bluuebunny/crossref_metadata_2025 huggingface dataset:
Leptomeningeal anti-tumor immunity follows unique signaling principles
Authors: Remsik Jan , Tong Xinran , Kunes Russell Z. , Li Min Jun , Osman Ahmed , Chabot Kiana , Sener Ugur T. , Wilcox Jessica A. , Isakov Danielle , Snyder Jenna , Bale Tejus A. , Chaligné Ronan , Pe’er Dana , Boire Adrienne
Published: March 2023

Metastasis to the cerebrospinal fluid (CSF)-filled leptomeninges, or leptomeningeal metastasis (LM), represents a fatal complication of cancer. Proteomic and transcriptomic analyses of human CSF reveal a substantial inflammatory infiltrate in LM. We find the solute and immune composition of CSF in the setting of LM changes dramatically, with notable enrichment in IFN-γ signaling. To investigate the mechanistic relationships between immune cell signaling and cancer cells within the leptomeninges, we developed syngeneic lung, breast, and melanoma LM mouse models. Here we show that transgenic host mice, lacking IFN-γ or its receptor, fail to control LM growth. Overexpression ofIfngthrough a targeted AAV system controls cancer cell growth independent of adaptive immunity. Instead, leptomeningeal IFN-γ actively recruits and activates peripheral myeloid cells, generating a diverse spectrum of dendritic cell subsets. These migratory, CCR7+ dendritic cells orchestrate the influx, proliferation, and cytotoxic action of natural killer cells to control cancer cell growth in the leptomeninges. This work uncovers leptomeningeal-specific IFN-γ signaling and suggests a novel immune-therapeutic approach against tumors within this space.
Drosophilamodel to clarify the pathological significance of OPA1 in autosomal dominant optic atrophy
Authors: Nitta Yohei , Osaka Jiro , Maki Ryuto , Hakeda-Suzuki Satoko , Suzuki Emiko , Ueki Satoshi , Suzuki Takashi , Sugie Atsushi
Published: March 2023

Autosomal dominant optic atrophy (DOA) is a progressive form of blindness caused by degeneration of retinal ganglion cells and their axons, mainly caused by mutations in the OPA1 mitochondrial dynaminlikeGTPase (OPA1) gene.OPA1encodes a dynamin-like GTPase present in the mitochondrial inner membrane. When associated with OPA1 mutations, DOA can present not only ocular symptoms but also multi-organ symptoms (DOA plus). DOA plus often results from point mutations in the GTPase domain, which are assumed to have dominant negative effects. However, the presence of mutations in the GTPase domain does not always result in DOA plus. Therefore, an experimental system to distinguish between DOA and DOA plus is needed. In this study, we found that loss-of-function mutations of thedOPA1gene inDrosophilacan imitate the pathology of optic nerve degeneration observed in DOA. We successfully rescued this degeneration by expressing the humanOPA1(hOPA1) gene, indicating thathOPA1is functionally interchangeable withdOPA1in the fly system. However, mutations previously identified did not ameliorate thedOPA1deficiency phenotype. By expressing both WT and DOA plus mutanthOPA1forms in the optic nerve ofdOPA1mutants, we observed that DOA plus mutations suppressed the rescue, facilitating the distinction between loss-of-function and dominant negative mutations inhOPA1. This fly model aids in distinguishing DOA from DOA plus and guides initialhOPA1mutation treatment strategies.
The ATP-bound State of the Uncoupling Protein 1 (UCP1) from Molecular Simulations
Authors: Jacobsen Luise , Lydersen Laura , Khandelia Himanshu
Published: March 2023

The uncoupling protein 1 (UCP1) dissipates the transmembrane (TM) proton gradient in the inner mitochondrial membrane (IMM) by leaking protons across the membrane, producing heat in the process. Such non-shivering production of heat in brown adipose tissue can combat obesity-related diseases. UCP1 associated proton leak is activated by free fatty acids and inhibited by purine nucleotides. The mechanism of proton leak remains unknown, in part due to the unavailability of high-resolution structures of the protein. As a result, the binding site of the activators (fatty acids) and inhibitors (nucleotides) is unknown. Using molecular dynamics simulations, we generate a conformational ensemble of UCP1. Using Metadynamics-based free energy calculations, we converge on the most likely ATP-bound conformation of UCP1. Our conformational ensemble provides a molecular basis of a breadth of prior biochemical data available for UCP1. Based on the simulations, we make the following testable predictions about the mechanisms of activation of proton leak and proton leak inhibition by ATP: (1) R277 plays the dual role of stabilising ATP at the binding site for inhibition, and acting as a proton surrogate for D28 in the absence of a proton during proton transport (2) the binding of ATP to UCP1 is mediated by residues R84, R92, R183, and S88 (3) R92 shuttles ATP from the E191-R92 gate in the inter-membrane space to the nucleotide binding site, and serves to increase ATP affinity (4) ATP can inhibit proton leak by controlling the ionisation states of matrix facing lysine residues such as K269 and K56 and (5) fatty acids can bind to UCP1 from the IMM either via the cavity between TM1 and TM2 or between TM5 and TM6. Our simulations set the platform for future investigations into the proton transport and inhibition mechanisms of UCP1.
Novel Endogenous Engineering Platform for Robust Loading and Delivery of Functional mRNA by Extracellular Vesicles
Authors: Zickler Antje M. , Liang Xiuming , Gupta Dhanu , Mamand Doste , Luca Mariacristina De , Corso Giulia , Errichelli Lorenzo , Hean Justin , Sen Titash , Elsharkasy Omnia M. , Kamei Noriyasu , Niu Zheyu , Zhou Guannan , Zhou Houze , Roudi Samantha , Wiklander Oscar P. B. , Görgens André , Nordin Joel Z. , Castilla-Llorente Virginia , Andaloussi Samir EL
Published: March 2023

Messenger RNA (mRNA) has emerged as an attractive therapeutic molecule for a plethora of clinical applications. Forin vivofunctionality, mRNA therapeutics require encapsulation into effective, stable, and safe delivery systems to protect the cargo from degradation and reduce immunogenicity. Here, a bioengineering platform for efficient mRNA loading and functional delivery using bionormal nanoparticles, Extracellular Vesicles (EVs), is established by expressing a highly specific RNA-binding domain fused to CD63 in EV producer cells stably expressing the target mRNA. The additional combination with a fusogenic endosomal escape moiety, VSVg, enables functional mRNA deliveryin vivoat doses substantially lower than currently used clinically with synthetic lipid-based nanoparticles. Importantly, the application of EVs loaded with effective cancer immunotherapy proves highly effective in an aggressive melanoma mouse model. This technology addresses substantial drawbacks currently associated with EV-based nucleic acid delivery systems and is a leap forward to clinical EV applications.

Graphical Abstract

(Figure created using BioRender)
Genetic and Environmental interactions contribute to immune variation in rewilded mice
Authors: Oyesola Oyebola , Downie Alexander E. , Howard Nina , Barre Ramya S. , Kiwanuka Kasalina , Zaldana Kimberly , Chen Ying-Han , Menezes Arthur , Lee Soo Ching , Devlin Joseph , Mondragón-Palomino Octavio , Silva Souza Camila Oliveira , Herrmann Christin , Koralov Sergei , Cadwell Ken , Graham Andrea L. , Loke P’ng
Published: March 2023

The relative and synergistic contributions of genetics and environment to inter-individual immune response variation remain unclear, despite its implications for understanding both evolutionary biology and medicine. Here, we quantify interactive effects of genotype and environment on immune traits by investigating three inbred mouse strains rewilded in an outdoor enclosure and infected with the parasite,Trichuris muris. Whereas cytokine response heterogeneity was primarily driven by genotype, cellular composition heterogeneity was shaped by interactions between genotype and environment. Notably, genetic differences under laboratory conditions can be decreased following rewilding, and variation in T cell markers are more driven by genetics, whereas B cell markers are driven more by environment. Importantly, variation in worm burden is associated with measures of immune variation, as well as genetics and environment. These results indicate that nonheritable influences interact with genetic factors to shape immune variation, with synergistic impacts on the deployment and evolution of defense mechanisms.
Emergence of power-law distributions in protein-protein interaction networks through study bias
Authors: Blumenthal David B. , Lucchetta Marta , Kleist Linda , Fekete Sándor P. , List Markus , Schaefer Martin H.
Published: March 2023

Protein-protein interaction (PPI) networks are power-law-distributed. However, the experimental procedures for detecting PPIs are affected by technical and study bias. For instance, cancer-associated proteins have received disproportional attention. Moreover, bait proteins in large-scale experiments tend to have many false-positive interaction partners. This raises the question of whether PL distributions in observed PPI networks could be explained by these biases alone. To assess this question, we studied the degree distribution of thousands of PPI networks of controlled provenance. Our findings are supported by mathematical models and extensive simulations and indicate that study bias and technical bias suffice to produce the observed PL distribution. It is, hence, problematic to derive hypotheses about the degree distribution and the true biological interactome from the PL distributions in observed PPI networks. Our study casts doubt on the use of the PL property of biological networks as a modeling assumption or quality criterion in network biology.
Structure of a fungal 1,3-β-glucan synthase
Authors: Zhao Chao-Ran , You Zi-Long , Chen Dan-Dan , Hang Jing , Wang Zhao-Bin , Wang Le-Xuan , Zhao Peng , Qiao Jie , Yun Cai-Hong , Bai Lin
Published: March 2023

1,3-β-Glucan is the major component of the fungal cell wall and is synthesized by 1,3-β-glucan synthase located in the plasma membrane, which is a molecular target of anti-fungal drugs echinocandins and the triterpenoid ibrexafungerp. In this study, we report the 3.0-Å resolution cryo-EM structure ofSaccharomyces cerevisiae1,3-β-glucan synthase, Fks1. The structure reveals a central catalytic region adopting a cellulose synthase fold with a cytosolic conserved GT-A type glycosyltransferase domain and a closed transmembrane glucan-transporting channel. We found that two extracellular disulfide bonds are crucial for Fks1 enzymatic activity. Structural comparison between Fks1 and cellulose synthases and structure-guided mutagenesis studies provided novel insights into the molecular mechanisms of the fungal 1,3-β-glucan synthase.
A conserved protein inhibitor brings under check the activity of RNase E in cyanobacteria
Authors: Liu Su-Juan , Lin Gui-Ming , Yuan Yu-Qi , Chen Wenli , Zhang Ju-Yuan , Zhang Cheng-Cai
Published: March 2023

RNase E is a major ribonuclease for RNA metabolism in bacteria. Because it has a large substrate spectrum and poor substrate specificity, its activity must be well controlled under different conditions. Only a few regulators of RNase E are known in bacteria, limiting our understanding on the posttranscriptional regulatory mechanisms operating in these organisms. Here we show that, RebA, a protein universally present in cyanobacteria, interacts with RNase E in the filamentous cyanobacteriumAnabaenaPCC 7120. Distinct from those known regulators of RNase E, RebA interacts with the 5’ sensor domain in the catalytic region of RNase E, and suppresses the cleavage activities of RNase E for all tested RNA substrates irrespective of their 5’-end status. Consistent with the inhibitory function of RebA on RNase E, conditional depletion of RNase E and overproduction of RebA caused formation of elongated cells, whereas the absence of RebA and overproduction of RNase E resulted in a shorter-cell phenotype. We further showed that the morphological changes caused by altered levels of RNase E or RebA are dependent on their physical interaction. The action of RebA represents a new mechanism, highly conserved in cyanobacteria, for RNase E regulation. Our findings provide insights into the regulation and the function of RNase E, and demonstrate the importance of balanced RNA metabolism in bacteria.
A phase-field model for non-small cell lung cancer under the effects of immunotherapy
Authors: Wagner Andreas , Schlicke Pirmin , Fritz Marvin , Kuttler Christina , Oden J. Tinsley , Schumann Christian , Wohlmuth Barbara
Published: March 2023

Formulating tumor models that predict growth under therapy is vital for improving patient-specific treatment plans. In this context, we present our recent work on simulating non-small-scale cell lung cancer (NSCLC) in a simple, deterministic setting for two different patients receiving an immunotherapeutic treatment.

At its core, our model consists of a Cahn-Hilliard-based phase-field model describing the evolution of proliferative and necrotic tumor cells. These are coupled to a simplified nutrient model that drives the growth of the proliferative cells and their decay into necrotic cells. The applied immunotherapy decreases the proliferative cell concentration. Here, we model the immunotherapeutic agent concentration in the entire lung over time by an ordinary differential equation (ODE). Finally, reaction terms provide a coupling between all these equations. By assuming spherical, symmetric tumor growth and constant nutrient inflow, we simplify this full 3D cancer simulation model to a reduced 1D model.

We can then resort to patient data gathered from computed tomography (CT) scans over several years to calibrate our model. For the reduced 1D model, we show that our model can qualitatively describe observations during immunotherapy by fitting our model parameters to existing patient data. Our model covers cases in which the immunotherapy is successful and limits the tumor size, as well as cases predicting a sudden relapse, leading to exponential tumor growth.

Finally, we move from the reduced model back to the full 3D cancer simulation in the lung tissue. Thereby, we show the predictive benefits a more detailed patient-specific simulation including spatial information could yield in the future.

Author summary

Lung cancer is one of the deadliest diseases, with low long-term survival rates. Its treatment is still very heuristic since patients respond to the same treatment plans differs significantly. Therefore, patient-specific models for predicting tumor growth and the treatment response are necessary for clinicians to make informed decisions about the patient’s therapy and avoid a trial and error based approach. We made a first small step in that direction by introducing a model for simulating cancer growth and its treatment inside a 3D lung geometry. In this model, we represented tumor cells by a volume fraction field that varies over space and time. We described their evolution by a system of partial differential equations, which include patient- and treatment-specific parameters capturing the different responses of patients to the therapies. Our simulation results were compared to clinical data and showed that we can quantitatively describe the tumor’s behavior with a suitable parameter set. This enabled us to change therapies in simulation runs and analyze how these changes could have impacted the patient’s health.
The combination of CD49b and CD229 reveals a subset of multipotent progenitors with short-term activity within the hematopoietic stem cell compartment
Authors: Somuncular Ece , Su Tsu-Yi , Dumral Özge , Johansson Anne-Sofie , Luc Sidinh
Published: March 2023

Hematopoiesis is maintained by hematopoietic stem cells (HSCs) that replenish all blood lineages throughout life. It is well-established that the HSC pool is functionally heterogeneous consisting of cells differing in longevity, self-renewal ability, cell proliferation, and lineage differentiation. Although HSCs can be identified through the Lineage−Sca-1+c-Kit+CD48−CD34−CD150+immunophenotype, the cell surface marker combination does not permit absolute purification of functional HSCs with long-term reconstituting ability. Therefore, prospective isolation of long-term HSCs is crucial for mechanistic understanding of the biological functions of HSCs and for resolving functional heterogeneity within the HSC population. Here, we show that the combination of CD229 and CD49b cell surface markers within the phenotypic HSC compartment identifies a subset of multipotent progenitor cells with high proliferative activity and short-term reconstituting ability. Thus, the addition of CD229 and CD49b to conventional HSC markers permits prospective isolation of functional HSCs by distinguishing MPPs in the HSC compartment.

SIGNIFICANCE STATEMENT

Blood cells are generated by rare stem cells, which based on their defining features of self-renewal and multipotent abilities, are used in transplantation as curative treatment for blood diseases. Despite their clinical importance, mechanisms of stem cell properties are elusive given the inability to isolate pure blood stem cells for prospective analyses. In this study, we demonstrate that stem cells can be isolated by excluding multipotent progenitors, marked by CD229 and CD49b, from the stem cell compartment. Our study has important implications for the analysis of mechanisms regulating stem cell function and is relevant for clinical applications of stem cells.
Self-delivering CRISPR RNAs for AAV Co-delivery and Genome Editingin vivo
Authors: Zhang Han , Kelly Karen , Lee Jonathan , Echeverria Dimas , Cooper David , Panwala Rebecca , Chen Zexiang , Gaston Nicholas , Newby Gregory A. , Xie Jun , Liu David R. , Gao Guangping , Wolfe Scot A. , Khvorova Anastasia , Watts Jonathan K. , Sontheimer Erik J.
Published: March 2023

Guide RNAs offer programmability for CRISPR-Cas9 genome editing but also add challenges for delivery. Chemical modification, which has been key to the success of oligonucleotide therapeutics, can enhance the stability, distribution, cellular uptake, and safety of nucleic acids. Previously, we engineered heavily and fully modified SpyCas9 crRNA and tracrRNA, which showed enhanced stability and retained activity when delivered to cultured cells in the form of the ribonucleoprotein complex. In this study, we report that a short, fully stabilized oligonucleotide (a “protecting oligo”), which can be displaced by tracrRNA annealing, can significantly enhance the potency and stability of a heavily modified crRNA. Furthermore, protecting oligos allow various bioconjugates to be appended, thereby improving cellular uptake and biodistribution of crRNAin vivo. Finally, we achievedin vivogenome editing in adult mouse liver and central nervous system via co-delivery of unformulated, chemically modified crRNAs with protecting oligos and AAV vectors that express tracrRNA and either SpyCas9 or a base editor derivative. Our proof-of-concept establishment of AAV/crRNA co-delivery offers a route towards transient editing activity, target multiplexing, guide redosing, and vector inactivation.
Penicillin-binding protein redundancy inBacillus subtilisenables growth during alkaline shock
Authors: Mitchell Stephanie L. , Kearns Daniel B. , Carlson Erin E.
Published: March 2023

Penicillin-binding proteins (PBPs) play critical roles in cell wall construction, cell shape, and bacterial replication. Bacteria maintain a diversity of PBPs, indicating that despite their apparent functional redundancy, there is differentiation across the PBP family. Seemingly redundant proteins can be important for enabling an organism to cope with environmental stressors. We sought to evaluate the consequence of environmental pH on PBP enzymatic activity inBacillus subtilis. Our data show that a subset ofB. subtilisPBPs change activity levels during alkaline shock and that one PBP isoform is rapidly modified to generate a smaller protein (i.e., PBP1a to PBP1b). Our results indicate that a subset of the PBPs are preferred for growth under alkaline conditions, while others are readily dispensable. Indeed, we found that this phenomenon could also be observed inStreptococcus pneumoniae, implying that it may be generalizable across additional bacterial species and further emphasizing the evolutionary benefit of maintaining many, seemingly redundant periplasmic enzymes.
Environments and host genetics influence the geographic distribution of plant microbiome structure
Authors: Wei Na , Tan Jiaqi
Published: March 2023

To understand how microbiota influence plant populations in nature, it is important to examine the geographic distribution of plant-associated microbiomes and the underlying mechanisms. However, we currently lack a fundamental understanding of the biogeography of plant microbiomes and the environmental and host genetic factors that shape their distribution.

Leveraging the broad distribution and extensive genetic variation in duckweeds (theLemnaspecies complex), we identified the key factors that influenced the geographic distribution of plant microbiome diversity and compositional variation.

In line with the pattern observed in microbial biogeography based on free-living environmental microbiomes, we observed higher bacterial richness in temperate regions relative to lower latitudes in duckweed microbiomes (with 10% higher in temperate populations). Our analyses revealed that temperature and sodium concentration in aquatic environments had a negative impact on duckweed bacterial richness, whereas temperature, precipitation, pH, and concentrations of phosphorus and calcium, along with duckweed genetic variation, influenced the geographic variation of duckweed bacterial community composition.

The findings add significantly to our understanding of host-associated microbial biogeography and provide insights into the relative impact of different ecological processes, such as selection by environments and host genetics, dispersal, and chance, on plant microbiome assembly. These insights have important implications for predicting plant microbiome vulnerability and resilience under changing climates and intensifying anthropogenic activities.
Multiple dynamic interactions from basal ganglia direct and indirect pathways mediate action selection
Authors: Li Hao , Jin Xin
Published: March 2023

The basal ganglia are known to be essential for action selection. However, the functional role of basal ganglia direct and indirect pathways in action selection remains unresolved. Here by employing cell-type-specific neuronal recording and manipulation in mice trained in a choice task, we demonstrate that multiple dynamic interactions from the direct and indirect pathways control the action selection. While the direct pathway regulates the behavioral choice in a linear manner, the indirect pathway exerts a nonlinear inverted-U-shaped control over action selection, depending on the inputs and the network state. We propose a new center (direct) - surround (indirect) - context (indirect) “Triple control” functional model of basal ganglia, which can replicate the physiological and behavioral experimental observations that cannot be simply explained by either the traditional “Go/No-go” or more recent “Co-activation” model. These findings have important implications on understanding the basal ganglia circuitry and action selection in health and disease.

In Brief

Using behavior analysis, in vivo electrophysiology, optogenetics and computational modeling in mice, Li and Jin unveiled the neuronal dynamics of basal ganglia direct and indirect pathways underlying action selection, and proposed a new “Triple-control” functional model of basal ganglia.
Protein supersaturation powers innate immune signaling
Authors: Gama Alejandro Rodriguez , Miller Tayla , Venkatesan Shriram , Lange Jeffrey J. , Wu Jianzheng , Song Xiaoqing , Bradford Dan , Unruh Jay R. , Halfmann Randal
Published: March 2023

Innate immunity protects us in youth but turns against us as we age. The reason for this tradeoff is unclear. Seeking a thermodynamic basis, we focused on death fold domains (DFDs), whose ordered polymerization has been stoichiometrically linked to innate immune signal amplification. We hypothesized that soluble ensembles of DFDs function as phase change batteries that store energy via supersaturation and subsequently release it through nucleated polymerization. Using imaging and FRET-based cytometry to characterize the phase behaviors of all 109 human DFDs, we found that the hubs of innate immune signaling networks encode large nucleation barriers that are intrinsically insulated from cross-pathway activation. We showed via optogenetics that supersaturation drives signal amplification and that the inflammasome is constitutively supersaturatedin vivo. Our findings reveal that the soluble “inactive” states of adaptor DFDs function as essential, yet impermanent, kinetic barriers to inflammatory cell death, suggesting a thermodynamic driving force for aging.
The association between disability and all-cause mortality in low and middle-income countries: a systematic review and meta-analysis
Authors: Smythe Tracey , Kuper Hannah
Published: March 2023

Background

There are at least one billion people with disabilities globally. On average they have poorer health, yet worse healthcare access. We aimed to systematically review the association between disability and mortality in low- and middle-income countries (LMICs).

Methods

We searched MEDLINE, Global Health, PsycINFO and EMBASE from 1st January 1990 to 14th November 2022. We included any longitudinal epidemiological study in any language with a comparator group that measured the association between disability and all-cause mortality in people of any age. Two reviewers independently assessed study eligibility, extracted data, and assessed risk of bias. We used a random-effects meta-analysis to calculate the pooled hazard ratio (HR) for all- cause mortality by disability status. We then conducted meta-analyses separately for different impairment and age groups.

Findings

We identified 6146 unique articles, of which 70 studies (81 cohorts) were included in the systematic review, from 22 countries. There was variability in the methods used to assess and report disability, as well as mortality. The meta-analysis included 53 studies, representing 62 cohorts (comprising 267,415people with disabilities). Pooled HRs for all-cause mortality were 2.06 (95%CI 1.80 - 2.34) for people with disabilities versus those without disabilities, with high heterogeneity between studies (τ²=0·24, I²=98%). This association varied by impairment type; from 1.32 (95%CI 1.13 – 1.55) for visual impairment to 3.39 (95%CI 0.90 – 12.76) for multiple impairments. The association was highest for children under 18 (4.46, 95%CI 3.01–6.59); and lower in people aged 15 – 49 (3·53, 95%CI 1·29–9·66); and older people over 60 years (1·97, 95%CI 1·63–2.38).

Conclusion

Disability increases the risk of all-cause mortality in LMICs, particularly in childhood. Interventions are needed to improve health of people with disabilities and reduce their risk of death.

Key messages

What is already known on this topic

Globally, people with different impairments have a higher risk of death than those without disabilities and many deaths will be avoidable.

What this study adds

People with disabilities in LMIC have two-fold higher mortality rates that those without disabilities. Disability is associated with a higher hazard of age-adjusted all-cause mortality across diverse LMIC settings and populations as well as impairment types. The risk of dying early is highest for children with disabilities.

How this study might affect research, practice or policy

Improved understanding of the association between disability and mortality will help to inform public health planning and policy, and the allocation of limited health-care resources to optimise healthy longevity for all populations worldwide. Without a focus on disability it may be difficult to reach SDG3 and other key global health targets.
α-synuclein oligomers displace monomeric α-synuclein from lipid membranes
Authors: Šneiderienė Greta , Czekalska Magdalena A. , Xu Catherine K. , Jayaram Akhila , Krainer Georg , Arter William E. , Peter Quentin , Castellana-Cruz Marta , Saar Kadi L. , Levin Aviad , Mueller Thomas , Fiedler Sebastian , Devenish Sean R. A. , Fiegler Heike , Kumita Janet R. , Knowles Tuomas P. J.
Published: March 2023

Parkinson’s disease (PD) is an increasingly prevalent and currently incurable neurodegenerative disorder linked to the accumulation of α-synuclein (αS) protein aggregates in the nervous system. While αS binding to membranes in its monomeric state is correlated to its physiological role, αS oligomerisation and subsequent aberrant interactions with lipid bilayers have emerged as key steps in PD-associated neurotoxicity. However, little is known of the mechanisms that govern the interactions of oligomeric αS (OαS) with lipid membranes and the factors that modulate such interactions. This is in large part due to experimental challenges underlying studies of OαS-membrane interactions due to their dynamic and transient nature. Here, we address this challenge by using a suite of microfluidics-based assays that enable in-solution quantification of OαS-membrane interactions. We find that OαS bind more strongly to highly curved, rather than flat, lipid membranes. By comparing the membrane-binding properties of OαS and monomeric αS (MαS), we further demonstrate that OαS bind to membranes with up to 150-fold higher affinity than their monomeric counterparts. Moreover, OαS compete with and displace bound MαS from the membrane surface, suggesting that disruption to the functional binding of MαS to membranes may provide an additional toxicity mechanism in PD. These findings present a unique binding mechanism of oligomers to model membranes, which can potentially be targeted to inhibit the progression of PD.

Abstract Figure
3,3′-(Phenylmethylene)bis(1-ethyl-3,4-dihydro-1H-2,1-benzothiazine-2,2,4-trione): single-crystal X-ray diffraction study, quantum-chemical calculations and Hirshfeld surface analysis
Authors: Shyshkina Mariia O. , Lega Dmitry A. , Shemchuk Liudmyla M. , Starchikova Irina L. , Shemchuk Leonid A.
Published: March 2023

The title compound, C27H26N2O6S2, possesses potential antimicrobial, analgesic, and anti-inflammatory activity. This compound has three tautomeric forms, which relative energies were estimated with quantum-chemical calculations. All these tautomers (dienol form7A, keto–enol form7B, and diketo form7C) were optimized by the M06–2X/cc-pVTZ method in a vacuum, using the PCM model with chloroform and DMSO as solvent. The diketo form of the title compound proved to be the most energetically favourable as compared to the keto–enol or dienol forms. The diketo form can exist as three possible stereoisomers with the same configuration of one stereogenic center and different configurations of the stereogenic centers at two other atoms:(R,R,R),(S,R,S)and(R,R,S). The(R,R,S)stereoisomer was found in the crystal phase. It was revealed that the thiazine rings of equivalent benzothiazine fragments have different conformations, (a sofa or a half-chair). The two bicyclic fragments connected through the phenylmethylene group are oriented almost orthogonal to each other, subtending a dihedral angle of 82.16(7)°.
The structure of the complex between the arsenite oxidase from Pseudorhizobium banfieldiae sp. strain NT-26 and its native electron acceptor cytochrome c
552
Authors: Poddar Nilakhi , Santini Joanne M. , Maher Megan J.
Published: March 2023

The arsenite oxidase (AioAB) from Pseudorhizobium banfieldiae sp. strain NT-26 catalyzes the oxidation of arsenite to arsenate and transfers electrons to its cognate electron acceptor cytochrome c
552 (cytc
552). This activity underpins the ability of this organism to respire using arsenite present in contaminated environments. The crystal structure of the AioAB/cytc
552 electron transfer complex reveals two A2B2/(cytc
552)2 assemblies per asymmetric unit. Three of the four cytc
552 molecules in the asymmetric unit dock to AioAB in a cleft at the interface between the AioA and AioB subunits, with an edge-to-edge distance of 7.5 Å between the heme of cytc
552 and the [2Fe–2S] Rieske cluster in the AioB subunit. The interface between the AioAB and cytc
552 proteins features electrostatic and nonpolar interactions and is stabilized by two salt bridges. A modest number of hydrogen bonds, salt bridges and relatively small, buried surface areas between protein partners are typical features of transient electron transfer complexes. Interestingly, the fourth cytc
552 molecule is positioned differently between two AioAB heterodimers, with distances between its heme and the AioAB redox active cofactors that are outside the acceptable range for fast electron transfer. This unique cytc
552 molecule appears to be positioned to facilitate crystal packing rather than reflecting a functional complex.
Employees' technology adoption in the context of smart tourism development: the role of technological acceptance and technological readiness
Authors: Cimbaljević Marija , Demirović Bajrami Dunja , Kovačić Sanja , Pavluković Vanja , Stankov Uglješa , Vujičić Miroslav
Published: March 2023

Purpose

The technology readiness and acceptance model were mostly employed as theoretical bases to analyze tourist behaviors of adoption of innovative technologies that are part of the smart tourism offer. This study attention now turns to the field of smart tourism human resource management and tries to establish a model to explain the relationship between general dimensions of personality with systematic specific dimensions toward ICT acceptance.

Design/methodology/approach

The authors adopted the TRAM model as a way to better understand and evaluate the causal relationships between the personality dimensions, factors of perception, attitudes and behavior of users regarding the acceptance and use of innovative technologies. Based on the empirical data of 478 employees operating in tourist organizations, travel agencies and hotels, the authors employed regression analysis as the basic method for examining the research hypotheses and causal relationships between variables in the presented model.

Findings

The analysis revealed that employees in the tourism sector are inclined to adopt new technology, and that technological readiness has an impact on attitudes and intentions toward the use of technologies. Moreover, the results show that the path between the dimensions of technological readiness and intention to use technologies is to a certain extent mediated through perceived ease of use and perceived usefulness.

Originality/value

This research is among the first empirical studies that examine technology readiness and adoption in the context of smart tourism development. Besides the findings extend the literature on the mediating effect of perceived usefulness and perceived ease of use between technology readiness index and technology acceptance behavior.
Linking training and development to employees’ attitudes and behaviors: the mediating role of engagement
Authors: Tien Thanh Pham , Thu Ha Nguyen
Published: March 2023

Purpose

Because employees’ positive attitudes and behaviors are important to ensure organizational performance, organizations attempt to carry out human resource practices to shape these attitudes and behaviors. This paper aims to examine this issue by focusing on the effects of training and development (TD) on employee engagement (EE), satisfaction (ES) and retention (ER).

Design/methodology/approach

For empirical analysis, the authors use structural equation modeling and data collected from employees in a developing economy.

Findings

TD is positively and directly associated with EE, ES and ER. In addition, EE is found to mediate the indirect effects of TD on ES and ER.

Practical implications

The findings suggest some practical implications for TD activities to enhance employees’ positive attitudes and behaviors.

Originality/value

To the best of the authors’ knowledge, this research is among the early attempts to examine the direct and indirect effects of TD on EE, ES and ER in a developing economy. The findings add to the growing literature suggesting that TD can contribute to the improvement of employees’ positive attitudes and behaviors.
Financial inclusion and environmental quality: does corruption control matter?
Authors: Tabash Mosab I. , Farooq Umar , El Refae Ghaleb A. , Abu-Rashed Jamal , Al-Faryan Mamdouh Abdulaziz Saleh
Published: March 2023

Purpose

Literature has widely discussed the relevant role of financial development in determining atmospheric quality. However, there has not been much discussion of how financial inclusion (FIC) plays its role in environmental quality. Thus, this research aims to unveil the role of financial inclusion in determining the CO2 emissions which serve as a proxy of environmental quality. In addition, this study examines the moderating role of corruption control (CC) in the nexus of FIC-CC.

Design/methodology/approach

The empirical results were based on 22 years of annual data from five Brazil, Russia, India, China and South Africa (BRICS) economies, covering the years 1996–2017. The authors use the autoregressive distributed lag (ARDL) model to check regression among variables.

Findings

The empirical findings first disclosed the positive impact of FIC whereas CC had an inverse impact on CO2 emissions. However, the moderating role of CC was observed in mitigating the adverse impact of FIC on ecological quality. In addition, the statistical analysis further showed an inverse impact of economic growth and foreign investment and a positive impact of trade volume and energy consumption on CO2 emissions.

Practical implications

This analysis states an important policy regarding integrated FIC and green environmental requirements. Additionally, the negative externality of FIC can be controlled by improving the CC.

Originality/value

This study complements the existing literature on FIC and environmental quality by adding the moderating role of CC.
Consumption inequality between farm and non-farm households in rural Vietnam
Authors: Pham Thong Le , Le Nghiem Tan , Ho Nhi Nhat Phuong , Le Thanh Cong
Published: March 2023

Purpose

This study aims to analyse the consumption inequality between farm and non-farm households in rural Vietnam, using the data from the 2016 Vietnam household living standards survey.

Design/methodology/approach

The present paper applies the “recentered influence functions (RIF)” in “Oaxaca-Blinder (OB)” type decomposition as proposed by Firpo et al. (2018) to allow for the flexible distribution of the outcome variables and the non-randomness of non-farm employment that violates the classical linearity assumption.

Findings

Non-farm households have significantly higher per capita consumption expenditure than farm households for the entire distribution. The gap in expenditure is large at low percentiles and narrowing with higher percentiles. At 10th percentile, the gap is estimated at 27.1%, but it is decreasing to 11.1% at 90th percentile. Most of the gaps are explained by the differences in the observed characteristics between farm and non-farm households such as ethnicity, education, income, internal transmittances and household composition. Non-farm households are endowed with more productive factors that result in higher per capita consumption expenditure.

Originality/value

Gaps in ethnicity and education are found to be key predictors of the inequality in consumption expenditures between farm and non-farm households, then, government policies that are aimed at increasing access to non-farm employment and education for ethnic minorities and for rural poor households are pathways to improve rural household welfare and hence reduce inequality.
New technologies for the conservation and preservation of cultural heritage through a bibliometric analysis
Authors: Prados-Peña María Belén , Pavlidis George , García-López Ana
Published: March 2023

Purpose

This study aims to analyze the impact of Artificial Intelligence (AI) and Machine Learning (ML) on heritage conservation and preservation, and to identify relevant future research trends, by applying scientometrics.

Design/methodology/approach

A total of 1,646 articles, published between 1985 and 2021, concerning research on the application of ML and AI in cultural heritage were collected from the Scopus database and analyzed using bibliometric methodologies.

Findings

The findings of this study have shown that although there is a very important increase in academic literature in relation to AI and ML, publications that specifically deal with these issues in relation to cultural heritage and its conservation and preservation are significantly limited.

Originality/value

This study enriches the academic outline by highlighting the limited literature in this context and therefore the need to advance the study of AI and ML as key elements that support heritage researchers and practitioners in conservation and preservation work.
Impact of managerial skills and ties on business model innovation: the role of exploitative and explorative learning
Authors: Bashir Makhmoor , Naqshbandi M. Muzamil , Yousaf Anish
Published: March 2023

Purpose

Research in the area of business model innovation (BMI) has focused on theoretical and exploratory discussions, thereby creating a lack of empirical evidence on the role of top management in BMI. The current study focuses on this research gap and provides empirical evidence by studying the impact of top managers’ managerial skills, managerial ties and entrepreneurial skills on BMI. It also seeks to explore the mediating influence of explorative and exploitative learning.

Design/methodology/approach

Data were collected from 200 respondents from top multinational firms in India covering six sectors, which was analyzed using structural equation modeling.

Findings

The findings reveal significant positive relationships of BMI with managerial skills, entrepreneur skills and managerial ties, and these relationships are found to be mediated by exploitative and explorative learning.

Practical implications

Given the increasing importance of BMI to organizational success, the study has highlighted that top managers’ skills and ties favorably influence BMI. Organizations can make related investments in training and capacity building by instituting appropriate programs in their organizations. In addition, organizations can exercise caution during recruitment by recruiting and selecting managers in top management teams who excel in managerial skills.

Originality/value

This study is one of the few to validate a comprehensive measurement model that highlights the influence of managerial skills, entrepreneur skills and managerial ties on BMI, explaining these associations with the mediating role of exploitative and explorative learning.
Undergraduates vs. postgraduates attitudes toward cooperative learning in online classes in different settings
Authors: Al Fadda Hind Abdulaziz , Haliem Rasha Osman Abdel , Mahdi Hassan Saleh , Alkhammash Reem
Published: March 2023

Purpose

Substantial changes in the education system and the shift to online classes during the lockdown have raised teachers’ attention to the idea of practicing cooperative learning in online environments. Cooperative learning activities enhance academic skills if designed effectively. This study aims to explore students’ attitudes toward cooperative learning in online learning environments.

Design/methodology/approach

This study is a descriptive study. A survey was administered to 50 graduate and postgraduate students of English as a Foreign Language.

Findings

Results indicated that the students had positive attitudes toward the integration of cooperative tasks in online environments. They also revealed no significant differences in the attitudes toward cooperative learning based on the students’ level (i.e. undergraduate or postgraduate) and that the students preferred small groups.

Originality/value

Cooperative learning is a widely researched topic, especially in higher education. However, most of the previous studies reported results of the implementation of cooperative learning in traditional classrooms. This study aimed to fill this gap by examining the impact of online tools on cooperative learning.
Benefits and challenges of wearable safety devices in the construction sector
Authors: Ibrahim Kabir , Simpeh Fredrick , Adebowale Oluseyi Julius
Published: March 2023

Purpose

Construction organizations must maintain a productive workforce without sacrificing their health and safety. The global construction sector loses billions of dollars yearly to poor health and safety practices. This study aims to investigate benefits derivable from using wearable technologies to improve construction health and safety. The study also reports the challenges associated with adopting wearable technologies.

Design/methodology/approach

The study adopted a quantitative design, administering close-ended questions to professionals in the Nigerian construction industry. The research data were analysed using descriptive and inferential statistics.

Findings

The study found that the critical areas construction organizations can benefit from using WSDs include slips and trips, sensing environmental concerns, collision avoidance, falling from a high level and electrocution. However, key barriers preventing the organizations from adopting wearable technologies are related to cost, technology and human factors.

Practical implications

The time and cost lost to H&S incidents in the Nigerian construction sector can be reduced by implementing the report of this study.

Originality/value

Studies on WSDs have continued to increase in developed countries, but Nigeria is yet to experience a leap in the research area. This study provides insights into the Nigerian reality to provide directions for practice and theory.
Mechanisms by which growth and succession limit the impact of fire in a south‐western Australian forested ecosystem
Authors: Zylstra Philip , Wardell‐Johnson Grant , Falster Daniel , Howe Melissa , McQuoid Nathan , Neville Simon
Published: March 2023

Forest wildfire impact is widely believed to increase with time since disturbance, presenting a dilemma for the persistence of fire‐sensitive species. However, in south‐western Australia, disturbance has been shown to increase wildfire likelihood for some decades before it again declines. It has been proposed that this trend occurs through ‘ecological controls’ on wildfire such as the self‐thinning of fire‐stimulated understorey growth.

Here, we analyse six proposed ecological controls using a surveyed chronosequence of a Eucalyptus jacksonii forest community. We quantify plant growth (growth and self‐pruning) and succession (changing plant traits, self‐thinning), along with consequent changes in surface and suspended litter. We then use a biophysical, mechanistic model to predict the dynamics of flame height and canopy scorch/consumption, along with suppression difficulty during wildfire conditions. To identify the importance of each potential ecological control, we separately manipulate them to grow hypothetical forests from 1 to 100 years; each with one of the controls removed. We then model flame height in each to compare with the original forest that had all controls present.

Fire initially promoted dense understorey regeneration, but ecological controls transferred this biomass from fuel (likely to ignite) to overstorey shelter (unlikely to ignite, creating a less flammable microclimate). The effect of these changes was to alter modelled fire behaviour, such that flame dimensions in mature forest were half those in regrowth, canopy damage greatly reduced, and fire suppression opportunities maximised. The primary controls were self‐thinning and self‐pruning.

Forest growth and succession explains observed trends in flammability dynamics in south‐western Australian forests, and the persistence of fire‐sensitive species over time. Approaches that cooperate with, rather than disrupt, these processes therefore provide a pathway to mitigate current climatic effects on fire.

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