bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure of the histone acetyltransferase NuA4 complex
Authors: Ji Liting , Zhao Lixia , Xu Ke , Gao Huihan , Zhou Yang , Kornberg Roger D. , Zhang Heqiao
Published: July 2022

NuA4, one of two major histone acetyltransferase complexes in Saccharomyces cerevisiae, specifically acetylates histone H4 and H2A, and therefore loosen the histone-DNA contacts, resulting in increased transcriptional activity. Here we present a near-atomic resolution structure of NuA4 complex through cryonic electron microscopy. The structure comprises six subunits and a total of 5,000 amino acids, within which Eaf1 and Eaf2 twist against each other and span from Actin-Arp4 module to the platform subunit Tra1, forming the backbone of NuA4. The locations of four missing components including Yaf9, and Esa1, Yng2 and Eaf6 of Piccolo module were indicated based on the structure. Intriguingly, our biochemical data showed that NuA4 doesn’t bind nucleosome in vitro, whereas possesses strong histone acetyltransferase activity. Its Piccolo module, which has long been regarded as the catalytic module of NuA4, acetylates the nucleosome substrate at almost the same efficiency, but is capable of binding nucleosome. Combining the structural and biochemical data give rise to a model in which the entire NuA4 adopts an auto-inhibited conformation, and undergoes structural rearrangements upon substrate and co-factor additions, restoring its capacity of nucleosome-binding and activity of hyper-acetylation.
Evidence of active oviposition avoidance to systemically applied imidacloprid in the Colorado Potato Beetle (Leptinotarsa decemlineata)
Authors: Edison Alitha , Michelbach Anja , Sowade Dominique , Schmidt Luise , Schäfer Martin , Nauen Ralf , Duchen Pablo , Xu Shuqing
Published: July 2022

Agricultural pests can develop behavioral resistance to insecticides via choosing to feed or oviposit on non-toxic hosts. As young larvae have relatively low mobility, oviposition preferences from female adults may play a critical role in shaping the evolutionary trajectory of pest populations. While oviposition avoidance of toxic hosts was found in different agriculture pests, it remains unclear whether such preferences can be learned from female adults. To address this question, we investigated feeding and oviposition preferences to imidacloprid in the Colorado Potato Beetle (CPB, Leptinotarsa decemlineata), a major potato pest. We first identified two CPB strains that have different levels of resistance to imidacloprid. Then, we performed choice assays in the two strains and found that both strains did not have an innate feeding avoidance to systemically applied imidacloprid at both larval and adult stages. Further oviposition choice assays showed that the susceptible strain preferred to lay eggs on insecticide-free plants while the resistant strain did not. Analysing moving patterns of the two strains suggested that the oviposition preference is likely due to active learning by the female adults. Together, these results indicate that CPB can have active oviposition avoidance, which might have contributed to the rapid global invasion of this agricultural pest.
Approximating Scaffold Printability Utilizing Computational Methods
Authors: Sedigh Ashkan , Ghelich Pejman , Quint Jacob , Samandari Mohamadmahdi , Tamayol Ali , Tomlinson Ryan E.
Published: July 2022

Bioprinting facilitates the generation of complex, three-dimensional (3D), cell-based constructs for various applications. Although multiple bioprinting technologies have been developed, extrusion-based systems have become the dominant technology due to the diversity of materials (bioinks) that can be utilized, either individually or in combination. However, each bioink has unique material properties and extrusion characteristics that affect bioprinting utility, accuracy, and precision. Here, we have extended our previous work to achieve high precision (i.e., repeatability) across samples by optimizing bioink-specific printing parameters. Specifically, we hypothesized that an adaptive neuro-fuzzy inference system (ANFIS) could be used as a computational method to address the imprecision in 3D bioprinting test data and uncover the optimal printing parameters for a specific bioink that result in high accuracy and precision. To test this hypothesis, we have implemented an ANFIS model consisting of four inputs (bioink concentration, printing pressure, speed, and temperature) and a single output to quantify the precision (scaffold bioprinted linewidth range). We validate our use of the bioprinting precision index (BPI) with both standard and normalized printability factors. In total, our results indicate that computational methods are a cost-efficient measure to improve the precision and robustness of extrusion 3D bioprinting with gelatin-based bioinks.
Optimised DNA isolation from marine sponges for natural sampler DNA (nsDNA) metabarcoding
Authors: Harper Lynsey R. , Neave Erika F. , Sellers Graham S. , Cunnington Alice V. , Arias María Belén , Craggs Jamie , MacDonald Barry , Riesgo Ana , Mariani Stefano
Published: July 2022

Marine sponges have recently been recognised as natural samplers of environmental DNA (eDNA) due to their effective water filtration and their ubiquitous, sessile and regenerative nature. However, laboratory workflows for metabarcoding of sponge tissue have not been optimised to ensure that these natural samplers achieve their full potential for community survey. We used a phased approach to investigate the influence of DNA isolation procedures on the biodiversity information recovered from sponges. In Phase 1, we compared three treatments of residual ethanol preservative in sponge tissue alongside five DNA extraction protocols. The results of Phase 1 informed which ethanol treatment and DNA extraction protocol should be used in Phase 2, where we assessed the effect of starting tissue mass on extraction success and whether homogenisation of sponge tissue is required. Phase 1 results indicated that ethanol preservative may contain unique and/or additional biodiversity information to that present in sponge tissue, but blotting tissue dry generally recovered more taxa and generated more sequence reads from the wild sponge species. Tissue extraction protocols performed best in terms of DNA concentration, taxon richness and proportional read counts, but the non-commercial tissue protocol was selected for Phase 2 due to cost-efficiency and greater recovery of target taxa. In Phase 2 overall, we found that homogenisation may not be required for sponge tissue and more starting material does not necessarily improve taxon detection. These results combined provide an optimised DNA isolation procedure for sponges to enhance marine biodiversity assessment using natural sampler DNA metabarcoding.
Immunodominant influenza epitope GILGFVFTL engage common and divergent TCRs when presented as a 9-mer or a 15-mer peptide
Authors: Bhojak Keshav , Kode Vasumathi , Miriam Coral M. , Lee Kayla , Ramesh Athulya , Sudheendra HV , Chakraborty Papia , Chaudhuri Amitabha
Published: July 2022

Antigen-specific T-cells are a powerful modality for treating cancer and other life-threatening viral and bacterial diseases. Technologies to identify and expand antigen-specific T-cells rapidly can shorten the time, and lower the cost of treatment. In this regard, screening short overlapping peptides to identify antigen-specific T-cells in ex vivo T-cell activation assay is becoming routine. Screening assays typically use 15-mer peptides to stimulate patient-derived, or healthy peripheral blood mononuclear cells to activate T-cells and identify expanded TCRs by next generation sequencing. Previous studies comparing the kinetics of T-cell activation using a 9 and a 15-mer peptide versions of a CMV immunodominant epitope demonstrated that 15-mer peptides induced CD8 T-cell activation at a slower kinetics reaching a lower magnitude compared to 9-mer peptides. The fact that 9-mer peptides are an optimal fit for the MHC class-I binding groove could explain this difference, with the 15-mer peptide requiring additional proteolytic processing before binding to the deeper binding groove of class-I MHC. Alternatively, the delay in kinetics and magnitude can result from the activation of a wider diversity of TCRs engaging novel epitopes generated from the 15-mer peptide whose activation profile may be different from the profile of TCRs that normally respond to the 9-mer immunodominant epitope. We sought to address these two possibilities by comparing T-cell engagement to the HLA-2-restricted GILGFVFTL epitope presented as a 9-mer, or a 15-mer peptide and analyzing CDR3 expansion as a measure of T-cell engagement diversity. This approach also addressed an important question as to whether optimal TCRs could be missed using a 15-mer peptide used routinely in screening assays.
Insights from Incorporating Quantum Computing into Drug Design Workflows
Authors: Lau Bayo , Emani Prashant S. , Chapman Jackson , Yao Lijing , Lam Tarsus , Merrill Paul , Warrell Jonathan , Gerstein Mark B. , Lam Hugo Y.K.
Published: July 2022

While many quantum computing (QC) methods promise theoretical advantages over classical counterparts, quantum hardware remains limited. Exploiting near-term QC in computer-aided drug design (CADD) thus requires judicious partitioning between classical and quantum calculations. We present HypaCADD, a hybrid classical-quantum workflow for finding ligands binding to proteins, while accounting for genetic mutations. We explicitly identify modules of our drug design workflow currently amenable to replacement by QC: non-intuitively, we identify the mutation-impact predictor as the best candidate. HypaCADD thus combines classical docking and molecular dynamics with quantum machine learning (QML) to infer the impact of mutations. We present a case study with the SARS-CoV-2 protease and associated mutants. We map a classical machine-learning module onto QC, using a neural network constructed from qubit-rotation gates. We have implemented this in simulation and on two commercial quantum computers. We find that the QML models can perform on par with, if not better than, classical baselines. In summary, HypaCADD offers a successful strategy for leveraging QC for CADD.
Mechano-epigenetic regulation of extracellular matrix homeostasis via Yap and Taz
Authors: Jones Dakota L. , Daniels Ryan N. , Jiang Xi , Locke Ryan C. , Evans Mary Kate , Bonnevie Edward D. , Srikumar Anjana , Nijsure Madhura P. , Boerckel Joel D. , Mauck Robert L. , Dyment Nathaniel A.
Published: July 2022

Cells integrate mechanical cues to direct fate specification to maintain tissue function and homeostasis. While disruption of these cues is known to lead to aberrant cell behavior and chronic diseases, such as tendinopathies, the underlying mechanisms by which mechanical signals maintain cell function is not well understood. Here, we show using a novel model of tendon de-tensioning that loss of tensile cues in vivo acutely changes nuclear morphology, positioning, and expression of catabolic gene programs. Using paired ATAC/RNAseq, we further identify that a loss of cellular tension rapidly reduces chromatin accessibility in the vicinity of Yap/Taz genomic targets while also increasing expression of genes involved in matrix catabolism. Overexpression of Yap results in a reduction of chromatin accessibility at matrix catabolic gene loci, while also reducing transcriptional levels. Concordantly, depletion of Yap/Taz elevates matrix catabolic expression. Finally, we demonstrate that overexpression of Yap not only prevents the induction of a broad catabolic program following a loss of cellular tension, but also preserves the underlying chromatin state from force-induced alterations. Taken together, these results provide novel mechanistic details by which mechanical signals regulate tendon cell function to preserve matrix homeostasis through a Yap/Taz axis.

Significance Statement

Cells integrate mechanical signals to regulate biological outputs within tissues. These processes are required for tissue function and homeostasis. Here, we show how mechanical cues (e.g. tension) directs tendon cell function and fate at a transcriptional and epigenetic level. Furthermore, we show that disruption of these mechanical cues leads to a disease-like cell state, indicating these mechanosensitive pathways could be important for diseases driven by perturbed mechanical signaling, such as tendinopathy. Finally, we demonstrate that genetic perturbation of a single protein can preserve cell and chromatin state following a loss of tension, supporting novel avenues for the development of innovative mechano-therapeutics.
Two-year interview and match outcomes of otolaryngology preference signaling
Authors: Chang C.W. David , Thorne Marc C. , Malekzadeh Sonya , Pletcher Steven D.
Published: July 2022

Objective

To present the first year-over-year data comparison of preference signaling for residency interviews in the otolaryngology application marketplace.

Study Design

Cross-sectional study conducted over 2 application cycles

Setting

Otolaryngology training programs in the United States.

Methods

Otolaryngology residency applicants were invited to participate in preference signaling during the 2021 and 2022 application cycles. Submissions were collected using a web-based interface. The distribution of signals among programs was evaluated descriptively and in relationship to program rankings. Surveys were sent to applicants to assess general attitudes and the number of interview invitations received from signaled and non-signaled programs. Surveys were sent to programs to evaluate use of signals and the impact on Match results.

Results

Programs received a range of signals from 0-66, with 50% of signals going to 24% of programs, which was similarly found in 2021. Programs of higher rank tended to receive more signals. Overall, greater than 87% of surveyed applicants received an interview offer from at least one program they signaled. In 2021 and 2022, applicants were 2.6 times more likely to get an interview from a signaled program than from a comparator non-signaled program. A greater positive impact on interview offer rate was seen for less competitive applicants. Signaling was viewed favorably by the vast majority surveyed applicants and programs.

Conclusions

Preference signaling for otolaryngology residency interviews demonstrates a promising mechanism to improve applicant visibility to programs during the application cycle. This impact is consistent over 2 application cycles.
Causal associations of education, lifestyle behaviors, and cardiometabolic traits with epigenetic age acceleration: a Mendelian randomization study
Authors: Kong Lijie , Ye Chaojie , Wang Yiying , Zheng Jie , Wang Shuangyuan , Lin Hong , Zhao Zhiyun , Li Mian , Xu Yu , Lu Jieli , Chen Yuhong , Xu Min , Wang Weiqing , Ning Guang , Bi Yufang , Wang Tiange
Published: July 2022

Background

GrimAge acceleration (GrimAgeAccel) and PhenoAge acceleration (PhenoAgeAccel) are DNA methylation-based markers of accelerated biological ageing, standing out in predicting mortality and age-related cardiometabolic morbidities. Causal risk factors for GrimAgeAccel and PhenoAgeAccel are unclear.

Objective

To evaluate causal associations of 18 common modifiable socioeconomic, lifestyle, and cardiometabolic factors with GrimAgeAccel and PhenoAgeAccel.

Methods

We performed two-sample univariable and multivariable Mendelian randomization (MR), using summary-level data for GrimAgeAccel and PhenoAgeAccel derived from a genome-wide association study of 34,710 European participants. We used the inverse-variance weighted method as the main analysis, supplemented by three sensitivity analyses.

Results

Eleven and eight factors were causally associated with GrimAgeAccel and PhenoAgeAccel, respectively. Smoking initiation was the strongest risk factor (β [SE]: 1.299 [0.107] years) for GrimAgeAccel, followed by higher alcohol intake, higher waist circumference, daytime napping, higher body fat percentage, higher BMI, higher C-reactive protein, higher triglycerides, childhood obesity, and type 2 diabetes; whereas education was the strongest protective factor (β [SE] per 1-SD increase in years of schooling: -1.143 [0.121] years). Higher waist circumference (β [SE]: 0.850 [0.269] years) and education (β [SE]: -0.718 [0.151] years) were the leading causal risk and protective factors for PhenoAgeAccel, respectively. Sensitivity analyses strengthened the robustness of these causal associations, and the multivariable MR analyses demonstrated independent direct effects of the strongest risk and protective factors on GrimAgeAccel and PhenoAgeAccel, respectively.

Conclusion

Our findings provide novel quantitative evidence on modifiable causal risk factors for epigenetic ageing, and hint at underlying contributors and intervention targets to the ageing process.

Key Points

Genetically predicted higher educational attainment is the strongest protective factor for both GrimAgeAccel and PhenoAgeAccel, independent of causal lifestyle and cardiometabolic risk factors.

Smoking is the leading causal lifestyle risk factor for GrimAgeAccel or PhenoAgeAccel, followed by alcohol intake and daytime napping. Adiposity traits are the leading causal cardiometabolic risk factors for GrimAgeAccel and PhenoAgeAccel, followed by type 2 diabetes, triglycerides, and C-reactive protein.

This study provides novel quantitative evidence on modifiable causal risk factors for accelerated epigenetic ageing, indicating underlying contributors to the ageing process and promising intervention targets to promote healthy longevity.
A u-shape association of serum uric acid with gout in US adults
Authors: Xinmiao Yan , Taolan Sun , Zixuan Zhao , Yanrong Luo , Hanbing Zhao , Han Zhao , Miaojing Li
Published: July 2022

Background

Serum uric acid (SUA) level is the strongest determinant of gout, and the relationship between hyperuricemia and gout has been found. However, the association between the across-full range of SUA level and gout also remains uncertain. We aimed to investigate the trend across an across-full range of SUA level and gout in the general population.

Materials and Methods

This study included 4,738 US adults from The National Health and Nutrition Examination Survey (NHANES). A generalized additive model was used to fit the non-linear trend between SUA level and gout.

Results

2,209 males and 2,469 females were included in our study, with the age range of 20∼80 years. The range of SUA level was from 0.8 to 15.1 mg/dL. About 5.9% of participants had gout. There was a U-shape association between SUA level and gout in univariable GAM (EDF = 3.881, p <0.001) and multivariable GAM (EDF = 3.795, p <0.001). The lowest risk of gout was observed in participants with SUA level of 5-6mg/dL. We evaluated the trend of SUA level with gout by gender. Both males and females with high SUA level have a high prevalence of gout. Male have a high prevalence of gout with low SUA level. The SUA level and prevalence of gout support a U-shape in males, while females show a linear shape.

Conclusion

This study showed that low as well as high SUA are associated with gout. Hypouricemia is a candidate predictor of gout in US adults.
Regulation of cell dynamics by rapid transport of integrins through the biosynthetic pathway
Authors: Lerche Martina , Mathieu Mathilde , Malerød Lene , Pedersen Nina Marie , Hamidi Hellyeh , Chastney Megan , Bruininks Bart Marlon Herwig , Kaptan Shreyas , Jacquemet Guillaume , Vattulainen Ilpo , Roca-Cusachs Pere , Brech Andreas , Perez Franck , Boncompain Gaelle , Miserey Stéphanie , Ivaska Johanna
Published: July 2022

Cells sense and respond to the extracellular matrix (ECM) milieu through integrin proteins. Integrin availability on the plasma membrane, regulated by endosomal receptor uptake and recycling, has been extensively studied and regulates cell dynamics in various normal and pathological contexts1–5. In contrast, the role of integrin transport through the biosynthetic pathway has been considered primarily as a mechanism to replenish the receptor pool and too slow to influence cell dynamics6. Here, we adopted the RUSH (Retention Using Selective Hooks) assay to synchronize integrin anterograde transport from the endoplasmic reticulum (ER), allowing spatial and temporal analysis of newly synthesized receptor traffic. We observe that the delivery of new integrins to the plasma membrane is polarized in response to specific ECM ligands, facilitates integrin recruitment specifically to the membrane-proximal tip of focal adhesions (FA) and contributes to cell protrusion and FA growth. We explain the augmented adhesion growth using a computational molecular clutch model7, where increased integrin availability drives recruitment of additional integrins. Notably, a subset of newly synthesized integrins undergo rapid traffic from the ER to the cell surface to facilitate localized cell spreading, seemingly bypassing the Golgi. This unconventional secretion is dependent on cell adhesion and mediated by Golgi reassembling stacking proteins (GRASPs) association with the PDZ-binding motif in the integrin α5 cytoplasmic tail. This spatially targeted delivery of integrins through the biosynthetic pathway may propel cell dynamics by rapidly altering adhesion receptor availability, providing cells with an additional degree of plasticity to respond to their environment.
Hotspot residues and resistance mutations in the nirmatrelvir-binding site of SARS-CoV-2 main protease: Design, identification, and correlation with globally circulating viral genomes
Authors: Padhi Aditya K. , Tripathi Timir
Published: July 2022

Since the onset of the COVID-19 pandemic, SARS-CoV-2 has acquired numerous variations in its intracellular proteins to quickly adapt, become more infectious, and ultimately develop drug resistance by mutating certain hotspot residues. To keep the emerging variants at bay, including Omicron and subvariants, FDA has approved the antiviral nirmatrelvir for mild-to-moderate and high-risk COVID-19 cases. Like other viruses, SARS-CoV-2 could acquire mutations in its main protease (Mpro) to adapt and develop resistance against nirmatrelvir. Employing a unique high-throughput protein design technique, the hotspot residues and signatures of adaptation of Mprohaving the highest probability of mutating and rendering nirmatrelvir ineffective were identified. Our results show that ∼40% of the designed mutations in Mproalready exist in the globally circulating SARS-CoV-2 lineages. The work provides a first-hand explanation of the resistance mutations in Mproand is crucial in comprehending viral adaptation, robust antiviral design, and surveillance of evolving Mprovariations.
The evolutionary constraints on angiosperm chloroplast adaptation
Authors: Robbins Elizabeth Hannah Joan , Kelly Steven
Published: July 2022

The chloroplast (plastid) arose via endosymbiosis of a photosynthetic cyanobacterium by a non-photosynthetic eukaryotic cell approximately 1.5 billion years ago. Although the plastid underwent rapid evolution by genome reduction, its rate of molecular evolution is low and its genome organisation is highly conserved. Here, we investigate the factors that have constrained the rate of molecular evolution of protein coding genes in the plastid genome. Through analysis of 773 angiosperm plastid genomes we show that there is substantial variation in the rate of molecular evolution between genes. We show that variation in the strength of purifying selection between genes is a major determinant of variation in the rate of molecular evolution. We further demonstrate that the distance of a gene from the likely origin of replication influences the rate at which it has evolved, consistent with time and distance dependent mutation gradients. In addition, we show that the amino acid composition of a gene product constraints its substitution tolerance, limiting its rate of molecular evolution. Finally, we demonstrate that the mRNA abundance of a gene is a key factor in determining its rate of molecular evolution, suggesting an interaction between transcription and DNA repair in the plastid. Collectively, we show that the location, composition, and expression of a plastid gene can account for ≥32% of the variation in its rate of molecular evolution. Thus, these three factors have exerted a substantial limitation on the capacity for adaptive evolution of plastid genes, and constrained the evolvability of the chloroplast.
Cryo-EM structures of α-synuclein filaments from Parkinson’s disease and dementia with Lewy bodies
Authors: Yang Yang , Shi Yang , Schweighauser Manuel , Zhang Xianjun , Kotecha Abhay , Murzin Alexey G. , Garringer Holly J. , Cullinane Patrick W. , Saito Yuko , Foroud Tatiana , Warner Thomas T. , Hasegawa Kazuko , Vidal Ruben , Murayama Shigeo , Revesz Tamas , Ghetti Bernardino , Hasegawa Masato , Lashley Tammaryn , Scheres Sjors H.W. , Goedert Michel
Published: July 2022

Parkinson’s disease (PD) is the most common movement disorder, with resting tremor, rigidity, bradykinesia and postural instability being major symptoms (1). Neuropathologically, it is characterised by the presence of abundant filamentous inclusions of α-synuclein in the form of Lewy bodies and Lewy neurites in some brain cells, including dopaminergic nerve cells of the substantia nigra (2). PD is increasingly recognised as a multisystem disorder, with cognitive decline being one of its most common non-motor symptoms. Many patients with PD develop dementia more than 10 years after diagnosis (3). PD dementia (PDD) is clinically and neuropathologically similar to dementia with Lewy bodies (DLB), which is diagnosed when cognitive impairment precedes parkinsonian motor signs or begins within one year from their onset (4). In PDD, cognitive impairment develops in the setting of well-established PD. Besides PD and DLB, multiple system atrophy (MSA) is the third major synucleinopathy (5). It is characterised by the presence of abundant filamentous α-synuclein inclusions in brain cells, especially oligodendrocytes (Papp-Lantos bodies). We previously reported the electron cryo-microscopy (cryo-EM) structures of two types of α-synuclein filaments extracted from the brains of individuals with MSA (6). Each filament type is made of two different protofilaments. Here we report that the cryo-EM structures of α-synuclein filaments from the brains of individuals with PD, PDD and DLB are made of a single protofilament (Lewy fold) that is markedly different from the protofilaments of MSA. These findings establish the existence of distinct molecular conformers of assembled α-synuclein in neurodegenerative disease.
LRP2 contributes to planar cell polarity-dependent coordination of motile cilia function
Authors: Bunatyan Lena , Margineanu Anca , Boutin Camille , Montcouquiol Mireille , Bachmann Sebastian , Christensen Erik Ilsø , Willnow Thomas E. , Christ Annabel
Published: July 2022

Motile cilia are protruding organelles on specialized epithelia that beat in a synchronous fashion to propel extracellular fluids. Coordination and orientation of cilia beating on individual cells and across tissues is a complex process dependent on planar cell polarity (PCP) signaling. Asymmetric sorting of PCP pathway components, essential to establish planar polarity, involves trafficking along the endocytic path, but the underlying regulatory processes remain incompletely understood. Here, we identified the endocytic receptor LRP2 as regulator of PCP component trafficking in ependyma, a multi-ciliated cell type that is involved in facilitating flow of the cerebrospinal fluid in the brain ventricular system. Lack of receptor expression in gene-targeted mice results in a failure to sort PCP core proteins to the anterior or posterior cell side and, consequently, in the inability to coordinate cilia arrangement and to aligned beating (loss of rotational and translational polarity). LRP2 deficiency coincides with a failure to sort NHERF1, a cytoplasmic LRP2 adaptor to the anterior cell side. As NHERF1 is essential to translocate PCP core protein Vangl2 to the plasma membrane, these data suggest a molecular mechanism whereby LRP2 interacts with PCP components through NHERF1 to control their asymmetric sorting along the endocytic path. Taken together, our findings identified the endocytic receptor LRP2 as a novel regulator of endosomal trafficking of PCP proteins, ensuring their asymmetric partition and establishment of translational and rotational planar cell polarity in the ependyma.
Non-overlapping requirements of ASNA-1 function for insulin secretion, cisplatin resilience, and growth revealed by genetic analysis of point mutants in C. elegans
Authors: Raj Dorota , Podraza-Farhanieh Agnieszka , Gallego Pablo , Kao Gautam , Naredi Peter
Published: July 2022

ASNA1 plays an essential role in cisplatin chemotherapy response, type 2 diabetes, and heart disease. It is also an important biomarker in the treatment response of many diseases. Biochemically, ASNA1 has two mutually exclusive redox modulated roles: a tail-anchored protein (TAP) targeting function in the reduced state and a holdase/chaperone function in the oxidized state. Assigning biochemical roles of ASNA-1 to biomedical functions is crucial for successful therapy development. Our previous work showed the relevance of the C. elegans ASNA-1 homolog in modeling cisplatin response and insulin secretion. Here we analyzed two-point mutants in highly conserved residues in C. elegans ASNA-1 and identified their importance in separating cisplatin response from its roles in insulin secretion. Further, using targeted depletion we showed asna-1 tissue requirements for C. elegans growth and development. We concluded that, targeting single residues in ASNA-1 affecting Switch I/II domain function, in comparison to complete knockdown counteracted cisplatin resistance without jeopardizing other important biological functions. Taken together, our study shows that effects on health caused by ASNA1 mutations can have different biochemical bases.
Characterising replisome disassembly in human cells
Authors: Jones Rebecca M. , Ruiz Joaquin Herrero , Scaramuzza Shaun , Nath Sarmi , Henklewska Marta , Natsume Toyoaki , Romero Francisco , Kanemaki Masato T. , Gambus Agnieszka
Published: July 2022

To ensure faultless duplication of the entire genome, eukaryotic replication initiates from thousands of replication origins. Replication forks emanating from origins move through the chromatin until they encounter forks from neighbouring origins, at which point they terminate. In the final stages of this process the replication machinery (replisome) is unloaded from chromatin and disassembled. Work from model organisms has elucidated that during replisome unloading, the MCM7 subunit of the terminated replicative helicase is polyubiquitylated and processed by p97/VCP segregase, leading to disassembly of the helicase and the replisome, which is built around it. In higher eukaryotes (worms, frogs, mouse embryonic stem cells), MCM7 ubiquitylation is driven by a Cullin2-based ubiquitin ligase, with LRR1 as a substrate receptor. To date, most of our knowledge of replication termination comes from model organisms and embryonic systems and little is known about how this process is executed and regulated in human somatic cells. Here we thus established methods to study replisome disassembly in human model cell lines. Using flow cytometry, immunofluorescence microscopy and chromatin isolation with western blotting, we can visualise unloading of the replisome (MCM7 and CDC45) from chromatin by the end of S-phase. We observe interaction of replicative helicase (CMG complex) with CUL2LRR1and ubiquitylation of MCM7 on chromatin, specifically in S-phase, suggesting that this is a replication-dependent modification. Importantly, we are able to show that replisome disassembly in this system also requires Cullin2, LRR1 and p97, demonstrating conservation of the mechanism. Moreover, we present evidence that the back-up mitotic replisome disassembly pathway is also recapitulated in human somatic cells. Finally, while we find that treatment with small molecule inhibitors against cullin-based ubiquitin ligases (CULi) and p97 (p97i) does lead to phenotypes of replisome disassembly defects, they also both lead to induction of replication stress in somatic cells, which limits their usefulness as tools to specifically target replisome disassembly processes in this setting.
Female managers' meaningful work and commitment: organizational contexts and generational differences
Authors: Kim Eun Jee , Park Sunyoung
Published: July 2022

Purpose

The aim of this research is to examine the relationships among family-friendly organizational culture, job characteristics, supervisor support, meaningful work, and organizational commitment for female managers. It also investigates generational differences in these relationships.

Design/methodology/approach

Data for the study were analyzed using multi-group structural equation modeling to examine the moderating role of generational differences.

Findings

This study investigates the role of meaningful work as an agent in terms of how it influences organizational commitment for female managers. Empirical results confirm the effect of family-friendly culture on supervisor support and meaningful work, which in turn impacts organizational commitment. The findings also revealed generational differences among Baby Boomers, Generation X, and Millennials in these relationships.

Originality/value

The findings highlight the significance of investigating meaningful work on organizational commitment by examining the relationships with organizational culture, supervisor support, and job characteristics across different generational groups.
Mitigating personal protective equipment (PPE) supply chain disruptions in pandemics – a system dynamics approach
Authors: Falagara Sigala Ioanna , Sirenko Mikhail , Comes Tina , Kovács Gyöngyi
Published: July 2022

Purpose

The coronavirus disease (COVID-19) pandemic has emerged as an unprecedented health crisis worldwide and heavily disrupted the healthcare supply chain. This study focuses on analysing the different types of disruptions occurring in personal protective equipment (PPE) supply chains during the COVID-19 pandemic and on proposing mitigation strategies that are fit to the global scale and many interdependencies that are characteristic for this pandemic. The authors construct a conceptual system dynamics model (SD) based on the literature and adjusted with the use of empirical data (interviews) to capture the complexity of a global supply chain and identify leverage points (mitigation strategies).

Design/methodology/approach

This research follows a mix-methods approach. First, the authors developed a conceptual framework based on four types of disruptions that usually occur during health emergencies (direct effect, policy, supply chain strategy, and behaviourally induced disruptions). Second, the authors collected and analysed data from interviews with experts in the PPE supply chain. Based on the interviews data, the authors developed a conceptual system dynamics (SD) model that allows to capture the complex and dynamic interplay between the elements of the global supply chain system, by highlighting key feedback loops, delays, and the way the mitigation strategies can impact on them. From this analysis, the authors developed four propositions for supply chain risk management (SCRM) in global health emergencies and four recommendations for the policy and decision makers.

Findings

The SD model highlights that without a combination of mitigation measures, it is impossible to overcome all disruptions. As such, a co-ordinated effort across the different countries and sectors that experience the disruptions is needed. The SD model also shows that there are important feedback loops, by which initial disruptions create delays and shortages that propagate through the supply chain network. If the co-ordinated mitigation measures are not implemented early at the onset of the pandemic, these disruptions will be persistent, creating potential shortages of PPE and other critical equipment at the onset of a pandemic – when they are most urgently needed.

Originality/value

This research enriches the understanding of the disruptions of PPE supply chains on the systems level and proposes mitigation strategies based on empirical data and the existing literature.
A novel soft gripper with enhanced gripping adaptability based on spring-reinforced soft pneumatic actuators
Authors: Cheng Peilin , Ye Yuze , Yan Bo , Lu Yebo , Wu Chuanyu
Published: July 2022

Purpose

Soft grippers have safer and more adaptable human–machine and environment–machine interactions than rigid grippers. However, most soft grippers with single gripping postures have a limited gripping range. Therefore, this paper aims to design a soft gripper with variable gripping posture to enhance the gripping adaptability.

Design/methodology/approach

This paper proposes a novel soft gripper consisting of a conversion mechanism and four spring-reinforced soft pneumatic actuators (SSPAs) as soft fingers. By adjusting the conversion mechanism, four gripping postures can be achieved to grip objects of different shapes, sizes and weights. Furthermore, a quasi-static model is established to predict the bending deformation of the finger. Finally, the bending angle of the finger is measured to validate the accuracy of the quasi-static model. The gripping force and gripping adaptability are tested to explore the gripping performance of the gripper.

Findings

Through experiments, the results have shown that the quasi-static model can accurately predict the deformation of the finger; the gripper has the most significant gripping force under the parallel posture, and the gripping adaptability of the gripper is highly enhanced by converting the four gripping postures.

Originality/value

By increasing the gripping posture, a novel soft gripper with enhanced gripping adaptability is proposed to enlarge the gripping range of the soft gripper with a single posture. Furthermore, a quasi-static model is established to analyze the deformation of SSPA.
Procurement system for resilient supply chain amid the COVID-19 pandemic: systematic literature review
Authors: Shivajee Veer , Singh Rajesh Kumar , Rastogi Sanjay
Published: July 2022

Purpose

This study aims to provide a rich learning opportunity from COVID-19 crisis for making resilient supply chain by adopting new strategies for the procurement system.

Design/methodology/approach

The systematic literature review has been conducted from the year 2012 to 2022 with the objective of developing procurement system for resilient supply chain. Fifty-four research papers are selected for this study.

Findings

The study exhibits that procurement function makes a significant contribution in creating supply chain resilience in the time of COVID-19 pandemic. The COVID-19 emergency has enforced companies to operate in new ways to face supply chain disruptions. The new strategies and actions appropriate for resilient procurement system have been identified.

Research limitations/implications

This study is limited to the papers that were indexed in the Scopus database. It has also been limited to the procurement function and supply chain resilience.

Practical implications

This research highlights strategies for supply chain resilience to improve the business performance in COVID-19 or similar types of crisis.

Originality/value

The originality of this paper is to identify the strategies and new practices followed in procurement function to improve the supply chain resilience. This study suggests directions for future research on the integration of procurement and manufacturing for making resilience in the supply chain.
Psychological needs as underlying forces of halal food purchase intention
Authors: Syed Sumera , Sh Ahmad Fauziah , Shah Syed Rashid Hussain
Published: July 2022

Purpose

During the past two decades, a tremendous increase in the trend of purchasing and consuming halal food has been witnessed both among Muslims and non-Muslims. However, the research on halal food is still inchoate and needs further exploration. Moreover, there is a dearth of research addressing the impact of intrinsic motivation on halal food purchase intention. This study aims to explore intrinsically motivated halal food purchase behaviour, by means of “self-determination theory,” which is based on innate psychological needs of autonomy, competence and relatedness.

Design/methodology/approach

A total of 308 responses were yielded from online questionnaires. Partial least squares-structural equation modeling (PLS-SEM) was then used to analyze the gathered data.

Findings

The results reveal that relatedness is the strongest driver of halal food purchase intention, followed by competence, while autonomy is found to be the weakest predictor of halal food purchase intention. The findings give marketers a new line to develop intrinsically motivated strategies with a special focus on close relationships.

Originality/value

To the best of the authors’ knowledge, this research is considered the first to explore the impact of “autonomy,” “competence” and “relatedness” on halal food purchase intention.
Understanding the subjective realties of social proof and usability for mobile banking adoption: using triangulation of qualitative methods
Authors: Alenizi Abdulrahman Saqer
Published: July 2022

Purpose

The existing technology adoption model (TAM) has ignored the importance of social proof of credibility such as risk, security and privacy. Also, this study aims to provide understanding how the issues of usability such as interactivity, compatibility and credibility can influence the mobile banking (MB) adoption of commercial and Islamic banks. This study has offered two theoretical models which may be helpful to understand the importance of social proof of credibility during MB adoption.

Design/methodology/approach

It is exploratory study therefore the researcher used triangulation of qualitative methods such as online banking app reviews, focused group and semi structured interviews are used to understand the behavior of customers toward MB adoption.

Findings

Consumers are actively involved to take recommendations from close sources, experts, customers and crowd opinion using interactive social media platforms (SMPs). The purpose to gather information is to save from usability, risk, security and privacy issues, especially when customers share their personal and financial information with the purpose to use MB. Results reveal that people with disabilities require MB app that has adjustable size, color, text and functions. The usability issues such as system design, response time, aesthetics, personalization, installation and service quality influenced the use of MB in Islamic banks.

Originality/value

Present study has offered social proof as TAM which highlights usefulness and credibility as important factors that can create social proof on SMPs. This study provides rich insights regarding what initiatives are required to resolve the issues of usability such as interactivity, compatibility and credibility that can influence the MB adoption of commercial and Islamic banks. Another major contribution of this study is to explore the issues of MB for people with disabilities and suggest how they can improve the service quality of MB for people with disabilities.
Leveraging the value from digitalization: a business model exploration of new technology-based firms in vertical farming
Authors: Thomson Linus
Published: July 2022

Purpose

The purpose of this paper is to investigate how new technology-based firms (NTBFs) overcome established notions of scale and scope through business model innovation, leveraging the value from digitalization.

Design/methodology/approach

The study adopts an exploratory research design, drawing on a novel data set of 50 publicly available interviews with vertical farming (VF) industry leaders and insiders who represent 36 different organizations from North America and Europe.

Findings

The study develops a framework showing how NTBFs leverage the value from digitalization via a paradoxical approach combining both efficiency and novelty value drivers.

Originality/value

The study extends current theorizing on the desirability of a combined business model approach leveraging both efficiency and novelty from digitalization. Furthermore, the study is among the first to investigate the unique and highly technological context of VF.
Creating digital ecosystem for small and medium enterprises: the role of dynamic capability, agile leadership and change readiness
Authors: Adhiatma Ardian , Fachrunnisa Olivia , Nurhidayati Nurhidayati , Rahayu Tina
Published: July 2022

Purpose

The digitization efforts for small and medium enterprises (SMEs) as a result of advances in information technology are challenging, with one of them being the creation of digital ecosystems for SMEs. This study aims to develop a model of the relationship between SMEs’ readiness to change, agile leadership and dynamic capability to implement a digital ecosystem for SMEs in the creative industry in Semarang, Central Java, Indonesia.

Design/methodology/approach

A survey methodology was used in this study. Respondents in this study were creative industry SMEs in Semarang, Central Java, Indonesia. SMEs in the creative industry sector were chosen as samples as they require digital technology to manage their business development, production and distribution, customer relationships and to innovate in their businesses. In total, 250 creative SMEs, selected based on a purposive random sampling method, were included in this study. Data were analyzed using structural equation model-partial least square.

Findings

This study provides current insights and future needs for implementing digital ecosystems in SMEs in Indonesia’s creative industries. It also identifies three critical conditions for dealing with Industry 4.0: organizational readiness to change, agile leadership and dynamic capability.

Originality/value

In response to information technology advancements, this study proposes a new model for implementing digital ecosystems for SMEs. Furthermore, this study adds knowledge about the concept of a service-oriented technology ecosystem to help SMEs operate more efficiently. It focuses on the interaction of entities to improve the system’s utility, gain benefits and promote information exchange.
Reflective thinking, ambiguity tolerance, and knowledge sharing: application of the motivation-opportunity-ability framework
Authors: Endres Megan Lee , Chowdhury Sanjib K.
Published: July 2022

Purpose

The purpose of this study is to apply the motivation–opportunity–ability (MOA) framework to investigate the relationships between ambiguity tolerance (AT), reflective thinking (RT) and performance in a complex task to predict knowledge-sharing intent.

Design/methodology/approach

In this study, 190 subjects performed a complex scheduling task in which they were randomly assigned to either participate in RT or not.

Findings

Results show that factors of the MOA framework positively predicted knowledge-sharing intent. In addition, RT significantly increased intention to share for individuals with low performance or with low AT.

Research limitations/implications

More research is needed to determine relationships between complex task performance and knowledge sharing, and the role of learning strategies, particularly self-directed ones such as RT. Future studies may use a larger sample size for more complex analysis.

Practical implications

RT may be used to create a sustainable and low-cost method of increasing knowledge sharing in complex tasks, without which those with low AT or low performance may not have participated.

Originality/value

The study supports the importance of contextual influences and points to how organizations can use RT in addition to individual motivation and ability to encourage knowledge sharing.