety zones (5°C vs 30°C, respectively). Since visuospatial cues clearly differentiated the threat and safety zones, the majority of the no-stress controls (69-75%) in both sexes exhibited optimal memory formation for the safety zone. In contrast, the majority of the stress-exposed mice in both sexes (69-75%) exhibited robust impairment in memory formation for the safety zone. Furthermore, while the control groups exhibited many robust correlations among various defensive behaviors, the stress-exposed mice in both sexes exhibited disorganized behaviors. Thus, stress severely impaired the proper establishment of safety memory and the structure of defensive behavior, effects that primarily occurred in a sex-independent manner.
Variants inLrrk2andSncadeficiency do not alter the course of primary encephalitis due to neurotropic reovirus T3D in newborn mice
Authors: Lunn Michaela O. , Rousso Christopher , Tomlinson Julianna J. , Brown Earl G. , Schlossmacher Michael G.
Published: September 2024

Variants of the leucine-rich repeat kinase-2 (LRRK2) and α-synuclein (SNCA) genes are associated with Parkinson’s disease risk. We previously demonstrated that twoLrrk2knock-in variants as well asSncaexpression alter survival rates from combined pneumonitis and encephalitis following intranasal inoculation of newborn mice with a double-stranded RNA virus: respiratory-enteric-orphan virus, serotype-3 strain Dearing (reovirus T3D). Here, we examined whether outcomes of direct inoculation of the brain by reovirus T3D, which invariably causes lethal encephalitis within 15 days, would also be modified by variants inLrrk2andSnca. When we inoculated newborn mice intracerebrally with 5×102plaque-forming units of reovirus T3D, we found that, when compared to wild-type littermates, Lrrk2 p.G2019S mutant mice and kinase-dead p.D1994S mutant animals showed the same time-to-death intervals post-infection, revealed no sex difference, and had similar viral titres in the brain. Furthermore, the reduction or absence of endogenous α-synuclein also did not alter the course of encephalitis in parallel studies. These outcomes are in contrast to those following the intranasal inoculation paradigm of newborn mice, in which Lrrk2 and wild-type α-synuclein were both protective in infection outcomes. Together, these findings suggest that the Parkinson’s disease-linkedLrrk2andSncagenes contribute predominantly to systemic, innate responses by the host following reovirus T3D exposure.
Tailocin-mediated interactions among Soft RotPectobacteriaceae
Authors: Borowicz Marcin , Krzyżanowska Dorota M. , Sobolewska Marta , Narajczyk Magdalena , Mruk Inez , Czaplewska Paulina , Pédron Jacques , Barny Marie-Anne , Yves Canto Pierre , Dziadkowiec Joanna , Czajkowski Robert
Published: September 2024

Bacteria carry phage-derived elements within their genomes, some of which can produce phage-like particles (tailocins) used as weapons to kill kin strains in response to environmental conditions. This study investigates the production and activity of tailocins by plant pathogenic bacteria:Pectobacterium,Dickeya,andMusicolagenera, which compete for niche, providing an attractive model to study the ecological role of tailocins. Microscopy revealed that most analyzed strains (88%) produced tailocins. Tailocin-mediated killing interactions were assessed across 351 strain pairs, showing thatDickeyaspp. had a higher likelihood of killing neighbors (57.1%) thanPectobacteriumspp. (21.6%). Additionally,Dickeyaspp. strains exhibited broader phylogenetic killing, targeting bothPectobacteriumspp. andMusicolasp., whilePectobacteriumspp. tailocins were genus-specific. Mutual killing was observed in 33.9% of interactions, predominantly withinDickeyaspp. Although tailocins were morphologically indistinguishable between producers, genomic analyses identified conserved clusters having distinct differences betweenPectobacteriumspp. andDickeyaspp tailocins. This suggests different origins of these particles. Induction experiments demonstrated that tailocin production was boosted by hydrogen peroxide, supporting the role of these particles in bacteria-bacteria competition during infection. Tailocins were detectable in infected potato tissue but not in river water, highlighting the particular ecological relevance of tailocins in plant environments.
Dnmt1-deficiency in PV interneurons alters cortical circuit function and leads to depression-like behavior
Authors: Linde Jenice , Nabbefeld Gerion , Graff Severin , Yildiz Can Bora , Pensold Daniel , Reichard Julia , Hermanns Marie , Kampa Bjoern , Urbach Anja , Musall Simon , Zimmer-Bensch Geraldine M.
Published: September 2024

Neuropsychiatric disorders, including major depressive disorder (MDD), are highly prevalent in modern society, arising from a complex interplay of genetic and environmental factors. Alterations in the function of cortical inhibitory GABAergic interneurons, along with dysregulations of epigenetic signatures and key regulators such as DNA methyltransferase 1 (DNMT1), have been implicated in these conditions. Through its role in catalyzing DNA methylation, DNMT1 modulates the synaptic activity of parvalbumin-expressing (PV) interneurons, which are essential for cortical inhibition. However, the functional consequences of DNMT1 activity in cortical interneurons at the network level and its impact on behavior remain unknown and must be explored to fully understand the disease implications of dysregulated DNMT1 expression and function. To address this, we utilized a conditional knockout mouse model with Dnmt1 deletion in PV interneurons. Our findings reveal that a Dnmt1 deficiency leads to increased spontaneous firing rates of cortical neurons, reduced cortical gamma oscillations, and altered visually evoked neural responses. Despite intact sensory perception, Dnmt1-deficient mice exhibited reduced physical activity, heightened anxiety-like behavior, and signs of anhedonia and apathy, which represent core features of MDD. These results underscore the critical role of DNMT1 in PV interneuron function and identify it as a potential target for MDD research.
Drive sustainable business performance with humane entrepreneurship, knowledge management: the mediation of sustainable business advantage and sustainable business model innovation
Authors: Le Thanh Tiep , Bùi Thị Tuyết Như , Le Anh Thu
Published: September 2024

Purpose

This study evaluates the important role of humane entrepreneurship (HE) on sustainable business advantage (SBA) and sustainable business performance (SBP) by exploring the mediating role of sustainable business model innovation (SBMI) under the influence of knowledge management (KM) in small and medium-sized enterprises (SMEs). Encouraging businesses to implement a combination of KM and HE facilitates the implementation of SBMI that brings value to businesses, communities and the environment in emerging economies.

Design/methodology/approach

This study uses an empirical quantitative research method using primary information based on data collected by questionnaires. The study sample resulted in 424 valid responses (66.77% response rate). The target audience of the study is middle and senior managers in SMEs. This study aims to perform structural modeling analysis with the maximum likelihood estimates method to examine structural relationships.

Findings

This study found a positive relationship between KM and HE to SBMI. At the same time, SBMI plays an important role for businesses to achieve SBA and SBP. Similarly, a positive relationship was also found between HE to SBA and SBP. And SBA strongly promotes SMEs to achieve SBP. In addition, the mediating role of SBMI and SBA is clarified to have a positive impact between HE–SBP and SBMI–SBP. HE plays an important role in motivating businesses to innovate sustainable business models, making it easier to gain sustainable competitive advantages, thereby bringing sustainable business results.

Practical implications

This research helps SMEs realize the importance of KM and HE in SBMI. At that time, SMEs take advantage of internal and external information sources and innovate their business models based on HE mechanisms. Applying HE mechanisms will allow businesses to innovate their business models by combining concerns between stakeholders and the social environment for sustainable development. Therefore, businesses will achieve their SBA toward SBP.

Originality/value

The present literature shows that there are few empirical studies on the mechanism mediating SBMI in the relationship between HE and SBP; and SBA in the link between SBMI and SBP. In addition, the impact of KM and HE on SBMI is also very important in the current context. The study's findings could have huge implications for entrepreneurs and senior managers in SMEs in emerging economies. Help them realize the importance of KM and HE for SBMI, thereby building strategic perspectives that help businesses achieve sustainable competitive advantages and increase SBP for businesses.
In AI, we do not trust! The nexus between awareness of falsity in AI-generated CSR ads and online brand engagement
Authors: Aljarah Ahmad , Ibrahim Blend , López Manuela
Published: September 2024

Purpose

Synthetic advertising, which involves creating or modifying ads through artificial intelligence (AI) technology, has recently transformed the field of media and advertising. Despite its emerging importance, our understanding of consumer perceptions in this context is limited. This study is one of the first to explore the impact of synthetic advertising on consumer behavior.

Design/methodology/approach

Across two between-subject experimental studies, using coffee shop customers in the USA, we tested how, why and when awareness of falsity in AI-generated corporate social responsibility (CSR) ads affects online brand engagement.

Findings

In Study 1, awareness of falsity in AI-generated CSR ads negatively impacts online brand engagement, with perceived sincerity mediating this relationship. Additionally, a higher level of CSR authenticity mitigates the negative effect of awareness of falsity on online brand engagement. CSR authenticity does not moderate the mediation effect of perceived sincerity in the relationship between awareness of falsity and online brand engagement. In Study 2, the relationship between awareness of falsity and online brand engagement is moderated by brand familiarity. Importantly, perceived sincerity only mediates this effect for unfamiliar brands, not familiar ones.

Practical implications

This study provides key insights for managers using AI to promote CSR initiatives. While AI can save time and budget, it may lead to negative consumer reactions due to perceptions of insincerity. To mitigate this, companies should focus on enhancing the authenticity of their CSR efforts and humanizing AI-generated ads. Additionally, established brands should be cautious of reduced consumer engagement with AI-generated content, while unfamiliar brands can benefit by emphasizing sincerity in their messaging.

Originality/value

This paper is one of the first studies that discuss how, why and when awareness of falsity in AI-generated corporate social responsibility ads affects online brand engagement.
Achieving supply chain sustainability: enhancing supply chain resilience, organizational performance, innovation and information sharing: empirical evidence from Chinese SMEs
Authors: Mehmood Saqib , Nazir Samera , Fan Jianqiang , Nazir Zarish
Published: September 2024

Purpose

This study aimed to explore the relationship between supply chain resilience (SCR) and organizational performance (OP), with innovation (INN) serving as a mediator and information sharing (IS) acting as a moderator.

Design/methodology/approach

The study comprehensively examined the connections between SCR, OP, INN and IS. An exploratory approach and quantitative methods were employed. The data were collected from small and medium-sized manufacturing enterprises of three cities Xian, Hainan and Guangzhou of China via online questionnaire surveys conducted through Emails and WeChat. SmartPLS-4 was used for data analysis.

Findings

The findings indicated that SCR has a positive effect on sustainability efforts. Additionally, INN and effective IS both mediated and moderated this relationship, playing crucial roles in improving sustainability within the supply chain.

Practical implications

The study offered practical insights for businesses to enhance their sustainability efforts. Managers can use these findings to develop strategies that improve SCR, foster INN and encourage effective IS, ultimately resulting in a more sustainable supply chain.

Originality/value

This study enriched the existing knowledge base by investigating the intricate relationships among SCR, OP, INN and IS, all within the context of achieving sustainability. By exploring these elements holistically, the research introduced originality and highlighted effective strategies for sustainable supply chain management.
Financial performance and tone of financial disclosures: The moderating effect of CEO narcissism
Authors: Marquez Illescas Gilberto , Sauer Stephen J. , Zebedee Allan A. , Zhou Linying
Published: September 2024

Using an experimental approach, this study shows that the effect of financial performance on tone is weaker in firms led by a more narcissistic chief executive officer (CEO) because narcissistic CEOs inflate the tone relatively more when reporting worse results. This suggests that factoring CEO narcissism into the assessment of the tone of financial disclosures is especially relevant in situations in which firms report negative financial information. Our findings demonstrate that the impact of CEO narcissism may not only exert a direct influence on firm‐level outcomes, such as the tone of financial disclosures, but it could also moderate the influence of other factors.
A cross‐cultural study of ESG impact on corporate performance and equity
Authors: Wu Lei , Zhai Zhenkai , Lv Yongbin
Published: September 2024

Utilising A‐share corporate data and quantitative and empirical methodologies, this study examines the potential influence of environmental, social, and governance (ESG) and Confucianism on two critical dimensions of corporate governance: corporate profitability and equity in compensation. The findings indicate that while ESG practices contribute to enhanced profitability, they are also associated with an increased disparity in fair pay, indicating more pronounced salary variations. Significantly, the incorporation of Confucian principles appears to moderate these disparities, aligning ESG efforts more closely with principles of equitable compensation. This research analyses the interplay between contemporary sustainability initiatives and traditional cultural norms, offering valuable insights for the formulation of balanced corporate management strategies.
Genome‐wide re‐sequencing reveals regulatory genes and variants involved in the regulation of intermittent fertilization intensity in Wenchang chickens
Authors: Wang Xiuping , Wang Lei , Hong Xing , Li Mingze , Gu Xianyuan , Liu Minhui , Li ShiJun
Published: September 2024

Intermittent fertilization intensity (IFI) is closely related to higher fertilization in chickens, but the genetic basis of IFI is not clearly understood. Here, we sampled a total of 939 Wenchang chickens with IFI. The IFI traits had negative correlation with the fertilization rate and exhibited huge phenotypic variations among individuals of the same strain. Based on SNPs derived from a subset of 499 whole genome data, a genome‐wide association study with mixed linear model and further linkage disequilibrium analysis were performed to test potential associations between IFI traits and genomic variants. We identified 35 SNP variants and a 19.82 kb linkage disequilibrium block on chr8 significantly associated with IFI. This block is in the intron of LOC101750715, which shows significant homology with the human LMO4. Therefore, LOC101750715 and LMO4 may regulate IFI. The oviduct's immune regulation is crucial for fertilization. LMO4, activated by IL‐6 and IL‐23, promotes inflammation in epithelial cells. Thus, LOC101750715 and LMO4 may affect fertilization by regulating oviductal inflammation, impacting IFI. Our findings will provide targets for molecular‐marker selection and genetic manipulation for lines of chickens with lower IFI.
Association between state‐level medical marijuana legalization and marijuana use during pregnancy: A population‐based study
Authors: Haider Mohammad Rifat , Karim Sabrina , Jayawardhana Jayani , Hansen Nathan B. , Haile Zelalem T.
Published: September 2024

Background and Objectives

Despite marijuana's association with adverse pregnancy and birth outcomes, its use during pregnancy increased over the last two decades. During this period, medical marijuana has been legalized in 38 states and the District of Columbia. States with legalized medical marijuana have observed increased marketing of marijuana and related products. This study aims to examine the association between state‐level medical marijuana legalization and marijuana use during pregnancy in the United States.

Methods

Using the 2015–2021 National Survey on Drug Use and Health, we evaluated the association between marijuana use in the past month among currently pregnant mothers (N = 4338) and legalized medical marijuana in their state of residence. Survey‐weighted descriptive, bivariate, and multivariable logistic regression analyzes were performed.

Results

About 5.7% of pregnant women reported using marijuana in the past month, and 59.0% lived in a state where medical marijuana was legalized across 2015–2021. Compared to those living in states without marijuana legalization, more pregnant women living in states with marijuana legalization reported using marijuana (4.6% vs. 6.5%). In the multivariable model, pregnant women residing in states with medical marijuana legalization were more likely to use marijuana than residents of states without legalization (adjusted Odds Ratio: 1.56; 95% Confidence Interval: 1.11–2.18).

Conclusion and Scientific Significance

This is the first known study to find that pregnant women living in states where medical marijuana is legalized are more likely to use marijuana during pregnancy. Pregnant women should be informed of adverse pregnancy and birth outcomes linked to marijuana use during pregnancy.
Is buprenorphine maternal dose associated with neonatal opioid withdrawal syndrome severity?
Authors: Marc Besnier , Marion Delouche , François Birault , Lakshmipriya Lebonheur
Published: September 2024

Background

Neonatal opioid withdrawal syndrome (NOWS) is a drug withdrawal syndrome occurring mainly after in utero opioid exposure. Buprenorphine is commonly used for opioid withdrawal. Studies are conflicted about a potential dose effect

Objective

The aim of our study was to investigate the impact of buprenorphine maternal maintenance therapy on the NOWS based on NOWS duration, birth weight and therapy.

Study Design

We conducted a retrospective study analysing data from infants admitted for NOWS in two Neonatal Intensive Care Unit between January 2010 and December 2020. Inclusion criteria: Nonpreterm infants born to mothers who were treated with buprenorphine or therapy during pregnancy and who had a Lipsitz score of 4 or higher.

Results

A total of 75 term newborns were hospitalized for the treatment of NOWS from mother substituted with buprenorphine during the study inclusion period. The duration of NOWS differed significantly between all dose cohorts, with higher doses of maternal buprenorphine maintenance correlating with longer length of NOWS duration. Infants exposed to high doses required 17 days [10; 23], while infants exposed to intermediate doses required 7 days [2; 16] and infants exposed to low doses required 3 days [2; 5], with p‐values < .003. Infants exposed to high doses required a longer time to regain their birth weight and higher morphine doses as therapy compared to others. Infants exposed to low doses, intermediate doses, and high doses of buprenorphine demonstrated dose‐dependent increases in the durations of hospitalization, respectively.

Conclusion and Scientific Significance

Increased doses of maternal buprenorphine during pregnancy are correlated with NOWS severity. Our study shows that increased doses of maternal buprenorphine during pregnancy are correlated with NOWS severity. Exploring low doses and having different ranges are a new argument to define the impact of maternal buprenorphine consumption.