bluuebunny/crossref_metadata_2025 huggingface dataset:
plasma: Partial LeAst Squares for Multiomics Analysis
Authors: Yamaguchi Kyoko , Abdelbaky Salma , Yu Lianbo , Oakes Christopher C. , Abruzzo Lynne V. , Coombes Kevin R.
Published: March 2023

Recent growth in the number and applications of high-throughput “omics” technologies has created a need for better methods to integrate multiomics data. Much progress has been made in developing unsupervised methods, but supervised methods have lagged behind. We present a novel algorithm,plasma, to learn models to predict time-to-event outcomes from multiomics data sets. Plasma uses two layers of existing partial least squares algorithms to first select components that covary with the outcome and then construct a joint Cox proportional hazards model. We applyplasmato the stomach adenocarcinoma (STAD) data from The Cancer Genome Atlas. We validate the model both by splitting the STAD data into training and test sets and by applying it to the subset of esophageal cancer (ESCA) containing adenocarcinomas. We use the other half of the ESCA data, which contains squamous cell carcinomas dissimilar to STAD, as a negative control. Our model successfully separates both the STAD test set (p = 2.73 × 10−8) and the independent ESCA validation data (p= 0.025) into high risk and low risk patients. It does not separate the negative control data set (ESCA squamous cell carcinomas,p= 0.57). The performance of the joint multiomics model is superior to that of the individually trained models. It is also superior to the performance of an unsupervised method (Multi Omics Factor Analysis; MOFA) that finds latent factors to be used as putative predictors in a post-hoc survival analysis. Many of the factors that contribute strongly to theplasmamodel can be justified from the biological literature.

Significance

To fill the unmet need for supervised multiomics methods, we introduceplasma, an algorithm based on partial least squares that integrates multiomics features into biologically relevant “components” that can predict patient outcomes.

Availability and Implementation

TheplasmaR package can be obtained from The Comprehensive R Archive Network (CRAN) athttps://CRAN.R-project.org/package=plasma. The latest version of the package can always be obtained from R-Forge athttps://r-forge.r-project.org/R/?group_id=1746. Source code and data for the analysis presented here can be obtained from GitLab, athttps://gitlab.com/krcoombes/plasma.

Contact

Email:kcoombes@augusta.edu

Supplementary Information

Supplementary material is available from the journal web site.
Including biotic interactions in species distribution models improves the understanding of species niche: a case of study with the brown bear in Europe
Authors: Lucas Pablo M. , Thuiller Wilfried , Talluto Matthew V. , Polaina Ester , Albrecht Jörg , Selva Nuria , Barba Marta De , Maiorano Luigi , Penteriani Vincenzo , Guéguen Maya , Balkenhol Niko , Dutta Trishna , Fedorca Ancuta , Frank Shane C. , Zedrosser Andreas , Afonso-Jordana Ivan , Ambarlı Hüseyin , Ballesteros Fernando , Bashta Andriy-Taras , Bilgin Cemal Can , Bogdanović Neda , Bojārs Edgars , Bojarska Katarzyna , Bragalanti Natalia , Brøseth Henrik , Chynoweth Mark W. , Ćirović Duško , Ciucci Paolo , Corradini Andrea , Angelis Daniele De , Hernando Miguel de Gabriel , Domokos Csaba , Dutsov Aleksander , Ertürk Alper , Filacorda Stefano , Frangini Lorenzo , Groff Claudio , Heikkinen Samuli , Hoxha Bledi , Huber Djuro , Huitu Otso , Ionescu Georgeta , Ionescu Ovidiu , Jerina Klemen , Jurj Ramon , Karamanlidis Alexandros A. , Kindberg Jonas , Kojola Ilpo , López-Bao José Vicente , Männil Peep , Melovski Dime , Mertzanis Yorgos , Molinari Paolo , Molinari-Jobin Anja , Mustoni Andrea , Naves Javier , Ogurtsov Sergey , Özüt Deniz , Palazón Santiago , Pedrotti Luca , Perović Aleksandar , Piminov Vladimir N. , Pop Ioan-Mihai , Popa Marius , Psaralexi Maria , Quenette Pierre-Yves , Rauer Georg , Reljic Slaven , Revilla Eloy , Saarma Urmas , Saveljev Alexander P. , Sayar Ali Onur , Şekercioğlu Cagan H. , Sergiel Agnieszka , Sîrbu George , Skrbinšek Tomaž , Skuban Michaela , Soyumert Anil , Stojanov Aleksandar , Tammeleht Egle , Tirronen Konstantin , Trajçe Aleksandër , Trbojević Igor , Trbojević Tijana , Zięba Filip , Zlatanova Diana , Zwijacz-Kozica Tomasz , Pollock Laura J.
Published: March 2023

Biotic interactions are expected to influence species’ responses to climate change, but they are usually not included when predicting future range shifts. We assessed the importance of biotic interactions to understand future consequences of climate and land use change for biodiversity using as a model system the brown bear (Ursus arctos) in Europe. By including biotic interactions using the spatial variation of energy contribution and habitat models of each food species, we showed that the use of biotic factors considerably improves our understanding of the distribution of brown bears. Predicted future range shifts, which included changes in the distribution of food species, varied greatly when considering various scenarios of change in biotic factors, warning about future indirect climate change effects. Our study confirmed that advancing our understanding of ecological networks of species interactions will improve future scenarios of biodiversity change, which is key for conserving biodiversity and ecosystem services.
Spatial Transcriptomic Cell-type Deconvolution Using Graph Neural Networks
Authors: Li Yawei , Luo Yuan
Published: March 2023

Spatially resolved transcriptomics performs high-throughput measurement of transcriptomes while preserving spatial information about the cellular organizations. However, many spatially resolved transcriptomic technologies can only distinguish spots consisting of a mixture of cells instead of working at single-cell resolution. Here, we present STdGCN, a graph neural network model designed for cell type deconvolution of spatial transcriptomic (ST) data that can leverage abundant single-cell RNA sequencing (scRNA-seq) data as reference. STdGCN is the first model incorporating the expression profiles from single cell data as well as the spatial localization information from the ST data for cell type deconvolution. Extensive benchmarking experiments on multiple ST datasets showed that STdGCN outperformed 14 published state-of-the-art models. Applied to a human breast cancer Visium dataset, STdGCN discerned spatial distributions between stroma, lymphocytes and cancer cells for tumor microenvironment dissection. In a human heart ST dataset, STdGCN detected the changes of potential endothelial-cardiomyocyte communications during tissue development.
Development and Evaluation of a Machine Learning Recursive Partitioning Decision Tree Algorithm to Optimize Urinalysis Parameters to Predict Urine Culture Positivity
Authors: Seheult Jansen N. , Stram Michelle N. , Contis Lydia , Pontzer Raymond E. , Hardy Stephanie , Wertz William , Baxter Carla M. , Ondras Michael , Kip Paula L. , Snyder Graham M. , Pasculle A. William
Published: March 2023

PittUDT, a recursive partitioning decision tree algorithm for predicting urine culture (UC) positivity based on macroscopic and microscopic urinalysis (UA) parameters, may significantly decrease the number of unnecessary UC. The reflex algorithm derivation included 38,361 paired UA and UC cases; the average patient age was 57.4 years and 70% of samples were from female patients. Receiver operating characteristic (ROC) analysis identified urine WBCs, leukocyte esterase, and bacteria as the best predictors of UC positivity, with area under the ROC curve of 0.79, 0.78, and 0.77, respectively. The test data comprised 9,773 cases, of which 2,571 (26.3%) had a positive UC result. Using the held-out test data set, the PittUDT algorithm met the pre-specified targets of a 30-60% total negative proportion (true negative plus false negative predictions) with a negative predictive value above 90%. These data show that a rule-based algorithm trained on UA data has adequate predictive ability for triaging urine specimens by identifying low risk urine specimens, which are unlikely to grow pathogenic organisms, with a false-negative proportion under 5%. Our study demonstrates the feasibility and performance of using a supervised machine learning approach to develop a human readable machine learning model to optimize UA parameters in a reflex protocol that can be deployed across multiple hospital sites and settings. Our work supports a UA reflex to UC protocol that has the capacity to optimize UA parameters to predict UC positivity and improve antimicrobial stewardship and UC utilization, a potential avenue for cost savings.
Augmentation of a neuroprotective myeloid state by hematopoietic cell transplantation
Authors: Mader Marius Marc-Daniel , Napole Alan , Wu Danwei , Shibuya Yohei , Scavetti Alexa , Foltz Aulden , Atkins Micaiah , Hahn Oliver , Yoo Yongjin , Danziger Ron , Tan Christina , Wyss-Coray Tony , Steinman Lawrence , Wernig Marius
Published: March 2023

Multiple sclerosis (MS) is an autoimmune disease associated with inflammatory demyelination in the central nervous system (CNS). Autologous hematopoietic cell transplantation (HCT) is under investigation as a promising therapy for treatment-refractory MS. Here we identify a reactive myeloid state in chronic experimental autoimmune encephalitis (EAE) mice and MS patients that is surprisingly associated with neuroprotection and immune suppression. HCT in EAE mice leads to an enhancement of this myeloid state, as well as clinical improvement, reduction of demyelinated lesions, suppression of cytotoxic T cells, and amelioration of reactive astrogliosis reflected in reduced expression of EAE- associated gene signatures in oligodendrocytes and astrocytes. Further enhancement of myeloid cell incorporation into the CNS following a modified HCT protocol results in an even more consistent therapeutic effect corroborated by additional amplification of HCT-induced transcriptional changes, underlining myeloid-derived beneficial effects in the chronic phase of EAE. Replacement or manipulation of CNS myeloid cells thus represents an intriguing therapeutic direction for inflammatory demyelinating disease.
Enzymatic Hydroxylation of Aliphatic C-H Bonds by a Mn/Fe Cofactor
Authors: Powell Magan M. , Rao Guodong , Britt R. David , Rittle Jonathan
Published: March 2023

Manganese cofactors activate strong chemical bonds in many essential enzymes. Yet very few manganese-dependent enzymes are known to functionalize ubiquitous carbon-hydrogen (C-H) bonds, and those that catalyze this important reaction display limited intrinsic reactivity. Herein, we report that the 2-aminoisobutyric acid hydroxylase fromRhodococcus wratislaviensisrequires manganese to functionalize a C-H bond possessing a bond dissociation enthalpy (BDE) exceeding 100 kcal/mol. Structural and spectroscopic studies of this enzyme reveal a redox-active, heterobimetallic manganese-iron active site that utilizes a manganese ion at the locus for O2activation and substrate coordination. Accordingly, this enzyme represents the first documented Mn-dependent monooxygenase in biology. Related proteins are widespread in microorganisms suggesting that many uncharacterized monooxygenases may utilize manganese-containing cofactors to accomplish diverse biological tasks.
Determinants of Disordered Protein Co-Assembly Into Discrete Condensed Phases
Authors: Welles Rachel M. , Sojitra Kandarp A. , Garabedian Mikael V. , Xia Boao , Wang Wentao , Guan Muyang , Regy Roshan M. , Gallagher Elizabeth R. , Hammer Daniel A. , Mittal Jeetain , Good Matthew C.
Published: March 2023

Cells harbor numerous mesoscale membraneless compartments that house specific biochemical processes and perform distinct cellular functions. These protein and RNA-rich bodies are thought to form through multivalent interactions among proteins and nucleic acids resulting in demixing via liquid-liquid phase separation (LLPS). Proteins harboring intrinsically disordered regions (IDRs) predominate in membraneless organelles. However, it is not known whether IDR sequence alone can dictate the formation of distinct condensed phases. We identified a pair of IDRs capable of forming spatially distinct condensates when expressed in cells. When reconstituted in vitro, these model proteins do not co-partition, suggesting condensation specificity is encoded directly in the polypeptide sequences. Through computational modeling and mutagenesis, we identified the amino acids and chain properties governing homotypic and heterotypic interactions that direct selective condensation. These results form the basis of physicochemical principles that may direct subcellular organization of IDRs into specific condensates and reveal an IDR code that can guide construction of orthogonal membraneless compartments.
High ResolutionSalmonellaSubtyping by the MLSTnext Method
Authors: Ma Zhihai , Gharizadeh Baback , Huang Steven , Jia Mo , Wu Florence , Wang Chunlin
Published: March 2023

The food industry needs a straightforward, efficient, widely applicable and cost-efficient method to not only detect, but also determine serovar and potential sources of multiple strains in food and environment. While Whole Genome Sequencing (WGS) can generate complete genomic profile of food pathogens, it is a laborious, time-consuming, and expensive method that necessitates pure isolates. As a result, it is unsuitable for samples with complex background, limiting its widespread application by food industry. However, traditional multilocus sequence typing (MLST) approaches do not provide sufficient single nucleotide polymorphism (SNP) information to effectively track- and-trace sources of contamination. In contrast, ChapterDx MLSTnext-NGS (next-generation sequencing)Salmonellaassay amplifies and sequences 47 polymorphic loci, evenly spanning theSalmonella entericagenome. As demonstrated in this study, the ChapterDx MLSTnext-NGSSalmonellacan identify serovar with high resolution, distinguishing between various strains of the same serovar and resolve co-presence of different strains in a single sample. Additionally, this assay can analyze up to thousand samples in a single sequencing run within 22 hours, making it a highly efficient and scalable method for the food industry. Moreover, the cost per sample of the ChapterDx MLSTnext-NGSSalmonellaassay is comparable to that of quantitative Polymerase Chain Reaction (qPCR), making it an affordable option. The assay uses ChapterDx amplification technology, allowing for the amplification of all 47 loci in a single-tube, single-step PCR reaction. This makes it one of the simplest NGS applications available. In summary, ChapterDx MLSTnext-NGSSalmonellaassay can be implemented in many diagnostic laboratories to address increasingly complex food safety issues.
Increased thermostability of an engineered flavin-containing monooxygenase to remediate trimethylamine in fish protein hydrolysates
Authors: Goris Marianne , Cea-Rama Isabel , Puntervoll Pål , Ree Rasmus , Almendral David , Sanz-Aparicio Julia , Ferrer Manuel , Bjerga Gro Elin Kjæreng
Published: March 2023

Protein hydrolysates made from marine by-products are very nutritious, but frequently contain trimethylamine (TMA) which has an unattractive fish-like smell. Bacterial trimethylamine monooxygenases can oxidize TMA into the odorless trimethylamineN-oxide (TMAO) and have been shown to reduce TMA-levels in a salmon protein hydrolysate. To make theMethylophaga aminisulfidivoranstrimethylamine monooxygenase, mFMO, more suitable for industrial application, we engineered it using the Protein Repair One-Stop Shop (PROSS) algorithm. All seven mutant variants, containing 8-28 mutations, displayed increases in melting temperature between 4.7 °C and 9.0 °C. The crystal structure of the most thermostable variant, mFMO_20, revealed the presence of four new stabilizing interhelical salt bridges, each involving a mutated residue. Finally, mFMO_20 significantly outperformed native mFMO in its ability to reduce TMA levels in a salmon protein hydrolysate at industrially relevant temperatures.

Importance

Marine by-products are a high-quality source for peptide ingredients, but the unpleasant fishy odour caused by TMA limits their access to the food market. This problem can be mitigated by enzymatic conversion of TMA into the odourless TMAO. Enzymes isolated from nature must be adapted to industrial requirements, however, such as the ability to tolerate high temperatures. This study has demonstrated that mFMO can be engineered to become more thermostable. Moreover, unlike the native enzyme, the best thermostable variant efficiently oxidized TMA in a salmon protein hydrolysate at industrial temperatures. Our results present an important next step towards application of this novel and highly promising enzyme technology in marine biorefineries.
Structure-Activity Relationships, Tolerability and Efficacy of Microtubule-Active 1,2,4-Triazolo[1,5-a]pyrimidines as Potential Candidates to Treat Human African Trypanosomiasis
Authors: Monti Ludovica , Liu Lawrence J. , Varricchio Carmine , Lucero Bobby , Alle Thibault , Yang Wenqian , Bem-Shalom Ido , Gilson Michael , Brunden Kurt R. , Brancale Andrea , Caffrey Conor R. , Ballatore Carlo
Published: March 2023

Tubulin and microtubules (MTs) are potential protein targets to treat parasitic infections and our previous studies have shown that the triazolopyrimidine (TPD) class of MT- active compounds hold promise as antitrypanosomal agents. MT-targeting TPDs include structurally related but functionally diverse congeners that interact with mammalian tubulin at either one or two distinct interfacial binding sites; namely, the seventh and vinca sites, which are found within or between α,β-tubulin heterodimers, respectively. Evaluation of the activity of 123 TPD congeners against culturedTrypanosoma bruceienabled a robust quantitative structure-activity relationship (QSAR) model and the prioritization of two congeners forin vivopharmacokinetics (PK), tolerability and efficacy studies. Treatment ofT. brucei-infected mice with tolerable doses of TPDs3and4significantly decreased blood parasitemia within 24 h. Further, two once-weekly doses of4at 10 mg/kg significantly extended the survival of infected mice relative to infected animals treated with vehicle. Further optimization of dosing and/or the dosing schedule of these CNS-active TPDs may provide alternative treatments for human African trypanosomiasis.
Control of neuronal excitation-inhibition balance by BMP-SMAD1 signaling
Authors: Okur Zeynep , Schlauri Nadia , Bitsikas Vassilis , Panopoulou Myrto , Ortiz Raul , Schwaiger Michaela , Karmakar Kajari , Schreiner Dietmar , Scheiffele Peter
Published: March 2023

Throughout life, neuronal networks in the mammalian neocortex maintain a balance of excitation and inhibition which is essential for neuronal computation. Deviations from a balanced state have been linked to neurodevelopmental disorders and severe disruptions result in epilepsy. To maintain balance, neuronal microcircuits composed of excitatory and inhibitory neurons sense alterations in neural activity and adjust neuronal connectivity and function. Here, we identified a signaling pathway in the adult mouse neocortex that is activated in response to elevated neuronal network activity. Over-activation of excitatory neurons is signaled to the network through the elevation of BMP2, a growth factor well-known for its role as morphogen in embryonic development. BMP2 acts on parvalbumin-expressing (PV) interneurons through the transcription factor SMAD1, which controls an array of glutamatergic synapse proteins and components of peri-neuronal nets. PV interneuron-specific disruption of BMP2-SMAD1 signaling is accompanied by a loss of PV cell glutamatergic innervation, underdeveloped peri-neuronal nets, and decreased excitability. Ultimately, this impairment of PV interneuron functional recruitment disrupts cortical excitation – inhibition balance with mice exhibiting spontaneous epileptic seizures. Our findings suggest that developmental morphogen signaling is re-purposed to stabilize cortical networks in the adult mammalian brain.
A transcriptome-based phylogeny of Scarabaeoidea confirms the sister group relationship of dung beetles and phytophagous pleurostict scarabs (Coleoptera)
Authors: Dietz Lars , Seidel Matthias , Eberle Jonas , Misof Bernhard , Pacheco Thaynara L. , Podsiadlowski Lars , Ranasinghe Sasanka , Gunter Nicole L. , Niehuis Oliver , Mayer Christoph , Ahrens Dirk
Published: March 2023

Scarab beetles (Scarabaeidae) are a diverse and ecologically important group of angiosperm-associated insects. As conventionally understood, scarab beetles comprise two major lineages: dung beetles and the phytophagous Pleurosticti. However, previous phylogenetic analyses have not been able to convincingly answer the question whether or not the two lineages form a monophyletic group. Here we report our results from phylogenetic analyses of more than 4,000 genes mined from transcriptomes of more than 50 species of Scarabaeidae and other Scarabaeoidea. Our results provide convincing support for the monophyly of Scarabaeidae, confirming the debated sister group relationship of dung beetles and phytophagous pleurostict scarabs. Supermatrix-based maximum likelihood and multispecies coalescent phylogenetic analyses strongly imply the subfamily Melolonthinae as currently understood being paraphyletic. We consequently suggest various changes in the systematics of Melolonthinae: Sericinae Kirby, 1837 stat. rest. and sensu n. to include the tribes Sericini, Ablaberini and Diphucephalini, and Sericoidinae Erichson, 1847 stat. rest. and sensu n. to include the tribes Automoliini, Heteronychini, Liparetrini, Maechidiini, Scitalini, Sericoidini, and Phyllotocini. Both subfamilies appear to consistently form a monophyletic sister group to all remaining subfamilies so far included within pleurostict scarabs except Orphninae. Our results represent a major step towards understanding the diversification history of one of the largest angiosperm-associated radiations of beetles.
Establishment and characterization of a newPseudomonas aeruginosainfection model using 2D airway organoids and dual RNA sequencing
Authors: Pleguezuelos-Manzano Cayetano , Beenker Wouter A. G. , van Son Gijs J.F. , Begthel Harry , Amatngalim Gimano D. , Beekman Jeffrey M. , Clevers Hans , den Hertog Jeroen
Published: March 2023

Pseudomonas aeruginosais a Gram-negative bacterium that is notorious for infections in the airway of cystic fibrosis (CF) subjects. Often, these infections become chronic, leading to higher morbidity and mortality rates. Bacterial quorum sensing (QS) coordinates the expression of virulence factors and the formation of biofilms at a population level. QS has become the focus of attention for development of alternatives to antimicrobials targetingP. aeruginosainfections. However, a better understanding of the bacteria-host interaction, and the role of QS in infection, is required. In this study, we set up a newP. aeruginosainfection model, using 2D airway organoids derived from healthy and CF individuals. Using dual RNA-sequencing, we dissected their interaction, focusing on the role of QS. As expected,P. aeruginosainduced epithelial inflammation. However, QS signaling did not affect the epithelial airway cells. The epithelium influenced several infection-related processes ofP. aeruginosa, including metabolic changes, induction of type 3 and type 6 secretion systems (T3SS and T6SS), and increased expression of antibiotic resistance genes, includingmexXYefflux pump and several porins. Interestingly, the epithelium influenced the regulation by QS of the type 2 (T2SS) and T6SS. Finally, we compared our model within vivo P. aeruginosatranscriptomic datasets, from samples directly isolated from the airways of CF subjects. This shows that our model recapitulates important aspects ofin vivoinfection, like enhanced denitrification, betaine/choline metabolism, increased antibiotic resistance, as well as an overall decrease of motility-related genes. This relevant infection model is interesting for future investigations, helping to reduce the burden ofP. aeruginosainfections in CF.
Hsc70-4 mediates internalization of environmental dsRNA at the surface ofDrosophilaS2 cells
Authors: Fletcher Sabrina Johanna , Tomé-Poderti Lorena , Mongelli Vanesa , Frangeul Lionel , Blanc Hervé , Verdier Yann , Vinh Joelle , Saleh Maria-Carla
Published: March 2023

The siRNA pathway is the primary antiviral defense mechanism in invertebrates and plants. The systemic nature of this defense mechanism is one of its more fascinating characteristics and the recognition and transport of double-stranded RNA (dsRNA) of viral origin is required for the systemic activity of the siRNA pathway. Indeed, cellular internalization of dsRNA from the environment is a widespread phenomenon among insects. Here we aimed to identify cell surface proteins that bind to extracellular dsRNA and mediate its internalization. To this end, we developed a novel co-immunoprecipitation protocol that we followed with proteomics analysis. Among the hits from our screens was Hsc70-4, a constitutively expressed member of the heat shock protein family that has been implicated in clathrin-mediated endocytosis. We found that silencing Hsc70-4 impaired dsRNA internalization. Surprisingly, despite lacking a predicted transmembrane domain, Hsc70-4 localizes to the cell membrane and this localization was preserved when Hsc70-4 was expressed in mammalian cells, suggesting a conserved role at the cell surface. Furthermore, Hsc70-4 shows a previously undescribed dsRNA-specific binding capacity. Our results show that Hsc70-4 is a key element of the dsRNA internalization process and its detailed study may facilitate the development of RNA interference (RNAi)-based technologies for pest and vector borne disease control.

Importance

To protect plants from pathogens or pests, the technology of “Host-induced gene silencing” has emerged as a powerful alternative to chemical treatments. This is an RNAi-based technology where small RNAs made in the plant silence the genes of the pests or pathogens that attack the plant. The small RNAs are generally derived from dsRNA expressed in transgenic plants. Alternatively, dsRNA can be sprayed onto the plant surface, where it can be taken up into the plant or ingested by pests. We have identified a cell surface protein that mediates the early steps of extracellular dsRNA internalization in insect cells. This could facilitate the development of new strategies for pest management.
Susceptibility of Cu(I) transport ATPases to sodium dodecyl sulfate. Relevance of the composition of the micellar phase
Authors: Recoulat Angelini Alvaro A. , Melian Noelia A. , González-Flecha F. Luis
Published: March 2023

Sodium dodecylsulfate (SDS) is a well-known protein denaturing agent. A less known property of this detergent is that it can activate or inactivate some enzymes at sub-denaturing concentrations. In this work we explore the effect of SDS at sub-denaturing concentrations on the ATPase activity of a hyper-thermophilic and a mesophilic Cu(I) ATPase reconstituted in mixed micelles of phospholipids and a non-denaturing detergent. We first develop an iterative procedure to evaluate the partition of SDS between the aqueous and the micellar phases. This procedure allows to determine the composition of micelles prepared with variable amphiphiles content. When incubating the enzymes with SDS in the presence of different amounts of phospholipids, it can be observed that higher SDS concentrations are required to obtain the same degree of inactivation when the initial concentration of phospholipids is increased. Notably, we found that, if represented as a function of the mole fraction of SDS in the micelle, the degree of inactivation obtained at different amounts of amphiphiles converges to a single inactivation curve. To interpret this result, we propose a simple model involving active and inactive enzyme molecules in equilibrium. This model allowed us to determine the Gibbs free energy change for the inactivation process and its derivative respect to the mole fraction of SDS in the micellar phase, this last being a measure of the susceptibility of the enzyme to SDS. Our results showed that the inactivation free energy changes are similar for both proteins, and indicate that the equilibrium is highly shifted towards the active form in both enzymes. Conversely, susceptibility to SDS is significantly lower for the hyperthermophilic ATPase, suggesting an inverse relation between thermophilicity and susceptibility to SDS.
Histone modifications regulate pioneer transcription factor binding and cooperativity
Authors: Sinha Kalyan , Bilokapic Silvija , Du Yongming , Malik Deepshikha , Halic Mario
Published: March 2023

Pioneer transcription factors have the ability to access DNA in compacted chromatin. Multiple transcription factors can bind together to a regulatory element in a cooperative way and cooperation between pioneer transcription factors Oct4 and Sox2 is important for pluripotency and reprogramming. However, the molecular mechanisms by which pioneer transcription factors function and cooperate remain unclear. Here we present cryo-EM structures of human Oct4 bound to a nucleosome containing human Lin28B and nMatn1 DNA sequences, which bear multiple binding sites for Oct4. Our structural and biochemistry data reveal that Oct4 binding induces changes to the nucleosome structure, repositions the nucleosomal DNA and facilitates cooperative binding of additional Oct4 and of Sox2 to their internal binding sites. The flexible activation domain of Oct4 contacts the histone H4 N-terminal tail, altering its conformation and thus promoting chromatin decompaction. Moreover, the DNA binding domain of Oct4 engages with histone H3 N-terminal tail, and posttranslational modifications at H3K27 modulate DNA positioning and affect transcription factor cooperativity. Thus, our data show that the epigenetic landscape can regulate Oct4 activity to ensure proper cell reprogramming.
Protection of catalytic cofactors by polypeptides as a driver for the emergence of primordial enzymes
Authors: Gutierrez-Rus Luis I. , Gamiz-Arco Gloria , Gavira J.A. , Gaucher Eric A. , Risso Valeria A. , Sanchez-Ruiz Jose M.
Published: March 2023

Enzymes catalyze the chemical reactions of life. For nearly half of known enzymes, catalysis requires the binding of small molecules known as cofactors. Polypeptide-cofactor complexes likely formed at a primordial stage and became starting points for the evolution of many efficient enzymes. Yet, evolution has no foresight so the driver for the primordial complex formation is unknown. Here, we use a resurrected ancestral TIM-barrel protein to identify one potential driver. Heme binding at a flexible region of the ancestral structure yields a peroxidation catalyst with enhanced efficiency when compared to free heme. This enhancement, however, does not arise from protein-mediated promotion of catalysis. Rather, it reflects protection of bound heme from common degradation processes and a resulting longer life time and higher effective concentration for the catalyst. Protection of catalytic cofactors by polypeptides emerges as a general mechanism to enhance catalysis and may have plausibly benefited primordial polypeptide-cofactor associations.
One Health Assessment of an Urban Temporary Settlement Reveals Gut Microbiome Serving as Antimicrobial Resistance Gene Reservoir
Authors: Napit Rajindra , Gurung Anupama , Poudel Ajit , Manadhar Prajwol , Chaudhary Ashok B. , Sharma Ajay Narayan , Raut Samita , Pradhan Saman Man , Joshi Jyotsna , Poyet Mathilde , Groussin Mathieu , Rajbhandari Rajesh M. , Karmacharya Dibesh B.
Published: March 2023

Antimicrobial resistance (AMR) is an emerging and growing global health challenge that could result in 10.2 million deaths annually by 2050. The unrestricted and haphazard use of antibiotics is contributing to the rapid emergence and spread of AMR, and the problem is exacerbated by release of untreated waste water from high-risk sources like hospitals into rivers. Bacteria often develop resistance through horizontal gene transfer mechanism and gut flora can act as a source for new Antimicrobial Resistance Genes (ARG). Upcoming methods like metagenomics can identify the resistance profile (AMR) of gut microbiome, and detect bacterial infections that otherwise go unnoticed. Our study focused on understanding the presence of AMR mutations and gene transfer dynamics in human, animal and environmental samples collected in one of the temporary settlements of Kathmandu (Nepal) using One Health approach. Current AMR reporting based on clinical cases is limited and does not provide information on specific pathogen and associated AMR genes-our study is an effort to contribute information to fulfill this gap.

Twenty-one samples were collected from a temporary settlement in Thapathali (Kathmandu), which included fecal samples from birds (n=3) and humans (n=14), and environmental samples (n=4). Microbiological assessment was carried out based on 16S sequence metagenomic analysis using MiSeq (Illumina, USA). Taxonomic classification on obtained 16S sequences were determined by using Metaphlan 2 and Qiime 2 bioinformatics tools. ShortBRED was used to classify ARG and virulence factors, and WAFFLE was used for horizontal gene transfer event prediction. The network analysis was carried out using Gephi v0.9 and the ResistoXplorer web tool to identify ARG in the collected samples.

Prevotella spp. was the dominant gut microbiome in humans. We detected diverse phages and viruses, including Stx-2 converting phages. 72 virulence factors and 53 ARG subtypes were detected, with poultry samples having the highest number of subtypes. The cluster and network analysis showed a strong association between gut microbiome and ARG, which was also supported by Horizontal Gene Transfer (HGT) analysis. One-Health interface showed ARG dynamics and revealed gut microbiomes of humans and animals serving as a reservoir for the circulating ARG.
(1S,2S)-2-[(S)-2,2,2-Trifluoro-1-hydroxyethyl]-1-tetralol
Authors: Radan Kristian , Cotman Andrej Emanuel , Lozinšek Matic
Published: March 2023

The crystal structure of the title enantiopure tetralol derivative {systematic name: (1S,2S)-2-[(S)-2,2,2-trifluoro-1-hydroxyethyl]-1,2,3,4-tetrahydronaphthalen-1-ol}, C12H13F3O2, synthesized by asymmetric transfer hydrogenation, was elucidated by low-temperature single-crystal X-ray diffraction. The enantiopure compound crystallizes in the Sohncke space group P212121 with one molecule in the asymmetric unit and features intramolecular as well as intermolecular O—H...O hydrogen bonding. The absolute configuration was established from anomalous dispersion effects.
Integrated reporting, audit quality: presence of environmental auditing in an international context
Authors: Hichri Abir
Published: March 2023

Purpose

This paper aims to investigate the effect of audit quality and environmental auditing on integrated reporting and the effect of environmental auditing on audit quality.

Design/methodology/approach

Data was collected from a sample of 300 international companies during the period 2010–2019. The author collected the data from the Thomson Reuters Eikon database, sustainability reports and annual reports. A multiple regression analysis was performed to test the hypotheses.

Findings

The finding of this study confirms a positive and significant relationship between audit quality and integrated reporting. It is also found that environmental auditing has a positive and significant effect on integrated reporting. Thus, this study found a positive and significant relationship between environmental auditing and audit quality.

Practical implications

The findings in this paper identify strategies for improving integrated reporting as a crucial element in the processing of financial and nonfinancial information, to help managers and investors and shareholders take a long-term perspective. Therefore, the results encourage companies to invest in economic, environmental and social aspects. This enables accounting professionals, stock exchange authorities and users of environmental and social information to be aware of the factors associated with environmental reporting, to improve the efficiency of those producing the audit service.

Originality/value

The originality of this study lies in its consideration of a particular aspect of auditing, namely, environmental auditing. However, despite the large body of research on auditing and integrated reporting, to the best of the author’s knowledge, this is the first study to examine the relationship between environmental auditing and integrated reporting. Furthermore, in this research, the author has emphasized the importance of the role played by environmental auditing on audit quality. This design has been neglected in previous studies. Finally, the choice of the field of investigation for the reliability of the data used and the generalization of the results obtained, enables us to make important contributions to the user of the information.
Vacation vengeance: an interpretive phenomenological analysis of revenge travel in India
Authors: Singh Snigdha , Srivastava Pallavi
Published: March 2023

Purpose

After each of the COVID-19-induced lockdowns, an unprecedented surge in leisure travel was observed, resulting in tourists flocking to places of tourist interest. This phenomenon was termed revenge travel in popular literature. The purpose of this study is to explore the phenomenon of revenge travel in detail through an academic lens. It examines the psychological and emotional motivations for revenge travel while studying the differences in travel behaviour pre- and post-pandemic.

Design/methodology/approach

The study applies an interpretive phenomenological approach to explore post-pandemic travel behaviour. Data were collected via personal in-depth semi-structured interviews. Thematic analysis of the transcripts was conducted to arrive at discussion themes.

Findings

Drawing on the established theories, the findings of the study indicate that lockdown fatigue coupled with mortality salience induced individuals towards leisure travel. This in turn led to mood alleviation and compensation for the deprivation undergone.

Practical implications

The study reveals important insights into post-pandemic preferences of travel destinations (off-beat locations near urban clusters), accommodation options (more travellers choosing home stays and stand-alone properties) and vacation itineraries (a gradual shift towards slow tourism with more focus on immersive experiences). Further, there are indications that hotels may develop “workcations” and “staycations” as a new line of offering.

Originality/value

The study adds to the small body of knowledge on revenge travel. It adopts a phenomenological approach, thereby capturing the “lived experiences” of the participants and providing an in-depth look into the psychological and emotional motivations of revenge travel that have not been explored previously. The study provides insights into the travellers' psychology post a period of withdrawal and restraint.
Bacterial diversity and co‐occurrence patterns differ across a world‐wide spatial distribution of habitats in glacier ecosystems
Authors: Zhang Liyan , Delgado‐Baquerizo Manuel , Hotaling Scott , Li Yi , Sun Xiangxin , Xu Yifei , Chu Haiyan
Published: March 2023

Glaciers cover nearly 10% of the Earth's surface and are unique biomes dominated by microbial communities that support key ecosystem processes. The melting of glaciers is among the most conspicuous consequences of global climate change, with impacts on microbial ecology and associated biogeochemistry. However, we are still missing an integrative understanding of microbial biodiversity from divergent habitats associated with glaciers.

Here, we compiled global microbiome metadata from 93 representative glaciers over 180 locations and used random forest, microbial ecological networks and structural equation modelling to evaluate the biodiversity and environmental factors associated with the glacier microbiomes of seven contrasting habitats: water, epilithic biofilm, cryoconite, mat, ice, sediment and permafrost soil.

The results showed that microbial diversity largely changed across habitats, with the highest in permafrost soil, followed by sediment, ice, mat, cryoconite, water and epilithic biofilm. More importantly, we provided critical evidence that the environmental and climatic factors associated with the microbiomes of glaciers varied with glacier habitats. Microbial diversity in water was highly correlated with latitude, cryoconite microbial diversity was significantly (p = 0.01) correlated with pH, and permafrost soil and sediment microbial diversity were mainly explained by temperature (17.05% and 13.37% respectively).

Using ecological association network analysis, we identified some tightly linked common microbial taxa (e.g. Proteobacteria and Bacteroidetes) that were present in all the habitats and were vulnerable to climatic factors, such as temperature and precipitation. This study demonstrated that microbial diversity, drivers and co‐occurrence patterns differ among glacier habitats globally, and diverse habitat‐dependent glacier microbiomes could serve as early warning sentinels for the study of life on glaciers and its potential future in a warming world.

Read the free Plain Language Summary for this article on the Journal blog.
Analyse de l'effet empirique de l'intégration économique sur la croissance sectorielle en Afrique Subsaharienne: quelle implication de la gouvernance?
Authors: Ayenagbo Kossi
Published: March 2023

L'objectif de ce papier est d'analyser le rôle de la gouvernance dans la relation entre l'intégration économique et la croissance sectorielle en Afrique Subsaharienne. L'approche économétrique est basée sur un modèle de panel dynamique de 33 pays d'Afrique Subsaharienne et plus spécifiquement sur les pays de l'UEMOA couvrant la période de 2002 à 2019. L'estimateur de la méthode des moments généralisés (GMM) et celui des moindres carrés corrigés des variables muettes (LSDVC) sont utilisés respectivement dans les deux contextes pour obtenir les résultats. Les résultats révèlent que l'intégration économique améliore significativement la croissance sectorielle notamment de l'agriculture et de l'industrie avec un effet plus important pour le secteur agricole. Les résultats montrent également que la qualité de la gouvernance améliore l'effet de l'intégration commerciale sur la croissance sectorielle beaucoup plus dans la zone UEMOA. Les résultats montrent également un effet significatif de l'investissement et de l'emploi. Ainsi, les décideurs publics dans l'objectif de croissance, doivent mettre en place des mesures d'amélioration de la qualité des indicateurs de la gouvernance.
COVID‐19 vaccine uptake rates, perceptions, and attitudes among dialysis patients: Experience across a national sample
Authors: Balzan Deborah , Agius Stefanie Marie , Farrugia Emanuel , Buttigieg Jesmar
Published: March 2023

Introduction

Dialysis patients are at increased risk of severe COVID‐19 infection making vaccination a priority. We explored COVID‐19 vaccine uptake and perceptions in our dialysis population, associated COVID‐19 infection, and hospitalization rates.

Methods

This is a single‐center retrospective study using telephone questionnaires and hospital records to investigate COVID‐19 vaccine uptake and attitudes behind vaccination status.

Results

A total of 230 patients were interviewed. Vaccine uptake was 97.8% (two doses) and 86.6% (booster dose), with 79.5% vaccinated at Renal Unit. Most (58.5%) cited healthcare worker advice as a contributing factor and 54% sought protection through vaccination. COVID‐19 hospitalization was higher in unvaccinated and patients vaccinated with one dose, compared to two doses (63.2% vs. 20%, p = 0.05) and booster dose (63.2% vs. 22.2%, p = 0.02).

Conclusion

Our dialysis population recognized the importance of COVID‐19 vaccination. Intensive patient education and easy access to the COVID‐19 vaccine may have facilitated vaccine uptake in these patients.
Maintenance of genetic diversity in subdivided populations using genomic coancestry matrices
Authors: Morales‐González Elisabeth , Villanueva Beatriz , Toro Miguel Á. , Fernández Jesús
Published: March 2023

For both undivided and subdivided populations, the consensus method to maintain genetic diversity is the Optimal Contribution (OC) method. For subdivided populations, this method determines the optimal contribution of each candidate to each subpopulation to maximize global genetic diversity (which implicitly optimizes migration between subpopulations) while balancing the relative levels of coancestry between and within subpopulations. Inbreeding can be controlled by increasing the weight given to within‐subpopulation coancestry (λ). Here we extend the original OC method for subdivided populations that used pedigree‐based coancestry matrices, to the use of more accurate genomic matrices. Global levels of genetic diversity, measured as expected heterozygosity and allelic diversity, their distributions within and between subpopulations, and the migration pattern between subpopulations, were evaluated via stochastic simulations. The temporal trajectory of allele frequencies was also investigated. The genomic matrices investigated were (i) the matrix based on deviations of the observed number of alleles shared by two individuals from the expected number under Hardy–Weinberg equilibrium; and (ii) a matrix based on a genomic relationship matrix. The matrix based on deviations led to higher global and within‐subpopulation expected heterozygosities, lower inbreeding and similar allelic diversity than the second genomic and pedigree‐based matrices when a relatively high weight was given to the within‐subpopulation coancestries (λ ≥ 5). Under this scenario, allele frequencies moved only slightly away from the initial frequencies. Therefore, the recommended strategy is to use the former matrix in the OC methodology giving a high weight to the within‐subpopulation coancestry.
Comparing restrictive versus liberal oxygen strategies for trauma patients: The TRAUMOX2 trial—Statistical analysis plan
Authors: Arleth Tobias , Baekgaard Josefine , Siersma Volkert , Klimek Markus , Hinkelbein Jochen , Rasmussen Lars Simon , Steinmetz Jacob ,   for The TRAUMOX2 Study Group
Published: March 2023

Background

The international advanced trauma life support guidelines recommend that all severely injured trauma patients receive supplemental oxygen based on very limited evidence. The TRAUMOX2 trial randomises adult trauma patients to a restrictive or liberal oxygen strategy for 8 h. The primary composite outcome consists of 30‐day mortality and/or development of major respiratory complications (pneumonia and/or acute respiratory distress syndrome). This manuscript presents the statistical analysis plan for TRAUMOX2.

Methods

Patients are randomised 1:1 in variable block sizes of four, six and eight, stratified by including centre (pre‐hospital base or trauma centre) and tracheal intubation at inclusion. The trial will include 1420 patients to be able to detect a 33% relative risk reduction with the restrictive oxygen strategy of the composite primary outcome with 80% power at the 5% significance level. We will conduct modified intention‐to‐treat analyses on all randomised patients and per‐protocol analyses for the primary composite outcome and key secondary outcomes. The primary composite outcome and two key secondary outcomes will be compared between the two allocated groups using logistic regression reported as odds ratios with 95% confidence intervals adjusted for the stratification variables as in the primary analysis. A p‐value below 5% will be considered statistically significant. A Data Monitoring and Safety Committee has been established to conduct interim analyses after inclusion of 25% and 50% of the patients.

Conclusion

This statistical analysis plan of the TRAUMOX2 trial will minimise bias and add transparency to the statistics applied in the analysis of the trial. The results will add evidence on restrictive and liberal supplemental oxygen strategies for trauma patients.

Trial Registration

EudraCT number: 2021–000556‐19; ClinicalTrials.gov identifier: NCT05146700 (date of registration: 7 December 2021).