bluuebunny/crossref_metadata_2025 huggingface dataset:
Decoding multicellular niche formation in the tumour microenvironment from nonspatial single-cell expression data
Authors: Yu Chengxin , Geuenich Michael J , Ge Sabrina , Jang Gun-Ho , Ju Tan Tiak , Zhang Amy , O’Kane Grainne M , Notta Faiyaz , Campbell Kieran R
Published: August 2024

Accurate inference of granular cell states that co-occur within the tumour microenvironment (TME) is central to defining pro- and anti-tumour environments. However, to reliably identify recurrent coexisting cell populations it is fundamental to analyze datasets encompassing a substantial number of tumour samples with a resolution sufficient to capture granular cell states. Here, we leverage eight scRNA-seq datasets of pancreatic ductal adenocarcinoma (PDAC) in a unique discovery-validation setup and find reproducible cell states, gene programs, and cellular niches that are predictive of specific clinical outcomes. Across tumours, we show highly consistent co-occurrence of cell states within and between lineages, including those reflecting known andde novocellular interactions alongside the formation of multi-cellular clusters such as tertiary lymphoid structures. In addition, we develop a novel probabilistic model to quantify multi-cellular communities directly from atlas-scale scRNA-seq datasets. This model identified cellular niches predictive of clinical outcomes including communities associated with response to therapy and with specific KRAS mutations. Together, this work lays the foundation for inferring reproducible multicellular niches directly from large nonspatial scRNA-seq atlases and linking their presence in individual patients to prognosis and therapy response.
OPA1 mediates cardiac function and metabolism: in silico and in vivo evidence
Authors: Fong-McMaster Claire , Pulente Serena M. , Kennedy Luke , Smith Tyler K.T. , Myers Stephanie , Kanaan Michel , Karam Charbel , Cope Matthew , Lorenzen-Schmidt Ilka , Goergen Craig J. , Fullerton Morgan D. , Cuperlovic-Culf Miroslava , Mulvihill Erin E. , Harper Mary-Ellen
Published: August 2024

OPA1 is an inner mitochondrial membrane protein that mediates diverse signaling processes. OPA1 is important for cardiac function and protects against cardiac insults such as ischemia reperfusion injury. We sought to further assess OPA1 in human and mouse cardiac pathologies, hypothesizing that OPA1 may also function in a protective manner in chronic heart failure. Bioinformatic analyses of histological and transcript data from the GTEx database indicated that OPA1 expression levels vary in the human heart, where elevated OPA1 transcript levels were correlated with fatty acid, branch chain amino acid and contractile gene signatures. To experimentally assess these correlations, mice with a 1.5-fold whole body OPA1 overexpression (OPA1-OE) were subjected to transverse aortic constriction surgery and displayed improved 2D and 4D cardiac functional parameters compared to WT mice. OPA1-OE mice had no induction of fibrotic transcript markers and displayed sustained transcript levels of fatty acid, branch chain amino acid and contractile markers. Maximal oxidative capacity was sustained in both WT and OPA1-OE cardiac myofibers post-TAC. These results further demonstrate the important role of OPA1 in mediating cardiac function and highlight protective signaling pathways.
Synthesis and in vitro evaluation shows disquaramide compounds are a promising class of anti-leishmanial drugs
Authors: Roys Hayden , Arykbayeva Assyl , Friedman Sarah K. , Gifford Gabriel , Palmer Eva R. , Rogers Alex , Tran Emily N. H. , Fry Lucy , Weaver Alexx , Bowlin Anne , Jones Meghan D. , Eledge Michael R. , Boehme Karl W. , Naumiec Gregory R. , Weinkopff Tiffany
Published: August 2024

An increasing number of treatment failures with current pharmaceutics, as well as a lack of a vaccine, demonstrates the need to develop new treatment options for leishmaniasis. Herein, we describe the synthesis and in vitro analysis of 24 disquaramide compounds targeting theLeishmania majorparasite. Of the compounds that were evaluated, six of them (13,19,20,22,24, and26) were capable of significantly decreasing the number of parasites by up to 42% compared to the control by day four. This demonstrates that disquaramides either impair parasite replication or have leishmancidal effects. Additionally, none of the disquaramide compounds tested displayed host cell cytotoxicity. These experiments provide evidence that disquaramides have the potential to be effective anti-leishmanial therapeutics.
Brain structure and activity predicting cognitive maturation in adolescence
Authors: Zhu Junda , Garin Clément M. , Qi Xue-Lian , Machado Anna , Wang Zhengyang , Ben Hamed Suliann , Stanford Terrence R. , Salinas Emilio , Whitlow Christopher T. , Anderson Adam W. , Zhou Xin Maizie , Calabro Finnegan J. , Luna Beatriz , Constantinidis Christos
Published: August 2024

Cognitive abilities of primates, including humans, continue to improve through adolescence1,2. While a range of changes in brain structure and connectivity have been documented3,4, how they affect neuronal activity that ultimately determines performance of cognitive functions remains unknown. Here, we conducted a multilevel longitudinal study of monkey adolescent neurocognitive development. The developmental trajectory of neural activity in the prefrontal cortex accounted remarkably well for working memory improvements. While complex aspects of activity changed progressively during adolescence, such as the rotation of stimulus representation in multidimensional neuronal space, which has been implicated in cognitive flexibility, even simpler attributes, such as the baseline firing rate in the period preceding a stimulus appearance had predictive power over behavior. Unexpectedly, decreases in brain volume and thickness, which are widely thought to underlie cognitive changes in humans5did not predict well the trajectory of neural activity or cognitive performance changes. Whole brain cortical volume in particular, exhibited an increase and reached a local maximum in late adolescence, at a time of rapid behavioral improvement. Maturation of long-distance white matter tracts linking the frontal lobe with areas of the association cortex and subcortical regions best predicted changes in neuronal activity and behavior. Our results provide evidence that optimization of neural activity depending on widely distributed circuitry effects cognitive development in adolescence.
Dynamic convergence of autism disorder risk genes across neurodevelopment
Authors: Fernandez Garcia Meilin , Retallick-Townsley Kayla , Pruitt April , Davidson Elizabeth , Dai Yi , Fitzpatrick Sarah E. , Sen Annabel , Cohen Sophie , Livoti Olivia , Khan Suha , Dossou Grace , Cheung Jen , Deans P.J. Michael , Wang Zuoheng , Huckins Laura , Hoffman Ellen , Brennand Kristen
Published: August 2024

Over a hundred risk genes underlie risk for autism spectrum disorder (ASD) but the extent to which they converge on shared downstream targets to increase ASD risk is unknown. To test the hypothesis that cellular context impacts the nature of convergence, here we apply a pooled CRISPR approach to target 29 ASD loss-of-function genes in human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells, glutamatergic neurons, and GABAergic neurons. Two distinct approaches (gene-level and network-level analyses) demonstrate that convergence is greatest in mature glutamatergic neurons. Convergent effects are dynamic, varying in strength, composition, and biological role between cell types, increasing with functional similarity of the ASD genes examined, and driven by cell-type-specific gene co-expression patterns. Stratification of ASD genes yield targeted drug predictions capable of reversing gene-specific convergent signatures in human cells and ASD-related behaviors in zebrafish. Altogether, convergent networks downstream of ASD risk genes represent novel points of individualized therapeutic intervention.
The Hemopurifier removes extracellular vesicles and microRNAs from renal perfusates following controlled oxygenated rewarming of discarded donor kidneys
Authors: de Necochea Campion Rosalia , Pesqueira Miguel , Vallejos Paul , McCullough Cameron , Bloesch Alessio , La Rosa Steven P.
Published: August 2024

Kidney transplantation is considered the benchmark treatment for end-stage kidney disease patients. Nevertheless, the demand for donor kidneys is continuously on the rise and the scarcity of suitable kidneys poses a significant hindrance for patients and healthcare providers. One approach is to extend the criteria for the use of kidneys from deceased brain death and deceased circulatory death donors. Use of these organs especially from these extended criteria donors is associated with ischemia reperfusion injury (IRI) and resultant delayed graft function (DGF) as well as increased rates of allograft rejection. One approach to try to lessen these complications as well as increase the time the assessment of organ viability is the use of machine perfusion on recovered kidneys. In this study we obtained perfusates from discarded organs that had undergone Controlled Oxygenated Rewarming. Perfusates were analyzed for extracellular vesicles (EVs), dsDNA associated with EVs and microRNAs. These perfusates were then pumped over the Aethlon Hemopurifier, a plasma separator with an affinity resin containing the lectinGalanthus nivalisagglutinin (GNA). Following treatment with the Hemopurifier, a diminution in extracellular vesicles, dsDNA associated with EVs and microRNAs was observed. These results support a future study of the Aethlon Hemopurifier as part of a machine perfusion circuit to explore if the device decreases these mediators in a dynamic circuit and is associated with improved function of retrieved kidneys.
Musicality enhances selective attention: spatiotemporal insights from precise separation of simultaneous neural responses
Authors: Manting Cassia Low , Pantazis Dimitrios , Gabrieli John , Lundqvist Daniel
Published: August 2024

1.

We precisely resolved simultaneous neural responses to their driving stimuli and classified them to different selective attention conditions towards specific melodies within mixtures. Magnetoencephalographic findings reveal the influence of participants’ musicality and task performance on the recruitment of cortical regions in bottom-up and top-down attentional processes. Across parietal regions, musicality and performance correlated positively with top-down attention at the left hemisphere, but negatively with bottom-up attention at the right. In the right prefrontal cortex, individuals who maintained selective attention over the tone duration performed better and were more musical. These results suggest that musical training boosts performance by enhancing top-down attention, reducing bottom-up distractions, and sustaining selective attention overtime, with these effects mediated by the frontoparietal cortex. This work advances our understanding of neural selective attention mechanisms in complex soundscapes and underscores the potential of musical training for cognitive enhancement. Our breakthrough approach effectively captures cognitive effects with frequency-tagging, creating new possibilities for scientific applications.
Decoding protein glycosylation by an integrative mass spectrometry-basedde novosequencing strategy
Authors: Gao Jing , Chen Hongxu , Yin Hongrui , Chen Xin , Yang Zhicheng , Wang Yuqiu , Wu Jianhong , Tian Yinping , Shao Hong , Wen Liuqing , Zhou Hu
Published: August 2024

Glycoproteins, representing over 50% of human proteins and most biopharmaceuticals, are crucial for regulating various biological processes. The complexity of multiple glycosylation sites, often leading to incomplete sequence coverage and ambiguous glycan modification profiles. Here, we developed an integrative mass spectrometry-based approach for decoding unknown glycoproteins, which is featured with the combination of deglycosylation-mediatedde novosequencing with glycosylation site characterization. We utilized enzymatic deglycosylation ofN-/O-glycan to achieve comprehensive sequence coverage. Additionally, EThcD fragmentation enables the identification of high-quality long peptides, facilitating precise protein assembly. We subsequently applied this method tode novosequencing of the highly glycosylated therapeutic fusion protein Etanercept (Enbrel®). We also sequenced three new tumor necrosis factor receptor (TNFR): Fc-fusion biologics with largely unknown sequences, unveiling subtle distinctions in the primary sequences. Furthermore, we characterizedN- andO-glycosylation modifications of these proteins at subunit, glycopeptide, and glycan levels. This strategy bridges the gap between thede novosequencing and glycosylation modification, providing complete information of the primary structure and glycosylation modifications for glycoproteins. Notably, our method could be a robust solution for accurate sequencing of the glycoproteins and has practical value not only in basic research but also in the biopharmaceutical industry.
Tracing the genetic diversity of the bread wheat D genome
Authors: Wang Zihao , Wang Wenxi , He Yachao , Xie Xiaoming , Yang Zhengzhao , Zhang Xiaoyu , Niu Jianxia , Peng Huiru , Yao Yingyin , Xie Chaojie , Xin Mingming , Hu Zhaorong , Sun Qixin , Ni Zhongfu , Guo Weilong
Published: August 2024

Bread wheat (Triticum aestivum) became a globally dominant crop after incorporating the D genome from donor speciesAegilops tauschii, while evolutionary history shaping the D genome during this process remains elusive. Here, we proposed a renewed evolutionary model linkingAe. tauschiiand hexaploid wheat D genome, based on an ancestral haplotype map covering a total of 762Ae. tauschiiand hexaploid wheat accessions. We dissected the evolutionary process ofAe. tauschiilineages and clarified L3 as the most ancient lineage. A few independent intermediate accessions were reported, demonstrating the low-frequent inter-sublineage geneflow enriched the diversity ofAe. tauschii. We discovered that the D genome of hexaploid wheat inherited from a unified ancestral template, but with a mosaic composition that is highly mixed by threeAe. tauschiiL2 sublineages located in the Caspian coastal region, suggesting the early agricultural activities facilitate the innovation of D genome compositions that finalized the success of hexaploidization. We further found that the majority (65.6%) of polymorphisms were attributed to novel mutations absent during the spreading of bread wheat, and also identified largeAe. tauschiiintrogressions from wildAegilopslineages, expanding the diversity of wheat D genome and introducing beneficial alleles. This work decoded the mystery of the wheat hexaploidization process and the evolutionary significance of the multi-layered origins of the genetic diversity of the bread wheat D genome.
Climate drives geographic variation in individualPeromyscus leucopusimmunity against zoonotic disease
Authors: Assis Vania R. , McCain Kailey , Munds Rachel A. , Brehm Allison M. , Orrock John L. , Martin Lynn B.
Published: August 2024

Geographic variation in host immunity could have major influences on disease dynamics, including zoonotic forms that affect humans. Such variation in immunity could be driven by variation in climate, either directly or, more likely, indirectly via resource availability. We compared the immune gene expression of wildPeromyscus leucopusmice, the primary reservoir for the bacterium that causes Lyme disease,Borrelia burgdorferi, among eight sites spanning 1,400 km of the northeastern United States. We discovered that climate conditions at sites strongly predicted immunity to the most common zoonotic pathogen in the U.S.: mice from warmer, wetter sites were more prepared to resistB. burgdorferiinfections. Our results reveal a novel pathway by which climate change could affect pathogen spillover or zoonotic epidemics generally.
Infection characteristics amongSerratia marcescenscapsule lineages
Authors: Anderson Mark T. , Himpsl Stephanie D. , Kingsley Leandra G. , Smith Sara N. , Bachman Michael A. , Mobley Harry L. T.
Published: August 2024

Serratia marcescensis a healthcare-associated pathogen that causes bloodstream infections, pneumonia, and urinary tract infections. The capsule polysaccharide ofS. marcescensis a critical fitness determinant during infection and recent work established the relationship between capsule locus (KL) genetic sequences within the species. Strains belonging to KL1 and KL2 capsule clades produce sialylated polysaccharides and represent the largest subpopulation of isolates from clinical origin while theS. marcescenstype strain and other environmental isolates were classified as KL5. In this work, the contribution of these and other capsules to pathogenesis in multiple infection models was determined. Using a murine tail vein injection model of bacteremia, clinical strains demonstrated capsule-dependent colonization of spleen, liver, and kidney following inoculation. The KL5 strain, in contrast, exhibited no loss of survival in this model when capsule genes were deleted. Furthermore, the wild-type KL5 strain was cleared more rapidly from both the spleen and liver compared to a KL1 strain. Similar results were observed in a bacteremic pneumonia model in that all tested strains of clinical origin demonstrated a requirement for capsule in both the primary lung infection site and for bloodstream dissemination to other organs. Finally, strains from each KL clade were tested for the role of capsule in internalization by bone marrow-derived macrophages. Only the sialylated KL1 and KL2 clade strains, representing the majority of clinical isolates, exhibited capsule-dependent inhibition of internalization, suggesting that capsule-mediated resistance to macrophage phagocytosis may enhance survival and antibacterial defenses during infection.

IMPORTANCE

Bacterial bloodstream infections result from evasion of the host innate immune system and stable colonization following an initial inoculation event from either an internal or external source. Capsule polysaccharides play a protective role forSerratia marcescensduring bacteremia but there is abundant genetic diversity at the capsule-encoding locus within the species. This study compares the infection characteristics ofS. marcescensisolates belonging to five different capsule types and defines the contributions to infection fitness for each type. By characterizing the differences in capsule dependence and infection potential betweenS. marcescensstrains, efforts to combat these life-threatening infections can be focused toward identifying strategies that target the most critical genetic lineages of this important opportunistic pathogen.
Dna2 nuclease resolves RNA:DNA hybrids at double-strand breaks
Authors: Mojumdar Aditya , Granger Courtney , Cobb Jennifer A.
Published: August 2024

DNA double-strand breaks (DSBs) are highly detrimental to cells, as improper repair can result in inheritable genetic rearrangements or cell death. The role of RNA:DNA hybrids (RDHs) in DSB repair remains poorly understood, but their transient accumulation and subsequent resolution are crucial for accurate repair. The absence of the end-joining factor Nej1 at DSBs significantly reduced RDH levels, which was linked to increased activity of the Dna2 nuclease. Dna2 limits the accumulation of hybrids at DSBs, with levels rising in the presence of a nuclease-dead Dna2 andRNH201deletion. Dna2 has a heightened preference for resolving RDHs with 5’ RNA overhangs compared to duplex substrates with 5’ DNA overhangs. This selective resolution by Dna2 helps restrict hybrid accumulation at DSBs and promotes resection, a function not shared by Exo1. This study underscores the multifunctional roles of canonical repair factors in ensuring efficient homology-directed repair.

Graphical Abstract
The physical chemistry of interphase loop extrusion
Authors: Tortora Maxime M.C. , Fudenberg Geoffrey
Published: August 2024

Loop extrusion constitutes a universal mechanism of genome organization, whereby structural maintenance of chromosomes (SMC) protein complexes load onto the chromatin fiber and generate DNA loops of increasingly-larger sizes until their eventual release. In mammalian interphase cells, loop extrusion is mediated by the cohesin complex, which is dynamically regulated by the interchange of multiple accessory proteins. Although these regulators bind the core cohesin complex only transiently, their disruption can dramatically alter cohesin dynamics, gene expression, chromosome morphology and contact patterns. Still, a theory of how cohesin regulators and their molecular interplay with the core complex modulate genome folding remains at large. Here we derive a model of cohesin loop extrusion from first principles, based onin vivomeasurements of the abundance and dynamics of cohesin regulators. We systematically evaluate potential chemical reaction networks that describe the association of cohesin with its regulators and with the chromatin fiber. Remarkably, experimental observations are consistent with only a single biochemical reaction cycle, which results in a unique minimal model that may be fully parameterized by quantitative protein measurements. We demonstrate how distinct roles for cohesin regulators emerge simply from the structure of the reaction network, and how their dynamic exchange can regulate loop extrusion kinetics over time-scales that far exceed their own chromatin residence times. By embedding our cohesin biochemical reaction network within biophysical chromatin simulations, we evidence how variations in regulatory protein abundance can alter chromatin architecture across multiple length- and time-scales. Predictions from our model are corroborated by biophysical and biochemical assays, optical microscopy observations, and Hi-C conformation capture techniques. More broadly, our theoretical and numerical framework bridges the gap betweenin vitroobservations of extrusion motor dynamics at the molecular scale and their structural consequences at the genome-wide level.
Oxytocin and vasopressin 1a receptor alterations in the superior temporal sulcus and hypothalamus in schizophrenia
Authors: Snowden Ariel W. , Schwartz Sarah E. , Smith Aaron L. , Goodman Mark M. , Freeman Sara M.
Published: August 2024

Schizophrenia is a chronic, severe psychiatric condition characterized in part by social impairments. As social cognitive functioning is a major predictor of successful life outcomes in schizophrenia, there is a critical need to determine the neurobiological basis of social impairments in schizophrenia. The current study used receptor autoradiography to examine vasopressin 1a (AVPR1a) and oxytocin receptor (OXTR) densities in the postmortem brain tissue of individuals who had schizophrenia (N=23) relative to unaffected matched controls (N=18). We analyzed the superior temporal sulcus, a brain region that is highly implicated in social perception and shows aberrant functioning in schizophrenia. GreaterAVPR1a binding densities were observed relative to OXTR. Increases in AVPR1a densities with advanced age in females who had schizophrenia were also observed. This finding in the superior temporal sulcus may explain a shift in positive symptom severity(paranoia/suspiciousness) that has been observed with advanced age in women with schizophrenia. In addition, increased OXTR and a trend toward increased AVPR1a densities were observed in the hypothalamus in schizophrenia. The hypothalamus synthesizes oxytocin and vasopressin in the brain and is the initiator of the hypothalamic-pituitary-adrenal axis, which facilitates the fight or flight stress response. These receptor systems may be upregulated to compensate for possibly low exogenous oxytocin and vasopressin release from the hypothalamus in schizophrenia. Our findings show age- and sex-dependent effects on nonapeptide receptor binding that shed light onto the neurobiology of the social brain in the progression of schizophrenia.
Clostridium scindens: an endocrine keystone species in the mammalian gut
Authors: Daniel Steven L. , Ridlon Jason M.
Published: August 2024

Clostridium scindensis a keystone human gut microbial taxonomic group that, while low in abundance, has a disproportionate effect on bile acid and steroid metabolism in the mammalian gut. Numerous studies indicate that the two most studied strains ofC. scindens(i.e., ATCC 35704 and VPI 12708) are important for a myriad of physiological processes in the host. We focus on both historical and current microbiological and molecular biology work on the Hylemon-Björkhem pathway and the steroid-17,20-desmolase pathway that were first discovered inC. scindens.Our most recent analysis now calls into question whether strains currently defined asC. scindensrepresent two separate taxonomic groups. Future directions include developing genetic tools to further explore the physiological role bile acid and steroid metabolism by strains ofC. scindens, and the causal role of these pathways in host physiology and disease.
Recontextualizing Eukaryogenesis via Computational Analysis of RNA Processing in 16,449 Archaeal Genomes
Authors: Kannan Srinivasan
Published: August 2024

The analysis of proteins related to RNA processing reveals intriguing aspects of the evolutionary transition from archaea to eukaryotes. Eukaryagenesis is the process in which the first eukaryote came into existence, with multiple hypotheses on the order of events. These hypothesis often focus on the mitochondria and cell skeletal structure, without much discussion on eukaryotic signature proteins(ESP). ESP is integral in increasing the longevity of RNA and for the increase in the variety of proteins able to be produced which ultimately increases fitness of eukaryotes. 16,449 genomes and 10 proteins were acquired and BLAST was run for each superclass for each protein. BLAST scores were compared between superclasses and analyzed. Results for proteins such as Prp9, Rex3, Histone H2A, H2B, and Histone 3 indicate that there is no substantial difference between BLAST results implying a transitional state consistent withE3model. The results for Smd3 and Ceg1 highlight that a group of Asgardarchaeota and Diaforarchaearchaea were different to other types of archaea. These groups likely underwent similar environmental pressures giving organisms with these genes higher fitness. These early genes evolved into their eukaryotic versions, while other genes like Histone 4, Abd1, and Lsm2 may have had ancestral prototypes present across archaea. Gene prototypes likely served different purposes, but the presence of such prototypes imply that evolution of the nucleus was likely independent from the presence of the mitochondria.
Heterologous Surface Display Reveals Conserved Complement Inhibition and Functional Diversification ofBorrelia burgdorferiElp Proteins
Authors: Hill Nathan , Matulina Lara M. , MacIntyre Cameron , Hassani M. Amine , Thomas Sheila , Luban Matteo , Ward Isabelle , Abdalla Amina , Leong John M. , Garcia Brandon L. , Lemieux Jacob E.
Published: August 2024

Lyme disease is a tick-borne spirochetosis with diverse clinical manifestations. Phenotypic variation amongBorrelia burgdorferistrains correlates with variable manifestations of Lyme disease in humans; this diversity is attributed in part to variation in surface-exposed lipoproteins, which are targets of the human antibody response and contribute to tissue adhesion, immune evasion, and other host interactions. ManyB. burgdorferilipoproteins are encoded as multi-copy gene families including the OspE/F- like leader peptide (Elp) protein family. To characterize Elp allelic variants, we adapted thePseudomonas syringaeice nucleation protein (INP) system to presentB. burgdorferilipoproteins on the surface ofEscherichia coli. We identified interactions with classical complement proteins and mapped binding regions in theE. colisystem. We validated interactions using recombinant proteins andB. burgdorferisurface display. By assessing potential interactions with extracellular matrix components, we identified a novel interaction between Elp proteins and perlecan, a component of mammalian basement membranes, and revealed the bifunctional nature of Elps. Our findings reveal that Elps have undergone functional diversification while maintaining classical complement inhibition mediated by potent and conserved C1s binding and demonstrate thatE. colisurface display offers an efficient, cost-effective, and relatively high throughput approach to characterizeB. burgdorferilipoproteins.
Deep mutational scanning of EccD3reveals the molecular basis of its essentiality in the mycobacterium ESX secretion system
Authors: Trinidad Donovan D. , Macdonald Christian B. , Rosenberg Oren S. , Fraser James S. , Coyote-Maestas Willow
Published: August 2024

Tuberculosis remains the deadliest infectious disease in the world and requires novel therapeutic targets. The ESX-3 secretion system, which is essential for iron and zinc homeostasis and thusM. tuberculosissurvival, is a promising target. In this study, we perform a deep mutational scan on the ESX-3 core protein EccD3in the model organismM. smegmatis. We systematically investigated the functional roles of 145 residues across the soluble ubiquitin-like domain, the conformationally distinct flexible linker, and selected transmembrane helices of EccD3. Our data combined with structural comparisons to ESX-5 complexes support a model where EccD3stabilizes the complex, with the hinge motif within the linker being particularly sensitive to disruption. Our study is the first deep mutational scan in mycobacteria, which could help guide drug development toward novel treatment of tuberculosis. This study underscores the importance of context-specific mutational analyses for discovering essential protein interactions within mycobacterial systems.
Patient mutations in DRP1 perturb synaptic maturation of cortical neurons
Authors: Baum TB , Bodnya C , Costanzo J , Gama V
Published: August 2024

With the advent of exome sequencing, a growing number of children are being identified withde novoloss of function mutations in the dynamin 1 like (DNM1L)gene encoding the large GTPase essential for mitochondrial fission, dynamin-related protein 1 (DRP1); these mutations result in severe neurodevelopmental phenotypes, such as developmental delay, optic atrophy, and epileptic encephalopathies. Though it is established that mitochondrial fission is an essential precursor to the rapidly changing metabolic needs of the developing cortex, it is not understood how identified mutations in different domains of DRP1 uniquely disrupt cortical development and synaptic maturation. We leveraged the power of induced pluripotent stem cells (iPSCs) harboring DRP1 mutations in either the GTPase or stalk domains to model early stages of cortical developmentin vitro. High-resolution time-lapse imaging of axonal transport in mutant DRP1 cortical neurons reveals mutation-specific changes in mitochondrial motility of severely hyperfused mitochondrial structures. Transcriptional profiling of mutant DRP1 cortical neurons during maturation also implicates mutation dependent alterations in synaptic development and calcium regulation gene expression. Disruptions in calcium dynamics were confirmed using live functional recordings of 100 DIV (days in vitro) mutant DRP1 cortical neurons. These findings and deficits in pre- and post-synaptic marker colocalization using super resolution microscopy, strongly suggest that altered mitochondrial morphology of DRP1 mutant neurons leads to pathogenic dysregulation of synaptic development and activity.
Methanol chemoreceptor MtpA- and flagellin protein FliC-dependent methylotaxis determines the spaciotemporal colonization of PPFM in the phyllosphere
Authors: Katayama Shiori , Shiraishi Kosuke , Kaji Kanae , Kawabata Kazuya , Tamura Naoki , Tani Akio , Yurimoto Hiroya , Sakai Yasuyoshi
Published: August 2024

Pink-pigmented facultative methylotrophs (PPFMs) capable of growth on methanol are dominant and versatile phyllosphere bacteria that provide positive effects on plant growth through symbiosis. However, the spatiotemporal behavior of PPFMs on plant surfaces and its molecular basis are unknown. Here we show thatMethylobacteriumsp. strain OR01 inoculated onto red perilla seeds colonized across the entire plant surface in the phyllosphere concomitant with the plant growth. FliC flagellin proteins required for motility were necessary for distributed colonization on plant leaves, but not for colonization at the leaf periphery. Methanol-sensing chemoreceptor MtpA-dependent chemotaxis (methylotaxis; chemotaxis toward methanol) facilitated the bacterial movement from the peripheral to the inner part of leaves and further entry into the stomatal cavity, indicating that methanol functions as a volatile messenger attracting PPFMs to particular leaf locations possibly to support with photosynthesis and to afford protection from pathogenic invasion.
A new dual-thickness semi-transparent beamstop for small-angle X-ray scattering
Authors: Wu Haijuan , Li Zhihong
Published: August 2024

An innovative dual-thickness semi-transparent beamstop designed to enhance the performance of small-angle X-ray scattering (SAXS) experiments is introduced. This design integrates two absorbers of differing thicknesses side by side into a single attenuator, known as a beamstop. Instead of completely stopping the direct beam, it attenuates it, allowing the SAXS detector to measure the transmitted beam through the sample. This approach achieves true synchronization in measuring both scattered and transmitted signals and effectively eliminates higher-order harmonic contributions when determining the transmission light intensity through the sample. This facilitates and optimizes signal detection and background subtraction. This contribution details the theoretical basis and practical implementation of this solution at the SAXS station on the 1W2A beamline at the Beijing Synchrotron Radiation Facility. It also anticipates its application at other SAXS stations, including that at the forthcoming High Energy Photon Source, providing an effective solution for high-precision SAXS experiments.
Factors affecting user intention to use social commerce continuously from a habit perspective
Authors: Handarkho Yonathan Dri
Published: August 2024

Purpose

This study proposes a theoretical model to explain user intention to continue engaging with Social Commerce (SC) from a habit perspective. The research uses social impact theory, user personal traits, and SC quality to explain how user habits are formed in SC, leading to continued usage.

Design/methodology/approach

The study collected data from 868 Indonesian respondents using a cross-sectional field design. SEM analysis confirmed the proposed theoretical model, calculating direct, indirect, and moderating effects.

Findings

The results showed that the social aspect is the dominant construct influencing users’ habit of using SC. Further, the outcome indicates that habit significantly predicts Continuity usage. Profoundly, subjective norms are the most significant predictors of habit, followed by self-efficacy, content quality, and herd behavior. Meanwhile, Trust and Social Support only indirectly affect Habit through self-efficacy and content quality, respectively, as mediators. Additionally, the moderating effect analysis revealed that age and gender play a role in habit formation.

Originality/value

This study specifically explores the factors affecting the development of habits in SC usage, leading to repeated behaviors. This area has not been thoroughly examined in previous research. Therefore, this study seeks to address this gap by investigating how habits are formed through social interactions on SC platforms. Understanding habit formation provides an alternative way of comprehending the continued use of SC, as it is considered a significant factor that leads to continued intention.
The macroeconomic overview of the alcohol industry: a perspective from the emerging market of Asia
Authors: Dsouza Sarah Lucia , Chopra Rita Rani , Nayak Raghavendra
Published: August 2024

Purpose

This study aims to analyze the relationship between the alcohol brewing industry and the macroeconomic variables of the emerging market of Asia.

Design/methodology/approach

The study uses secondary data for the period of 32 years and applies the autoregressive distributed lag-error correction method (ARDL-ECM) approach to understand short- and long-run dynamics in the alcohol industry by considering macroeconomic variables.

Findings

The findings of the study confirm the existence of a long-run relationship between the alcohol brewing industry and the macroeconomic variables considered for this study.

Research limitations/implications

The authors present a few limitations of this study. First, this study uses secondary data originating from one of the emerging markets of Asia. Second, the study is solely conducted from an economic perspective rather than from a social or health perspective. Finally, the study considers the data originating from the organized sector of the alcohol industry of India.

Practical implications

The study will be helpful to the researchers in guiding the future course of research in the area of the alcohol industry. This study can be helpful to the policymakers in framing the National Alcohol and taxation Policy. This study also helps both the producers and exporters to strategize sustainable production and trade of alcoholic beverages.

Originality/value

To the best of the authors’ knowledge, this study is the first of its kind to analyze the alcohol industry from the macroeconomic perspective through the ARDL-ECM approach.
Intrinsically motivating the crowds: the role of feedback information in crowdsourcing contests
Authors: Wang Mengmeng , Zhang Chun , Zhu Tingting
Published: August 2024

Purpose

The purpose of this study is to explore the motivational role of feedback information (positive and negative) provided by the firm in the face of participant heterogeneity, in terms of past success experience, under the research setting of crowdsourcing contests.

Design/methodology/approach

Taking insights from feedback studies and the dynamics of self-regulation theory, four theoretical hypotheses are proposed. An integrated dataset of 4,880 contest-participant pairs, which is obtained from an online contest platform and a survey, is empirically analyzed.

Findings

Empirical analysis shows that both positive feedback and negative feedback are able to stimulate the inner needs of participants. Notably, negative (positive) feedback becomes more (less) effective in intrinsically motivating crowds as they gain more successful experience during contest participation.

Originality/value

This study brings some new knowledge for the intrinsic motivation of crowds by exploring its antecedents, which have been undervalued in extant literature. The motivational role of feedback information is particularly explored.
An equilibrium analysis of blockchain integration strategies in the livestock meat supply chain considering consumers’ preference for quality trust
Authors: Jiang Yiping , Zhou Shanshan , Chu Jie , Fu Xiaoling , Lin Junyi
Published: August 2024

Purpose

This paper aims to explore blockchain integration strategies within a three-level livestock meat supply chain in which consumers have a preference for quality trust in livestock meat products. The paper investigates three questions: First, how does consumers’ preference for quality trust affect blockchain integration and transaction decisions among supply chain participants? Second, under what circumstances will retailers choose to participate in the blockchain? Finally, how can other factors such as blockchain costs and supplier–retailer partnership value affect integration decisions?

Design/methodology/approach

This paper formulates a supply chain network equilibrium model and employs the logarithmic-quadratic proximal prediction-correction method to obtain equilibrium decisions. Extensive numerical studies are conducted using a pork supply chain network to analyze the implications of blockchain integration for different supply chain participants.

Findings

The results reveal several key insights: First, suppliers’ increased blockchain integration, driven by higher quality trust preference, can negatively affect their profits, particularly, with excessive trust preferences and high blockchain costs. Second, an increase in consumers’ preference for quality trust expands the range of unit operating costs for retailers engaging in blockchain. Finally, the supplier–retailer partnership drives retailer blockchain participation, facilitating enhanced information sharing to benefit the entire supply chain.

Originality/value

This study provides original insights into blockchain integration strategies in an agricultural supply chain through the application of the supply chain network equilibrium model. The investigation of several key factors on equilibrium decisions provides important managerial implications for different supply chain participants to address consumers’ preference for quality trust and enhance overall supply chain performance.
Cospeciation is not the dominant driver of plant–pollinator codiversification in specialized pollination systems
Authors: TAENGON Channongxouang , FENG Ying , ZHANG Yuanye , ALUTHWATTHA Sasith Tharanga , CHEN Jin , WANG Gang
Published: August 2024

This study systematically rejects the long‐standing notion of cospeciation as the dominant driver of codiversification between flowering plants and their specialist pollinators. Through cophylogenetic analysis of six classical specialized pollination systems, the research finds that cospeciation events are consistently outnumbered by non‐cospeciation events, such as host‐switch, duplication, and association losses. The findings support a more dynamic and diffuse codiversification paradigm, highlighting the importance of considering a broader range of evolutionary events in understanding plant–pollinator codiversification. This new understanding is robust across diverse pollination systems and has significant implications for conservation strategies in the face of environmental change.
Cognitive symptoms in veterans with migraine or traumatic brain injury: A Million Veteran Program study
Authors: Herbert Matthew S. , Merritt Victoria C. , Afari Niloofar ,   Million Veteran Program, Gasperi Marianna
Published: August 2024

Objective

To examine the spectrum and severity of cognitive symptoms in veterans with migraine, traumatic brain injury (TBI), or both; and to evaluate the extent to which psychiatric conditions contribute to the relationship of migraine and TBI with cognitive symptoms.

Background

Migraine contributes significantly to global disability, with veterans facing additional burdens due to high comorbidity of TBI and psychiatric conditions. Understanding the intersection of these conditions is crucial for improving veterans’ health‐care outcomes.

Methods

This observational study used self‐reported data from 338,217 veterans enrolled in the Million Veteran Program (MVP) to assess cognitive symptoms using the Medical Outcomes Study Cognitive Functioning Scale Revised (MOS‐Cog‐R) and psychiatric conditions in veterans with migraine only, TBI only, both, or neither.

Results

Of the participants, 30,080/338,217 (8.9%) veterans reported migraine, 31,906/338,217 (9.4%) reported TBI, and 7828/338,217 (2.3%) reported both migraine and TBI. Veterans with only migraine or only TBI reported similar levels of cognitive symptoms (M = 74.19, standard deviation [SD] = 25.18; M = 73.87, SD = 24.98, respectively), which were substantially higher than veterans without these conditions (M = 62.52, SD = 27.90). Veterans with both conditions reported the most cognitive symptoms (M = 83.01, SD = 22.13) and psychiatric conditions (depression = 5041/7828 [64.4%], anxiety = 3735/7828 [47.7%], post‐traumatic stress disorder = 4243/7828 [54.2%]). The association of migraine and TBI with cognitive symptoms persisted beyond the influence of psychiatric conditions (B = −2.20, standard error = −0.36, p < 0.001).

Conclusion

Veterans with migraine reported cognitive challenges analogous to veterans with TBI, indicating a need for careful attention to cognitive symptoms in veterans with migraine. Further, the associations of migraine and TBI with cognitive symptoms in veterans were not explained by psychiatric conditions. These findings encourage future research to elucidate the association between self‐reported and objective cognitive symptoms and to identify factors, including environmental exposure and genetic influences, contributing to cognitive impairment to optimize the assessment and treatment of veterans with migraine.
Ablation behavior and mechanisms of Cf/(CrZrHfNbTa)C‒SiC high‐entropy composite at temperatures up to 2450°C
Authors: Hu Yang , Ni Dewei , Chen Bowen , Cai Feiyan , Zou Xuegang , Zhang Fan , Ding Yusheng , Zhang Xiangyu , Dong Shaoming
Published: August 2024

The oxide layer formed by ultra‐high melt point oxides (ZrO2, HfO2) and SiO2 glassy melt is the key to the application of traditional thermal structural materials in extremely high‐temperature environment. However, the negative effect of ZrO2 and HfO2 phase transitions on the stability of oxide layer and rapid volatilization of low viscosity SiO2 melt limit its application in aerospace. In this study, the ablation behavior of Cf/(CrZrHfNbTa)C‒SiC high‐entropy composite was explored systematically via an air plasma ablation test, under a heat flux of 5 MW/m2 at temperatures up to 2450°C. The composite presents an outstanding ablation resistance, with linear and mass ablation rates of 0.9 µm/s and 1.82 mg/s, respectively. This impressive ablation resistance is attributed to the highly stable oxide protective layer formed in situ on the ablation surface, which comprises a solid skeleton of (Zr, Hf)6(Nb, Ta)2O17 combined with spherical particles and SiO2 glassy melt. The irregular particles provide a solid skeleton in the oxides protective layer, which increased stability of the oxide layer. Moreover, the spherical particles have a crystal structure similar to that of Ta2O5 and are uniformly distributed in SiO2 glassy melt, which hinder the flow of SiO2 glassy melt and enhance its viscosity to a certain degree. And it reduces the volatilization of SiO2. In summary, the stable oxide layer was formed by irregular particles oxide and the SiO2 glassy melt with certain viscosity, thereby resulting in the impressive ablation resistance of the composite. This study fills a gap in ablation research on the (CrZrHfNbTa)C system.
Risks in the design of regional hydrogen hub systems: A review and commentary
Authors: Karplus Valerie J. , Iacob Ioana , Moore Emily J. , Morgan M. Granger
Published: August 2024

Early investments in regional hydrogen systems carry two distinct types of risk: (1) economic risk that projects will not be financially viable, resulting in stranded capital, and (2) environmental risk that projects will not deliver deep reductions in greenhouse gas emissions and through leaks, perhaps even contribute to climate change. This article systematically reviews the literature and performs analysis to describe both types of risk in the context of recent efforts in the United States and worldwide to support the development of “hydrogen hubs” or regional systems of hydrogen production and use. We review estimates of hydrogen production costs and projections of how future costs are likely to change over time for different production routes, environmental impacts related to hydrogen and methane leaks, and the availability and effectiveness of carbon capture and sequestration. Finally, we consider system‐wide risks associated with evolving regional industrial structures, including job displacement and underinvestment in shared components, such as refueling. We conclude by suggesting a set of design principles that should be applied in developing early hydrogen hubs if they are to be a successful step toward creating a decarbonized energy system.