bluuebunny/crossref_metadata_2025 huggingface dataset:
Detailed Social Network Interactions and Gut Microbiome Strain-Sharing Within Isolated Honduras Villages
Authors: Pullman Jackson , Beghini Francesco , Alexander Marcus , Shridhar Shivkumar Vishnempet , Prinster Drew , Brito Ilana L. , Christakis Nicholas A.
Published: April 2023

When humans assemble into face-to-face social networks, they create an extended environment that permits exposure to the microbiome of other members of a population. Social network interactions may thereby also shape the composition and diversity of the microbiome at individual and population levels. Here, we use comprehensive social network and detailed microbiome sequencing data in 1,098 adults across 9 isolated villages in Honduras to investigate the relationship between social network structure and microbiome composition. Using both species-level and strain-level data, we show that microbial sharing occurs between many relationship types, notably including non-familial and non-household connections. Using strain-sharing data alone, we can confidently predict a wide variety of relationship types (AUC ~0.73). This strain-level sharing extends to second-degree social connections in a network, suggesting the importance of the extended network with respect to microbiome composition. We also observe that socially central individuals are more microbially similar to the overall village than those on the social periphery. Finally, we observe that clusters of microbiome species and strains occur within clusters of people in the village social networks, providing the social niches in which microbiome biology and phenotypic impact are manifested.
Environmental and genetic influence on rate and spectrum of spontaneous mutations inEscherichia coli
Authors: Gifford Danna R. , Bhattacharyya Anish , Geim Alexandra , Marshall Eleanor , Krašovec Rok , Knight Christopher G.
Published: April 2023

Spontaneous mutations are the ultimate source of novel genetic variation on which evolution operates. Although mutation rate is often discussed as a single parameter in evolution, it comprises multiple distinct types of changes at the level of DNA. Moreover, the rates of these distinct changes can be independently influenced by genomic background and environmental conditions. Using fluctuation tests, we characterised the spectrum of spontaneous mutations inEscherichia coligrown in low and high glucose environments. These conditions are known to affect the rate of spontaneous mutation in wild-type MG1655, but not in a ΔluxSdeletant strain —a gene with roles in both quorum sensing and the recycling of methylation products used inEscherichia coli’s DNA repair process. We find an increase in AT>GC transitions in the low glucose environment, suggesting that processes relating to the production or repair of this mutation could drive the response of overall mutation rate to glucose concentration. Interestingly, this increase in AT>GC transitions is maintained by the glucose non-responsive ΔluxSdeletant. Instead, an elevated rate of GC>TA transversions, more common in a high glucose environment, leads to a net non-responsiveness of overall mutation rate for this strain. Our results show how relatively subtle changes, such as the concentration of a carbon substrate or loss of a regulatory gene, can substantially influence the amount and nature of genetic variation available to selection.
Layer Dependence of Monocular and Binocular Responses in Human Ocular Dominance Columns at 7T using VASO and BOLD
Authors: Akbari Atena , Gati Joseph S , Zeman Peter , Liem Brett , Menon Ravi S
Published: April 2023

The neurons located in the striate cortex (V1) preferentially respond to the input from one eye or another, forming a fingerprint-like pattern of ocular dominance columns (ODCs). At this mesoscopic scale, accessible by ultra-high field fMRI, V1 is supplied/drained by a network of surface (pial) vessels that connect to descending/ascending tangential vessels that penetrate the cortex and supply/drain a capillary bed whose density is also layer dependent. In this study, we measured the layer dependence of monocular and binocular responses of ocular dominance columns in V1 at 7T using Blood Oxygenation Level Dependent (BOLD) and VAscular Space Occupancy (VASO) contrasts. Our results indicate that the microvascular blood volume changes that give rise to VASO are well confined to the site of neural activity across the layers of the cortex and between the columns. Pial veins dominate the BOLD response and mix the signal between columns. When the GRE BOLD response was examined in only the VASO specific voxels (thus eliminating the pial vein signal), the laminar profile was very similar to VASO, however, the columnar response was still blurred. Caution needs to be exercised in the interpretation of signal changes in BOLD at the mesoscale both in terms of feedforward/feedback effects and inhibitory and excitatory effects.

Highlights

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VASO produced laminar profiles that were consistent with the known layer-dependent neuronal response to monocular and binocular stimulations.

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VASO better differentiated the response between columns belonging to the left and right eyes.

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GRE BOLD signal spatial specificity was poor in both laminar and columnar directions, however, when the pial veins were suppressed, the laminar BOLD signal was very similar to the VASO signal.

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Caution needs to be exercised when interpreting cognitive neuroscience BOLD studies at the mesoscale level due to the confounding effects of pial and sub-pial veins and venules.
Photoreceptor disc incisures form as an adaptive mechanism ensuring the completion of disc enclosure
Authors: Lewis Tylor R. , Phan Sebastien , Castillo Carson M. , Kim Keun-Young , Coppenrath Kelsey , Thomas William , Hao Ying , Skiba Nikolai P. , Horb Marko E. , Ellisman Mark H. , Arshavsky Vadim Y.
Published: April 2023

The first steps of vision take place within a stack of tightly packed disc-shaped membranes, or “discs”, located in the outer segment compartment of photoreceptor cells. In rod photoreceptors, discs are enclosed inside the outer segment and contain deep indentations in their rims called “incisures”. The presence of incisures has been documented in a variety of species, yet their role remains elusive. In this study, we combined traditional electron microscopy with three-dimensional electron tomography to demonstrate that incisures are formed only after discs become completely enclosed. We also observed that, at the earliest stage of their formation, discs are not round as typically depicted but rather are highly irregular in shape and resemble expanding lamellipodia. Using genetically manipulated mice and frogs and measuring outer segment protein abundances by quantitative mass spectrometry, we further found that incisure size is determined by the molar ratio between peripherin-2, a disc rim protein critical for the process of disc enclosure, and rhodopsin, the major structural component of disc membranes. While a high perpherin-2 to rhodopsin ratio causes an increase in incisure size and structural complexity, a low ratio precludes incisure formation. Based on these data, we propose a model whereby normal rods express a modest excess of peripherin-2 over the amount required for complete disc enclosure in order to ensure that this important step of disc formation is accomplished. Once the disc is enclosed, the excess peripherin-2 incorporates into the rim to form an incisure.
Microengineered 2D and 3D modular neuronal networks represent structure-function relationship
Authors: Habibey Rouhollah , Striebel Johannes , Latiftikhereshki Roshanak , Schmieder Felix , Latifi Shahrzad
Published: April 2023

Brain function is substantially linked to the highly organized structure of neuronal networks. Emerging three-dimensional (3D) neuronal cell culture technologies attempt to mimic the complexity of brain circuits asin vitromicrophysiological systems. Nevertheless, structures ofin vitroassembled neuronal circuits often varies between samples and changes over time that makes it challenging to reliably record network functional output and link it to the network structure. Hence, engineering neuronal structures with pre- defined geometry and reproducible functional features are essential to modelin vivoneuronal circuits in a robust way. Here, we engineered thin microchannel devices to assemble 2D and 3D modular networks. Microchannel devices were coupled with multi-electrode array (MEA) electrophysiology system to enable long-term electrophysiology recordings from microengineered circuits. Each network was composed of 64 micromodules which were connected through micron size channels to their adjacent modules. Microstructures physically confined neurons to the recording electrodes that considerably enhanced the electrophysiology readout efficiency. In addition, microstructures preserved modular network structure over weeks. Modular circuits within microfluidic devices showed consistent spatial patterns of activity over weeks, which was missing in the randomly formed circuits. Number of physical connections per module was shown to be influencing the measured activity and functional connectivity parameters, that represents the impact of network structure on its functional output. We show that microengineered 3D modular networks with a profound activity and higher number of functional connections recapitulate key functional features of developing cortex. Structurally and functionally stable 2D and 3D network mimic the modular architecture of brain circuits and offers a robust and reproduciblein vitromicrophysiolopgical system to serve basic and translational neuroscience research.
Validation of a murine proteome-wide phage display library for the identification of autoantibody specificities
Authors: Rackaityte Elze , Proekt Irina , Miller Haleigh S. , Ramesh Akshaya , Brooks Jeremy F. , Kung Andrew F. , Mandel-Brehm Caleigh , Yu David , Zamecnik Colin , Bair Rebecca , Vazquez Sara E. , Sunshine Sara , Abram Clare L. , Lowell Clifford A. , Rizzuto Gabrielle , Wilson Michael R. , Zikherman Julie , Anderson Mark S. , DeRisi Joseph L.
Published: April 2023

Autoimmunity is characterized by loss of tolerance to tissue-specific as well as systemic antigens, resulting in complex autoantibody landscapes. Here, we introduce and extensively validate the performance characteristics of a murine proteome-wide library for phage display immunoprecipitation and sequencing (PhIP-seq), to profile mouse autoantibodies. This system and library were validated using seven genetic mouse models across a spectrum of autoreactivity. Mice deficient in antibody production (Rag2-/-and μMT) were used to model non-specific peptide enrichments, while cross-reactivity was evaluated using anti-ovalbumin B cell receptor (BCR)-restricted OB1 mice as a proof of principle. The PhIP-seq approach was then utilized to interrogate three distinct autoimmune disease models. First, serum fromLyn-/-IgD+/-mice with lupus-like disease was used to identify nuclear and apoptotic bleb reactivities, lending support to the hypothesis that apoptosis is a shared origin of these antigens. Second, serum from non-obese diabetic (NOD) mice, a polygenic model of pancreas-specific autoimmunity, enriched peptides derived from both insulin and predicted pancreatic proteins. Lastly,Aire-/-mouse sera were used to identify numerous auto-antigens, many of which were also observed in previous studies of humans with autoimmune polyendocrinopathy syndrome type 1 (APS1) carrying recessive mutations in AIRE. Among these were peptides derived from Perilipin-1, a validated autoimmune biomarker of generalized acquired lipodystrophy in humans. Autoreactivity to Perilipin-1 correlated with lymphocyte infiltration in adipose tissue and underscores the approach in revealing previously unknown specificities. These experiments support the use of murine proteome-wide PhIP-seq for antigenic profiling and autoantibody discovery, which may be employed to study a range of immune perturbations in mouse models of autoimmunity.
Emergence and rapid dissemination of highly pathogenic avian influenza virus H5N1 clade 2.3.4.4b in wild birds, Chile
Authors: Ariyama Naomi , Pardo-Roa Catalina , Muñoz Gabriela , Aguayo Carolina , Ávila Claudia , Mathieu Christian , Brito Barbara , Medina Rafael , Johow Magdalena , Neira Victor
Published: April 2023

In December 2022, HPAI H5N1 clade 2.3.4.4b emerged in Chile. We detected the virus in 93 wild bird samples and sequenced the whole genome of nine Chilean strains from pelicans and gulls. Phylogenetic analysis suggests at least two different HPAI viral clusters in South America.
ThePPE25 (Rv1787) - PE18 (Rv1788) - PPE26 (Rv1789)gene cluster encodes an interacting protein pair and is involved in immune evasion byMycobacterium tuberculosis
Authors: Mukku Ravi Prasad , Poornima Kokavalla , Chakraborty Korak , Raghunand Tirumalai R.
Published: April 2023

Mycobacterium tuberculosis (M. tb)the causative agent of human tuberculosis, encodes multiple virulence factors to subvert host immune responses. One such class of proteins is encoded by the multigenicPE_PPEfamily which accounts for 10% of its coding potential. A number of these genes occur in clusters, of which thePPE25(Rv1787)-PE18(Rv1788)-PPE26(Rv1789)locus alone, is organised in aPPE-PE-PPEarrangement. We establish here that this cluster is co-operonic inM. tb, and identify for the first time, PPE25::PPE26 as the sole interacting protein pair encoded by this cluster. RecombinantM. smegmatisstrains expressingPPE25, PE18, andPPE26, exhibited enhanced survival in THP-1 macrophages, with infected cells displaying increased levels of the anti-inflammatory cytokineIL-10, and reduced levels of the pro-inflammatory cytokineIL-12. Macrophages infected with recombinantM. smegmatisexpressingPPE26showed increased phosphorylation of the MAP kinase p38, consistent with the known TLR2 binding activity of PPE26. In contrast to strains expressing the individual cluster genes, the recombinant expressing the entirePPE25-PE18-PPE26operon showed no change in intra-macrophage CFUs, suggestive of an inhibitory role for the PPE25::PPE26 complex in CFU enhancement. Taken together, our findings implicate thePPE25-PE18-PPE26cluster in playing an immune evasion role in the pathophysiology ofM. tb.
High-resolution cryo-electron microscopy of the human CDK-activating kinase for structure-based drug design
Authors: Cushing Victoria I. , Koh Adrian F. , Feng Junjie , Jurgaityte Kaste , Bahl Ash K. , Ali Simak , Kotecha Abhay , Greber Basil J.
Published: April 2023

Rational design of next-generation therapeutics can be facilitated by high-resolution structures of drug targets bound to small-molecule inhibitors. However, application of structure-based methods to macromolecules refractory to crystallisation has been hampered by the often-limiting resolution and throughput of cryogenic electron microscopy (cryo-EM). Here, we use high-resolution cryo-EM to determine structures of the CDK-activating kinase, a master regulator of cell growth and division, in its free and nucleotide-bound states and in complex with 14 inhibitors at up to 1.8 Å resolution. Our structures provide detailed insight into inhibitor interactions and networks of water molecules in the active site of cyclin- dependent kinase 7. Our data support a previously proposed mechanism contributing to inhibitor selectivity, thereby providing the basis for rational design of next-generation therapeutics. Additionally, our results establish a methodological framework for the use of high-resolution cryo-EM in structure-based drug design.
Anti-tumor Efficacy ofin situVaccination Using Bacterial Outer Membrane Vesicles
Authors: Caproni Elena , Corbellari Riccardo , Tomasi Michele , Isaac Samine J. , Tamburini Silvia , Zanella Iaria , Grigolato Martina , Gagliardi Assunta , Benedet Mattia , Baraldi Chiara , Croia Lorenzo , Di Lascio Gabriele , Valensin Silvia , Bellini Erika , Parri Matteo , Grandi Alberto , Grandi Guido
Published: April 2023

In situvaccination (ISV) is a promising cancer immunotherapy strategy, consists in the intratumoral administration of immunostimulatory molecules (adjuvants). The rationale is that tumor antigens are abundant at the tumor site and therefore to elicit an effective anti-tumor immune response all is needed is an adjuvant, which can turn the immunosuppressive environment into an immunologically active one. Bacterial Outer Membrane Vesicles (OMVs) are potent adjuvants since they contain a number of microbe-associated molecular patterns (MAMPs) naturally present in the outer membrane and in the periplasmic space of Gram-negative bacteria. Therefore, they appear particularly indicted for ISV. In this work we first show that the OMVs fromE. coli BL21(DE3)Δ60strain promote a strong anti-tumor activity when intratumorally injected into the tumors of two different mouse models. Tumor inhibition correlates with a rapid infiltration of DCs and NK cells. We also show that the addition of neo-epitopes to OMVs synergizes with the vesicle adjuvanticity, as judged by a two-tumor mouse models. Overall, our data support the use of the OMVs in ISV and suggests that ISV efficacy could benefit from the addition of properly selected tumor-specific neo-antigens.
Gallionellaceae in rice root plaque: metabolic roles in iron oxidation, nutrient cycling, and plant interactions
Authors: Chan Clara S. , Dykes Gretchen E. , Hoover Rene L. , Limmer Matt A. , Seyfferth Angelia L.
Published: April 2023

On the roots of wetland plants such as rice, Fe(II) oxidation forms Fe(III) oxyhydroxide-rich plaques that modulate plant nutrient and metal uptake. The microbial roles in catalyzing this oxidation have been debated and it is unclear if these iron-oxidizers mediate other important biogeochemical and plant interactions. To investigate this, we studied the microbial communities, metagenomes, and geochemistry of iron plaque on field-grown rice, plus the surrounding rhizosphere and bulk soil. Plaque iron content (per mass root) increased over the growing season, showing continuous deposition. Analysis of 16S rRNA genes showed abundant Fe(II)-oxidizing and Fe(III)-reducing bacteria (FeOB and FeRB) in plaque, rhizosphere, and bulk soil. FeOB were enriched in relative abundance in plaque, suggesting FeOB affinity for the root surface. Gallionellaceae FeOBSideroxydanswere enriched during vegetative and early reproductive rice growth stages, while aGallionellawas enriched during reproduction through grain maturity, suggesting distinct FeOB niches over the rice life cycle. FeRBAnaeromyxobacterandGeobacterincreased in plaque later, during reproduction and grain ripening, corresponding to increased plaque iron. Metagenome-assembled genomes revealed that Gallionellaceae may grow mixotrophically using both Fe(II) and organics. TheSideroxydansare facultative, able to use non-Fe substrates, which may allow colonization of rice roots early in the season. FeOB genomes suggest adaptations for interacting with plants, including colonization, plant immunity defense, utilization of plant organics, and nitrogen fixation. Together, our results strongly suggest that rhizoplane and rhizosphere FeOB can specifically associate with rice roots, catalyzing iron plaque formation, with the potential to contribute to plant growth.

Importance

In waterlogged soils, iron plaque forms a reactive barrier between the root and soil, collecting phosphate and metals such as arsenic and cadmium. It is well established that iron-reducing bacteria solubilize iron, releasing these associated elements. In contrast, microbial roles in plaque formation have not been clear. Here we show that there is a substantial population of iron oxidizers in plaque, and furthermore, that these organisms (SideroxydansandGallionella) are distinguished by genes for plant colonization and nutrient fixation. Our results suggest that iron-oxidizing and iron-reducing bacteria form and remodel iron plaque, making it a dynamic system that represents both a temporary sink for elements (P, As, Cd, C, etc.) as well as a source. In contrast to abiotic iron oxidation, microbial iron oxidation results in coupled Fe-C-N cycling, as well as microbe-microbe and microbe-plant ecological interactions that need to be considered in soil biogeochemistry, ecosystem dynamics, and crop management.
Circadian rhythm disruptions associated with opioid use disorder in the synaptic proteomes of the human dorsolateral prefrontal cortex and nucleus accumbens
Authors: Puig Stephanie , Xue Xiangning , Salisbury Ryan , Shelton Micah A. , Kim Sam-Moon , Hildebrand Mariah A. , Glausier Jill R. , Freyberg Zachary , Tseng George C. , Yocum Anastasia K. , Lewis David A. , Seney Marianne L. , MacDonald Matthew L. , Logan Ryan W.
Published: April 2023

Opioid craving and relapse vulnerability is associated with severe and persistent sleep and circadian rhythm disruptions. Understanding the neurobiological underpinnings of circadian rhythms and opioid use disorder (OUD) may prove valuable for developing new treatments for opioid addiction. Previous work indicated molecular rhythm disruptions in the human brain associated with OUD, highlighting synaptic alterations in the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc)—key brain regions involved in cognition and reward, and heavily implicated in the pathophysiology of OUD. To provide further insights into the synaptic alterations in OUD, we used mass-spectrometry based proteomics to deeply profile protein expression alterations in bulk tissue and synaptosome preparations from DLPFC and NAc of unaffected and OUD subjects. We identified 55 differentially expressed (DE) proteins in DLPFC homogenates, and 44 DE proteins in NAc homogenates, between unaffected and OUD subjects. In synaptosomes, we identified 161 and 56 DE proteins in DLPFC and NAc, respectively, of OUD subjects. By comparing homogenate and synaptosome protein expression, we identified proteins enriched specifically in synapses that were significantly altered in both DLPFC and NAc of OUD subjects. Across brain regions, synaptic protein alterations in OUD subjects were primarily identified in glutamate, GABA, and circadian rhythm signaling. Using time-of-death (TOD) analyses, where the TOD of each subject is used as a time-point across a 24- hour cycle, we were able to map circadian-related changes associated with OUD in synaptic proteomes related to vesicle-mediated transport and membrane trafficking in the NAc and platelet derived growth factor receptor beta signaling in DLPFC. Collectively, our findings lend further support for molecular rhythm disruptions in synaptic signaling in the human brain as a key factor in opioid addiction.
Machine learning from the CARDAMON trial identifies a carfilzomib-specific mutational response signature
Authors: Walker Ieuan G , D’arcy Venetia , Khandelwal Garima , Anderson Georgina , Aubareda Anna , Wilson William , Fitzsimons Evelyn , Galas-Filipowicz Daria , Foster Kane , Popat Rakesh , Ramasamy Karthik , Streetly Matthew , Bygrave Ceri , Benjamin Reuben , de Tute Ruth M. , Camilleri Marquita , Chavda Selina J , Pang Gavin , Dadaga Tushhar , Kamora Sumaiya , Cavenagh James , Phillips Elizabeth H. , Clifton-Hadley Laura , Owen Roger G , Herrero Javier , Yong Kwee , Chapman Michael A
Published: April 2023

Precision medicine holds great promise to improve outcomes in cancer, including haematological malignancies. However, there are few biomarkers that influence choice of chemotherapy in clinical practice. In particular, multiple myeloma requires an individualized approach as there exist several active therapies, but little agreement on how and when they should be used and combined. We have previously shown that a transcriptomic signature can identify specific bortezomib- and lenalidomide-sensitivity. However, gene expression signatures are challenging to implement clinically. We reasoned that signatures based on the presence or absence of gene mutations would be more tractable in the clinical setting, though examples of such signatures are rare. We performed whole exome sequencing as part of the CARDAMON trial, which employed carfilzomib-based therapy. We applied advanced machine learning approaches to discover mutational patterns predictive of treatment outcome. The resulting model accurately predicted progression-free survival (PFS) both in CARDAMON patients and in an external validation set of patients from the CoMMpass study who had received carfilzomib. The signature was specific for carfilzomib therapy and was strongly driven by genes on chromosome 1p36. Importantly, patients predicted to be carfilzomib-sensitive had a longer PFS when treated with carfilzomib/lenalidomide/dexamethasone than with bortezomib/carfilzomib/dexamethasone. However, in those predicted to be carfilzomib-insensitive, the latter therapy may have been capable of eradicating carfilzomib-resistant clones. We propose that the signature can be used to make rational therapeutic decisions and could be incorporated into future clinical trials.
Antimalarial Drug Resistance Profiling ofPlasmodium falciparumInfections in India Using Next-Generation Sequencing
Authors: Kale Sonal , Uplekar Swapna M. , Bandyopadhyay Nabamita , Rao Pavitra N. , Ali Syed Z. , Sharma S.K. , Tandel Nikunj , Patel Ankita , Singh Ranvir , Dank Aaron , Ravishankaran Sangamithra , Lakshmi Priya G Sri , Asokan Aswin , Eapen Alex , Singh Om. P. , Carlton Jane M. , Mallick Prashant K.
Published: April 2023

Background

Tracking the emergence and spread of antimalarial drug resistance has become critical to sustaining progress towards the control and eventual elimination of malaria in South Asia, especially India.

Methods

An amplicon sequencing protocol was used for high-throughput molecular surveillance of antimalarial drug resistance in a total of 158 isolates at three sites in India: Chennai, Nadiad and Rourkela. Five genes of thePlasmodium falciparumimplicated in antimalarial resistance were investigated here;Pfcrtfor chloroquine resistance,Pfdhfrfor pyrimethamine resistance,Pfdhpsfor sulfadoxine resistance,Pfk13for artemisinin resistance andPfmdr1for resistance to multiple antimalarials.

Results

Mutations in the propeller domain of PfK13 were observed in two samples only, however these mutations are not validated for artemisinin resistance. A high proportion of parasites from theP. falciparumdominant site Rourkela showed wild-typePfcrtandPfdhfrhaplotypes, while mutantPfcrtandPfdhfrhaplotypes were fixed at theP. vivaxdominant sites Chennai and Nadiad. The wild-type PfDHPS haplotype was predominant across all study sites. Finally, we observed the largest proportion of suspected multi-clonal infections at Rourkela, which has the highest transmission ofP. falciparumamong our study sites.

Conclusion

This is the first simultaneous high-throughput next generation sequencing of five completeP. falciparumgenes from infected patients in India.
Tissue-specific vulnerability to apoptosis in Machado-Joseph disease
Authors: Ferreira Ana F. , Raposo Mafalda , Shaw Emily D. , Ashraf Naila S. , Medeiros Filipa , Brilhante Maria de Fátima , Perkins Matthew , Vasconcelos João , Kay Teresa , do Carmo Costa Maria , Lima Manuela
Published: April 2023

Machado-Joseph disease (MJD) is a dominant neurodegenerative disease caused by an expanded CAG repeat in theATXN3gene encoding the ataxin-3 protein. Several cellular processes, including transcription and apoptosis, are disrupted in MJD. To gain further insights into the extent of dysregulation of mitochondrial apoptosis in MJD, and to evaluate if expression alterations of specific apoptosis genes/proteins could be used as transcriptional biomarkers of disease, the levels ofBCL2, BAXandTP53and theBCL2/BAXratio, an indicator of susceptibility to apoptosis, were assessed in blood andpost-mortembrain samples from MJD subjects and MJD transgenic mice and controls. While patients show reduced levels of bloodBCL2transcripts, this measurement displays low accuracy to discriminate patients from matched controls. However, increased levels of bloodBAXtranscripts and decreasedBCL2/BAXratio are associated with earlier onset, indicating a possible association with MJD pathogenesis.Post-mortemMJD brains show increasedBCL2/BAXtranscript ratio in the dentate cerebellar nucleus (DCN) and increased BCL2/BAX insoluble protein ratio in the DCN and pons, suggesting that in these regions, severely affected by degeneration in MJD, cells show signs of apoptosis resistance. Interestingly, a follow-up study of 18 patients further shows that bloodBCL2andTP53transcript levels increase over time in MJD patients. Furthermore, while the similar levels of bloodBCL2, BAX, andTP53transcripts observed in preclinical subjects and controls is mimicked by pre-symptomatic MJD mice, the expression profile of these genes in patient brains is partially replicated by symptomatic MJD mice. Globally, our findings indicate that there is tissue-specific vulnerability to apoptosis in MJD subjects and that this tissue dependent behavior is partially replicated in a MJD mouse model.
Predicting splicing patterns from the transcription factor binding sites in the promoter with deep learning
Authors: Lin Tzu-Chieh , Tsai Cheng-Hung , Shiau Cheng-Kai , Huang Jia-Hsin , Tsai Huai-Kuang
Published: April 2023

Background

Alternative splicing is a crucial mechanism of post-transcriptional modification responsible for the transcriptome plasticity and proteome diversity of a metazoan cell. Although many splicing regulations around the exon/intron regions have been discovered, the relationship between promoter-bound transcription factors and the downstream alternative splicing remains largely unexplored.

Results

In this study, we present computational approaches to decipher the regulation relationship connecting the promoter-bound transcription factor binding sites (TFBSs) and the splicing patterns. We curated a fine data set, including DNase I hypersensitive sites sequencing and transcriptome in fifteen human tissues from ENCODE. Specifically, we proposed different representations of TF binding context and splicing patterns to tackle the associations between the promoter and downstream splicing events. Our results demonstrated that the convolutional neural network (CNN) models learned from the TF binding changes in the promoter to predict the splicing pattern changes. Furthermore, through anin silicoperturbation-based analysis of the CNN models, we identified several TFs that considerably reduced the model performance of splicing prediction.

Conclusion

In conclusion, our finding highlights the potential role of promoter-bound TFBSs in influencing the regulation of downstream splicing patterns and provides insights for discovering alternative splicing regulations.
Evolutionary trajectories of secondary replicons in multipartite genomes
Authors: Dranenko Natalia O. , Rodina Aleksandra D. , Demenchuk Yaroslav V. , Gelfand Mikhail S. , Bochkareva Olga O.
Published: April 2023

Most bacterial genomes have a single chromosome that may be supplemented by smaller, dispensable plasmids. However, approximately 10% of bacteria with completely sequenced genomes, mostly pathogens and plant symbionts, have more than one stable large replicon. Some secondary replicons are species-specific, carrying pathogenicity or symbiotic factors. Other replicons are common on at least the genus level, carry house-keeping genes, and may have a size of several million base pairs.

We analyzed the abundance and sizes of large secondary replicons in different groups of bacteria and identified two patterns in the evolution of multipartite genomes. In nine genera of four families,Pseudoalteromonadaceae, Burkholderiaceae, Vibrionaceae, andBrucellaceae, we observed a positive correlation between the sizes of the chromosome and the secondary replicon with the slope in the range of 0.6–1.2. This indicates that in these genera the replicons evolve in a coordinated manner, with comparable rates of gene gain/loss, hence supporting classification of such secondary replicons as ‘chromids’. The second, more common pattern, features gene gains and losses mainly occurring in the primary replicon, yielding a stable size of the secondary replicon. Such secondary replicons are usually present in only a low fraction of the genus’ species. Hence, such replicons behave as ‘megaplasmids’. A mixed situation was observed in symbiotic genera from theRhizobiaceaefamily where the large secondary replicons are of stable size, but present in all species. These results may provide a general framework for understanding the evolution of genome complexity in prokaryotes.

Significance

Large secondary replicons are observed in representatives of many taxonomic groups of bacteria. Traditionally, they are referred to assecond chromosomes, chromids, ormegaplasmids, with little consistency, in particular because their evolution remains understudied. Here we demonstrate that the sizes of secondary replicons follow two main evolutionary trends: replicons whose size scales linearly with the size of the main chromosome (the suggested termchromids) typically contain numerous essential genes (rRNA, tRNA, ribosomal proteins), while large secondary replicons of stable size (termedmegaplasmids) contain fewer or none such genes.
Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy
Authors: Rhymes Elena R. , Simkin Rebecca L. , Qu Ji , Villarroel-Campos David , Surana Sunaina , Tong Yao , Shapiro Ryan , Burgess Robert W. , Yang Xiang-Lei , Schiavo Giampietro , Sleigh James N.
Published: April 2023

Charcot-Marie-Tooth disease (CMT) is a genetic peripheral neuropathy caused by mutations in many functionally diverse genes. The aminoacyl-tRNA synthetase (ARS) enzymes, which transfer amino acids to partner tRNAs for protein synthesis, represent the largest protein family genetically linked to CMT aetiology, suggesting pathomechanistic commonalities. Dominant intermediate CMT type C (DI-CMTC) is caused byYARS1mutations driving a toxic gain-of-function in the encoded tyrosyl-tRNA synthetase (TyrRS), which is mediated by exposure of consensus neomorphic surfaces through conformational changes of the mutant protein. In this study, we first showed that human DI-CMTC-causing TyrRSE196Kmis-interacts with the extracellular domain of the BDNF receptor TrkB, an aberrant association we have previously characterised for several mutant glycyl-tRNA synthetases linked to CMT type 2D (CMT2D). We then performed temporal neuromuscular assessments ofYarsE196Kmice modelling DI-CMT. We determined thatYarsE196Khomozygotes display a selective, age-dependent impairment inin vivoaxonal transport of neurotrophin-containing signalling endosomes, phenocopying CMT2D mice. This impairment is replicated by injection of recombinant TyrRSE196K, but not TyrRSWT, into muscles of wild-type mice. Augmenting BDNF in DI-CMTC muscles, through injection of recombinant protein or muscle-specific gene therapy, resulted in complete axonal transport correction. Therefore, this work identifies a non-cell autonomous pathomechanism common to ARS-related neuropathies, and highlights the potential of boosting BDNF levels in muscles as a therapeutic strategy.
Glial Draper signaling triggers cross-neuron plasticity in bystander neurons after neuronal cell death
Authors: Wang Yupu , Zhang Ruiling , Huang Sihao , Valverde Parisa Tajalli-Tehrani , Lobb-Rabe Meike , Ashley James , Venkatasubramanian Lalanti , Carrillo Robert A.
Published: April 2023

Neuronal cell death and subsequent brain dysfunction are hallmarks of aging and neurodegeneration, but how the nearby healthy neurons (bystanders) respond to the cell death of their neighbors is not fully understood. In theDrosophilalarval neuromuscular system, bystander motor neurons can structurally and functionally compensate for the loss of their neighbors by increasing their axon terminal size and activity. We termed this compensation as cross-neuron plasticity, and in this study, we demonstrated that theDrosophilaengulfment receptor, Draper, and the associated kinase, Shark, are required in glial cells. Surprisingly, overexpression of the Draper-I isoform boosts cross-neuron plasticity, implying that the strength of plasticity correlates with Draper signaling. Synaptic plasticity normally declines as animals age, but in our system, functional cross-neuron plasticity can be induced at different time points, whereas structural cross-neuron plasticity can only be induced at early stages. Our work uncovers a novel role for glial Draper signaling in cross-neuron plasticity that may enhance nervous system function during neurodegeneration and provides insights into how healthy bystander neurons respond to the loss of their neighboring neurons.
Unbiased spectral cytometry immunome characterization predicts COVID-19 mRNA vaccine failure in older adults and patients with lymphoid malignancies
Authors: H-Vazquez Juan , Cal-Sabater Paloma , Arribas-Rodríguez Elisa , Fiz-López Aida , Perez-Segurado Candido , Martín-Muñoz Álvaro , Prado Ángel De , de la Fuente Graciani Ignacio , González Sonia Pérez , Gutiérrez Sara , Tellería Pablo , Novoa Cristina , Rello Silvia Rojo , Garcia-Blesa Antonio , Sedano Rosa , Martínez García Ana María , Pérez Sonsoles Garcinuño , Domínguez-Gil Marta , García Cristina Hernán , Guerra Mª Mercedes , Muñoz-Sánchez Eduardo , Barragan-Pérez Cristina , Morales Soraya Diez , Donnarumma Oriana Casazza , Pollo Daniel Ramos , Solla Natalia Santamarta , Álvarez Manzanares Paula Mª , Bravo Sara , Alonso Cristina García , Nieto Ángel Tesedo , López Moreno Elisabet Carmen , Cabrera Sanz María Esther , Olmedo Sara Borge , de Paula Ortiz Miguel , Asenjo Alberto Castellanos , Alonso Jenifer Gay , Garrote José A. , Arranz Eduardo , Eiros José María , Santiago Fernando Rescalvo , Villegas Carolina Quevedo , Tamayo Eduardo , Orduña Antonio , Dueñas Carlos , Peñarrubia María Jesús , Cuesta-Sancho Sara , Montoya María , Bernardo David
Published: April 2023

COVID-19 affects the population unequally with a higher impact on aged and immunosuppressed people. Hence, we assessed the effect of SARS-CoV-2 vaccination in immune compromised patients (older adults and oncohematologic patients), compared with healthy counterparts. While the acquired humoral and cellular memory did not predict subsequent infection 18 months after full immunization, spectral and computational cytometry revealed several subsets within the CD8+T-cells, B-cells, NK cells, monocytes and CD45RA+CCR7-Tγδ cells differentially expressed in further infected and non-infected individuals not just following immunization, but also prior to that. Of note, up to 7 subsets were found within the CD45RA+CCR7-Tγδ population with some of them being expanded and other decreased in subsequently infected individuals. Moreover, some of these subsets also predicted COVID-induced hospitalization in oncohematologic patients. Therefore, we hereby have identified several cellular subsets that, even before vaccination, strongly related to COVID-19 vulnerability as opposed to the acquisition of cellular and/or humoral memory following vaccination with SARS-CoV- 2 mRNA vaccines.

An in depth and unbiased spectral cytometry characterization of the immune system before and after COVID-19 vaccination can predict not just subsequent PCR-confirmed infection, but also COVID-induced hospitalization in immune compromised patients.
Accountability and music: accounting, emotions and responses to the 1913 concert for Giuseppe Verdi
Authors: Giovannoni Elena , Giorgino Maria Cleofe , Di Pietra Roberto
Published: April 2023

Purpose

This study aims to explore the engagement between accounting and music in the social and relational construction of accountability. The authors conceive this construction as a dynamic and recursive interplay between the giving of different accounts and the responses that these accounts provoke. The authors investigate the emotional dimension of this interplay, as it is also triggered by music, feeding back into how accountability is constructed and evolves over time.

Design/methodology/approach

This study relies upon a historical analysis of archival and secondary sources about the main music concert organized in 1913 by the founder of “Accademia Chigiana”, one of the leading music academies in Italy. The concert celebrated the first centenary of the birth of Giuseppe Verdi, a worldwide famous Italian music composer, and icon of Italian national sentiment.

Findings

This study shows that music and accounting were profoundly intertwined in the social and relational construction of accountability for the 1913 concert. Accountability evolved through different accounts, also linked to music, and the complex emotional reactions these accounts provoked in the audiences, citizens, media and institutions, leading to always further responses and accounts in the ongoing construction of accountability.

Originality/value

This study extends prior literature on the chameleonic nature of accountability, as well as on its relational and emotional dimensions. The study shows that accountability is relationally constructed and evolves over time through the giving of accounts and the emotional reaction they provoke from others, feeding into further responses and accounts of the accountable subject. The authors show how the chameleonic nature of accountability permeates not only the accounts and the relations of accountability but also the subjects giving and demanding the accounts: these subjects change as chameleons through their interactions and emotions, feeding into the dynamic construction of accountability. The authors also show how arts, like music, can participate in the chameleonic nature of accountability and of its subjects, precisely by engaging with their emotional reactions and responses.
Modeling and verification of helicopter roll-on takeoff based on optimal control theory
Authors: Deng JingHui , Chen Jinhe , Wang ZhengZhong
Published: April 2023

Purpose

The paper aims to establish a comprehensive optimization analysis model for a helicopter roll on the ground and take off based on optimal control method. The trajectory and control of the entire process are studied, and the key factors affecting the helicopter takeoff distance are analyzed.

Design/methodology/approach

First, based on the equivalent stiffness and damping, the landing gear model is established, and a six-degree-of-freedom helicopter model is formed. Then, the simulation of the roll-on takeoff is transformed into a nonlinear optimal control problem (NOCP). Meanwhile, a hybrid single-multiple shooting method-based transcription process is used for discretizing the problem, leading to a finite nonlinear programming model, which is solved by sequential quadratic programming. Finally, the process was calculated and compared with flight test data, which verified the feasibility of the NOCP. The influence of takeoff weight, takeoff power and liftoff airspeed on the takeoff distance of the helicopter was analyzed.

Findings

The results show that the takeoff weight can be increased by 17% under the maximum takeoff power, which is roll-on takeoff at an altitude of 0 m. When the helicopter takes off with the maximum weight at an altitude of 5000 m, the liftoff airspeed should be over 49.2 km/h.

Originality/value

The novelty of this paper lies in the comprehensive consideration of helicopter taxiing and taking-off phases, and the application of optimal control theory to establish a comprehensive analysis model, which can quickly analyze the maximum takeoff weight, takeoff distance, optimal liftoff speed and so on. Meanwhile, the method is verified based on the flight data.
Exploring the economics of conversational search sessions
Authors: Ghosh Souvick , Gogoi Julie , Chua Kristen
Published: April 2023

Purpose

Turn-taking is beneficial to conversational search success, but the increase in turns and time can also increase the cognitive load of the user. Therefore, in this research paper, the authors view conversational search sessions through the lens of economic theory and use the economic models of search to analyze the various costs and benefits of information-seeking interactions.

Design/methodology/approach

First, the authors built a cost-benefit model for conversational search sessions by defining action types and performing an intellectual mapping of actual sessions into sequences of these actions (using thematic analyses). The authors used the hypothesized cost and benefit actions (obtained from the user-system dialogs), along with the number of turns, utterances and time-related parameters, to propose the mathematical model. Next, the authors tested the model empirically by comparing the model scores to the user satisfaction and task success scores (collected through questionnaires). By representing each session as a bag of actions, the authors developed linear regression models to predict task success and user satisfaction.

Findings

Through feature analysis and significance testing, the authors identify the different parameters that contribute significantly to user satisfaction and task success scores. Error analysis shows that the model predicts task success and user satisfaction reasonably well, with the average prediction error being 0.5 for both (on a 5-point scale).

Originality/value

The authors' research is an initial step toward building a mathematical model for predicting user satisfaction and task success in conversational search sessions.
How to do the right thing
Authors: Messer Ron Peter
Published: April 2023

Purpose

This paper aims to make suggestions for addressing the apparent failure of business schools to communicate good ethical decision-making skills to students studying in postsecondary institutions.

Design/methodology/approach

At the beginning of university management classes, a form is distributed to students outlining a short scenario that requires a course of action. The two questions asked, based on this decision context, are (i) is it ethical to offer bribes to secure construction contracts in countries where this practice is considered an acceptable way of conducting business and (ii) has the student completed an ethics course at the university?

Findings

The scenario described is what occurred at SNC Lavalin, a Canadian construction company that was charged and convicted with offering illegal inducements to foreign officials (in Libya) to secure large government construction contracts. Ethically, the “right” decision would be to not offer bribes; this is because they are illegal when offered both in the Canada and in foreign jurisdictions. The response results to the survey questionnaire showed that 21% of the students thought that bribery was acceptable, if it was a customary business practice in the country where the transaction occurred, and 93% of these students had taken an ethics course. It was interesting to note that almost all the students, who had not taken a business ethics courses, thought that bribery is not acceptable under the circumstances described.

Originality/value

To address the apparent failure to communicate good ethical decision-making skills, this essay suggests that when teaching business ethics, there should a clearer focus on (i) the distinction between morality and ethics; (ii) the problem posed by relativism; and (iii) the reasoning behind ethical standards. This approach is novel in that it makes sense from the perspective of both a business practitioner and university educator.