bluuebunny/crossref_metadata_2025 huggingface dataset:
Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis
Authors: Shelton Spencer D. , House Sara , Ramesh Vijayashree , Chen Zhenkang , Wei Tao , Wang Xun , Llamas Claire B. , Venigalla Siva Sai Krishna , Menezes Cameron J. , Zhao Zhiyu , Gill Jennifer G. , DeBerardinis Ralph J. , Morrison Sean J. , Tasdogan Alpaslan , Mishra Prashant
Published: September 2023

Mitochondrial DNA (mtDNA) mutations are frequently observed in cancer, but their contribution to tumor progression is controversial. To evaluate the impact of mtDNA variants on tumor growth and metastasis, we created human melanoma cytoplasmic hybrid (cybrid) cell lines transplanted with wildtype mtDNA or pathogenic mtDNA encoding variants that partially or completely inhibit oxidative phosphorylation. Homoplasmic pathogenic mtDNA cybrids reliably established tumors despite dysfunctional oxidative phosphorylation. However, pathogenic mtDNA variants disrupted spontaneous metastasis of subcutaneous tumors and decreased the abundance of circulating melanoma cells in the blood. Pathogenic mtDNA did not induce anoikis or inhibit organ colonization of melanoma cells following intravenous injections. Instead, migration and invasion were reduced, indicating that limited circulation entry functions as a metastatic bottleneck amidst mtDNA dysfunction. Furthermore, analysis of selective pressure exerted on the mitochondrial genomes of heteroplasmic cybrid lines revealed a suppression of pathogenic mtDNA allelic frequency during melanoma growth. Collectively, these findings demonstrate that functional mtDNA is favored during melanoma growth and enables metastatic entry into the blood.
Bone Morphogenetic Protein (BMP) signaling upregulates expression of ID1 and ID3 in pancreatitis and pancreatic ductal adenocarcinoma
Authors: Raghunathan Megha , Scully Kathleen M. , Wehrmaker Amanda , Murad Rabi , Lowy Andrew M. , Maurer H. Carlo , DelGiorno Kathleen E. , Itkin-Ansari Pamela
Published: September 2023

Identification of biological modulators of pancreatic ductal adenocarcinoma (PDAC) initiation and progression is of critical importance as it remains one of the deadliest cancers. We have previously shown that ID1 and ID3 are highly expressed in human PDAC and function to repress expression of E47 target genes involved in acinar cell differentiation and quiescence. Here, mining of large bulk RNA-seq and single cell RNA-seq (scRNA-seq) datasets has associated high expression of ID1 and ID3 with poor PDAC patient survival. We show that upregulated expression of ID1 and ID3 in human PDAC cells occurs in response to canonical BMP signaling through pSMAD1/5/9. Conversely, treatment with Noggin, an endogenous BMP antagonist, or with DMH1 and LDN193189, small molecule inhibitors of BMP receptors, reduced expression of ID1, ID3 and cell cycle control genes. Based on our RNA-seq and immunohistochemical analyses, upregulation of BMP signaling to ID1 and ID3 is an early event that occurs in human pancreatic intraepithelial neoplasia (PanIN) and murine models of pre-neoplastic lesions induced by mutant Kras. Strikingly, the same result was observed in a murine model of pancreatitis induced by the cholecystokinin (CCK) analog caerulein. Moreover, we show that caerulein is sufficient to induce BMP signaling and expression of ID1 and ID3 in a cell-autonomous manner in non-transformed rodent exocrine pancreas cells. Together, the data suggest that canonical BMP signaling upregulates expression of ID1 and ID3 early in pancreas pathogenesis and that pancreatic cancer cells remain addicted to this important signaling circuit as the disease progresses. Future exploration of druggable targets within this pathway could be of therapeutic benefit in the treatment of pancreatitis and PDAC.
Replication protein-A, RPA, plays a pivotal role in the maintenance of recombination checkpoint in yeast meiosis
Authors: Sampathkumar Arivarasan , Chen Zhong , Tang Yuting , Fujita Yurika , Ito Masaru , Shinohara Akira
Published: September 2023

DNA double-strand breaks (DSBs) activate DNA damage responses (DDR) in both mitotic and meiotic cells. A single-stranded DNA (ssDNA) binding protein, Replication protein-A (RPA) binds to the ssDNA formed at DSBs to activate ATR/Mec1 kinase for the response. Meiotic DSBs induce homologous recombination monitored by a meiotic DDR called the recombination checkpoint that blocks the pachytene exit in meiotic prophase I. In this study, we showed the essential role of RPA in the maintenance of the recombination checkpoint duringS. cerevisiaemeiosis. The depletion of an RPA subunit, Rfa1, in a recombination-defectivedmc1mutant, fully alleviates the pachytene arrest with the persistent unrepaired DSBs. RPA depletion decreases the activity of a meiosis-specific CHK2 homolog, Mek1 kinase, which in turn activates the Ndt80 transcriptional regulator for pachytene exit. These support the idea that RPA is a sensor of ssDNAs for the activation of meiotic DDR. Rfa1 depletion also accelerates the prophase I delay in thezip1mutant defective in both chromosome synapsis and the recombination, suggesting that the accumulation of ssDNAs rather than defective synapsis triggers prophase I delay in thezip1mutant.
Trapping non-cognate nucleotide upon initial binding for replication fidelity control in SARS-CoV-2 RNA dependent RNA polymerase
Authors: Romero Moises E. , McElhenney Shannon J. , Yu Jin
Published: September 2023

Abstract

The RNA dependent RNA polymerase (RdRp) in SARS-CoV-2 is a highly conserved enzyme responsible for viral genome replication/transcription. Here we investigate computationally natural non-cognate vs cognate nucleotide addition cycle (NAC) and intrinsic nucleotide selectivity during the viral RdRp elongation, focusingprechemicallyfrom initial nucleotide substrate binding (enzyme active site open) to insertion (active site closed) of RdRp in contrast with one-step only substrate binding process. Current studies have been first carried out using microsecond ensemble equilibrium all-atom molecular dynamics (MD) simulations. Due to slow conformational changes (from the open to closed) accompanying nucleotide insertion and selection, enhanced or umbrella sampling methods have been further employed to calculate free energy profiles of the non-cognate NTP insertion. Our studies show notable stability of noncognate dATP and GTP upon initial binding in the active-site open state. The results indicate that while natural cognate ATP and Remdesivir drug analogue (RDV-TP) are biased to be stabilized in the closed or insertion state, the natural non-cognate dATP and GTP can be well trapped inoff-pathinitial binding configurations. Current work thus presents an intrinsic nucleotide selectivity mechanism of SARS-CoV-2 RdRp for natural substrate fidelity control in viral genome replication.
Heterogeneity and genomic evolution of metastatic prostate cancer
Authors: Wu Sijia , Lu Zhennan , Wang Yanfei , Zhou Xiaobo , Huang Liyu
Published: September 2023

Background

Metastasis is the primary cause of prostate cancer-related deaths. However, the underlying molecular mechanisms and evolutionary patterns remain largely uncharacterized.

Methods

We evaluate the heterogeneity and genomic evolution of prostate cancer with multi-organ metastases. The samples include 32 primary samples, 23 lymph node metastases, 22 bone metastases, 16 liver metastases, and four pelvic mess metastases. They are analyzed to identify the mutated genes enriched in metastatic samples, selected by metastases, and leading to different long-distance migrations. These metastasis-related alterations constitute a Mscore for evaluating the metastatic risk of primary prostate tumors.

Results

Our analysis discovers 21 metastasis-related mutated genes in total. Of them, 14 genes are finally selected for metastatic risk prognosis, including the mutations ofARandKMT2Cwith high prediction ability. A Mscore established with these 14 characteristics by the xgboost model displays its ability to classify primary tumors and metastases. This score can further divide primary prostate tumors from the TCGA cohort into two groups. The two subsets present significantly differential survival risks. This score can also identify metastasis-featured primary tumors for breast cancer, bladder cancer, liver cancer, and uterine corpus endometrial carcinoma.

Conclusion

Our research proposes 14 molecular features potentially driving prostate cancer metastasis. The Mscore established on them can estimate the metastatic risk of primary tumors.
Neutralization of SARS-CoV-2 EG.5/EG.5.1 by sera from ZF2001 RBD-dimer and its next-generation vaccines
Authors: An Yaling , Zhou Xuemei , Tao Lifeng , Xie Haitang , Yang Chenxi , Li Dedong , Wang Ruyue , Hu Hua , Liu Kefang , Dai Lianpan , Xu Kun , Gao George F.
Published: September 2023

SARS-CoV-2 Omicron EG.5 and EG.5.1 are surging in several areas of the world, including China. Compared with XBB.1, EG.5 contains additional mutations of F456L and S486P in the spike protein receptor binding domain (RBD) and its subvariant EG.5.1 carries a further spike mutation Q52H. The immune escape potential of EG.5/EG.5.1 is of great concern. In this study, we evaluated the neutralization activities of sera from participants who received COVID-19 inactivated vaccines, protein subunit vaccine ZF2001 or a booster vaccination of Delta-BA.5 RBD-heterodimer protein vaccine, and participants who had a breakthrough infection during a wave of BF.7/BA.5.2 circulation in December 2022. Neutralization profiles elicited by bivalent RBD-heterodimer vaccine candidates containing XBB.1.5 antigen were evaluated in a murine model. We found that EG.5 and EG.5.1 displayed similar immune evasion potential to XBB.1 and XBB.1.5. The Delta-BA.5 RBD-heterodimer booster induced higher neutralizing titers against the tested XBB subvariants, including EG.5 and EG.5.1, than breakthrough infection by BF.7 or BA.5.2. In addition, Delta-XBB.1.5 and BQ.1.1-XBB.1.5 RBD-heterodimer vaccines induced high neutralizing activities against XBB sub-variants in a murine model, suggesting that next-generation COVID-19 vaccines with updated components must be developed to enhance the protection efficacy against the circulating SARS-CoV-2 strains.
Baloxavir marboxil use for critical human infection of avian influenza A H5N6 virus
Authors: Guan Wenda , Qu Rong , Shen Lihan , Mai Kailin , Pan Weiqi , Lin Zhengshi , Chen Liping , Dong Ji , Zhang Jiawei , Feng Pei , Weng Yunceng , Yu Minfei , Guan Peikun , Zhou Jinchao , Tu Chuanmeizi , Wu Xiao , Wang Yang , Yang Chunguang , Ling Yun , Le Sheng , Zhan Yangqing , Li Yimin , Liu Xiaoqing , Zou Heyan , Huang Ziqi , Zhou Hongxia , Wu Qiubao , Zhang Wenjie , He Jiayang , Xu Teng , Zhong Nanshan , Yang Zifeng
Published: September 2023

Background

Recent increase in human infections of highly pathogenic avian influenza H5N6 virus and its high mortality have raised concerns.

Methods

To analyze evolution of outcomes, longitudinal clinical data and specimens were collected from five patients infected with H5N6 virus after admission. All patients received antiviral treatment either sequentially or in combination of oseltamivir with baloxavir. Severity of illness, and viral load in sputum, urine and blood, and cytokine levels in serum and sputum were serially analyzed.

Results

When delayed oseltamivir showed poor effects on high respiratory viral load, baloxavir was prescribed and viral load had a rapid reduction. All patients developed acute respiratory distress syndrome (ARDS) and sepsis within one week after disease onset, three patients died eventually. Nonsurvivors had more severe preexisting condition, extrapulmonary organ dysfunction and insufficient H5N6 virus-specific antibody response. Grouped by delta SOFA on the sample collection date, serum levels of IL-1α, IL-1β, IL-1RA, MIF, Mig, MIP-1α, IFN-γ, IL-12p40, IL-16, IL-18, IL-2Rα, IL-6, basic FGF, G-CSF, HGF, M-CSF, SCF were identified as indicator cytokines reflecting sepsis progression; and sputum levels of IL-18, IL-6, HGF, M-CSF were indicators of ARDS progression. Comparisons of cytokine levels before, during and after baloxavir treatment suggested that, baloxavir may also reduce a few indicator cytokines in sputum and serum that related to viral load and multi-organ dysfunction.

Conclusions

Baloxavir can effectively reduce viral load and few proinflammatory cytokines associated with deterioration. However, disease outcome is determined by severity of preexisting conditions and multi-organ dysfunction.

Highlights

(1)

Baloxavir potently decreased viral load in avian influenza H5N6 human infections.

(2)

Preexisting conditions, extrapulmonary dysfunction and systemic inflammation determined prognosis of H5N6 patients.

(3)

Indicator cytokines in sputum and serum reflecting ARDS and sepsis progression respectively, were identified in H5N6 patients.
Comparative pangenomic insights into the distinct evolution of virulence factors among grapevine trunk pathogens
Authors: Garcia Jadran F. , Morales-Cruz Abraham , Cochetel Noé , Minio Andrea , Figueroa-Balderas Rosa , Rolshausen Philippe E. , Baumgartner Kendra , Cantu Dario
Published: September 2023

The permanent organs of grapevines (V. viniferaL.), like other woody perennials, are colonized by various unrelated pathogenic ascomycete fungi secreting cell wall-degrading enzymes and phytotoxic secondary metabolites that contribute to host damage and disease symptoms. Trunk pathogens differ in the symptoms they induce and the extent and speed of damage. Isolates of the same species often display a wide virulence range, even within the same vineyard. This study focuses onEutypa lata,Neofusicoccum parvum, andPhaeoacremonium minimum, causal agents of Eutypa dieback, Botryosphaeria dieback, and Esca, respectively. We sequenced fifty isolates from viticulture regions worldwide and built nucleotide-level, reference-free pangenomes for each species. Through examining genomic diversity and pangenome structure, we analyzed intraspecific conservation and variability of putative virulence factors, focusing on functions under positive selection, and recent gene-family dynamics of contraction and expansion. Our findings reveal contrasting distributions of putative virulence factors in the core, dispensable, and private genomes of each pangenome. For example, CAZymes were prevalent in the core genomes of each pangenome, whereas biosynthetic gene clusters were prevalent in the dispensable genomes ofE. lataandP. minimum. The dispensable fractions were also enriched in Gypsy transposable elements and virulence factors under positive selection (polyketide synthases genes inE. lataandP. minimumglycosyltransferases inN. parvum). Our findings underscore the complexity of the genomic architecture in each species and provide insights into their adaptive strategies, enhancing our understanding of the underlying mechanisms of virulence.
STING activation counters glioblastoma by vascular alteration and immune surveillance
Authors: Joseph Justin V. , Blaavand Mathilde S. , Cai Huiqiang , Vernejoul Fabienne , Knopper Rasmus W. , Lindhardt Thomas B. , Skipper Kristian A. , Axelgaard Esben , Reinert Line , Mikkelsen Jacob G. , Borghammer Per , Degn Søren E. , Perouzel Eric , Hager Henrik , Hansen Brian , Kalucka Joanna M. , Vendelbo Mikkel , Paludan Søren R. , Thomsen Martin K.
Published: September 2023

Glioblastoma (GBM) is an aggressive brain tumor with a median survival of 15 months and has limited treatment options. Immunotherapy with checkpoint inhibitors has shown minimal efficacy in combating GBM, and large clinical trials have failed. New immunotherapy approaches and a deeper understanding of immune surveillance of GBM are needed to advance treatment options for this devastating disease. In this study, we used two preclinical models of GBM: orthotopically delivering either GBM stem cells or employing CRISPR-mediated tumorigenesis by adeno-associated virus, to establish immunologically proficient and non-inflamed tumors, respectively. After tumor development, the innate immune system was activated through long-term STING activation by a pharmacological agonist, which reduced tumor progression and prolonged survival. Recruitment and activation of cytotoxic T-cells were detected in the tumors, and T-cell specificity towards the cancer cells was observed. Interestingly, prolonged STING activation altered the tumor vasculature, inducing hypoxia and activation of VEGFR, as measured by a kinome array and VEGF expression. Combination treatment with anti-PD1 did not provide a synergistic effect, indicating that STING activation alone is sufficient to activate immune surveillance and hinder tumor development through vascular disruption. These results guide future studies to refine innate immune activation as a treatment approach for GBM, in combination with anti-VEGF to impede tumor progression and induce an immunological response against the tumor.
The protein phosphatase-2A subunit PR130 is linked to cytotoxic protein aggregate formation in mesenchymal pancreatic ductal adenocarcinoma cells
Authors: Nguyen Alexandra , Leydecker Alessa K. , Mustafa Al-Hassan M. , Murr Janine , Butter Falk , Krämer Oliver H.
Published: September 2023

Protein phosphatase-2A (PP2A) is a major source of cellular serine/threonine phosphatase activity. PP2A B-type subunits regulate the intracellular localization and the catalytic activity of PP2A-A/PP2A-C complexes towards individual proteins. There is limited knowledge on how PP2A B-type subunits regulate biologically important functions and if these subunits determine the growth and drug responsiveness of tumor cells. Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with poor prognosis. Mesenchymal PDAC subtypes are more aggressive and metastasis-prone than epithelial subtypes. We show that mesenchymal PDAC cells express significantly higher levels of the PP2A B-type subunit PR130 and its mRNAPpp2r3athan epithelial PDAC cells (n=38). Among 17 PP2A B-type subunits, this differential regulation is unique forPpp2r3aand PR130. The higher levels of PR130 in mesenchymal PDAC cells are linked to their vulnerability to the PP2A inhibitor phendione. Phendione induces apoptosis and an accumulation of cytotoxic protein aggregates in such cells. These processes occur independently of the major tumor suppressor p53, which is frequently mutated in PDAC cells. Proteomic analyses reveal that phendione upregulates the chaperone heat shock protein HSP70 in mesenchymal PDAC cells. Inhibition of HSP70 promotes phendione-induced apoptosis. We additionally disclose that phendione promotes a proteasomal degradation of PR130. Genetic elimination of PR130 sensitizes mesenchymal PDAC cells to phendione-induced apoptosis and protein aggregate formation. These data illustrate pharmacologically amenable, selective dependencies of mesenchymal PDAC cells on PP2A-PR130 and HSP70. PP2A inhibition triggers a harmful accumulation of protein aggregates in neurons. This undesired mechanism might be exploited to kill mesenchymal tumor cells.

Abstract Figure

HIGHLIGHTS

➢ The PP2A subunit PR130 is a molecular marker of mesenchymal PDAC cells

➢ The small molecule PP2A inhibitor phendione selectively kills mesenchymal PDAC cells

➢ Phendione decreases PR130 through proteasomes and selectively increases the heat shock protein 70 kDa in mesenchymal PDAC cells

➢ HSP70 promotes cell survival upon inhibition of PP2A

➢ PP2A-PR130 regulates the accumulation of cytotoxic protein aggregates in mesenchymal PDAC cells
Rho of plant GTPases with geranylgeranylation motif modulate monoterpene indole alkaloid biosynthesis inCatharanthus roseus
Authors: Bomzan Dikki Pedenla , Sharma Anuj , Cruz Pamela Lemos , Carqueijeiro Ines , Bellenger Léo , Rai Avanish , Thippesh Akshay Kumar , Venkatesha S.C. , Parihar Durgesh , Ducos Eric , Courdavault Vincent , Nagegowda Dinesh A.
Published: September 2023

Rho Of Plant (ROP) GTPases function as molecular switches that control signaling processes essential for growth, development, and defense. However, their role in specialized metabolism is poorly understood. Previously, we demonstrated that inhibition of protein geranylgeranyl transferase (PGGT-I) negatively impacts the biosynthesis of monoterpenoid indole alkaloids (MIA) inCatharanthus roseus, indicating the involvement of prenylated proteins in signaling. Here, we show through biochemical, molecular andin plantaapproaches that specific geranylgeranylated ROPs modulateC. roseusMIA biosynthesis. Among the sixC. roseusROP GTPases (CrROPs), only CrROP3 and CrROP5, having a C- terminal CSIL motif, were specifically prenylated by PGGT-I. Additionally, both of their transcripts showed higher expression in most parts compared to otherCrROPs. Protein- protein interaction studies revealed that both CrROP3 and CrROP5, but not CrROP2 (lacking CSIL motif), interacted with CrPGGT-I. Further, CrROP3 and CrROP5 exhibited nuclear localization, whereas CrROP2 was localized to plasma membrane.In plantafunctional studies revealed that silencing ofCrROP3andCrROP5negatively affected MIA biosynthesis, while their overexpression upregulated MIA formation. In contrast, silencing and overexpression ofCrROP2had no effect on MIA biosynthesis. Moreover, overexpression of ΔCrROP3and ΔCrROP5mutants lacking the CSIL motif failed to enhance MIA biosynthesis. Taken together, these results implicate that CrROP3 and CrROP5 have positive regulatory role on MIA biosynthesis and thus shed light on how geranylgeranylated ROP GTPases mediate the modulation of specialized metabolism inC. roseus.
Bacteria conjugate ubiquitin-like proteins to interfere with phage assembly
Authors: Hör Jens , Wolf Sharon G. , Sorek Rotem
Published: September 2023

Multiple immune pathways in humans conjugate ubiquitin-like proteins to virus and host molecules as a means of antiviral defense. Here we studied an anti-phage defense system in bacteria, comprising a ubiquitin-like protein, ubiquitin-conjugating enzymes E1 and E2, and a deubiquitinase. We show that during phage infection, this system specifically conjugates the ubiquitin-like protein to the phage central tail fiber, a protein at the tip of the tail that is essential for tail assembly as well as for recognition of the target host receptor. Following infection, cells encoding this defense system release a mixture of partially assembled, tailless phage particles, and fully assembled phages in which the central tail fiber is obstructed by the covalently attached ubiquitin-like protein. These phages exhibit severely impaired infectivity, explaining how the defense system protects the bacterial population from the spread of phage infection. Our findings demonstrate that conjugation of ubiquitin-like proteins is an antiviral strategy conserved across the tree of life.
Structure and evolution of Alanine/Serine Decarboxylases and the engineering of theanine production
Authors: Wang Hao , Zhu Biying , Qiao Siming , Dong Chunxia , Wan Xiaochun , Gong Weimin , Zhang Zhaoliang
Published: September 2023

Ethylamine (EA), the precursor of theanine biosynthesis, is synthesized from alanine decarboxylation by alanine decarboxylase (AlaDC) in tea plants. AlaDC evolves from serine decarboxylase (SerDC) through neofunctionalization and has lower catalytic activity. However, lacking structure information hinders the understanding of the evolution of substrate specificity and catalytic activity. In this study, we solved the X-ray crystal structures of AlaDC fromCamellia sinensis(CsAlaDC) and SerDC fromArabidopsis thaliana(AtSerDC). Tyr341of AtSerDC or the corresponding Tyr336of CsAlaDC is essential for their enzymatic activity. Tyr111of AtSerDC and the corresponding Phe106of CsAlaDC determine their substrate specificity. Both CsAlaDC and AtSerDC have a distinctive zinc finger and have not been identified in any other Group II PLP-dependent amino acid decarboxylases. Based on the structural comparisons, we conducted mutation screen of CsAlaDC. The results indicated that the mutation of L110F or P114A in the CsAlaDC dimerization interface significantly improved the catalytic activity by 110% and 59%, respectively. Combining a double mutant of CsAlaDCL110F/P114Awith theanine synthetase increased theanine production 672% in anin vitrosystem. This study provides the structural basis for the substrate selectivity and catalytic activity of CsAlaDC and AtSerDC and provides a route to more efficient biosynthesis of theanine.
“CandidatusSiderophilus nitratireducens”: a psychrophilic,nap-dependent nitrate-reducing iron oxidizer within the new order Siderophiliales
Authors: Corbera-Rubio Francesc , Stouten Gerben R. , Bruins Jantinus , Dost Simon F. , Merkel Alexander Y. , Müller Simon , van Loosdrecht Mark C. M. , van Halem Doris , Laureni Michele
Published: September 2023

Nitrate leaching from agricultural soils is increasingly found in groundwater, a primary source of drinking water worldwide. This nitrate influx can potentially stimulate the biological oxidation of iron in anoxic groundwater reservoirs. Nitrate-reducing iron-oxidizing (NRFO) bacteria have been extensively studied in laboratory settings, yet their ecophysiology in natural environments remains largely unknown. To this end, we established a pilot-scale filter on nitrate-rich groundwater to elucidate the structure and metabolism of nitrate-reducing iron-oxidizing microbiomes under oligotrophic conditions mimicking natural groundwaters. The enriched community stoichiometrically removed iron and nitrate consistently with NRFO metabolism. Genome-resolved metagenomics revealed the underlying metabolic network between the dominant iron-dependent denitrifying autotrophs and the less abundant organoheterotrophs. The most abundant genome belonged to a newCandidateorder, named Siderophiliales. This new species, “CandidatusSiderophilus nitratireducens”, carries central genes to iron oxidation (cytochromec cyc2), carbon fixation (rbc), and for the sole periplasmic nitrate reductase (nap). To our knowledge, this is the first report ofnap-based lithoautotrophic growth, and we demonstrate that iron oxidation coupled to dissimilatory reduction of nitrate to nitrite is thermodynamically favourable under realistic Fe3+/Fe2+andconcentration ratios. Ultimately, by bridging the gap between laboratory investigations and real-world conditions, this study provides insights into the intricate interplay between nitrate and iron in groundwater ecosystems, and expands our understanding of NRFOs taxonomic diversity and ecological role.
Comparative Analysis of Multiple Consensus Genomes of the Same Strain of Marek’s Disease Virus Reveals Intrastrain Variation
Authors: Ortigas-Vasquez Alejandro , Pandey Utsav , Renner Daniel , Bowen Chris , Baigent Susan J. , Dunn John , Cheng Hans , Yao Yongxiu , Read Andrew F. , Nair Venugopal , Kennedy Dave A. , Szpara Moriah L.
Published: September 2023

Current strategies to understand the molecular basis of Marek’s disease virus (MDV) virulence primarily consist of cataloguing divergent nucleotides between strains with different phenotypes. However, each MDV strain is typically represented by a single consensus genome despite the confirmed existence of mixed viral populations. To assess the reliability of single-consensus interstrain genomic comparisons, we obtained two additional consensus genomes of vaccine strain CVI988 (Rispens) and two additional consensus genomes of the very virulent strain Md5 by sequencing viral stocks and cultured field isolates. In conjunction with the published genomes of CVI988 and Md5, this allowed us to perform 3-way comparisons between consensus genomes of the same strain. We found that consensus genomes of CVI988 can vary in as many as 236 positions involving 13 open reading frames (ORFs). In contrast, we found that Md5 genomes varied only in 11 positions involving a single ORF. Phylogenomic analyses showed all three Md5 consensus genomes clustered closely together, while also showing that CVI988GenBank.BACdiverged from CVI988Pirbright.laband CVI988USDA.PA.field. Comparison of CVI988 consensus genomes revealed 19 SNPs in the unique regions of CVI988GenBank.BACthat were not present in either CVI988Pirbright.labor CVI988USDA.PA.field. Finally, we evaluated the genomic heterogeneity of CVI988 and Md5 populations by identifying positions with >2% read support for alternative alleles in two ultra-deeply sequenced samples. We were able to confirm that both populations of CVI988 and Md5 were mixed, exhibiting a total of 29 and 27 high-confidence minor variant positions, respectively. We did not find any evidence of minor variants in the positions corresponding to the 19 SNPs in the unique regions of CVI988GenBank.BAC. Taken together, our findings confirm that consensus genomes of the same strain of MDV can vary and suggest that multiple consensus genomes per strain are needed in order to maximize the accuracy of interstrain genomic comparisons.
Algorithms for the identification of prevalent diabetes in the All of Us Research Program validated using polygenic scores – a new resource for diabetes precision medicine
Authors: Szczerbinski Lukasz , Mandla Ravi , Schroeder Philip , Porneala Bianca C. , Li Josephine H. , Florez Jose C. , Mercader Josep M. , Manning Alisa K. , Udler Miriam S.
Published: September 2023

OBJECTIVE

The study aimed to develop and validate algorithms for identifying people with type 1 and type 2 diabetes in the All of Us Research Program (AoU) cohort, using electronic health record (EHR) and survey data.

RESEARCH DESIGN AND METHODS

Two sets of algorithms were developed, one using only EHR data (EHR), and the other using a combination of EHR and survey data (EHR+). Their performance was evaluated by testing their association with polygenic scores for both type 1 and type 2 diabetes.

RESULTS

For type 1 diabetes, the EHR-only algorithm showed a stronger association with T1D polygenic score (p=3×10−5) than the EHR+. For type 2 diabetes, the EHR+ algorithm outperformed both the EHR-only and the existing AoU definition, identifying additional cases (25.79% and 22.57% more, respectively) and showing stronger association with T2D polygenic score (DeLongp=0.03 and 1×10−4, respectively).

CONCLUSIONS

We provide new validated definitions of type 1 and type 2 diabetes in AoU, and make them available for researchers. These algorithms, by ensuring consistent diabetes definitions, pave the way for high-quality diabetes research and future clinical discoveries.

GRAPHICAL ABSTRACT

Article Highlights

a.

Why did we undertake this study?

This study was conducted to develop and validate algorithms for identifying type 1 and type 2 diabetes cases in the All of Us Research Program (AoU).

b.

What is the specific question(s) we wanted to answer?

Can accurate algorithms for type 1 and type 2 diabetes identification be developed and validated using AoU cohort Electronic Health Record (EHR) and survey data? Do the identified diabetes cases show association with polygenic scores in diverse populations?

c.

What did we find?

We developed a new validated type 1 diabetes definition and expanded upon the existing type 2 diabetes definition.

d.

What are the implications of our findings?

The developed algorithms can be universally implemented in AoU for identifying study participants for well-defined case-control diabetes studies.
Graphical reduction and analysis small-angle neutron scattering program: GRASP
Authors: Dewhurst C. D.
Published: September 2023

GRASP is a scientific software application designed for the graphical inspection, reduction and analysis of multidetector data produced by the small-angle neutron scattering (SANS) instruments at the Institut Laue–Langevin and other neutron sources around the world. The first developments of GRASP began more than 20 years ago and were written in MATLAB, allowing rapid development of scientific code, with much of the data handling, matrix manipulation, mathematical tools, user interface and graphical tools integrated at a high level in the underlying MATLAB platform. By their very nature, multidimensional data are often best appreciated in graphical form. GRASP deals with many of the diverse requirements for data reduction and analysis of SANS data using a general set of tools and reduction algorithms suited to 2D multidetector data. A further fundamental architectural inclusion is a third dimension of data manipulation, thereby easily allowing parametric analysis and cross referencing of series data such as composition, kinetic measurements, temperature, magnetic field, angle or time of flight, often considered as a single `measurement'. This article serves as a reference document for users of the software, and outlines the architecture and strategy of the program. An overview of some of the features, capabilities, peripheral user modules and neutron scattering tools is presented.
Crystal structure and Hirshfeld surface analysis of 1-(2-amino-4-methyl-1,3-thiazol-5-yl)ethan-1-one
Authors: Huseynov Elnur Z. , Akkurt Mehmet , Brito Ivan , Bhattarai Ajaya , Rzayev Rovnag M. , Asadov Khammed A. , Maharramov Abel M.
Published: September 2023

In the title compound, C6H8N2OS, all atoms except for the methyl H atoms are coplanar, with a maximum deviation of 0.026 (4) Å. In the crystal, pairs of molecules are linked by N—H...N hydrogen bonds, forming R
2
2(8) ring motifs. Dimers are connected by N—H...O hydrogen bonds, forming layers parallel to the (102) plane. Consolidating the molecular packing, these layers are connected by C—H...π interactions between the center of the 1,3-thiazole ring and the H atom of the methyl group attached to it, as well as C=O...π interactions between the center of the 1,3-thiazole ring and the O atom of the carboxyl group. According to a Hirshfeld surface study, H...H (37.6%), O...H/H...O (16.8%), S...H/H...S (15.4%), N...H/H...N (13.0%) and C...H/H...C (7.6%) interactions are the most significant contributors to the crystal packing.
A fuzzy logic evolution of the functional resonance analysis method (FRAM) to assess risk in ground operation
Authors: Tengiz Ertan , Unal Gulay
Published: September 2023

Purpose

The basis of safe flight is the management of risks. This paper aims to present a new process-based risk assessment model, with an approach to calculate the risk score.

Design/methodology/approach

Since thousands of minor changes occur within ground operations, it is difficult to calculate how much risk these variations will pose. This paper proposes a risk assessment model fed from analysis of ground operation processes using functional resonance analysis method (FRAM) and fuzzy logic.

Findings

FRAM is used to detect variations in ground operation. Using the FRAM analysis, it has been revealed how much risk the process steps described in the procedures involve. The risk score was calculated by combining the probability value obtained from the airline’s database and the severity assessment of the expert group in fuzzy logic. The risk level can be monitored dynamically with the transfer of events in the airline’s database to the process-based risk assessment model.

Originality/value

FRAM analysis, which is used to detect function variations before undesirable risk occurs, has brought a proactive approach to risk assessment. The process-based risk assessment model allows the creation of new safety parameter indicators to be followed to reduce the risk level of the function with a high-risk level. The proposed approach can be used for other operational areas in aviation as well.
Does the analytical hierarchy process help appraisers make better decisions? A quasi-experimental approach for property investment comparables
Authors: Aihie Vincent Uwaifiokun , Oyetunji Abiodun Kolawole , Omotayo Temitope , Ekundayo Damilola
Published: September 2023

Purpose

Income from investment properties can fluctuate depending on the state of the economy. The idea that there is always a potential exit (sale) value whenever the property stops performing at its optimum or deflation in the economy will always appeal to investors. To determine housing prices, investors would rely on a direct comparison approach (DCA) of recent substitute sales in the open market. Appraisers use this approach to develop an opinion of value when there is a plethora of recent sales to analyse.

Design/methodology/approach

The study was designed to establish the use of the analytical hierarchy process (AHP) approach as a support tool for deciding property appraisals. A case study of an industrial single-storey stand-alone building with grade-level parking in the south-east of Calgary, Canada, was investigated with the AHP approach. The result was cross-referenced with the DCA.

Findings

Using a consistency index of 0.077321 and a consistency ratio of 0.085912, the matrix multiplication was determined to be 0.456706. The average valuations derived from the adjusted price per square foot using the direct comparison method and the unadjusted price per square foot using the AHP were deemed the best value estimate in the light of available comparables. The implications of the findings suggest that AHP, as a quantitative technique, can support and validate the use of similar non-recent sale comparables when appraising investment properties with the DCA.

Originality/value

AHP is an alternative aid in quantitatively deciding the most significant value attribute for comparison before subjective adjustments. When intuitively applied in the DCA, these subjective adjustments almost always lead to an overvaluation of properties.
Characterizing digital service innovation: phases, actors, functions and interactions in the context of a digital service platform
Authors: Narvaiza Lorea , Campos José Antonio , Martín-Peña María Luz , Díaz-Garrido Eloísa
Published: September 2023

Purpose

Digital service innovation (DSI) is a type of technological innovation that is recognized in practice in the innovation structure of companies. Given the breadth of digital technologies that enable digital services and the variety of these services, analysis is needed to discern the nature of these services, as well as the process that culminates in co-innovation. The literature on DSI is fragmented and spread across multiple research areas. This fragmentation impedes conceptualization of the elements that constitute DSI. This paper describes the nature of DSI through the process and elements of initiation, adoption and routinization of DSI in the context of digital service platforms (DSPs).

Design/methodology/approach

This paper presents a single exploratory case study of a provider of a leading digital solution in customer relations. The data analysis is based on abductive reasoning.

Findings

The paper conceptualizes the nature of DSI and describes the process and elements of DSI (phases, actors, functions and interactions). It contributes to building a common language for DSI research in service management. The analysis shows that DSI in DSPs is synonymous with co-innovation. This paper offers insight into how co-innovation occurs, using hybrid agile methodologies with the coordination of multiple actors and multilateral interactions.

Originality/value

The originality and value of the study reside in its conceptualization and analysis of what is meant by DSI. The components of the service and the technological requirements for not only provision but also ideation and development appear to be inseparable. The study unveils the mechanisms that turn a digital service solution into a co-innovative proposal. This knowledge can facilitate scalability in digital services.
Getting along and getting ahead: voice trails of status pursuit
Authors: Khan Nabila , Dyaram Lata , Dayaram Kantha , Burgess John
Published: September 2023

Purpose

Integrating individual and relational centric voice literature, the authors draw on self-presentation theory to analyse the role of status pursuit in employee voice. Status pursuit is believed to be ubiquitous as it is linked to access to scarce resources and social order pecking.

Design/methodology/approach

The authors present a cross-level conceptual model outlining relational nuances of employee status pursuit that drive upward voice.

Findings

The model integrates status pursuit with peer- and leader-related facets, focusing on three targets of voice: immediate leader (supervisor), diagonal leader (supervisor of another team/unit) and co-workers. The model highlights how employee voice can be directed to diverse targets, and depending on interpersonal attributes, how it serves as underlying links for upward voice.

Originality/value

While employee voice can help to address important workplace concerns, it can also be used to advance employees' self-interest. Though there is a wealth of research on the importance of employee voice to organisational performance and individual wellbeing, especially through collective representation such as trade unions, there is a lack of literature on how employees navigate the social-relational work setting to promote their interests and develop status.
Oil spills removal from seawater surface by magnetic biochar composite derived from Heglig tree bark and cobalt ferrite
Authors: Amar Ibrahim A. , Alzarouq Aeshah , Mohammed Wajdan , Zhang Mengfei , Matroed Noarhan
Published: September 2023

Purpose

This study aims to explore the possibility of using magnetic biochar composite (MBCC) derived from Heglig tree bark (HTB) powder (agricultural solid waste) and cobalt ferrite (CoFe2O4, CFO) for oil spill removal from seawater surface.

Design/methodology/approach

One-pot co-precipitation route was used to synthesize MBCC. The prepared materials were characterized by X-ray diffraction, scanning electron microscopy-energy dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy. The densities of the prepared materials were also estimated. Crude, diesel engine and gasoline engine oils were used as seawater pollutant models. The gravimetric oil removal (GOR) method was used for removing oil spills from seawater using MBCC as a sorbent material.

Findings

The obtained results revealed that the prepared materials (CFO and MBCC) were able to remove the crude oil and its derivatives from the seawater surface. Besides, when the absorbent amount was 0.01 g, the highest GOR values for crude oil (31.96 ± 1.02 g/g) and diesel engine oil (14.83 ± 0.83 g/g) were obtained using MBCC as an absorbent. For gasoline engine oil, the highest GOR (27.84 ± 0.46 g/g) was attained when CFO was used as an absorbent.

Originality/value

Oil spill removal using MBCC derived from cobalt ferrite and HTB. Using tree bark as biomass (eco-friendly, readily available and low-cost) for magnetic biochar preparation also is a promising method for minimizing agricultural solid wastes (e.g. HTB) and obtaining value-added-products.
The assessment of structural behaviours of steel framing system – affordable house system design
Authors: Hashim Nor Salwani , De’nan Fatimah , Naaim Nurfarhah
Published: September 2023

Purpose

Nowadays, residential buildings have become increasingly important due to the growing communities. The purpose of this study is to investigate the behavior of a steel structural framing system that incorporates lightweight load-bearing walls and slabs, and to compare the weight of materials used in cold-formed and hot-finished steel structural systems for affordable housing.

Design/methodology/approach

Four types of models consisting of 243 members were simulated. Model 1 is a cold-formed steel structural framing system, while Model 2 is a hot-finished steel structural framing system. Both Models 1 and 2 use lightweight wall panels and lightweight composite slabs. Models 3 and 4 are made with brick walls and precast reinforced concrete systems, respectively. These structures use different wall and slab materials, namely, brick walls and precast reinforced concrete. The analysis includes bending behavior, buckling resistance, shear resistance and torsional rotation analysis.

Findings

This study found that using thinner steel sections can increase the deflection value. Meanwhile, increasing member length and the ratio of slenderness will decrease buckling resistance. As the applied load increases, buckling deformation also increases. Furthermore, decreasing shear area causes a reduction in shear resistance. Thicker sections and the use of lightweight materials can decrease the torsional rotation value.

Originality/value

The weight comparison of the steel structures shows that Model 1, which is a cold-formed steel structure with lightweight wall panels and lightweight composite slabs, is the most suitable model due to its lightweight and affordability for housing. This model can also be used as a reference for the optimal design of modular structural framing using cold-formed steel materials in the field of civil engineering and as a promotional tool.
THE URBAN LEFT IN POWER: Comparing the Profiles of ‘Municipal Socialists’ and the ‘New Urban Left’ in Swiss Cities
Authors: Antoniazza Baptiste , Mach André , Strebel Michael Andrea
Published: September 2023

Today, many cities in post‐industrial societies are strongholds of left and progressive political forces. Almost 100 years ago, left parties had instituted municipal socialism in several European cities. In this article, we compare these two periods of left urban rule by focusing on the long‐term changes over the last 120 years in the socio‐demographic profile of urban left elites in four major Swiss cities. Our analysis of left elected representatives at six key dates highlights the main differences between the municipal socialists of the interwar period and the new urban left that rules contemporary cities. The former are members of the working class, blue‐collar workers without university education, while the latter are members of the upper‐middle class, highly educated sociocultural professionals. The results of our analysis contribute to a better understanding of the sociological composition of urban left‐progressive political forces, an aspect that is somewhat neglected in recent research on the urban left. We discuss the potential political implications and further research avenues for contemporary debates in urban studies, in terms of urban policy priorities and political mobilization.