bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract1,3-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

SUMMARYRNase 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

AbstractFormulating 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 summaryLung 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

ABSTRACTHematopoiesis 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 STATEMENTBlood 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

AbstractGuide 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

AbstractPenicillin-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

AbstractTo 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

SummaryThe 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 BriefUsing 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

SummaryInnate 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

AbstractBackgroundThere 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).MethodsWe 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.FindingsWe 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).ConclusionDisability 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 messagesWhat is already known on this topicGlobally, people with different impairments have a higher risk of death than those without disabilities and many deaths will be avoidable.What this study addsPeople 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 policyImproved 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

AbstractParkinson’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
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

PurposeThe 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/approachThe 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.FindingsThe 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/valueThis 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.