bluuebunny/crossref_metadata_2025 huggingface dataset:
Low gH/gL (sub)species-specific antibody levels indicate elephants at risk of fatal elephant endotheliotropic herpesvirus hemorrhagic disease
Authors: Hoornweg Tabitha E. , Schaftenaar Willem , Rutten Victor P.M.G. , de Haan Cornelis A.M.
Published: June 2023

Elephant endotheliotropic herpesviruses (EEHVs), of which seven species and multiple subspecies are currently distinguished, naturally infect either Asian (Elephas maximus) or African elephants (Loxodontaspecies). While all adult elephants are latently infected with at least one EEHV (sub)species, EEHV infections in young elephants may lead to acute, fatal hemorrhagic disease (EEHV-HD). The disease is primarily observed in calves with low to non-detectable EEHV-specific antibodies, suggesting it is the result of an uncontrolled primary infection. Yet, young elephants showing high antibody levels in serological assays based on EEHV(1A) gB, which detect antibodies against multiple EEHV (sub)species, are not necessarily protected against EEHV-HD. To better determine which animals are at risk of EEHV-HD, we developed gB and gH/gL ELISAs for all Asian elephant EEHV (sub)species and assessed their specificity using 396 sera from 164 Asian elephants kept in Europeans zoos. Antibody levels measured against gB of different EEHV (sub)species correlated strongly with one another, indicating gB-specific antibodies are highly cross-reactive. In contrast, antibody responses towards gH/gL of different EEHV (sub)species were far less correlated and could be used to distinguish between infections with different (sub)species. Subsequently, antibody responses in sera of 23 EEHV-HD fatalities were analyzed. Whereas high antibody levels against gB could be detected in sera of multiple EEHV-HD fatalities, all fatalities had low antibody levels against gH/gL of the EEHV (sub)species they succumbed to. Overall, our data indicate that (sub)species-specific gH/gL ELISAs may be used to identify animals at risk of developing EEHV-HD upon infection with a particular EEHV (sub)species.
HSP90 inhibitor NVP-HSP990 alleviates rotavirus infection
Authors: Cao Yi , Zhu Qingmin , Wu Xiaoping , Xie Zhunyi , Yang Chengying , Guo Yanyan , Meng Dongwei , Zhou Xinyuan , Wu Yuzhang , Li Jintao , He Haiyang
Published: June 2023

Rotavirus (RV) infection is a significant cause of hospitalization and mortality in infants and young children. Although conventional symptomatic treatments usually appear effective, tens of thousands of infants and young children still die each year due to the absence of safe and effective anti-RV drugs. Heat shock protein 90 (HSP90) is usually required for efficient viral infection; however, due to unsatisfactory antiviral efficacy and toxicity, there has been no HSP90-targeting agents applied for clinical antiviral therapy currently. Here, we demonstrated that NVP-HSP990, a novel small-molecule HSP90 inhibitor with excellent oral bioavailability and brain penetration, was a potent inhibitor of RV infection with much bigger selectivity index (SI) than traditional HSP990 inhibitors. NVP-HSP990 potently inhibited RV replicationin vitrowithout blocking infection establishment. NVP-HSP990 remarkably restored gene expressions of most KEGG pathways disturbed by RV infection in intestinal cells, except some inflammatory pathways (IL-17, TNF, etc.). To be noted, NVP-HSP990 significantly altered gene expressions in MAPK signaling pathway and inhibited RV-induced activation of MAPK as well as disruption of tight junctions in Caco-2 cells. More importantly, NVP-HSP990 effectively alleviated RV diarrhea, competently inhibited RV replication, and obviously prevented pathological lesions of intestine in BALB/c suckling mice. Therefore, our results suggested that NVP-HSP990 can be a promising antiviral drug candidate against RV infection.
Genome-resolved meta-omics unveils rock-hosted lifestyle of enigmatic DPANN archaea
Authors: Takamiya Hinako , Kouduka Mariko , Kato Shingo , Suga Hiroki , Oura Masaki , Yokoyama Tadashi , Suzuki Michio , Mori Masaru , Kanai Akio , Suzuki Yohey
Published: June 2023

Recent successes in the cultivation of DPANN archaea with their hosts have demonstrated an episymbiotic lifestyle, whereas the lifestyle of DPANN archaea in natural habitats remains controversial. A free-living lifestyle is speculated in oxygen-deprived fluids circulated through rock fractures, where apparent hosts of DPANN archaea are lacking. Alternatively, DPANN archaea may be isolated from their hosts attached to rock surfaces. To understand the ecology of rock-hosted DPANN archaea, rocks rather than fluids should be directly characterized. Here, we show the dominance of Pacearchaeota, one of the widespread and enigmatic lineages of DPANN archaea, in a deep-sea hydrothermal vent chimney. Metagenomic analysis of the rock sample revealed a symbiotic lifestyle of the chimney Pacearchaeota, based on the lack of biosynthetic genes for nucleotides, amino acids, cofactors, and lipids. Genome-resolved metaproteomic analysis clarified the co-occurrence of bacteria actively fixing carbon and nitrogen and thermophilic archaea in the rock habitat. Pacearchaeota has ecological advantages in colonizing the chimney rock interior, because the availability of nutrients and space is limited by silica deposition from hydrothermal fluids. We propose that the diversification of rock-hosted DPANN archaea could be profoundly influenced by coexisting microbes and minerals.
DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2
Authors: Bjarnason Sveinn , McIvor Jordan A.P. , Prestel Andreas , Demény Kinga S. , Bullerjahn Jakob T. , Kragelund Birthe B. , Mercadante Davide , Heidarsson Pétur O.
Published: June 2023

More than 1600 human transcription factors orchestrate the transcriptional machinery to control gene expression and cell fate. Their function is conveyed through intrinsically disordered regions (IDRs) containing activation or repression domains but lacking quantitative structural ensemble models prevents their mechanistic decoding. Here we integrate single-molecule FRET and NMR spectroscopy with molecular simulations showing that DNA binding can lead to complex changes in the IDR ensemble and accessibility. The C-terminal IDR of pioneer factor Sox2 is highly disordered but its conformational dynamics are guided by weak and dynamic charge interactions with the folded DNA binding domain. Both DNA and nucleosome binding induce major rearrangements in the IDR ensemble without affecting DNA binding affinity. Remarkably, interdomain interactions are redistributed in complex with DNA leading to variable exposure of two activation domains critical for transcription. Charged intramolecular interactions allowing for dynamic redistributions may be common in transcription factors and necessary for sensitive tuning of structural ensembles.
A scalable platform for efficient CRISPR-Cas9 chemical-genetic screens of DNA damage-inducing compounds
Authors: Lin Kevin , Chang Ya-Chu , Billmann Maximilian , Ward Henry N. , Le Khoi , Hassan Arshia , Bhojoo Urvi , Chan Katherine , Costanzo Michael , Moffat Jason , Boone Charles , Bielinsky Anja-Katrin , Myers Chad L.
Published: June 2023

Current approaches to define chemical-genetic interactions (CGIs) in human cell lines are resource-intensive. We designed a scalable chemical-genetic screen platform by generating a DNA damage response (DDR)-focused custom sgRNA library. We performed five proof-of-principle compound screens and found that the compounds’ known modes-of-action (MoA) were enriched among the compounds’ CGIs. These scalable screens recapitulated expected CGIs at a comparable signal-to-noise ratio (SNR) relative to genome-wide screens. Furthermore, time-resolved CGIs, captured by sequencing screens at various time points, suggested an unexpected, late time point interstrand-crosslinking (ICL) repair pathway response to camptothecin-induced DNA damage. Our approach can facilitate screening compounds at scale and produce biologically informative CGI profiles.
Screening for variable drug responses using human iPSC cohorts
Authors: Platani Melpomeni , Jiang Hao , Davidson Lindsay , Hariharan Santosh , Doyonnas Regis , Lamond Angus I. , Swedlow Jason R.
Published: June 2023

We have developed a laboratory-based drug screening platform that uses a cohort of human induced pluripotent stem cell (hiPSC) lines, derived from different donors, to predict variable drug responses of potential clinical relevance. This builds on recent findings that pluripotent hiPSC lines express a broad repertoire of gene transcripts and proteins, whose expression levels reflect the genetic identity of the donor. We demonstrate that a cohort of hiPSC lines from different donors can be screened efficiently in their pluripotent state, using high-throughput Cell Painting assays. Variable phenotypic responses between hiPSC lines were detected with a wide range of clinically approved drugs, in use across multiple disease areas. Furthermore, information on mechanisms of drug-cell interactions underlying the observed variable responses was derived by using quantitative proteomic analysis to compare sets of hiPSC lines that had been stratified objectively, based upon variable response, Cell Painting data. We propose that information derived from comparative drug screening, using curated libraries of hiPSC lines from different donors, can help to improve the delivery of safe new drugs suitable for a broad range of genetic backgrounds and sexual diversity within human populations.
Supraclavicular brown adipocytes originate fromTbx1+myoprogenitors
Authors: Huang Zan , Gu Chenxin , Zhang Zengdi , Arianti Rini , Swaminathan Aneesh , Tran Kevin , Battist Alex , Kristóf Endre , Ruan Hai-Bin
Published: June 2023

Brown adipose tissue (BAT) dissipates energy as heat, contributing to temperature control, energy expenditure, and systemic homeostasis. In adult humans, BAT mainly exists in supraclavicular areas and its prevalence is associated with cardiometabolic health. However, the developmental origin of supraclavicular BAT remains unknown. Here, using genetic fate mapping in mice, we demonstrate that supraclavicular brown adipocytes do not develop from thePax3+/Myf5+epaxial dermomyotome that gives rises to interscapular BAT. Instead, theTbx1+lineage that specifies the pharyngeal mesoderm marks the majority of supraclavicular brown adipocytes.Tbx1Cre-mediated ablation of peroxisome proliferator-activated receptor gamma (PPARγ) or PR/SET Domain 16 (PRDM16), components of the transcriptional complex for brown fat determination, leads to supraclavicular BAT paucity or dysfunction, thus rendering mice more sensitive to cold exposure. Moreover, human deep neck BAT expresses higher levels of theTBX1gene than subcutaneous neck white adipocytes. Taken together, our observations reveal location-specific developmental origins of BAT depots and call attention toTbx1+lineage cells when investigating human relevant supraclavicular BAT.
Cochaperones convey the energy of ATP hydrolysis for directional action of Hsp90
Authors: Vollmar Leonie , Schimpf Julia , Hermann Bianca , Hugel Thorsten
Published: June 2023

The molecular chaperone and heat shock protein Hsp90 is part of many protein complexes in eukaryotic cells. Together with its cochaperones, Hsp90 is responsible for the maturation of hundreds of clients. Although having been investigated for decades, it still is largely unknown which components are necessary for a functional complex and how the energy of ATP hydrolysis is used to enable cyclic operation. Here we use single-molecule FRET to show how cochaperones introduce directionality into Hsp90’s conformational changes during its interaction with the client kinase Ste11. Most interestingly, three cochaperones are needed to couple ATP turnover to these conformational changes. All three are therefore essential for a functional cyclic operation, which requires coupling to an energy source. Finally, our findings show how the formation of sub-complexes in equilibrium followed by a directed selection of the functional complex can be the most energy efficient pathway for kinase maturation.
Borrelia PeptideAtlas: A proteome resource of commonBorrelia burgdorferiisolates for Lyme research
Authors: Reddy Panga Jaipal. , Sun Zhi , Wippel Helisa H. , Baxter David , Swearingen Kristian , Shteynberg David D. , Midha Mukul K. , Caimano Melissa J. , Strle Klemen , Choi Yongwook , Chan Agnes P. , Schork Nicholas J. , Moritz Robert L.
Published: June 2023

Lyme disease, caused by an infection with the spirocheteBorrelia burgdorferi, is the most common vector-borne disease in North America.B. burgdorferistrains harbor extensive genomic and proteomic variability and further comparison is key to understanding the spirochetes infectivity and biological impacts of identified sequence variants. To achieve this goal, both transcript and mass spectrometry (MS)-based proteomics was applied to assemble peptide datasets of laboratory strains B31, MM1, B31-ML23, infective isolates B31-5A4, B31-A3, and 297, and other public datasets, to provide a publicly available Borrelia PeptideAtlas (http://www.peptideatlas.org/builds/borrelia/). Included is information on total proteome, secretome, and membrane proteome of theseB. burgdorferistrains. Proteomic data collected from 35 different experiment datasets, with a total of 855 mass spectrometry runs, identified 76,936 distinct peptides at a 0.1% peptide false-discovery-rate, which map to 1,221 canonical proteins (924 core canonical and 297 noncore canonical) and covers 86% of the total base B31 proteome. The diverse proteomic information from multiple isolates with credible data presented by the Borrelia PeptideAtlas can be useful to pinpoint potential protein targets which are common to infective isolates and may be key in the infection process.
Inhibition of the Notch signal transducer CSL by Pkc53E-mediated phosphorylation to fend off parasitic immune challenge inDrosophila
Authors: Deichsel Sebastian , Frankenreiter Lisa , Fechner Johannes , Gahr Bernd M. , Zimmermann Mirjam , Mastel Helena , Preis Irina , Preiss Anette , Nagel Anja C.
Published: June 2023

Notch signalling activity regulates hematopoiesis inDrosophilaand vertebrates alike. Parasitoid wasp infestation ofDrosophilalarvae, however, requires a timely downregulation of Notch activity to allow the formation of encapsulation-active blood cells. Here we show that theDrosophilaCSL transcription factor Suppressor of Hairless [Su(H)] is phosphorylated at Serine 269 in response to parasitoid wasp infestation. As this phosphorylation interferes with the DNA-binding of Su(H), it reversibly precludes its activity. Accordingly, phospho-deficientSu(H)S269Amutants are immune compromised. A screen for kinases involved in Su(H) phosphorylation identified Pkc53E, required for normal hematopoiesis as well as for parasitoid immune response. Genetic and molecular interactions support the specificity of the Su(H)-Pkc53E relationship. Moreover, phorbol ester treatment inhibits Su(H) activityin vivoand in human cell culture. We conclude that Pkc53E targets Su(H) during parasitic wasp infestation, thereby remodeling the blood cell population required for wasp egg encapsulation.
Antibodies against Elapidae and Viperidae snake venoms: in vivo neutralization and mechanistic insights
Authors: Kumar Amit , Madni Zaid Kamal , Chaturvedi Shivam , Salunke Dinakar M.
Published: June 2023

Snake envenomation results in a range of clinical sequelae, and effective therapy is yet to be discovered. Anti-snake venom antibodies are being considered as a potent strategy. We developed venom-neutralizing humanized antibody scFvs and elucidated biochemical and structural mechanisms associated with the inhibition of toxicity. Tomlinson I and J human antibody scFv libraries were screened againstNaja najaandEchis carinatusvenoms, and seven unique antibody scFvs were obtained. Further, specific toxins of snake venom interacting with each of these scFvs were identified, and phospholipase A2 (PLA2) was found to be prominently captured by the phage-anchored antibody scFvs. Proteomic analysis of whole venom also revealed PLA2 to be the most abundant toxin in both venom samples. The scFvs binding to PLA2 were used to performin vivosurvival assay using the mouse model andin vitrotoxin inhibition assays. scFv N194, which binds to acidic PLA2, showed considerable survival inNaja najavenom-challenged mice and conferred up to 50% protection. A combination of two scFvs, E113 and E10, both interacting with basic PLA2, exhibited synergistically enhanced survival of 33% inEchis carinatusvenom-challenged mice, compared to 16% survival conferred by an equal amount of individual scFvs. Furthermore, these scFvs demonstrated inhibition of venom-induced myotoxicity and hemolysis which corroborate the survival data. Structural studies highlighted possible modes of PLA2 neutralization by scFv through the engagement of CDRs with C-terminal myotoxic loop and interfacial region, which are crucial for PLA2 toxicity.
High-confidence placement of difficult-to-fit fragments into electron density by using anomalous signals - a case study using hits targeting SARS-CoV-2 non-structural protein 1
Authors: Ma Shumeng , Mykhaylyk Vitaliy , Bowler Matthew W. , Pinotsis Nikos , Kozielski Frank
Published: June 2023

The identification of multiple simultaneous orientations of small molecule inhibitors binding to a protein target is a common challenge. It has recently been reported that the conformational heterogeneity of ligands is widely underreported in the Protein Data Bank, which is likely to impede optimal exploitation to improve affinity of these ligands1. Significantly less is even known about multiple binding orientations for fragments (< 300 Da) although this information would be essential for subsequent fragment optimisation using growing, linking or merging and rational structure-based design. Here we use recently reported fragment hits for the SARS-CoV-2 non-structural protein 1 (nsp1) N-terminal domain to propose a general procedure for unambiguously identifying binding orientations of 2-dimensional fragments containing either sulphur or chloro substituents within the wavelength range of most tunable beamlines. By measuring datasets at two energies, using a tuneable beamline operating in vacuum and optimised for data collection at very low X-ray energies, we show that the anomalous signal can be used to identify multiple orientations in small fragments containing sulphur and/or chloro substituents or to verify recently reported conformations. Although in this specific case we identified the positions of sulphur and chlorine in fragments bound to their protein target, we are confident that this work can be further expanded to additional atoms or ions which often occur in fragments. Finally, our improvements in the understanding of binding orientations will also serve to advance the rational optimisation of SARS-CoV-2 nsp1 targeting fragment hits.
Substrates and Cyclic Peptide Inhibitors of the Oligonucleotide Activated SIRT7
Authors: Bolding Julie E. , Nielsen Alexander L. , Jensen Iben , Hansen Tobias N. , Ryberg Line A. , Jameson Samuel T. , Harris Pernille , Peters Günther H. J. , Denu John M. , Rogers Joseph M. , Olsen Christian A.
Published: June 2023

The sirtuins are NAD+-dependent lysine deacylases, comprising seven isoforms (SIRT1–7) in humans, which are involved in the regulation of a plethora of biology, including gene expression and metabolism. The sirtuins share a common hydrolytic mechanism but display preferences for different ε-N-acyllysine substrates. SIRT7 deacetylates targets in nuclei and nucleoli but remains one of the lesser studied of the seven isoforms; in part, because of a lack of chemical tools to specifically probe SIRT7 activity. Here we expressed SIRT7 and, using small-angle X-ray scattering, reveal SIRT7 to be a monomeric enzyme with low degree of globular flexibility in solution. We developed a fluorogenic assay for investigation of the substrate preferences of SIRT7 and to evaluate compounds that modulate its activity. We report several mechanism-based SIRT7 inhibitors as well asde novocyclic peptide inhibitors selected from mRNA-display library screening that exhibit selectivity for SIRT7 over other sirtuin isoforms and stabilize SIRT7 in cells.
Notch signalling influences cell fate decisions and HOX gene induction in axial progenitors
Authors: Cooper Fay , Souilhol Celine , Haston Scott , Gray Shona , Boswell Katy , Gogolou Antigoni , Frith Thomas , Stavish Dylan , James Bethany M , Bose Dan , Dale Jacqueline Kim , Tsakiridis Anestis
Published: June 2023

The generation of the post-cranial embryonic body relies on the coordinated production of spinal cord neurectoderm and presomitic mesoderm cells from neuromesodermal progenitors (NMPs). This process is orchestrated by pro-neural and pro-mesodermal transcription factors that are co-expressed in NMPs together with Hox genes, which are critical for axial allocation of NMP derivatives. NMPs reside in a posterior growth region, which is marked by the expression of Wnt, FGF and Notch signalling components. While the importance of Wnt and FGF in influencing the induction and differentiation of NMPs is well established, the precise role of Notch remains unclear. Here, we show that the Wnt/FGF-driven induction of NMPs from human embryonic stem cells (hESCs) relies on Notch signalling. Using hESC-derived NMPs and chick embryo grafting, we demonstrate that Notch directs a pro-mesodermal character at the expense of neural fate. We show that Notch also contributes to activation ofHOXgene expression in human NMPs, partly in a non cell-autonomous manner. Finally, we provide evidence that Notch exerts its effects via the establishment of a negative feedback loop with FGF signalling.
Structure and dynamics of differential ligand binding in the human ρ-type GABAAreceptor
Authors: Cowgill John , Fan Chen , Haloi Nandan , Tobiasson Victor , Zhuang Yuxuan , Howard Rebecca J. , Lindahl Erik
Published: June 2023

The neurotransmitter γ-aminobutyric acid (GABA) drives critical inhibitory processes in and beyond the nervous system, partly via ionotropic type-A receptors (GABAARs). Pharmacological properties of ρ-type GABAARs are particularly distinctive, yet the structural basis for their specialization remains unclear. Here we present cryo-EM structures of a lipid-embedded human ρ1 GABAAR, including a partial intracellular domain, under apo, inhibited, and desensitized conditions. An apparent resting state, determined first in the absence of modulators, was recapitulated with the specific inhibitor (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid and blocker picrotoxin, and provided a rationale for bicuculline insensitivity. Comparative structures, mutant recordings, and molecular simulations with and without GABA further explained the sensitized but slower activation of ρ1 relative to canonical subtypes. Combining GABA with picrotoxin also captured an apparent uncoupled intermediate state. This work reveals structural mechanisms of gating and modulation with applications to ρ-specific pharmaceutical design, and to our biophysical understanding of ligand-gated ion channels.
Mapping the architecture of the initiating phosphoglycosyl transferase fromS. entericaO-antigen biosynthesis in a liponanoparticle
Authors: Dodge Greg J. , Anderson Alyssa J. , He Yi , Liu Weijing , Viner Rosa , Imperiali Barbara
Published: June 2023

Bacterial cell surface glycoconjugates are critical for cell survival and for interactions between bacteria and their hosts. Consequently, the pathways responsible for their biosynthesis have untapped potential as therapeutic targets. The localization of many glycoconjugate biosynthesis enzymes to the membrane represents a significant challenge for expressing, purifying, and characterizing these enzymes. Here, we leverage cutting-edge methods to stabilize, purify, and structurally characterize WbaP, a phosphoglycosyl transferase (PGT) fromSalmonella enterica(LT2) O-antigen biosynthesis without detergent solubilization from the lipid bilayer. From a functional perspective, these studies establish WbaP as a homodimer, reveal the structural elements responsible for oligomerization, shed light on the regulatory role of a domain of unknown function embedded within WbaP, and identify conserved structural motifs between PGTs and functionally unrelated UDP-sugar dehydratases. From a technological perspective, the strategy developed here is generalizable and provides a toolkit for studying small membrane proteins embedded in liponanoparticles beyond PGTs.
Changing protein-DNA interactions promote ORC binding site exchange during replication origin licensing
Authors: Zhang Annie , Friedman Larry J. , Gelles Jeff , Bell Stephen P
Published: June 2023

During origin licensing, the eukaryotic replicative helicase Mcm2-7 forms head-to-head double hexamers to prime origins for bidirectional replication. Recent single-molecule and structural studies revealed that one molecule of the helicase loader ORC can sequentially load two Mcm2-7 hexamers to ensure proper head-to-head helicase alignment. To perform this task, ORC must release from its initial high-affinity DNA binding site and “flip” to bind a weaker, inverted DNA site. However, the mechanism of this binding-site switch remains unclear. In this study, we used single-molecule Förster resonance energy transfer (sm-FRET) to study the changing interactions between DNA and ORC or Mcm2-7. We found that the loss of DNA bending that occurs during DNA deposition into the Mcm2-7 central channel increases the rate of ORC dissociation from DNA. Further studies revealed temporally-controlled DNA sliding of helicase-loading intermediates, and that the first sliding complex includes ORC, Mcm2-7, and Cdt1. We demonstrate that sequential events of DNA unbending, Cdc6 release, and sliding lead to a stepwise decrease in ORC stability on DNA, facilitating ORC dissociation from its strong binding site during site switching. In addition, the controlled sliding we observed provides insight into how ORC accesses secondary DNA binding sites at different locations relative to the initial binding site. Our study highlights the importance of dynamic protein-DNA interactions in the loading of two oppositely-oriented Mcm2-7 helicases to ensure bidirectional DNA replication.

Significance Statement

Bidirectional DNA replication, in which two replication forks travel in opposite directions from each origin of replication, is required for complete genome duplication. To prepare for this event, two copies of the Mcm2-7 replicative helicase are loaded at each origin in opposite orientations. Using single-molecule assays, we studied the sequence of changing protein-DNA interactions involved in this process. These stepwise changes gradually reduce the DNA-binding strength of ORC, the primary DNA binding protein involved in this event. This reduced affinity promotes ORC dissociation and rebinding in the opposite orientation on the DNA, facilitating the sequential assembly of two Mcm2-7 molecules in opposite orientations. Our findings identify a coordinated series of events that drive proper DNA replication initiation.
The principles of peptide selection by the transporter associated with antigen processing
Authors: Lee James , Oldham Michael L. , Manon Victor , Chen Jue
Published: June 2023

The adaptive immune response eliminates infected and cancer cells through the recognition of antigenic peptides displayed by major compatibility complex class I (MHC-I) molecules1, 2. A single transporter, the transporter associated with antigen processing (TAP), supplies nearly the entire peptide repertoire for the many MHC-I alleles3–5. A fundamental unresolved question is how TAP transports peptides with vast sequence diversity. Here, using cryo-electron microscopy (cryo-EM), we determined seven structures of human TAP in the presence and absence of peptides with different sequences and lengths. We observe that peptides are suspended in the transmembrane cavity of TAP with the peptide N-and C-termini anchored at two distal binding pockets. The central residues of the peptide are unrestricted, making few contacts with TAP. A minimum of eight residues is required to bridge the two binding pockets, aligning with the lower length limit for MHC-I binding6, 7. Mutations in TAP that disrupt hydrogen bonds with the peptide termini nearly abolish MHC-I surface expression, indicating that binding depends on interactions with mainchain atoms at the two termini. By utilizing two spatially separated binding pockets and concentrating interactions at the two ends of the peptide, TAP functions as a molecular caliper, selecting peptides for length while permitting sequence diversity.
Mitochondrial genomes of Pleistocene megafauna retrieved from recent sediment layers of two Siberian lakes
Authors: Seeber PA , Batke L , Dvornikov Y , Schmidt A , Wang Y , Stoof-Leichsenring KR , Moon KL , Vohr SH , Shapiro B , Epp LS
Published: June 2023

Ancient environmental DNA (aeDNA) from lake sediments has yielded remarkable insights for the reconstruction of past ecosystems, including suggestions of late survival of extinct species. However, translocation and lateral inflow of DNA in sediments can potentially distort the stratigraphic signal of the DNA. Using three different approaches on two short lake sediment cores of the Yamal peninsula, West Siberia, with ages spanning only the past hundreds of years, we detect DNA and identified mitochondrial genomes of multiple mammoth and woolly rhinoceros individuals—both species that have been extinct for thousands of years on the mainland. The occurrence of clearly identifiable aeDNA of extinct Pleistocene megafauna (e.g., > 400K reads in one core) throughout these two short subsurface cores, along with specificities of sedimentology and dating, confirm that processes acting on regional scales, such as extensive permafrost thawing, can influence the aeDNA record and should be accounted for in aeDNA paleoecology.
Leveraging the Adolescent Brain Cognitive Development Study to improve behavioral prediction from neuroimaging in smaller replication samples
Authors: Makowski Carolina , Brown Timothy T. , Zhao Weiqi , Hagler Donald J. , Parekh Pravesh , Garavan Hugh , Nichols Thomas E. , Jernigan Terry L. , Dale Anders M.
Published: June 2023

Magnetic resonance imaging (MRI) is a popular and useful non-invasive method to map patterns of brain structure and function to complex human traits. Recently published observations in multiple large scale studies cast doubt upon these prospects, particularly for prediction of cognitive traits from structural and resting state functional MRI, which seems to account for little behavioral variability. We leverage baseline data from thousands of children in the Adolescent Brain Cognitive DevelopmentSM(ABCD®) Study to inform the replication sample size required with both univariate and multivariate methods across different imaging modalities to detect reproducible brain-behavior associations. We demonstrate that by applying multivariate methods to high-dimensional brain imaging data, we can capture lower dimensional patterns of structural and functional brain architecture that correlate robustly with cognitive phenotypes and are reproducible with only 41 individuals in the replication sample for working memory-related functional MRI, and ∼100 subjects for structural MRI. Even with 100 random re-samplings of 50 subjects in the discovery sample, prediction can be adequately powered with 98 subjects in the replication sample for multivariate prediction of cognition with working memory task functional MRI. These results point to an important role for neuroimaging in translational neurodevelopmental research and showcase how findings in large samples can inform reproducible brain-behavior associations in small sample sizes that are at the heart of many investigators’ research programs and grants.
Deciphering Phage-Host Specificity Based on the Association of Phage Depolymerases and Bacterial Surface Glycan with Deep Learning
Authors: Yang Yiyan , Dufault-Thompson Keith , Yan Wei , Cai Tian , Xie Lei , Jiang Xiaofang
Published: June 2023

Phage tailspike proteins are depolymerases that target diverse bacterial surface glycans with high specificity, determining the host-specificity of numerous phages. To address the challenge of identifying tailspike proteins due to their sequence diversity, we developed SpikeHunter, an approach based on the ESM-2 protein language model. Using SpikeHunter, we successfully identified 231,965 tailspike proteins from a dataset comprising 8,434,494 prophages found within 165,365 genomes of five common pathogens. Among these proteins, 143,035 tailspike proteins displayed strong associations with serotypes. Moreover, we observed highly similar tailspike proteins in species that share closely related serotypes. We found extensive domain swapping in all five species, with the C-terminal domain being significantly associated with host serotype highlighting its role in host range determination. Our study presents a comprehensive cross-species analysis of tailspike protein to serotype associations, providing insights applicable to phage therapy and biotechnology.
Scalable covariance-based connectivity inference for synchronous neuronal networks
Authors: Kim Taehoon , Chen Dexiong , Hornauer Philipp , Kumar Sreedhar Saseendran , Schröter Manuel , Borgwardt Karsten , Hierlemann Andreas
Published: June 2023

We present a novel method for inferring connectivity from large-scale neuronal networks with synchronous activity. Our approach leverages Dynamic Differential Covariance to address the associated computational challenges. First, we analyze spike trains generated from Leaky Integrate-and-Fire network simulations and evaluate the performance of several off-the-shelf multivariate connectivity inference methods. Next, we introduce a new approach, Fractional Dynamic Differential Covariance (FDDC), and demonstrate that it consistently outperforms the other methods. Finally, we apply FDDC to experimental data to assess the topological organization of inferred graphs of in vitro neural network recordings obtained using high-density microelectrode arrays (HD-MEAs). Our results indicate that FDDC-derived graphs exhibit a significant negative correlation between small-worldness and measures of network synchrony. In contrast, graphs inferred through the well-established pairwise correlation method do not show such a correlation. This finding implies that the graphs obtained through FDDC provide stronger evidence in support of the theoretical notion that networks with clustered connections tend to exhibit higher levels of synchronizability. We hypothesize that our findings have implications for the development of scalable connectivity inference methods for large-scale neural network data.
Good practices in COVID-19 risk reduction adopted by Australian construction enterprises
Authors: Seneviratne Krisanthi , Perera Srinath , Ginigaddara Buddhini , Jin Xiaohua , Tang Liyaning , Osei Kyei Robert
Published: June 2023

Purpose

This research investigated the impacts of COVID-19 on construction enterprises and good practices adopted by the enterprises in reducing COVID-19 risks. The Sendai Framework (TSF) is widely accepted as a strategic roadmap to reduce disaster risks throughout the life cycle of a disaster. As such, with the aim of enhancing the resilience of Australian construction enterprises, the identified good practices were mapped with TSF priorities to consolidate COVID-19 risk reduction practices that can be adopted by Australian construction enterprises.

Design/methodology/approach

Case study research approach was used, and three case studies were conducted with small, medium and large construction enterprises. Small, medium and large enterprises were selected based on the Australian Bureau of Statistics classification of the business size. Data were collected through semi-structured interviews conducted with three executive members from the three enterprises. Data were analysed using content analysis.

Findings

The study found that construction enterprises faced demand and supply side impacts. Infrastructure projects, funded by public sector clients and larger enterprises were least affected. Investments and demand for residential and other building projects were reduced by private sector clients, affecting small and medium enterprises. Findings also show that the construction enterprises adopted good practices in identifying, managing, investing on resilience and recovery that align with TSF priorities. All three enterprises agreed on some common good practices on risk identification, risk management and effective recovery. Different views were shared on investments related to disaster resilience.

Practical implications

This study contributes to mitigate the COVID-19 impacts on construction enterprises and subsequent economic and social impacts.

Originality/value

This research found how Australian construction enterprises survived during COVID-19. The study adopted TSF to construction and COVID-19 context while consolidating COVID-19 risk reduction practices.
Prospects, drivers of and barriers to artificial intelligence adoption in project management
Authors: Shang Gao , Low Sui Pheng , Lim Xin Ying Valen
Published: June 2023

Purpose

The rise of artificial intelligence (AI) and differing attitudes towards its adoption in the building and environment (B&E) industry has an impact upon whether companies can meet changing demand and remain relevant and competitive. The emergence of Industry 4.0 technologies, coupled with the repercussions of COVID-19, increases the urgency and opportunities offered that companies must react to, as disruptive technologies impact how project management (PM) professionals work and necessitate acquisition of new skills. This paper attempts to identify the drivers of and barriers to, as well as the general perception and receptiveness of local PM professionals towards, AI adoption in PM and thereby propose potential strategies and recommendations to drive AI adoption in PM.

Design/methodology/approach

This study employs both quantitative and qualitative approaches to examine the findings gathered. A survey questionnaire was used as the primary method of gathering quantitative data from 60 local PM professionals. Statistical tests were performed to analyse the data. To substantiate and validate the findings, in-depth interviews with several experienced industry professionals were performed.

Findings

It is found that top drivers include support from top management and leadership, organisational readiness and the need for greater work productivity and efficiency. Top barriers were found to be the high cost of AI implementation and maintenance and the lack of top-down support and skilled employees trained in AI. These findings could be attributed to the present state of AI technologies being new and considerably underutilised in the industry. Hence, substantial top-down support with the right availability of resources and readiness, both in terms of cost and skilled employees, is paramount to kick-start AI implementation in PM.

Originality/value

Little research has been done on the use of AI in PM locally. AI's potential to improve the productivity and efficiency of PM processes in the B&E industry cannot be overlooked. An understanding of the drivers of, barriers to and attitudes towards AI adoption can facilitate more intentional and directed oversight of AI's strategic roll-out at both the governmental and corporate levels and thus mitigate potential challenges that may hinder the implementation process in the future.
The growth effects of financial integration in the ASEAN countries
Authors: Vo Duc Hong , Ho Chi Minh
Published: June 2023

Purpose

Financial integration has played an essential role in achieving economic growth in the members of the Association of Southeast Asian Nations (ASEAN). However, its effects on economic growth in the region in the long run have been underexamined. This paper examines these effects for the ASEAN member countries.

Design/methodology/approach

A fully modified ordinary least squares (FMOLS) estimation is used to take into account two critical econometric issues in panel data analysis, including (1) cross-sectional dependence and (2) slope heterogeneity. The dynamic ordinary least squares estimation is also used for robustness analysis. The authors use the generalized least squares estimation to examine the effects in the short run.

Findings

This study’s empirical results confirm the important role of financial integration to economic growth in the ASEAN countries in the short term. However, the effects appear to disappear in the long term. The authors also find capital, labor, and human development positively contribute to economic growth in the region. International trade plays a significant role in supporting economic growth in the ASEAN in the short run. However, its effect seems to weaken in the long run.

Originality/value

The growth effects of financial integration in the ASEAN region in the long term have largely been neglected. As such, the authors examine these effects using updated data on financial integration. The authors extend this study’s analysis by considering foreign direct investment and financial depth as the alternative proxies for financial integration. Other estimation technique is also used as the robustness check.
The propensity towards indebtedness and savings behaviour of undergraduate students: the moderating role of financial literacy
Authors: Owusu Godfred Matthew Yaw , Ossei Kwakye Teddy , Duah Henry
Published: June 2023

Purpose

This study investigates how students' propensity towards indebtedness affects their savings behaviour. Additionally, the study examines the moderating role of financial literacy in the relationship between propensity towards indebtedness and savings behaviour.

Design/methodology/approach

Questionnaires were administered to undergraduate students from the University of Ghana Business School. A total of 370 valid responses were used in the empirical analysis. The hypothesised relationships were tested using partial least square – structural equation modelling.

Findings

The structural model results suggest that students' propensity towards indebtedness is negatively related to their savings behaviour. Further, the results demonstrate that financial literacy moderates the negative association between students' propensity towards debt and savings behaviour.

Originality/value

This study highlights students' propensity towards indebtedness and how it impacts their savings behaviour.
Hybrids and heritage resources: rethinking the social foundation of historic environment records in England
Authors: Illsley William R.
Published: June 2023

Purpose

By reconsidering the concept of the historic environment, the aim of this study is to better understand how heritage is expressed by examining the networks within which the cultural performances of the historic environment take place. The goal is to move beyond a purely material expression and seek the expansion of the cultural dimension of the historic environment.

Design/methodology/approach

Conceptually, the historic environment is considered a valuable resource for heritage expression and exploration. The databases and records that house historic environment data are venerated and frequented entities for archeologists, but arguably less so for non-specialist users. In inventorying the historic environment, databases fulfill a major role in the planning process and asset management that is often considered to be more than just perfunctory. This paper approaches historic environment records (HERs) from an actor network perspective, particularizing the social foundation and relationships within the networks governing the historic environment and the environment's associated records.

Findings

The paper concludes that the performance of HERs from an actor-network perspective is a hegemonic process that is biased toward the supply and input to and from professional users. Furthermore, the paper provides a schematic for how many of the flaws in heritage transmission have come about.

Originality/value

The relevance here is largely belied by the fact that HERs as both public digital resources and as heritage networks were awaiting to be addressed in depth from a theoretical point of view.
Trade in value-added in developing countries: Does monetary policy matter?
Authors: Okah Efogo Françoise , Epo Boniface Ngah
Published: June 2023

Purpose

This paper appraises the effects of monetary policy on trade in value-added (TiVA) using a panel of 38 developing countries spanning the period 1990 to 2019. Specifically, the authors subsequently summon the theory of trade in intermediate products within the New Keynesian framework for open economies that comprises price rigidity to verify this relationship and thereon control for robustness by correcting for endogeneity and unbalanced panel effect.

Design/methodology/approach

The authors mobilize the within estimator corrected for cross sectional dependence as well as the two-stage-least squares fixed effect estimator which corrects for endogeneity. For robustness, the authors also use the Hausman–Taylor estimator to control for endogeneity and random effects in annualized data and the least squares dummy variable corrected estimator.

Findings

Results suggest that the monetary policy instruments such as inflationary gaps and anticipatory inflationary outcomes significantly affect TiVA in developing countries only in the short term with no long-term effect. In addition to contributing to the scanty empirical literature, the authors provide relevant insights on monetary policy tools that can be mobilized in fashioning a global value chain penetration and upgrading strategies.

Originality/value

The authors convoke the theory of trade in intermediate products casted into the New Keynesian framework comprising price rigidity to verify the relationship between TiVA and monetary policy (b) verify for robustness by correcting for endogeneity and unbalanced panel effect.
Supervisor incivility and counterproductive work behavior: the role of job and personal resources
Authors: Naeem Rana Muhammad , Weng Qingxiong (Derek) , Hameed Zahid , Arain Ghulam Ali , Islam Zia Ul
Published: June 2023

Purpose

Studies show that supervisor incivility can have detrimental consequences for subordinates. However, little is known about the job and personal resources that can reduce the effect of supervisor incivility on subordinates' counterproductive work behavior (CWB). Based on the Job Demand-Resources (JD-R) model, we investigate social job crafting (job resource) and internal locus of control (LOC; personal resource) as buffers on the relationship between supervisor incivility and subordinates' CWB toward the organization.

Design/methodology/approach

Two field studies to test our proposed hypotheses were conducted. A two-wave time-lagged design was used and data was collected from 115 supervisors and 318 subordinates from a large electricity provider company (study 1) and 121 employee–coworker dyads from a large insurance company (study 2).

Findings

Across the two studies it was found that supervisor incivility positively relates to subordinates' CWB toward the organization. Further, this relationship was weaker for individuals with high internal LOC and those who engaged in social job crafting.

Practical implications

The findings are helpful for HR managers to figure out how to stop supervisor incivility through civility training and motivating employees to social job crafting behavior.

Originality/value

This study implies that social job crafting (job resource) and internal LOC (personal resource) are essential factors that can reduce the effects of supervisor incivility on subordinates' CWB toward the organization.