bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural studies of hepatitis C virus non-structural protein-5b of genotype 4a
Authors: Gaber Hanaa , Niessing Dierk , Protzer Ulrike , Janowski Robert
Published: April 2022

Hepatitis C virus genotype 4a non-structural protein-5b is an RNA-dependent RNA-polymerase responsible for the efficient virus genome replication. It has been of great interest as a drug target. The availability of the crystal structure of HCV genotype 4a NS5b would facilitate the structure-based drug design. Here we report the X-ray structure of NS5b solved at 3.1 Å resolution, setting the groundwork for the above-described therapeutic strategy.

Synopsis

X-ray structure of hepatitis C virus genotype 4a non-structural protein-5b, RNA-dependent RNA-polymerase responsible for the efficient virus genome replication.
Culexarchaeia, a novel archaeal class of anaerobic generalists inhabiting geothermal environments
Authors: Kohtz Anthony J. , Jay Zackary J. , Lynes Mackenzie , Krukenberg Viola , Hatzenpichler Roland
Published: April 2022

Geothermal environments, including terrestrial hot springs and deep-sea hydrothermal sediments, often contain many poorly understood lineages of archaea. Here, we recovered ten metagenome-assembled genomes (MAGs) from geothermal sediments and propose that they constitute a new archaeal class within the TACK superphylum, “Candidatus Culexarchaeia”, named after the Culex Basin in Yellowstone National Park. Culexarchaeia harbor distinct sets of proteins involved in key cellular processes that are either phylogenetically divergent or are absent from other closely related TACK lineages, with a particular divergence in cell division and cytoskeletal proteins. Metabolic reconstruction revealed that Culexarchaeia have the capacity to metabolize a wide variety of organic and inorganic substrates. Notably, Culexarchaeia encode a unique modular, membrane associated, and energy conserving [NiFe]-hydrogenase complex that potentially interacts with heterodisulfide reductase (Hdr) subunits. Comparison of this [NiFe]-hydrogenase complex with similar complexes from other archaea suggests that interactions between membrane associated [NiFe]-hydrogenases and Hdr may be more widespread than previously appreciated in both methanogenic and non-methanogenic lifestyles. The analysis of Culexarchaeia further expands our understanding of the phylogenetic and functional diversity of lineages within the TACK superphylum and the ecology, physiology, and evolution of these organisms in extreme environments.
Conduction velocity along a key white matter tract is associated with autobiographical memory recall ability
Authors: Clark Ian A. , Mohammadi Siawoosh , Callaghan Martina F. , Maguire Eleanor A.
Published: April 2022

Conduction velocity is the speed at which electrical signals travel along axons and is a crucial determinant of neural communication. Inferences about conduction velocity can now be made in vivo in humans using a measure called the magnetic resonance (MR) g-ratio. This is the ratio of the inner axon diameter relative to that of the axon plus the myelin sheath that encases it. Here, in the first application to cognition, we found that variations in MR g-ratio, and by inference conduction velocity, of the parahippocampal cingulum bundle were associated with autobiographical memory recall ability in 217 healthy adults. This tract connects the hippocampus with a range of other brain areas. We further observed that the association seemed to be with inner axon diameter rather than myelin content. The extent to which neurites were coherently organised within the parahippocampal cingulum bundle was also linked with autobiographical memory recall ability. Moreover, these findings were specific to autobiographical memory recall, and were not apparent for laboratory-based memory tests. Our results offer a new perspective on individual differences in autobiographical memory recall ability, highlighting the possible influence of specific features of white matter microstructure when recalling detailed memories of our real-life past experiences.
Phylogenetic and Ecological Trends in Specialization: Disentangling the Drivers of Ectoparasite Host Specificity
Authors: Brown Alexis M. , Speer Kelly A. , Teixeira Tiago , Clare Elizabeth , Simmons Nancy B. , Balbuena Juan A. , Dick Carl W. , Dittmar Katharina , Perkins Susan
Published: April 2022

Ecological specialization reflects both evolutionary and ecological processes. For parasitic taxa, ecological specialization can be assessed as the degree to which a parasite species will associate with certain host species, a property known as host specificity.

Ectoparasitic bat flies have been previously reported as highly host specific, presumably due to a history of coevolution with their bat hosts. However, there is conflicting evidence of coevolution between bats and bat flies. Resource-driven competition between parasite individuals and between species may also be important in explaining patterns of bat fly specificity.

To test the importance of evolutionary and ecological factors on bat fly specificity, we collected and identified 21 bat fly species from 16 host bat species from the State of Rio de Janeiro in Brazil. We generated a bat fly species phylogeny from molecular data, estimatedd’specialization values (a metric of specificity), and used linear and cophylogenetic models to compare the importance of various drivers of parasite ecological specialization.

We found that bat fly co-occurrence frequency (a proxy for interspecific competition) and mean infection intensity (a proxy for intraspecific competition) best predicted patterns of bat fly specialization. Co-occurrence frequency had a significantly negative association with specialization, while mean infection intensity has a significantly positive association with specialization. Coevolutionary congruence had a small effect size and did not significantly predict parasite specialization.

We found multiple shifts toward more generalized host niches across the bat fly phylogeny. Our results suggest that ecological processes such as resource-driven competition may be more important than evolutionary processes in shaping bat fly host specialization networks.

Bat flies showed variable degrees of host specialization, parasitized phylogenetically distant host species, and showed low phylogenetic congruence to their hosts. This suggests that as a group, bat flies may show flexibility in their host preference phenotypes and may change their host associations in the face of environmental disturbance.
Cardiac hemodynamics and ventricular stiffness of sea-run cherry salmon (Oncorhynchus masou masou) differ critically from those of landlocked masu salmon
Authors: Usui Yuu , Kimoto Misaki , Hanashima Akira , Hashimoto Ken , Mohri Satoshi
Published: April 2022

Ventricular diastolic mechanical properties are important determinants of cardiac function and are optimized by changes in cardiac structure and physical properties. Oncorhynchus masou masou is an anadromous migratory fish of the Salmonidae family, and several ecological studies on it have been conducted; however, the cardiac functions of the fish are not well known. Therefore, we investigated ventricular diastolic function in landlocked (masu salmon) and sea-run (cherry salmon) types at 29–30 months post fertilization. Pulsed-wave Doppler echocardiography showed that the atrioventricular inflow waveforms of cherry salmon were biphasic with early diastolic filling and atrial contraction, whereas those of masu salmon were monophasic with atrial contraction. In addition, end-diastolic pressure–volume relationship analysis revealed that the dilatability per unit myocardial mass of the ventricle in cherry salmon was significantly suppressed compared to that in masu salmon, suggesting that the ventricle of the cherry salmon was relatively stiffer (relative ventricular stiffness index; p = 0.0263). Contrastingly, the extensibility of cardiomyocytes, characterized by the expression pattern of Connectin isoforms in their ventricles, was similar in both types. Histological analysis showed that the percentage of the collagen accumulation area in the compact layer of cherry salmon increased compared with that of the masu salmon, which may contribute to ventricle stiffness. Although the heart mass of cherry salmon was about 11-fold greater than that of masu salmon, there was no difference in the morphology of the isolated cardiomyocytes, suggesting that the heart of the cherry salmon grows by cell division of cardiomyocytes, but not cell hypertrophy. The cardiac physiological function of the fish varies with differences in their developmental processes and life history. Our multidimensional analysis of the O. maosu heart may provide a clue to the process by which the heart acquires a biphasic blood-filling pattern, i.e., a ventricular diastolic suction.
The ϕPA3 Phage Nucleus is Enclosed by a Self-Assembling, 2D Crystalline Lattice
Authors: Nieweglowska ES , Brilot AF , Méndez-Moran M , Baek M , Li J , Kokontis C , Cheng Y , Baker D , Bondy-Denomy J , Agard DA
Published: April 2022

A growing number of jumbo bacteriophages, with genomes exceeding 200 kb, have been found to establish a Phage Nucleus—a micron-scale, proteinaceous structure encompassing the replicating phage DNA. Bacteriophage and host proteins associated with replication and transcription are concentrated inside the Phage Nucleus while nucleotide synthesis, translation, and numerous other host and exogenous proteins are effectively excluded, including CRISPR-Cas and restriction endonuclease host defense systems. Here, we show that fragments of the Phage Nucleus isolated from ϕPA3 infected Pseudomonas aeruginosa cells form a square lattice and demonstrate that the recombinantly purified primary Phage Nuclear Enclosure (PhuN) protein spontaneously assembles into sheets also constructed from a square lattice which we resolve to 3.8 Å by cryo-EM. Our structure reveals that the flexible termini and large loops mediate adaptable inter-tetramer contacts that drive shell assembly into a C2-symmetric lattice. While the interfaces between subunits are mostly well packed, two of the interfaces are open, forming clear channels that likely have important functional implications for the transport of proteins, mRNA, and small molecules.
Computational Design of Two New Vitamin K Epoxide Reductase Inhibitors
Authors: Cao Chuqiu , Adhikari Sambid , Huang Peishan , Siegel Justin B.
Published: April 2022

Vitamin K epoxide reductase (VKOR) inhibitors are commonly used to treat atrial fibrillation and ischemic stroke. However, due to the side effects and poor absorbance of existing drugs, there is urgent need for developing better VKOR inhibitor drugs. In this work, computational bioisosteric replacement and chemical intuition were used to design two novel VKOR inhibitors. The new candidates are predicted to have improved ADMET and binding properties compared to existing drugs.
CRISPRedict: The case for simple and interpretable efficiency prediction for CRISPR-Cas9 gene editing
Authors: Konstantakos Vasileios , Nentidis Anastasios , Krithara Anastasia , Paliouras Georgios
Published: April 2022

The development of the CRISPR-Cas9 technology has provided a simple yet powerful system for targeted genome editing. Compared with previous gene-editing tools, the CRISPR-Cas9 system identifies target sites by the complementarity between the guide RNA (gRNA) and the DNA sequence, which is less expensive and time-consuming, as well as more precise and scalable. To effectively apply the CRISPR-Cas9 system, researchers need to identify target sites that can be cleaved efficiently and for which the candidate gRNAs have little or no cleavage at other genomic locations. For this reason, numerous computational approaches have been developed to predict cleavage efficiency and exclude undesirable targets. However, current design tools cannot robustly predict experimental success as prediction accuracy depends on the assumptions of the underlying model and how closely the experimental setup matches the training data. Moreover, the most successful tools implement complex machine learning and deep learning models, leading to predictions that are not easily interpretable.

Here, we introduce CRISPRedict, a simple linear model that provides accurate and inter-pretable predictions for guide design. Comprehensive evaluation on twelve independent datasets demonstrated that CRISPRedict has an equivalent performance with the currently most accurate tools and outperforms the remaining ones. Moreover, it has the most robust performance for both U6 and T7 data, illustrating its applicability to tasks under different conditions. Therefore, our system can assist researchers in the gRNA design process by providing accurate and explainable predictions. These predictions can then be used to guide genome editing experiments and make plausible hypotheses for further investigation. The source code of CRISPRedict along with instructions for use is available at https://github.com/VKonstantakos/CRISPRedict.
Sus1 maintains a normal lifespan through regulation of TREX-2 complex-mediated mRNA export
Authors: Lim Suji , Liu Yan , Rhie Byung-Ho , Kim Chun , Ryu Hong-Yeoul , Ahn Seong Hoon
Published: April 2022

Eukaryotic gene expression requires multiple cellular events, including transcription and RNA processing and transport. Sus1, a common subunit in both the Spt-Ada-Gcn5 acetyltransferase (SAGA) and transcription and export complex-2 (TREX-2) complexes, is a key factor in coupling transcription activation to mRNA nuclear export. Here we present that the SAGA DUB module and TREX-2 regulates distinctly yeast replicative lifespan in a Sir2-dependent and - independent manner, respectively. The growth and lifespan impaired by SUS1 loss depend on TREX-2 but not on the SAGA DUB module. Notably, an increased dosage of the mRNA export factors Mex67 and Dbp5 rescues the growth defect, shortened lifespan, and nuclear accumulation of poly(A)+ RNA in sus1Δ cells, suggesting that boosting the mRNA export process restores the mRNA transport defect and damage in the growth and lifespan of sus1Δ cells. Moreover, Sus1 is required for the proper association of Mex67 and Dbp5 with the nuclear rim. Together, these data suggest that Sus1 links transcription and mRNA nuclear export to the lifespan control pathway, indicating that prevention of an abnormal accumulation of nuclear RNA is necessary for maintaining a normal lifespan.
A full spectrum PNGase activity analysis of R328 mutations on NGLY1
Authors: Yuan Shuying , Chen Yanwen , Zou Lin , Lu Xinrong , Liu Ruijie , Zhang Shaoxing , Chen Li , Sun Guiqin
Published: April 2022

In humans, N-glycanase 1 (NGLY1; Peptide: N-glycanase, PNGase) is responsible for the deglycosylation of misfolded glycoproteins. Pathogenic mutations in NGLY1 cause a clinical condition known as congenital disorder of deglycosylation (NGLY1-CDDG), a rare autosomal recessive disease first reported in 2012. Although NGLY1-CDDG was diagnosed through whole-exome or whole-genome sequencing and by evaluating the expression levels of NGLY1, the clinical relevance of a detected mutation in NGLY1 needs to be further confirmed. In this study, an in vitro enzymatic assay system was established to evaluate the thermal stability and substrate specificity of NGLY1, as well as the optimum reaction conditions for its activity. A panel of all mutations at the amino acid site R328 in NGLY1 was subjected to this assay. The results revealed that R328A, R328D, R328E, R328F, R328G, R328I, R328P, R328V, R328W, and R328Y were dysfunctional mutations (10/19); NGLY1 mutations with R328H and R328T exhibited similar activity as wild-type NGLY1 (2/19); and NGLY1 mutations with R328C, R328K, R328L, R328M, R328N, R328Q, and R328S showed decreased activity (7/19) compared to wild-type NGLY1. In addition, the effect of potential regulatory compounds, including N-acetyl-L-cysteine and dithiothreitol, on NGLY1 was examined. This in vitro assay may serve as a standard protocol to facilitate rapid diagnosis of all mutations on NGLY1 and a practical screening method for drugs and compounds with potential therapeutic value for NGLY1-CDDG patients.
Excess ribosomal protein production unbalances translation in Fragile X Syndrome
Authors: Seo Sang S. , Louros Susana R. , Anstey Natasha , Gonzalez-Lozano Miguel A. , Harper Callista B. , Verity Nicholas C. , Dando Owen , Thomson Sophie R. , Darnell Jennifer C. , Kind Peter C. , Li Ka Wan , Osterweil Emily K.
Published: April 2022

Dysregulated protein synthesis is a core pathogenic mechanism in Fragile X Syndrome (FX). The mGluR Theory of FX predicts that pathological synaptic changes arise from the excessive translation of mRNAs downstream of mGlu1/5 activation. Here, we use a combination of CA1 pyramidal neuron-specific TRAP-seq and proteomics to identify the overtranslating mRNAs supporting exaggerated mGlu1/5-induced long-term synaptic depression (mGluR-LTD) in the FX mouse model (Fmr1-/y). Surprisingly, our results identify a robust translation of ribosomal proteins (RPs) upon mGlu1/5 stimulation that coincides with a reduced translation of long mRNAs encoding synaptic proteins. These changes are mimicked and occluded in Fmr1-/y neurons. Inhibiting RP translation significantly impairs mGluR-LTD and prevents the length-dependent shift in the translating population. Together, these results suggest that pathological changes in FX result from a length-dependent alteration in the translating population that is supported by excessive RP translation.
Dyslexia associated gene, KIAA0319, regulates cell cycle during human neuroepithelium development
Authors: Paniagua Steven , Cakir Bilal , Hu Yue , Kiral Ferdi Ridvan , Tanaka Yoshiaki , Xiang Yangfei , Patterson Benjamin , Gruen Jeffrey R. , Park In-Hyun
Published: April 2022

Reading Disability (RD), also known as dyslexia, is defined as difficulty processing written language in individuals with normal intellectual capacity and educational opportunity. The prevalence of RD is between 5% and 17%, and the heritability ranges from 44% to 75%. Genetic linkage analysis and genome-wide association studies (GWAS) have identified several genes and regulatory elements linked to RD and reading ability. However, their functions and molecular mechanisms are not well understood. Prominent among these is KIAA0319, encoded in the DYX2 locus of human chromosome 6p22. Association of KIAA0319 has been independently replicated in multiple independent studies and languages. Rodent models suggest that KIAA0319 is involved in neuronal migration, but its precise function is unknown. This studies aim to determine the mechanisms by which KIAA0319 affects reading and language performance. We hypothesize that KIAA0319 plays a critical role in neuronal development. RT-qPCR and quantitative immunofluorescence in the cortical neurons differentiated from H7 hESC show regulatory effects on proliferation and differentiation of neuronal progenitor cells. Knockdown of KIAA0319 expression promotes early exit from the neuroepithelial cell stage and drives cells into cell cycle arrested neuronal progenitor cell stage. This suggests that KIAA0319 act by regulating neurogenesis in the reading related centers of the brain by targeting the cell cycle of proliferative cells. This demonstrates how subtle changes in expression could affect an isolated trait such as reading without global brain effects.
A dominant negative mutation uncovers cooperative control of caudal Wolffian Duct development by Sprouty genes
Authors: Altés Gisela , Vaquero Marta , Cuesta Sara , Anerillas Carlos , Macià Anna , Espinet Carme , Ribera Joan , Bellusci Saverio , Klein Ophir D. , Yeramian Andree , Dolcet Xavi , Egea Joaquim , Encinas Mario
Published: April 2022

The Wolffian Ducts (WD) are paired epithelial tubules central to the development of the mammalian genitourinary tract. Outgrowths from the WD known as the ureteric buds (UB) generate the collecting ducts of the kidney. Later during development, the caudal portion of the WD will form the vas deferens, epididymis and seminal vesicle in males, and will degenerate in females. While the genetic pathways controlling the development of the UB are firmly established, less is known about those governing development of WD portions caudal to the UB. Sprouty proteins are inhibitors of receptor tyrosine kinase (RTK) signaling in vivo. We have recently shown that homozygous mutation of a conserved tyrosine (Tyr53) of Spry1 results in UB defects indistinguishable from that of Spry1 null mice. Here we show that heterozygosity for the Spry1 Y53A allele causes caudal WD developmental defects consisting on ectopically branched seminal vesicles in males and persistent WD in females, without affecting kidney development. Detailed analysis reveals that this phenotype also occurs in Spry1+/- mice but with a much lower penetrance, indicating that removal of tyrosine 53 generates a dominant negative mutation in vivo. Supporting this notion, concomitant deletion of one allele of Spry1 and Spry2 also recapitulates the genital phenotype of Spry1Y53A/+ mice with high penetrance. Mechanistically, we show that unlike the effects of Spry1 in kidney development, these caudal WD defects are independent of Ret signaling, but can be completely rescued by lowering the genetic dosage of Fgf10. In conclusion, mutation of tyrosine 53 of Spry1 generates a dominant-negative allele that uncovers fine-tuning of caudal WD development by Sprouty genes.
Inflammatory cytokines rewire the proinsulin interaction network in human islets
Authors: Tran Duc , Pottekat Anita , Lee Kouta , Raghunathan Megha , Loguercio Salvatore , Mir Saiful , Paton Adrienne W. , Paton James C. , Arvan Peter , Kaufman Randal J. , Itkin-Ansari Pamela
Published: April 2022

Aberrant biosynthesis and secretion of the insulin precursor proinsulin occurs in both Type I and Type II diabetes (T1D, T2D). Inflammatory cytokines are implicated in pancreatic islet stress in both forms of diabetes but the mechanisms remain unclear. Here we examined how the diabetes associated cytokines interleukin-1β and interferon-γ alter proinsulin interactions with proteins that regulate its folding, trafficking, and secretion. Human islets treated with cytokines exhibited secretion of proinsulin, IL6 and nitrite, as well as evidence of endoplasmic reticulum (ER) stress. Unbiased proinsulin Affinity Purification-Mass Spectrometry revealed a proinsulin interactome reshaped by cytokines relative to controls. Cytokine treatment increased proinsulin binding to multiple ER chaperones and oxidoreductases, including the major ER chaperone BiP. Moreover, increased BiP binding was an adaptive response required to maintain proinsulin folding in the inflammatory environment. Cytokines also regulated novel interactions between proinsulin and T1D and T2D GWAS candidate proteins not previously known to interact with proinsulin (e.g., Ataxin-2) and these GWAS proteins formed a tight network with each other. Finally, cytokines induced proinsulin interactions with a cluster of microtubule motor proteins. Consistent with a role for these proteins in proinsulin trafficking and release, chemical destabilization of microtubules with Nocodazole exacerbated cytokine induced proinsulin secretion. Together, the data quantitatively map the proinsulin interactome rewired by cytokines, shedding new light on how human proinsulin biosynthesis is dysregulated by an inflammatory environment.
A Comprehensive Roadmap of Human Placental Development in vitro
Authors: Slamecka Jaroslav , Tristan Carlos A. , Ryu Seungmi , Chu Pei-Hsuan , Weber Claire , Deng Tao , Gedik Yeliz , Ormanoglu Pinar , Michael Sam , Voss Ty C. , Simeonov Anton , Singeç Ilyas
Published: April 2022

Human pluripotent stem cells (hPSCs) represent a powerful model system to study early developmental processes. However, lineage specification into trophectoderm (TE) remains poorly understood and access to well-characterized placental cells for biomedical research is limited, largely depending on fetal tissues or cancer cell lines. Here, we developed novel strategies enabling highly efficient TE specification that generates cytotrophoblast (CTB) and multinucleated primary syncytiotrophoblast (STB) followed by establishment of trophoblast stem cells (TSCs) capable of differentiating into extravillous trophoblast (EVT) and STB after long-term expansion. We confirmed stepwise induction of lineage- and cell-type-specific genes and substantiated typical features of placental cells using morphological, biochemical, integrated multi-omics, and single-cell analyses. Our data provide conclusive evidence that conventional hPSCs can be directly and exclusively converted into TE, thereby providing an unlimited source of diverse placental cell types suitable for a broad range of biomedical applications.
Amoeboid Cell Migration through Regular Arrays of Micropillars under Confinement
Authors: Sadjadi Zeinab , Vesperini Doriane , Laurent Annalena M. , Barnefske Lena , Terriac Emmanuel , Lautenschläger Franziska , Rieger Heiko
Published: April 2022

Migrating cells often encounter a wide variety of topographic features—including the presence of obstacles—when navigating through crowded biological environments. Unravelling the impact of topography and crowding on the dynamics of cells is key to better understand many essential physiological processes such as the immune response. We study how migration and search efficiency of HL-60 cells differentiated into neutrophils in quasi two-dimensional environments are influenced by the lateral and vertical confinement and spatial arrangement of obstacles. A microfluidic device is designed to track the cells in confining geometries between two parallel plates with distance h, in which identical micropillars are arranged in regular pillar forests. We find that at each cell-pillar contact event, the cell spends a finite time near the pillar surface, which is independent of the height h and the interpillar spacing e. At low pillar density regime, the directional persistence of cells reduces with decreasing h or e, influencing their diffusivity and first-passage properties. The dynamics is strikingly different at high pillar density regime, where the cells are in simultaneous contact with more than one pillar; the cell velocity and persistence are distinctly higher compared to dilute pillar configurations with the same h. Our simulations reveal that the interplay between cell persistence and cell-pillar interactions can dramatically affect cell diffusivity and, thus, its first-passage properties.
RNase H1 exists as phase-separated assemblies in association with elongating RNA Polymerase II during active transcription
Authors: Das Rituparna , Dey Anusree , Misra Hari S. , Uppal Sheetal
Published: April 2022

R-loops are three stranded nucleic acid structures consisting of a RNA/DNA hybrid and a single stranded displaced DNA. RNase H1 is an endonuclease which specifically degrades the RNA moiety in RNA-DNA hybrids. Here, we report that RNase H1 interacts with transcription elongation machinery during active transcription in a liquid-liquid phase separation (LLPS) dependent manner. We show that RNase H1 interacts with nascent RNA, and transcription elongation machinery in Hela cells, using in-situ nascent RNA labelling and Proximity ligation assay. Further, RNase H1 was found to exhibit properties of liquid-like condensates both in vitro and in vivo. Interestingly, RNase H1 interaction with elongating RNA Polymerase II can be disrupted by chemicals that perturb LLPS. Importantly, we show that LLPS is important for regulation of R-loop levels in the cell. Based on our results, we propose that RNase H1 exists as phase-separated assemblies in association with elongating RNA Polymerase II during active transcription.
CMTM6 mediates cisplatin resistance in OSCC by regulating AKT/c-MYC driven ribosome biogenesis
Authors: Mohapatra Pallavi , Mohanty Sibasish , Ansari Shamima Azma , Shriwas Omprakash , Ghosh Arup , Rath Rachna , Das Majumdar Saroj Kumar , Swain Rajeeb K , Raghav Sunil K , Dash Rupesh
Published: April 2022

CMTM6, a type 3 transmembrane protein, is known to stabilize the expression of programmed cell death ligand 1 (PD-L1) and hence facilitates the immune evasion of tumor cells. Recently, we demonstrated that CMTM6 is a major driver of cisplatin resistance in oral squamous cell carcinomas (OSCC). However, the detailed mechanism how CMTM6 rewires cisplatin resistance in OSCC is yet to be explored. RNA sequencing analysis of cisplatin resistant OSCC lines stably expressing NtShRNA and CMTM6 ShRNA revealed that CMTM6 might be a potential regulator of ribosome biogenesis network. Knocking down CMTM6 significantly inhibited transcription of 47S precursor rRNA and hindered the nucleolar structure, indicating reduced ribosome biogenesis. When CMTM6 was ectopically over expressed in CMTM6KD cells, almost all ribosomal machinery components were rescued. Mechanistically, CMTM6 induced the expression of C-Myc, which promotes RNA polymerase I mediated rDNA transcription. In addition to this, CMTM6 also found to regulate the AKT–mTORC1-dependent ribosome biogenesis and protein synthesis in cisplatin resistant lines. The nude mice and zebrafish xenograft experiments indicate that blocking ribosome synthesis either by genetic inhibitor (CMTM6KD) or by pharmacological inhibitor (CX-5461), significantly restores cisplatin medicated cell death in chemoresistant OSCC. Overall, our study suggests that CMTM6 is a major regulator of ribosome biogenesis network and targeting ribosome biogenesis network is a viable target to overcome chemoresistance in OSCC. The novel combination of CX-5461 and cisplatin deserves further clinical investigation in advanced OSCC.
Smart handheld medical device with patient-specific force regulation mechanism
Authors: Cheng Zhuoqi , He Jiale , Lin Pengjie , He Min , Guo Jing , Chen Xinwei , Cai Shuting , Xiong Xiaoming
Published: April 2022

Purpose

The purpose of this paper is to design a smart handheld device with force regulating function, which demonstrates the concept of patient-specialized tools.

Design/methodology/approach

This handheld device integrates an electrical bioimpedance (EBI) sensor for tissue measurement and a constant force regulation mechanism for ensuring stable tool–tissue contact. Particular focuses in this study are on the design of the constant force regulation mechanism whose design process is through genetic algorithm optimization and finite element simulation. In addition, the output force can be changed to the desired value by adjusting the cross-sectional area of the generated spring.

Findings

The following two specific applications based on ex vivo tissues are used for evaluating the designed device. One is in terms of safety of interaction with delicate tissue while the other is for compensating involuntary tissue motion. The results of both examples show that the handheld device is able to provide an output force with a small standard deviation.

Originality/value

In this paper, a handheld device with force regulation mechanism is designed for specific patients based on the genetic algorithm optimization and finite element simulation. The device can maintain a steady and safe interaction force during the EBI measurement on fragile tissues or moving tissues, to improve the sensing accuracy and to avoid tissue damage. Such functions of the proposed device are evaluated through a series of experiments and the device is demonstrated to be effective.
Leveraging capabilities for digitally supported process improvement: a framework for combining Lean and ERP
Authors: Liutkevičienė Indrė , Rytter Niels Gorm Malý , Hansen David
Published: April 2022

Purpose

Enterprise resource planning (ERP) and Lean are both widely used approaches to business process improvement. However, research is limited on their interactions when implemented in combination, leveraging the advantages of both. The purpose of this paper is to propose a generic framework for implementing ERP and Lean in combination to develop digitally supported business process improvement capability and improved competitiveness.

Design/methodology/approach

Principles and elements for the framework were derived from the extant literature and subsequently applied as input for solution incubation using design science research (DSR) in a five-year case study. Study results and learnings enabled solution refinement and the development of a generic framework for digital supported process improvement capabilities.

Findings

The paper presents a case study narrative and proposes a framework for digitally supported business process improvement capability based on Lean and enabled digitally by ERP. The framework delivers tangible productivity and quality improvements deployed, and an increase of continuous improvement capability.

Originality/value

This paper provides a novel generic framework and a set of guidelines for implementing Lean and ERP in SMEs and/or service companies to improve their business process excellence. The paper contributes to the scientific literature by providing insights on how SMEs and service operations can integrate Lean and ERP methods, digitalize and streamline processes in the organization and build continuous improvement capabilities.
Social capital and institutional complexity in Svalbard: the case of avalanche disaster management
Authors: Tiller Rachel Gjelsvik , Ross Ashley D. , Nyman Elizabeth
Published: April 2022

Purpose

Resilience can be understood as the ability of communities to adapt to disturbances in a way that reduces chronic vulnerability and promotes growth. Disaster scholars assert that resilience is developed through a set of adaptive capacities across multiple domains, including society, the economy, the built and natural environments, and sociopolitical institutions. These adaptive capacities have been thought to be networked, but little is known about how they are connected. The authors explore how institutional capacity and social capital intersect to influence change adaptation, using a case from the Artic: Longyearbyen in the Svalbard archipelago.

Design/methodology/approach

The authors use case study methods that integrate original interviews of Longyearbyen residents with news articles and public documents to analyze emergent themes related to institutional capacity, social capital and disaster risk reduction.

Findings

Analyses reveal that implementation gaps in hazard and disaster programs and policies, coupled with high turnover of staff in key positions, have created accountability issues indicative of low institutional capacity and weak social capital between the public and government. Additionally, high turnover of the population of the community, within the context of the legacy as a mining company town, is accompanied by social divisions and low trust between diverse cultural groups in the community. This lack of social capital provides little support for institutional capacity to effectively mitigate risk posed by climate change.

Originality/value

This study illuminates institutional capacity building needs directly related to disaster resilience for cases of complex institutional arrangements and developing democracy.
Financing constraints and innovation performance: the moderating role of the network location of cross-border innovation cooperation among Internet enterprises
Authors: Zhang Yilin , Gao Changyuan , Wang Jing
Published: April 2022

Purpose

This study aims to explore the relationship between financing constraints and the innovation performance of Internet enterprises in the cross-border innovation cooperation network. The study also analyzes the moderating effect of the location of the cross-border innovation cooperation network.

Design/methodology/approach

The authors selected patent data, related transaction data and other data of A-share listed companies on Shanghai and Shenzhen stock exchanges from 2014 to 2019. The generalized moment estimation method of instrumental variables (IV-GMM) method was used to analyze the relationship between financing constraints and the innovation performance of Internet firms and the moderating effect of the cross-border innovation cooperation network location. The threshold value of the moderating effect of the network structure hole was calculated with the threshold model.

Findings

The empirical results show a significant inverted U-shaped relationship between financing constraints and the innovation performance in the cross-border innovation cooperation network of Internet enterprises. Network centrality positively moderates this relationship. There is a threshold for the adjustment effect of network-structural holes, and the adjustment intensity of structural holes changes before and after the threshold.

Originality/value

This study provides a new perspective for Internet firms in innovation cooperation networks to alleviate the negative impact of financing constraints on innovation performance. The inverted U-shaped relationship between financing constraints and the innovation performance of Internet enterprises is in two stages. The moderating range of network centrality and the structural hole besides the threshold of the moderating effect of a structural hole are detailed.
A game model design using test bed for Malware analysis training
Authors: Khalid Marium , Afzal Mehreen , Iqbal Waseem
Published: April 2022

Purpose

This article aims to provide an interactive model for hands on training of malware analysis. Cyberwar games are the highly stylized representation of cyber conflicts in a simulation model. Game models are helpful in understanding the phenomenon of cyber attacks as well as to evolve new techniques of detection. Cyber security trainings are generally very challenging. Cyber test beds make such trainings easy both for trainees and trainers. However, it is not feasible for each organization to build a network for the sole purpose of hands-on training for employees. Therefore, it is desirable to build an interactive environment that is interesting and free of cost as well.

Design/methodology/approach

After exploring existing cyberwar games and their techniques, limitation and strengths, this paper presents a design to merge the cyber attacks into a unique model of war game for detection and analysis of malware. This research designs a malware analysis testbed using online free resources. The authors have used the platform of Cyber Defense Technology Experimental Research (DETER). This study proposed model of a testbed that supports malware reverse engineering scenarios, exercise logs and analysis to develop reverse engineering tactics.

Findings

The proposed cyber testbed is an automated system that can be used as a platform to train cyber warriors. A few features of the proposed testbed are as follows: testbed provides real or seemingly real malware communication with the real world. It includes automated decisions for the detection of malicious behavior without human intervention. The author gives a design to develop free of cost mechanism for remote learning of highly technical cyber security areas, and this simulation is for malware analysis.

Originality/value

Cyberwar games are built for strengthening offensive and defensive capabilities in cyberspace. For this purpose, many simulations, as well as emulation platforms, can be found. Some are free and open-source, whereas others are commercial and quite expensive. Existing testbeds have limitations in respect of cyberwar games for creating innovative scenarios. Existing literature does not offer any attack and response scenario developed for malware detection through some existing open-source and online simulation or emulation environments. This research includes an analysis of the existing platforms as well as the design of a new model for malware analysis and training.
Investigating the drivers of wearable technology adoption for healthcare in South America
Authors: Bianchi Constanza , Tuzovic Sven , Kuppelwieser Volker G.
Published: April 2022

Purpose

This empirical study examines the drivers of consumer intention to adopt wearable technology for healthcare in a South American country. Specifically, it proposes and tests a model of nonuser consumer intention to adopt fitness trackers for healthcare purpose in Chile.

Design/methodology/approach

This study draws on the technology acceptance framework UTAUT2 to develop and test a conceptual model of wearable technology adoption. Data were collected through an online survey applied to 470 nonusers of wearable technology in Santiago, Chile.

Findings

Findings indicate that hedonic motivation, social influence and perceived usefulness have the strongest influence on intention to adopt fitness trackers in Chile for healthcare. In addition, health motivation is an indirect predictor of consumer's intention to adopt wearable technology through its effect on perceived usefulness.

Practical implications

The study contributes to a better understanding of consumer intention to adopt wearable technology for healthcare objectives in a less developed country in South America. Findings are useful for wearable technology managers, retail business and public policymakers.

Originality/value

Despite the vast growth and importance of wearable technology for healthcare purposes, academic research considering less developed countries is scarce, especially the South American region. The proposed model and findings can extend this research gap. Theoretical and managerial implications are discussed as well as implications for public policy.
How do firms upgrade innovation capabilities through the coevolution of post-merger integration and network reconstruction? A multiple-case study of Chinese companies
Authors: Chen Feiqiong , Wang Wenjing , Zhu Jieru
Published: April 2022

Purpose

Post-merger integration (PMI) is driven by coevolving processes. This paper examines the coevolution of dynamic integration strategy and network reconstruction and explores how these processes systematically enable emerging market acquirers to upgrade innovation capabilities.

Design/methodology/approach

This paper conducts a multi-case study based on four Chinese overseas acquisitions of manufacturing firms. The data were collected from interviews and archival documentation.

Findings

This study develops a coevolutionary framework of dynamic integration strategy and network reconstruction to explain processes and mechanisms of an acquirer’s innovation capability upgrading. This framework identifies three network motivations, namely, network access, network connection and network synergy. Under different network motivations, dynamic transitions of the acquirer’s integration strategy coevolve with multi-level reconstruction of its networks. Collectively, they are important mechanisms driving innovation capability moves from imitation innovation to asportation and reimitation innovation and then to independent innovation.

Originality/value

This paper responds to a recent call for more insights into the dynamics of PMI and contributes to the research on emerging market multinational corporations’ post-acquisition integration. By integrating the M&A and networks literature, the paper provides evidence of unexplored mechanism of network changes during PMI. It reveals that how acquirers manage the dynamics of PMI to gradually achieve multi-level reconstruction of their networks. Based on a coevolutionary framework, the paper provides a process perspective on how the coevolution of PMI and network reconstruction promotes the upgrading of innovation capabilities.
The impacts of negative problem orientation on perceived risk and travel intention in the context of COVID-19: a PLS-SEM approach
Authors: Şengel Ümit , Genç Gökhan , Işkın Merve , Çevrimkaya Mustafa , Assiouras Ioannis , Zengin Burhanettin , Sarıışık Mehmet , Buhalis Dimitrios
Published: April 2022

Purpose

The COVID-19 pandemic, which appeared in China in late 2019, has affected the world psychologically, socially and economically in 2020. Tourism is one of the areas where the effects of COVID-19 have been felt most clearly. The study aims to determine the effect of negative problem orientation (NPO) and perceived risk related to the COVID-19 pandemic on travel and destination visit intention.

Design/methodology/approach

This study employed a convenience and probabilistic sampling method for collecting data from 531 respondents using an online questionnaire. Partial least square structural equation modeling (PLS-SEM) was used for testing research model.

Findings

According to the findings, NPO and perceived risk related to the pandemic were found to have direct and indirect effects on the travel behavior of tourists. The results of this research provide theoretical and practical implications for hospitality and travel businesses on topics such as the psychological effects of the pandemic and the travel behaviors of tourists.

Originality/value

It is estimated that the pandemic will also affect tourist behavior due to its effects on human psychology. For this reason, a study conducted in the context of tourist behavior theories is expected to contribute to the literature, managers and future of the tourism.
The role of environmental incentives in greening the small and medium-sized enterprises: a developing economy perspective
Authors: Rajapakse R.M.D.A.P. , Azam S.M.Ferdous , Khatibi Ali
Published: April 2022

Purpose

The utilisation of market-based approaches (MBAs) than command-control approaches (CCAs) is still at the embryonic stage to stimulate the green behaviour of small and medium-sized enterprises (SMEs) in developing economies. The study aims to elucidate the association between environmental incentives (EIs), green responsiveness (GR) and environmental performance (EP).

Design/methodology/approach

A quantitative dominant research design is adopted with qualitative support. The study model is developed by integrating legitimacy theory (LT) and the natural resource-based view (NRBV). The cross-sectional data were gathered from the upper echelon of 395 SMEs in Sri Lanka, and 10 subsequent interviews were conducted. The partial least squares approach of structural equation modelling (PLS-SEM) was used to evaluate the hypothesised relationships.

Findings

The results found evidence to demonstrate that EIs positively link with GR and EP and GR mediates this association. Further, the study revealed that although MBAs are established, the SME sector is less aware of EIs such as tax concessions, tax reliefs, low interest, soft loans and discounts on eco-materials.

Practical implications

The results provide valuable insights to enhance environmental sustainability. The owners of SMEs should strategically use environmental inducements to overcome resource poverty to engage in green practices. The regulators and policymakers should develop the incentive policies and provide the mechanisms to disseminate the required skills and technologies to SMEs.

Originality/value

According to the authors' best knowledge, this is one of the pioneering empirical studies on EIs, GR and EP with mediating effects in Sri Lanka.