bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-omic spatial profiling reveals the unique virus-driven immune landscape of COVID-19 placentitis
Authors: Pugh Matthew , Fennell Éanna , Leahy Ciara I , Perry Tracey , Hargitai Beata , Marton Tamas , Hunter Kelly J. , Halford Graham , Yilmaz Hale Onder , Stamataki Zania , Reynolds Gary , Hill Harriet J. , Willcox Benjamin E. , Steven Neil , Thornton Catherine A. , Dojcinov Stefan D. , Culhane Aedin , Murray Paul G. , Taylor Graham S.
Published: November 2022

COVID-19 placentitis, a rare complication of maternal SARS-CoV-2 infection, only shows detectable virus in the placenta of a subset of cases. We provide a deep multi-omic spatial characterisation of placentitis from obstetrically complicated maternal COVID-19 infection. We found that SARS-CoV-2 infected placentas have a distinct transcriptional and immunopathological signature. This signature overlaps with virus-negative cases supporting a common viral aetiology. An inverse correlation between viral load and disease duration suggests viral clearance over time. Quantitative spatial analyses revealed a unique microenvironment surrounding virus-infected trophoblasts characterised by PDL1-expressing macrophages, T-cell exclusion, and interferon blunting. In contrast to uninfected mothers, ACE2 was localised to the maternal side of the placental trophoblast layer of almost all mothers with placental SARS-CoV-2 infection, which may explain variable susceptibility to placental infection. Our results demonstrate a pivotal role for direct placental SARS-CoV-2 infection in driving the unique immunopathology of COVID-19 placentitis.

Graphical Abstract
Hand preference and the corpus callosum: Is there really no association?
Authors: Raaf Nora , Westerhausen René
Published: November 2022

Originating from a series of morphometric studies conducted in the 1980s, it appears a widely held belief in cognitive neuroscience that the corpus callosum is larger in non-right handers than in right handers (RH). However, a recent meta-analysis challenges this belief by not finding significant differences in corpus callosum size between handedness groups. Yet, relying on the available published data, the meta-analysis was not able to account for a series of factors potential influencing its outcome, such as confounding effects of brain size differences and a restricted spatial resolution of previous callosal segmentation strategies. To address these remaining questions, we here analysed the midsagittal corpus callosum of N = 1057 participants from the Human Connectome Project (HCP 1200 Young Adults) to compare handedness groups based on consistency (e.g., consistent RH vs. mixed handers, MH) and direction of hand preference (e.g., RH vs. left handers). A possible relevance of brain-size differences was addressed by analysing callosal variability by both using forebrain volume (FBV) as covariate and utilising relative area (callosal area/thickness divided by FBV) as dependent variable. Callosal thickness was analysed at 100 measuring points along the structure to achieve high spatial resolution to detect subregional effects. However, neither of the conducted analyses was able to find significant handedness-related differences in callosal and the respective effect-sizes estimates were small. For example, comparing MH and consistent RH, the effect sizes for difference in callosal area were below a Cohen’sd= 0.1 (irrespective of how FBV was included), and narrow confidence intervals allowed to exclude effects above |d| = 0.2. Analysing thickness, effect sizes were belowd= 0.2 with confidence intervals not extending above |d| = 0.3. In this, the possible range of population effect sizes of hand preference on callosal morphology appears well below the effects commonly reported for factors like age, sex, or brain size. Effects on cognition or behaviour accordingly can be considered small, questioning the common practise to attribute performance differences between handedness groups to differences in callosal architecture.
Incorporating Pre-training Paradigm for Antibody Sequence-Structure Co-design
Authors: Gao Kaiyuan , Wu Lijun , Zhu Jinhua , Peng Tianbo , Xia Yingce , He Liang , Xie Shufang , Qin Tao , Liu Haiguang , He Kun , Liu Tie-Yan
Published: November 2022

Antibodies are versatile proteins that can bind to pathogens and provide effective protection for human body. Recently, deep learning-based computational antibody design has attracted popular attention since it automatically mines the antibody patterns from data that could be complementary to human experiences. However, the computational methods heavily rely on the high-quality antibody structure data, which is quite limited. Besides, the complementarity-determining region (CDR), which is the key component of an antibody that determines the specificity and binding affinity, is highly variable and hard to predict. Therefore, data limitation issue further raises the difficulty of CDR generation for antibodies. Fortunately, there exists a large amount of sequence data of antibodies that can help model the CDR and alleviate the reliance on structured data. By witnessing the success of pre-training models for protein modeling, in this paper, we develop an antibody pre-trained language model and incorporate it into the (antigen-specific) antibody design model in a systemic way. Specifically, we first pre-train an antibody language model based on the sequence data, then propose a one-shot way for sequence and structure generation of CDR to avoid the heavy cost and error propagation from an autoregressive manner, and finally leverage the pre-trained antibody model for the antigen-specific antibody generation model with some carefully designed modules. Through various experiments, we show that our method achieves superior performance over previous baselines on different tasks, such as sequence and structure generation, antigen-binding CDR-H3 design.
Characterisation of fasting and postprandial NMR metabolites: insights from the ZOE PREDICT 1 Study
Authors: Bermingham Kate M , Mazidi Mohsen , Franks Paul W , Maher Tyler , Valdes Ana M , Linenberg Inbar , Wolf Jonathan , Hadjigeorgiou George , Spector Tim D , Menni Cristina , Ordovas Jose M , Berry Sarah E , Hall Wendy L
Published: November 2022

Background

Postprandial metabolomic profiles and their inter-individual variability are not well characterised. Here we describe postprandial metabolite changes, their correlations with fasting values and their inter- and intra-individual variability following a standardised meal in the ZOE PREDICT 1 cohort.

Methods

In the ZOE PREDICT 1 study (n= 1,002 (NCT03479866)), 250 metabolites, mainly lipids, were measured by Nightingale NMR panel in fasting and postprandial (4 and 6 h after a 3.7 MJ mixed nutrient meal, with a second 2.2 MJ mixed nutrient meal at 4 h) serum samples. For each metabolite, inter- and intra-individual variability over-time was evaluated using linear mixed modelling and intraclass-correlation coefficients (ICC) calculated.

Results

Postprandially, 85% (of 250 metabolites) significantly changed from fasting at 6h (47% increased, 53% decreased; Kruskal-Wallis), with 37 measures increasing by >25%, and 14 increasing by >50%. The largest changes were observed in very large lipoprotein particles and ketone bodies. Seventy-one percent of circulating metabolites were strongly correlated (Spearman’s rho >0.80) between fasting and postprandial timepoints, and 5% were weakly correlated (rho <0.50). The median ICC of the 250 metabolites was 0.91 (range 0.08-0.99). The lowest ICCs (ICC<0.40, 4% of measures) were found for glucose, pyruvate, ketone bodies (β-hydroxybutyrate, acetoacetate, acetate) and lactate.

Conclusions

In this large-scale postprandial metabolomic study, circulating metabolites were highly variable between individuals following a mixed challenge meal. Findings suggest that a meal challenge may yield postprandial responses divergent from fasting measures, specifically for glycolysis, essential amino acid, ketone body and lipoprotein size metabolites.
Reproducible switching between a walled and cell wall-deficient lifestyle of actinomycetes using gradient agar plates
Authors: Lubbers Maarten , van Wezel Gilles P. , Claessen Dennis
Published: November 2022

The cell wall is a shape-defining structure that envelopes almost all bacteria, protecting them from biotic and abiotic stresses. Paradoxically, some filamentous actinomycetes have a natural ability to shed their cell wall under influence of hyperosmotic stress. These wall-deficient cells can revert to their walled state when transferred to a medium without osmoprotection but often lyse due to their fragile nature. Here, we designed plates with an osmolyte gradient to reduce cell lysis and thereby facilitating the transition between a walled and wall-deficient state. These gradient plates allow determining of the osmolyte concentration where switching takes place, thereby enabling careful and reproducible comparison between mutants affected by switching. Exploring these transitions could give valuable insights into the ecology of actinomycetes and their biotechnological applications.

HIGHLIGHTS

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Using agar plates with a gradient of osmoprotectants, revertant Streptomycetes can gradually revert to a walled state, thereby dramatically decreasing lysis.

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Our method allows precise determination of the osmolyte concentration where reversion takes place, allowing careful and reproducible comparison between mutants.

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Gradient agar plates can also be used to study chemical differentiation in Streptomycetes as a response to osmotic stress.
Inhibition of proline tyrosine kinase 2 (Pyk2) phosphorylation during adherent-invasiveEscherichia coliinfection inhibits intra-macrophage replication and inflammatory cytokine release
Authors: Li Xiang , Ormsby Michael J. , Fallata Ghaith , Meikle Lynsey M. , Xu Damo , Wall Daniel M.
Published: November 2022

Adherent-invasiveEscherichia coli(AIEC) have been implicated in the aetiology of Crohn’s Disease (CD). They are characterized by an ability to adhere to and invade intestinal epithelial cells, and to replicate intracellularly in macrophages resulting in inflammation. Proline-rich tyrosine kinase 2 (PYK2) has previously been identified as a risk locus for inflammatory bowel disease through genome wide association studies. It is overexpressed in patients with colorectal cancer, a major long-term complication of CD. Here we show that Pyk2 levels are significantly increased during AIEC infection of murine macrophages while an inhibitor of Pyk2, PF-431396 hydrate, significantly decreased intramacrophage AIEC numbers. Imaging flow cytometry indicated that Pyk2 inhibition blocked intramacrophage replication of AIEC with no change in the overall number of infected cells, but a significant reduction in bacterial burden per cell. This reduction in intracellular bacteria resulted in a 20-fold decrease in tumour necrosis factor α secretion by cells post-AIEC infection. These data demonstrate a key role for Pyk2 in modulating AIEC intracellular replication and associated inflammation and may provide a new avenue for future therapeutic intervention in CD.
Efficient mechano-enzymatic hydrolysis of polylactic acid under moist-solid conditions
Authors: Pérez-Venegas Mario , Friščić Tomislav , Auclair Karine
Published: November 2022

Quantitative mechano-enzymatic depolymerisation of polylactic acid to lactic acid was achieved at 55°C using theHumicola insolenscutinase enzyme in moist-solid reaction mixtures. The resulting lactic acid was easily recovered, and the crude product was pure enough to be used in further synthesis of a value-added compound, a known benzimidazole-based drug precursor. The presented mechano-enzymatic depolymerisation strategy enables the closed-loop recycling of untreated polylactic acid under mild conditions, using a renewable, non-toxic catalyst and producing minimum solvent waste.
The global groundwater resistome: core antibiotic resistance genes, their dynamics and drivers
Authors: Kampouris Ioannis D. , Bengtsson-Palme Johan , Babin Doreen , Gallego Sara , Li Bing , Smalla Kornelia , Berendonk Thomas U. , Klümper Uli
Published: November 2022

Despite the importance of groundwater as a drinking water resource, currently, no comprehensive picture regarding the global levels of antibiotic resistance genes (ARGs) in groundwater environments exists. Moreover, the biotic and abiotic factors that shape the groundwater resistome on the global scale remain to be explored. Herein, we attempted to fill this knowledge gap throughin silicore-analysis of publicly available global groundwater metagenomes. First, nine ARGs encoding resistance to aminoglycosides (aadA,aph(3’), andant(3’’)), sulfonamides (sul1 andsul2), β-lactams (blaOXAandblaTEM), tetracyclines (tet(C)) and macrolides (msr(E)) were identified to constitute the core groundwater resistome with high detection and abundance levels. Second, the global drivers of groundwater resistome composition were identified by applying a structural equation model with mixed effects to disentangle the individual contributions of each abiotic and biotic factor. Most notably, global effects of the origin of groundwater samples on the resistome were detected with samples from high-income countries (HICs) constantly displaying lower ARG and mobile genetic element (MGE) abundances than those from low-and-middle-income countries (LMICs). While these effects were consistent across antibiotic classes, biotic factors such as interactions of the groundwater microbiome with fungal or bacterial natural producers of antibiotics, or the co-occurrence of ARGs on mobile genetic elements (MGEs) played significant roles in shaping abundance patterns of resistance towards individual antibiotic classes. Only few ARGs correlated to individual bacterial genera, with microbial community composition in general weakly associated with resistome composition. In conclusion, we provide a first global picture of the resistome of low-anthropogenic impacted groundwater environments and the underlying anthropogenic and biotic drivers shaping it, which can be used as a baseline in future surveillance of antibiotic resistance.
Species-conserved mechanisms of abstract rule learning promote cognitive flexibility in complex environments
Authors: Bähner Florian , Popov Tzvetan , Boehme Nico , Hermann Selina , Merten Tom , Zingone Hélène , Koppe Georgia , Meyer-Lindenberg Andreas , Toutounji Hazem , Durstewitz Daniel
Published: November 2022

Rapid learning in complex and changing environments is a hallmark of intelligent behavior. Humans achieve this in part through abstract concepts applicable to multiple, related situations. It is unclear, however, whether some of the underlying computational mechanisms also exist in other species. We combined behavioral, computational and electrophysiological analyses of a multidimensional rule-learning paradigm in rats and humans. We report that both species infer task rules by sequentially testing different hypotheses, rather than learning the correct action for all possible combinations of task-related cues. Neural substrates of hypothetical rules were detected in prefrontal network activity of both species. This species-conserved mechanism reduces task dimensionality and explains key experimental observations: sudden behavioral transitions and facilitated learning after prior experience. Our findings open the black box of hypothesis testing in rodents and provide a foundation for the translational investigation of impaired cognitive flexibility.
Chronic Alcohol Drinking Drives Sex-Specific Differences in Affective Behavior and Medial Prefrontal Cortex Activity in CRF1:Cre:Tdtomato Transgenic Rats
Authors: Quadir SG , Arleth GM , Cone MG , High MW , Ramage MC , Effinger DP , Echeveste-Sanchez M , Herman MA
Published: November 2022

Alcohol use disorders (AUDs) are characterized by compulsive alcohol use, loss of control over intake, and a negative emotional state during abstinence. While AUDs are associated with both mood and chronic pain disorders, the relationship between these associations remains unclear. Corticotropin releasing factor-1 receptor (CRF1) has been implicated in alcohol (EtOH) use, affective states, and pain sensitivity; often in a sex-dependent manner. Using CRF1-cre transgenic rats, we found no sex differences in basal affective behavior with the exception of mechanical sensitivity, where females were more sensitive to mechanical stimuli. Following baseline testing, rats began EtOH (or water) drinking under intermittent access conditions. Females consumed more alcohol in the first week, but overall EtOH intake was not significantly different between males and females. Following 3-4 weeks of drinking, rats were tested again for negative affect. EtOH drinking decreased mechanical sensitivity, but no other group effects were observed. However, individual EtOH intake was directly correlated with anxiety- and depressive-like behavior in both sexes. Interestingly, EtOH intake inversely correlated with thermal sensitivity in males only. There were no group differences in CRF1+ neuronal activity in either prelimbic or infralimbic cortices, but final session EtOH intake was significantly correlated with activity in CRF1+ neurons in the infralimbic cortex. Together, our results suggest complex interplay between affective state, EtOH drinking, and the role of prefrontal cortex CRF1-containing neurons in mediating these behaviors. Additionally, these results highlight the importance of examining individual differences in AUD-related behaviors.

SIGNIFICANCE STATEMENT

Despite alcohol use disorders being extremely comorbid with mood and pain disorders, there is still a limited understanding of the interaction and directionality between the them. To investigate this problem, rats were tested for affective behavior before and after being allowed to drink alcohol for 6 weeks. While baseline behavior did not predict subsequent intake, alcohol intake predicted both anxiety- and depressive-like behavior. These findings were accompanied by increased activity of the corticotropin releasing factor 1 containing neurons in the infralimbic region of the prefrontal cortex. Together, these findings reveal a new mechanism for understanding alcohol use.
Membrane Voltage Dynamics of Parvalbumin Interneurons Orchestrate Hippocampal Theta Rhythmicity
Authors: Tseng Hua-an , Mount Rebecca A. , Lowet Eric , Gritton Howard J. , Cheung Cyrus , Han Xue
Published: November 2022

Hippocampal network activity at theta frequencies (5-10Hz) is important for behavior. However, it remains unclear how behaviorally-relevant network theta rhythms arise and interact with cellular dynamics to dictate spike timing. We performed membrane voltage (Vm) imaging of individual CA1 pyramidal cells and parvalbumin interneurons with simultaneous local field potential (LFP) recordings in mice during locomotion. We found that Vm theta rhythms organize spike timing in both cell types regardless of behavioral conditions, but the Vm of parvalbumin interneurons is better synchronized with LFP. The temporal relationships between spikes and LFP theta reliably reflect the Vm-LFP relationships in parvalbumin cells, but not in pyramidal cells. Thus, cellular theta rhythms broadly organize spike timing in CA1 neurons, and parvalbumin interneurons are critical in coordinating network theta rhythms.

One-Sentence Summary

Cellular membrane voltage of parvalbumin interneurons organizes spiking and network dynamics in the hippocampus.
The GLM-Spectrum: A multilevel framework for spectrum analysis with covariate and confound modelling
Authors: Quinn Andrew J , Atkinson Lauren Z , Gohil Chetan , Kohl Oliver , Pitt Jemma , Zich Catharina , Nobre Anna C , Woolrich Mark W
Published: November 2022

The frequency spectrum is a central method for representing the dynamics within electrophysiological data. Some widely used spectrum estimators make use of averaging across time segments to reduce noise in the final spectrum. The core of this approach has not changed substantially since the 1960s, though many advances in the field of regression modelling and statistics have been made during this time. Here, we propose a new approach, the General Linear Model (GLM) Spectrum, which reframes time averaged spectral estimation as multiple regression. This brings several benefits, including the ability to do confound modelling, hierarchical modelling and significance testing via non-parametric statistics.

We apply the approach to a dataset of EEG recordings of participants who alternate between eyes-open and eyes-closed resting state. The GLM-Spectrum can model both conditions, quantify their differences, and perform denoising through confound regression in a single step. This application is scaled up from a single channel to a whole head recording and, finally, applied to quantify age differences across a large group-level dataset. We show that the GLM-Spectrum lends itself to rigorous modelling of within- and between-subject contrasts as well as their interactions, and that the use of model-projected spectra provides an intuitive visualisation. The GLM-Spectrum is a flexible framework for robust multi-level analysis of power spectra, with adaptive covariance and confound modelling.
Distributed Compact Plasma Reactor Sterilization for Planetary Protection in Space Missions
Authors: Choudhury Bhaswati , Revazishvili Tamara , Lozada Maria , Roy Sarthak , Mastro Emma Noelle , Portugal Sherlie , Roy Subrata
Published: November 2022

This paper presents a proof-of-concept study establishing effectiveness of the Active Plasma Sterilizer (APS) for sterilization in planetary protection. The APS uses Compact Portable Plasma Reactors (CPPRs) to produce surface dielectric barrier discharge, a type of cold plasma, using ambient air to generate and distribute reactive species like ozone used for decontamination. Sterilization tests were performed with pathogenic bacteria (Escherichia coli and Bacillus subtilis) on materials (Aluminum, Polycarbonate, Kevlar and Orthofabric) relevant to space missions. Results show that the APS can achieve 4 to 5 log reductions of pathogenic bacteria on four selected materials, simultaneously at 11 points within 30 minutes, using power of 13.2 ± 2.22 W. Spatial sterilization data shows the APS can uniformly sterilize several areas of a contaminated surface within 30 minutes. Ozone penetration through Kevlar and Orthofabric layers was achieved using the CPPR with no external agent assisting penetration. Preliminary material compatibility tests with SEM analysis of the APS exposed materials showed no significant material damage. Thus, this study shows the potential of the APS as a light-weight sustainable sterilization technology for planetary protection with advantages of uniform spatial decontamination, low processing temperatures, low exposure times, material compatibility and the ability to disinfect porous surfaces.
Sustained Modulation of Deep Brain Circuits with Focused Ultrasonic Waves
Authors: Webb Taylor D. , Wilson Matthew G. , Odeen Henrik , Kubanek Jan
Published: November 2022

Transcranial focused ultrasound has the potential to noninvasively and systematically modulate deep brain circuits and impart sustained, neuroplastic effects in awake subjects. The intersection of these properties is critical for effective treatments of brain disorders, yet remains to be shown. Harnessing the full potential of transcranial ultrasound, we delivered 30-second stimuli into deep brain targets (left/right lateral geniculate nucleus) of non-human primates while they performed a visual discrimination task. This brief stimulation induced sustained and target-specific behavioral preference that persisted up to 15 minutes following the ultrasound offset. The polarity of the behavioral and neural effects suggested that ultrasound excited the stimulated circuits. The ultrasound was delivered into the deep brain daily for a period of more than 6 months, which enabled us to evaluate the safety of longterm stimulation. There were no detrimental effects on the animals’ discrimination accuracy over the course of this stimulation regimen. This study demonstrates ultrasound’s capacity to condition deep brain circuits in a safe and treatment-relevant manner in awake subjects, and provides a basis for effective and safe translations into humans.

Highlights

Transcranial ultrasound induces effective and sustained modulation of deep brain circuits.

The deep brain modulation biases choice behavior of non-human primates.

The deep brain modulation produces sustained elevation of high gamma activity.

The stimulation, applied daily for several months, is safe.
rRNA transcription is integral to liquid-liquid phase separation and maintenance of nucleolar structure
Authors: Dash Soma , Lamb Maureen C. , Lange Jeffrey J. , McKinney Mary C. , Tsuchiya Dai , Guo Fengli , Zhao Xia , Corbin Timothy J. , Kirkman MaryEllen , Delventhal Kym , Moore Emma L. , McKinney Sean , Shiang Rita , Trainor Paul A.
Published: November 2022

Beginning with transcription of ribosomal RNA (rRNA) by RNA Polymerase (Pol) I in the nucleolus, ribosome biogenesis is intimately tied to cell growth and proliferation. Perturbation of ribosome biogenesis has been previously shown to affect nucleolar structure, yet the underlying mechanism is unknown. We generated loss-of-function mouse mutants of Pol I subunits,Polr1a, Polr1b, Polr1candPolr1d, thereby genetically inhibiting rRNA transcription and ribosome biogenesis. Pol I mutant embryos are preimplantation lethal and have fewer nucleoli. Using hiPSCs triple labeled for the three nucleolar compartments, we observe two phenotypes upon Pol I inhibition: a single condensed nucleolus, and fragmented nucleoli. We find that when rRNA transcription is inhibited, the viscosity of the granular compartment of the nucleolus is increased disrupting its liquid-liquid phase separation properties, which results in a condensed nucleolus. Taken together, our data suggests that Pol I function and rRNA transcription are required for maintaining nucleolar structure and integrity.
Impact of combinatorial histone modifications on acetyllysine recognition by the ATAD2 and ATAD2B bromodomains
Authors: Phillips Margaret , Malone Kiera L. , Boyle Brian W. , Montgomery Cameron , Kressy Isabelle A. , Joseph Faith M. , Bright Kathleen M. , Boyson Samuel P. , Chang Sunsik , Nix Jay C. , Young Nicolas L. , Jeffers Victoria , Frietze Seth E. , Glass Karen C.
Published: November 2022

The ATPase family AAA+ domain containing 2 (ATAD2) protein, and its paralog ATAD2B, have a C-terminal bromodomain that functions as a ‘reader’ of acetylated lysine residues on histone proteins. Using a structure-function approach, we investigated the ability of the ATAD2 and ATAD2B bromodomains to select acetylated lysine among multiple histone post-translational modifications. Isothermal titration calorimetry experiments revealed that the ATAD2 and ATAD2B bromodomains selectively recognize distinct patterns of acetylated lysine residues on the N-terminal tails of histone proteins. Adjacent methylation or phosphorylation marks were found to either enhance or weaken the recognition of acetylated lysine by the ATAD2/B bromodomains. Complementary structural studies provide mechanistic insights into how residues within the bromodomain binding pocket coordinate the acetyllysine group in the context of adjacent post- translational modifications. Furthermore, we investigated how sequence changes in amino acids of the histone ligands, either as ‘onco’ mutations or as histone variants, impact the recognition of an adjacent acetylated lysine residue. In summary, our study highlights how the interplay between multiple combinations of histone modifications influences the ‘reader’ activity of the ATAD2 and ATAD2B bromodomains, resulting in distinct binding modes of the two bromodomains.

KEY POINTS

Multiple independent ATAD2 gene duplication events are evident during metazoan evolution, indicating expansion of functionality in the ATAD2 gene family and suggesting distinct functions for ATAD2 and ATAD2B.

High-resolution structures of the ATAD2 and ATAD2B bromodomains in complex with their histone ligands demonstrate how multiple post-translational modifications are coordinated.

Recognition of different subsets acetylated histone ligands by the ATAD2 and ATAD2B bromodomains is driven by unique features within the binding pockets of these paralogous proteins.

Onco-histone mutations and histone variants that change the amino acid sequence of the histone tails modulate the ATAD2 and ATAD2B bromodomain activity.

This study demonstrates how the combinatorial activity of multiple post- translational modifications forms a histone code and influences the recognition of acetylated lysine by bromodomain-containing proteins.
ShigellaIpaH9.8 limits GBP1-dependent LPS release from intracytosolic bacteria to suppress caspase-4 activation
Authors: Goers Lisa , Kim Kyungsub , Canning Patrick J. , Stedman Teagan C. , Mou Xiangyu , Ernst Nadja Heinz , Coers Jörn , Lesser Cammie F.
Published: November 2022

Pyroptosis is an inflammatory form of cell death induced upon the recognition of invading microbes. During an infection, pyroptosis is enhanced in interferon-gamma (IFNγ) exposed cells due to the actions of members of the guanylate binding protein (GBP) family. GBPs promote activation of caspase-4 (CASP4) by enhancing its interactions with lipopolysaccharide (LPS), a component of the outer envelope of Gram-negative bacteria. Once activated, CASP4 promotes the formation of non-canonical inflammasomes, signaling platforms that mediate pyroptosis. To establish an infection, intracellular bacterial pathogens, likeShigellaspecies, inhibit pyroptosis. The pathogenesis ofShigellais dependent on its type III secretion system, which injects ~30 effector proteins into host cells. Upon entry into host cells,Shigellaare encapsulated by GBP1, followed by GBP2, GBP3, GBP4, and in some cases, CASP4. It has been suggested that the recruitment of CASP4 to bacteria leads to its activation. Here, we demonstrate that twoShigellaeffectors, OspC3 and IpaH9.8, cooperate to inhibit CASP4-mediated pyroptosis. We show that in the absence of OspC3, an inhibitor of CASP4, IpaH9.8 inhibits pyroptosis via its known degradation of GBPs. We find that, while some LPS is present within the host cell cytosol of epithelial cells infected with wild typeShigella, in the absence of IpaH9.8, increased amounts are shed in a GBP1-dependent manner. Furthermore, that additional IpaH9.8 targets, likely GBPs, promote CASP4 activation, even in the absence of GBP1. These observations suggest that by promoting LPS release, GBP1 provides CASP4 access to LPS, thus promoting host cell death via pyroptosis.

Significance Statement

Non-canonical inflammasomes mediate the death of intestinal epithelial cells in response to invading Gram-negative bacterial pathogens. CASP4 is activated upon binding to LPS. Recent studies have suggested that GBP1 recruits and enables the activation of CASP4 on the surface of intracytosolic bacteria. This has led to the proposal that non-canonical inflammasomes assemble on the bacterial surface due to GBP1-mediated access of CASP4 to the membrane-embedded lipid A component of LPS. Here, we show that by targeting the degradation of GBPs,ShigellaIpaH9.8 limits the release of LPS from intracellularShigellainto the host cell cytosol in a GBP1-dependent manner. Furthermore, we find evidence to suggest that in the absence of GBP1, other members of the GBP family promote CASP4 activation.
Diversified repertoire of phage resistance inKlebsiella pneumoniaeand bidirectional steering effects impacting antibiotic susceptibility
Authors: Nang Sue C. , Lu Jing , Yu Heidi H. , Wickremasinghe Hasini , Azad Mohammad A. K. , Han Meiling , Zhao Jinxin , Rao Gauri , Bergen Phillip J. , Velkov Tony , Sherry Norelle , McCarthy David T. , Aslam Saima , Schooley Robert T. , Howden Benjamin P. , Barr Jeremy J. , Zhu Yan , Li Jian
Published: November 2022

Bacteriophage (phage) therapy is rising as a promising anti-infective option to combat antimicrobial resistance; however, its clinical utilization is severely hindered by the potential emergence of phage resistance. Fortunately, certain phage resistance mechanisms can restore bacterial antibiotic susceptibility, making the combination of phages with antibiotics a potential strategic approach. Here, we demonstrated that phage resistance can also lead to increased antibiotic resistance and provided mechanistic insights into bacterial phage defense mechanisms. We discovered a repertoire of phage resistance mechanisms inKlebsiella pneumoniae, including the disruption of phage binding site (fhuA::Tn andtonB::Tn), extension of phage latent period (mnmE::Tn andrpoN::Tn) and increased mutation frequency (mutS::Tn andmutL::Tn). Different from the prevailing view that phage resistance re-sensitizes antibiotic-resistant bacteria, we revealed a bidirectional steering effect on the bacterial antibiotic susceptibility. Specifically, it was uncovered that, whilerpoN::Tn became more susceptible to colistin,mutS::Tn andmutL::Tn caused increased resistance to rifampicin and colistin. Our findings highlight the diversified strategies utilized byK. pneumoniaeto overcome phage infection and the parallel effect on the antibiotic susceptibility. Mechanism-guided phage steering represents a rational strategy that should be incorporated into phage therapy to better inform clinical decisions.
Splicing quality control mediated by DHX15 and its G-patch activator, SUGP1
Authors: Feng Qing , Krick Keegan , Chu Jennifer , Burge Christopher B.
Published: November 2022

Pre-mRNA splicing is surveilled at different stages by quality control (QC) mechanisms. The leukemia-associated DExH-box family helicasehDHX15/scPrp43, is known to disassemble spliceosomes after splicing. Here, using rapid protein depletion and analysis of nascent and mature RNA to enrich for direct effects, we identified a widespread splicing QC function for DHX15 in human cells, consistent with recentin vitrostudies. We found that suboptimal introns with weak splice sites, multiple branch points, and cryptic introns are repressed by DHX15, suggesting a general role in promoting splicing fidelity. We identified SUGP1 as a G-patch factor that activates DHX15’s splicing QC function. This interaction is dependent on both DHX15’s ATPase activity and on SUGP1’s ULM domain. Together, our results support a model in which DHX15 plays a major role in splicing QC when recruited and activated by SUGP1.
The SARS-CoV-2 protein ORF3c is a mitochondrial modulator of innate immunity
Authors: Stewart Hazel , Lu Yongxu , O’Keefe Sarah , Valpadashi Anusha , Cruz-Zaragoza Luis Daniel , Michel Hendrik A. , Nguyen Samantha K. , Carnell George W. , Lukhovitskaya Nina , Milligan Rachel , Jungreis Irwin , Lulla Valeria , Davidson Andrew D. , Matthews David A. , High Stephen , Rehling Peter , Emmott Edward , Heeney Jonathan L. , Edgar James R. , Smith Geoffrey L. , Firth Andrew E.
Published: November 2022

The SARS-CoV-2 genome encodes a multitude of accessory proteins. Using comparative genomic approaches, an additional accessory protein, ORF3c, has been predicted to be encoded within the ORF3a sgmRNA. Expression of ORF3c during infection has been confirmed independently by ribosome profiling. Despite ORF3c also being present in the 2002-2003 SARS-CoV, its function has remained unexplored. Here we show that ORF3c localises to mitochondria during infection, where it inhibits innate immunity by restricting IFN-β production, but not NF-κB activation or JAK-STAT signalling downstream of type I IFN stimulation. We find that ORF3c acts after stimulation with cytoplasmic RNA helicases RIG-I or MDA5 or adaptor protein MAVS, but not after TRIF, TBK1 or phospho-IRF3 stimulation. ORF3c co-immunoprecipitates with the antiviral proteins MAVS and PGAM5 and induces MAVS cleavage by caspase-3. Together, these data provide insight into an uncharacterised mechanism of innate immune evasion by this important human pathogen.
Single-molecule analysis of receptor-β-arrestin interactions in living cells
Authors: Grimes Jak , Koszegi Zsombor , Lanoiselée Yann , Miljus Tamara , O’Brien Shannon L. , Stepniewski Tomasz M , Medel-Lacruz Brian , Baidya Mithu , Makarova Maria , Owen Dylan M. , Shukla Arun K. , Selent Jana , Hill Stephen J. , Calebiro Davide
Published: November 2022

β-arrestin plays a key role in G protein-coupled receptor (GPCR) signaling and desensitization. Despite recent structural advances, the mechanisms that govern receptor–β-arrestin interactions at the plasma membrane of living cells remain elusive. Here, we combine single-molecule microscopy with molecular dynamics simulations to dissect the complex sequence of events involved in β-arrestin interactions with both receptors and the lipid bilayer. In contrast to the currently widely accepted model, we show that β-arrestin spontaneously inserts into the lipid bilayer and transiently interacts with receptors via lateral diffusion on the plasma membrane. Moreover, we show that following receptor interaction, the plasma membrane stabilizes β-arrestin in a membrane-bound, active-like conformation, allowing it to diffuse to clathrin coated pits separately from the activating receptor. These results challenge our current understanding of β-arrestin function at the plasma membrane, revealing a new critical role for β-arrestin pre-association with the lipid bilayer in facilitating its interactions with receptors and subsequent activation.
Synthesis and structure of high-purity BaCe0.25Mn0.75O3: an improved material for thermochemical water splitting
Authors: Bell Robert T. , Strange Nicholas A. , Plattenberger Dan A. , Shulda Sarah , Park James Eujin , Ambrosini Andrea , Heinselman Karen N. , Sugar Joshua D. , Parilla Philip A. , Coker Eric N. , McDaniel Anthony , Ginley David S.
Published: November 2022

Solar thermochemical hydrogen production (STCH) via redox-active metal oxides is an approach for direct solar-driven hydrogen generation typically using a high-temperature redox cycle involving refractory oxides and steam. Typical cycles involve high-temperature reduction of oxides to form oxygen vacancies, followed by lower temperature reaction between oxygen vacancies and steam where the oxide is re-oxidized and the steam is reduced to hydrogen. Only a few materials have demonstrated reversible cycling under the typically harsh STCH conditions (e.g. 1500°C reduction, 900°C re-oxidation) and critical questions remain on the true reversibility of non-stoichiometric multi-cation oxide systems, significantly hampered by the lack of single-phase samples for these material systems. To date, most STCH processes have relied on CeO2 as a benchmark active material, but more recently, the 12R phase of BaCe0.25Mn0.75O3 (BCM) has demonstrated greater hydrogen-generation potential at lower peak temperatures. However, previous reports of 12R-BCM have included large fractions, > 10 wt%, of secondary phases, which complicate analysis of the stability and performance. A comprehensive understanding of the redox mechanism and reversibility of the process in BCM can only be achieved with nearly single-phase samples which, to date, have been difficult to produce. Here two approaches to BCM synthesis are reported: solid state and sol–gel-based routes. It is demonstrated that both routes can be tuned to produce the 12R structure with > 97 wt% yield when annealed ≥1450°C. Herein synchrotron-based diffraction measurements of rhombohedral 12R-BCM enabled characterization of the anisotropy between thermal expansion along the c-axis and within the ab plane. The impact of high-temperature redox cycling on the stability and phase fraction of the 12R-BCM polytype was also investigated. These results offer two viable routes for synthesis of high-purity 12R-BCM critically needed for evaluating the efficacy of BCM as a STCH material and validate its ability to split water at lower temperatures over extended numbers of redox cycles.
Linking knowledge acquisition, knowledge dissemination, and manufacturing SMEs’ sustainable performance: the mediating role of knowledge application
Authors: Al Koliby Ibraheem Saleh , Mohd Suki Norazah , Abdullah Haim Hilman
Published: November 2022

Purpose

This study aims to examine the impact of knowledge acquisition and dissemination on the sustainable performance of small- and medium-sized enterprises (SMEs). Additionally, the mediating role of knowledge application in this relationship is investigated.

Design/methodology/approach

Data collected from 428 manufacturing SMEs in Malaysia were analyzed using the partial least squares structural equation modeling approach.

Findings

The results reveal that knowledge acquisition significantly impacts the sustainable performance of manufacturing SMEs, and knowledge application partially mediates this impact. Cutting-edge knowledge from within or outside the organization enables a deeper understanding of information regarding new products/services, a list of competing suppliers, consumer preferences and so on.

Research limitations/implications

This study combined the knowledge-based view theory and the triple bottom line framework into a unified conceptual framework and examined the impact of knowledge acquisition and dissemination on manufacturing SMEs’ sustainable performance as well as the mediating role of knowledge application on manufacturing SMEs’ sustainable performance.

Practical implications

Manufacturing SMEs should emphasize knowledge application in business operations and encourage employees to develop and enhance their knowledge acquisition and dissemination to leverage knowledge in ways that enhance business operations, produce new products and generate new knowledge assets.

Originality/value

This study is unique in that it highlights the partially mediated effects of knowledge application on the linkages between knowledge acquisition and manufacturing SMEs’ sustainable performance and the fully mediated effects of knowledge application on the association between knowledge dissemination and sustainable performance of manufacturing SMEs.
The truant distributor: retain or replace?
Authors: Kamath Renuka , Agrawal Pankaj , Ahmed Shoaib
Published: November 2022

Learning outcomes

This case highlights the challenges faced by a young and inexperienced Area Sales Manager (ASM), early in her career. This is an often-encountered situation by fresh graduates. Through the analysis of the case, the students will be able to: ■ understand challenges a young manager faces in taking over a new, unfamiliar and underperforming territory; ■ analyze and learn to manage data and identify performance gaps in the territory, by selecting the right metrics; ■ learn the factors for evaluating the performance of current intermediaries (distributors); and ■ appreciate the importance of managing all stakeholders – internal team and building a strong relationship with the intermediaries – both distributors and retailers.

Case overview/synopsis

Kavita Kaur, the new Area Sales Manager at Broadway India Pvt. Ltd. (BIPL), had just taken over the Chhattisgarh sales territory in January 2020. Fresh out of a B-school, it was her first job, and her allotted territory was severely lagging growth at only 1%, compared to an all-India country growth at 13% in 2019, over the previous year. The territory was operated by established intermediaries (distributors) with long associations with BIPL. Based on her data analyses of distributors’ performance, Kaur started her retail visit with the highest selling distributor’s area (Sharda Agencies) to confirm her understanding of what the data had shown her. Following her retail visit and a meeting with Sharda Agencies, the situation turned for the worse. An email bordering to a threat from him took her aback. Kaur now had to make a choice to ensure growth in her new territory. Her options were between placating the current distributor or appointing a new one – should she retain or replace? Both had their own risks.

Complexity academic level

This case is intended for use at the postgraduate level in courses such as sales management, channel management and strategic marketing courses, as well as in executive management programs. The case is relevant from the context of channel management in India, where channel intermediaries can be very demanding. The case will give students a practical hands-on decision-making situation, where there are complexities of quantitative and qualitative nature. It will also help young graduates prepare for real life situations where the assigned territory is struggling in performance and a lot is expected from the new recruits.

Supplementary materials

Teaching notes are available for educators only.

Subject code

CSS 8: Marketing.
Achieving sustainability in South African commercial properties: the impact of innovative technologies on energy consumption
Authors: Moghayedi Alireza , Hübner Dylan , Michell Kathy
Published: November 2022

Purpose

This study aims to examine the concept of innovative technologies and identify their impacts on the environmental sustainability of commercial properties in South Africa. This slow adoption is attributed to South Africa’s energy building regulation, SANS 204, which does not promote energy-conscious commercial property development. Furthermore, it was observed that buildings waste significant amounts of energy as electrical appliances are left on when they are not in use, which can be prevented using innovative technologies.

Design/methodology/approach

The researchers attempted to evaluate the impact of innovative technologies through an overarching constructivist mixed-method paradigm. The research was conducted using a multi-case study approach on green buildings which had innovative technologies installed. The data collection took the form of online, semi-structured interviews, where thematic analysis was used to identify emergent themes from the qualitative data, and descriptive statistics was used to evaluate the quantitative data.

Findings

It was found that implementing innovative technologies to reduce the energy consumption of commercial buildings could achieve energy savings of up to 23%. Moreover, a commercial building’s carbon footprint can be reduced to 152CO2/m2 and further decreased to 142CO2/m2 through the adoption of a Photovoltaics plant. The study further found that innovative technologies improved employee productivity and promoted green learning and practices.

Originality/value

This research demonstrated the positive impact innovative technologies have on energy reduction and the sustainability of commercial properties. Hence, facility managers should engage innovative technologies when planning a commercial development or refurbishment.
The impact of servitization on trade credit in manufacturing firms: a signaling theory perspective
Authors: Wang Weijiao , Chen Shanshan , Shao Jinan , Chu Junfei , Yuan Zhe
Published: November 2022

Purpose

The aim of this study is to empirically test the link between servitization and trade credit in manufacturing firms as well as the boundary conditions of this link.

Design/methodology/approach

Using a unique dataset of 4,974 observations covering 838 manufacturing firms publicly listed in the United States during 1990–2020, this study examines the impact of servitization on trade credit and the moderating impacts of financial slack and service relatedness based on fixed-effect regression models.

Findings

The authors find that servitization shows a U-shaped relationship with trade credit. Besides, financial slack negatively moderates this U-shaped relationship whereas service relatedness has no significant impact on this relationship.

Originality/value

This paper is the first to empirically verify the influence of servitization on trade credit in manufacturing firms based on longitudinal secondary data and signaling theory. The research findings can provide several important theoretical and managerial implications for scholars and practitioners in operations management.