bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor Cytokine-Induced Hepatic Gluconeogenesis Contributes to Cancer Cachexia: Insights from Full Body Single Nuclei Sequencing
Authors: Liu Ying , Dantas Ezequiel , Ferrer Miriam , Liu Yifang , Comjean Aram , Davidson Emma E. , Hu Yanhui , Goncalves Marcus D. , Janowitz Tobias , Perrimon Norbert
Published: May 2023

A primary cause of death in cancer patients is cachexia, a wasting syndrome attributed to tumor-induced metabolic dysregulation. Despite the major impact of cachexia on the treatment, quality of life, and survival of cancer patients, relatively little is known about the underlying pathogenic mechanisms. Hyperglycemia detected in glucose tolerance test is one of the earliest metabolic abnormalities observed in cancer patients; however, the pathogenesis by which tumors influence blood sugar levels remains poorly understood. Here, utilizing aDrosophilamodel, we demonstrate that the tumor secreted interleukin-like cytokine Upd3 induces fat body expression ofPepck1andPdk, two key regulatory enzymes of gluconeogenesis, contributing to hyperglycemia. Our data further indicate a conserved regulation of these genes by IL-6/JAK STAT signaling in mouse models. Importantly, in both fly and mouse cancer cachexia models, elevated gluconeogenesis gene levels are associated with poor prognosis. Altogether, our study uncovers a conserved role of Upd3/IL-6/JAK-STAT signaling in inducing tumor-associated hyperglycemia, which provides insights into the pathogenesis of IL-6 signaling in cancer cachexia.

Graphical Abstract
Resistance to anti-orthopoxviral drug tecovirimat (TPOXX®) during the 2022 mpox outbreak in the US
Authors: Smith Todd G. , Gigante Crystal M. , Wynn Nhien T. , Matheny Audrey , Davidson Whitni , Yang Yong , Condori Rene Edgar , O’Connell Kyle , Kovar Lynsey , Williams Tracie L. , Yu Yon C. , Petersen Brett W. , Baird Nicolle , Lowe David , Li Yu , Satheshkumar Panayampalli S. , Hutson Christina L.
Published: May 2023

Background

During the 2022 multinational outbreak of monkeypox virus (MPXV) clade IIb, the antiviral drug tecovirimat (TPOXX®) was deployed in the US on a large scale for the first time ever. The MPXV F13L gene homolog encodes the target of tecovirimat, and single amino acid changes in the F13 protein are known to cause resistance to tecovirimat in orthopoxviruses (OPXV).

Methods

Whole genome metagenomic sequencing and amplicon-based sequencing targeting the F13L gene was used to identify nine mutations previously reported to cause resistance in other OPXV along with ten novel mutations that have been identified from the 2022 mpox outbreak. A cytopathic effect assay, previously established at CDC as part of WHO smallpox research, was adapted to MPXV for tecovirimat phenotype testing of virus isolated from mpox patients.

Results

As of March 2023, in total, 70 isolates from 40 patients were tested, and 50 of these isolates from 26 patients were found to have a resistant phenotype. Most resistant isolates were associated with severely immunocompromised mpox patients on multiple courses of TPOXX treatment; while isolates with F13 mutations identified by routine surveillance of patients not treated with TPOXX have remained sensitive.

Conclusions

These data indicate that tecovirimat resistance is developing in immunocompromised patients treated with TPOXX and that for isolates that we have analyzed, the frequency of resistant viruses remain relatively low (< 1%) compared to the total number of patients treated with TPOXX. These findings inform our understanding of when tecovirimat resistance is likely to occur and highlight the need for additional OPXV therapeutics.
A C/ebpα isoform-specific differentiation program in primary myelocytes
Authors: Garcia-Cuellar Maria-Paz , Akan Selin , Slany Robert K.
Published: May 2023

The transcription factor CCAAT-enhancer binding factor alpha (C/ebpα) is a master controller of myeloid differentiation that is expressed as long (p42) and short (p30) isoform. Mutations within theCEBPAgene selectively deleting p42 are frequent in human acute myeloid leukemia. Here we investigated the individual genomics and transcriptomics of p42 and p30. Both proteins bound to identical sites across the genome. For most targets, they induced a highly similar transcriptional response with the exception of a few isoform-specific genes. Amongst those we identified early growth response 1 (Egr1) and tribbles 1 (Trib1) as key targets selectively induced by p42 that are also underrepresented inCEBPA-mutated AML. Egr1 executed a program of myeloid differentiation and growth arrest. Oppositely, Trib1 established a negative feedback loop through activation of Erk1/2 kinase thus placing differentiation under control of signaling. Unexpectedly, differentiation elicited either by removal of an oncogenic input or by G-CSF did not peruse C/ebpα as mediator but rather directly affected the cell cycle core by upregulation of p21/p27 inhibitors. This points to functions downstream of C/ebpα as intersection point where transforming and differentiation stimuli converge and this finding offers a new perspective for therapeutic intervention.
A gene silencing pipeline to interrogate human cDC1 and pDC development and functions
Authors: Luo Xinlong , Lahaye Xavier , Jaeger Alix , Michea-Veloso Paula , Manel Nicolas , Dalod Marc
Published: May 2023

Type 1 conventional dendritic cells (cDC1s) and plasmacytoid dendritic cells (pDCs) are thought to be critical for anti-tumor or antiviral immunity. In vitro differentiation systems have unlocked the ability to produce large numbers of these cells. However, a method is lacking to systematically identify the cell-intrinsic factors controlling their differentiation and functions that remain therefore poorly understood, in contrast to the situation in mice. Here, we developed a workflow for efficient gene silencing and its tracing in human cDC1s/pDCs generated in vitro. As proof of concept, we confirmed the key role of IRF8 in their development, and of IRF7/MyD88 in human pDC production of interferons-α/λ. We found that SAMHD1 and RAB7B promote human cDC1 differentiation, while SEPT3 promotes human pDC differentiation. We also found that PPT1 and RAB5 are required for optimal differentiation of pDCs and cDC1s. Finally, we identified BCL11A, PPT1 and RAB7 as novel HIV-1 restriction factors in cDC1s/pDCs. This approach will enable broader genetic screens to advance our understanding of human cDC1s/pDCs and harness them against viral infections or cancer.
The contribution of an X chromosome QTL to non-Mendelian inheritance and unequal chromosomal segregation inA. freiburgense
Authors: Al-Yazeedi Talal , Adams Sally , Tandonnet Sophie , Turner Anisa , Kim Jun , Lee Junho , Pires-daSilva Andre
Published: May 2023

Auanema freiburgenseis a trioecious nematode with co-existing males, females, and selfing hermaphrodites. Crosses of XO males with XX females result in a low percentage of XO sons due to the elimination of the nullo-X spermatids by the fathers. This process yields most viable sperm containing an X chromosome, leading to a higher transmission probability of the X chromosome compared to expected transmission via random segregation. The mechanism underlying this process involves the asymmetric distribution of essential cellular organelles during sperm formation, which likely depends on the X chromosome. Specifically, sperm components segregate with the X chromosome daughter cell, while other components are discarded in the nullo-X daughter cell. Here we found that intercrossing two strains ofA. freiburgenseresults in lines in which males produce viable nullo-X sperm. Thus, crosses of those hybrid males with females result in a high percentage of sons. To uncover the genetic basis of nullo-spermatid elimination and X-chromosome drive, we generated a genome assembly forA. freiburgenseand genotyped the intercrossed lines. We identified a QTL encompassing several genes on the X chromosome that are associated with its non-Mendelian inheritance observed inA. freiburgense. This finding provides valuable clues to the underlying factors involved in asymmetric organelle partitioning during male meiotic division and thus non-Mendelian transmission of the X chromosome and sex ratios.
Neuropeptide Y signaling regulates recurrent excitation in the auditory midbrain
Authors: Silveira Marina A. , Drotos Audrey C. , Pirrone Trinity M. , Versalle Trevor S. , Bock Amanda , Roberts Michael T.
Published: May 2023

Neuropeptides play key roles in shaping the organization and function of neuronal circuits. In the inferior colliculus (IC), which is located in the auditory midbrain, Neuropeptide Y (NPY) is expressed by a large class of GABAergic neurons that project locally as well as outside the IC. The IC integrates information from numerous auditory nuclei making the IC an important hub for sound processing. Most neurons in the IC have local axon collaterals, however the organization and function of local circuits in the IC remains largely unknown. We previously found that neurons in the IC can express the NPY Y1 receptor (Y1R+) and application of the Y1R agonist, [Leu31, Pro34]-NPY (LP-NPY), decreases the excitability of Y1R+neurons. To investigate how Y1R+neurons and NPY signaling contribute to local IC networks, we used optogenetics to activate Y1R+neurons while recording from other neurons in the ipsilateral IC. Here, we show that 78.4% of glutamatergic neurons in the IC express the Y1 receptor, providing extensive opportunities for NPY signaling to regulate excitation in local IC circuits. Additionally, Y1R+neuron synapses exhibit modest short-term synaptic plasticity, suggesting that local excitatory circuits maintain their influence over computations during sustained stimuli. We further found that application of LP-NPY decreases recurrent excitation in the IC, suggesting that NPY signaling strongly regulates local circuit function in the auditory midbrain. Together, our data show that excitatory neurons are highly interconnected in the local IC and their influence over local circuits is tightly regulated by NPY signaling.
Structure and dynamics of cholesterol-mediated aquaporin-0 arrays and implications for lipid rafts
Authors: Chiu Po-Lin , Orjuela Juan D. , de Groot Bert L. , Aponte-Santamaría Camilo , Walz Thomas
Published: May 2023

Aquaporin-0 (AQP0) tetramers form square arrays in lens membranes through a yet unknown mechanism, but lens membranes are enriched in sphingomyelin and cholesterol. Here, we determined electron crystallographic structures of AQP0 in sphingomyelin/cholesterol membranes and performed molecular dynamics (MD) simulations to establish that the observed cholesterol positions represent those seen around an isolated AQP0 tetramer and that the AQP0 tetramer largely defines the location and orientation of most of its associated cholesterol molecules. At a high concentration, cholesterol increases the hydrophobic thickness of the annular lipid shell around AQP0 tetramers, which may thus cluster to mitigate the resulting hydrophobic mismatch. Moreover, neighboring AQP0 tetramers sandwich a cholesterol deep in the center of the membrane. MD simulations show that the association of two AQP0 tetramers is necessary to maintain the deep cholesterol in its position and that the deep cholesterol increases the force required to laterally detach two AQP0 tetramers, not only due to protein–protein contacts but also due to increased lipid–protein complementarity. Since each tetramer interacts with four such ‘glue’ cholesterols, avidity effects may stabilize larger arrays. The principles proposed to drive AQP0 array formation could also underlie protein clustering in lipid rafts.
T-FINDER: A highly sensitive, pan-HLA platform for functional T cell receptor and ligand discovery
Authors: Schmid Theresa , Cetin Miray , Pinamonti Veronica , Fuentes Ana Mellado , Kromer Kristina , Lerner Taga , Zhang Jing , Boschert Tamara , Herzig Yonatan , Ehlert Christopher , Fisch Laura , Dragan Valeriia , Kouwenhoven Arlette , Schoubroeck Bertrand Van , Wils Hans , Hove Carl Van , Platten Michael , Green Edward , Stevenaert Frederik , Felix Nathan J. , Lindner John M.
Published: May 2023

Effective, unbiased, high-throughput methods to functionally identify both class II and class I HLA-presented T cell epitopes and their cognate T cell receptors (TCRs) are essential for and prerequisite to diagnostic and therapeutic applications, yet remain underdeveloped. Addressing this bottleneck, we established T-FINDER (T cell Functional Identification and (Neo)-antigen Discovery of Epitopes and Receptors), a platform that rapidly deconvolutes CD4 and CD8 TCR reactivities to targets physiologically processed and presented by an individual’s unmanipulated, complete HLA haplotype. By using a highly sensitive TCR signaling reporter capable of detecting even low-affinity TCR:ligand interactions, T-FINDER not only robustly identifies unknown peptide:HLA ligands from complex antigen libraries, but also rapidly screens and functionally validates the specificity of complex TCR libraries against known or predicted targets. To demonstrate its pan-HLA presentation capacity, we apply the platform to multiple TCR-based applications, including glioma, celiac disease, and rheumatoid arthritis, providing unique biological insights and showcasing T-FINDER’s potency and versatility.
CRISPR-based diagnostics detects invasive insect pests
Authors: Shashank Pathour R. , Parker Brandon M. , Rananaware Santosh R. , Plotkin David , Couch Christian , Yang Lilia G. , Nguyen Long T. , Prasannakumar N. R. , Braswell W. Evan , Jain Piyush K. , Kawahara Akito Y.
Published: May 2023

Rapid identification of organisms is essential across many biological and medical disciplines, from understanding basic ecosystem processes and how organisms respond to environmental change, to disease diagnosis and detection of invasive pests. CRISPR-based diagnostics offers a novel and rapid alternative to other identification methods and can revolutionize our ability to detect organisms with high accuracy. Here we describe a CRISPR-based diagnostic developed with the universal cytochrome-oxidase 1 gene (CO1). The CO1 gene is the most sequenced gene among Animalia, and therefore our approach can be adopted to detect nearly any animal. We tested the approach on three difficult-to-identify moth species (Keiferia lycopersicella, Phthorimaea absoluta, andScrobipalpa atriplicella) that are major invasive pests globally. We designed an assay that combines recombinase polymerase amplification (RPA) with CRISPR for signal generation. Our approach has a much higher sensitivity than other real time-PCR assays and achieved 100% accuracy for identification of all three species, with a detection limit of up to 120 fM forP. absolutaand 400 fM for the other two species. Our approach does not require a lab setting, reduces the risk of cross-contamination, and can be completed in less than one hour. This work serves as a proof of concept that has the potential to revolutionize animal detection and monitoring.
The emergence of human gastrulation uponin vitroattachment
Authors: De Santis Riccardo , Rice Eleni , Croft Gist , Yang Min , Rosado-Olivieri Edwin A. , Brivanlou Ali H.
Published: May 2023

While studied extensively in model systems, human gastrulation remains obscure. This process starts upon blastocyst implantation into the uterine wall, which is assumed to occur after 14 days post-fertilization. The scarcity and limited access to fetal biological material as well as ethical considerations limit our understanding of the cellular and molecular portrait of human gastrulation.In vitroculture of natural human blastocysts shed light on the second week of human development, unveiling an unexpected level of self-organization embedded in the pre-gastrulating embryo, yet whether they can undergo gastrulation uponin vitroattachment remains elusive. Blastocyst models calledblastoids, which are derived from human pluripotent stem cells, provide the opportunity to reconstitute post-implantation human developmentin vitrowith unlimited biological material. Here we show that humanblastoidsbreak symmetry and undergo gastrulation uponin vitroattachment. scRNA-seq of these models replicate the transcriptomic signature of the natural human gastrula, recapitulating aspects of the second to the third week of human development. Surprisingly, analysis of developmental timing reveals that in bothblastoidmodels and naturalin vitroattached human embryos, the onset of gastrulation as defined by molecular makers, can be traced to time scales equivalent to 12 days post-fertilization, which appeals for a reconsideration of the onset of human gastrulation upon extendedin vitroculture.
Gametophytic epigenetic regulators MEDEA and DEMETER synergistically suppress ectopic shoot formation in Arabidopsis
Authors: Rajabhoj Mohit , Sankar Sudev , Bondada Ramesh , Shanmukhan Anju P , Prasad Kalika , Maruthachalam Ravi
Published: May 2023

The gametophyte to sporophyte transition facilitates the alternation of generations in a plant life cycle. The epigenetic regulators DEMETER(DME) and MEDEA(MEA) synergistically control central cell proliferation and differentiation, ensuring proper gametophyte to sporo-phyte transition inArabidopsis. Mutant alleles ofDMEandMEAare female gametophyte lethal, eluding the recovery of recessive homozygotes to examine their role in the sporophyte. Here, we exploited the paternal transmission of these mutant alleles coupled with CENH3-haploid inducer to generatemea-1;dme-2 sporophytes. Strikingly, the simultaneous loss of function of MEA and DME leads to the emergence of ectopic shoot meristems at the apical pole of the plant body axis.DMEandMEAare expressed in the developing shoot apex and regulate the expression of various shoot-promoting factors. Chromatin immunoprecipitation(ChIP), DNA methylation and gene expression analysis revealed several shoot regulators as potential targets of MEA and DME. Knockdown of upregulated shoot-promoting factors STM, CUC2, and PLT5 rescued the ectopic shoot phenotypes. Our findings reveal a previously unrecognized synergistic role of MEA and DME in restricting the meristematic activity at the shoot apex during sporophytic development to orchestrate the plant architecture.
Longitudinal analysis of memory T follicular helper cells and antibody response following CoronaVac vaccination
Authors: Zhou Pengcheng , Cao Cheng , Ji Tuo , Zheng Ting , Dai Yaping , Liu Min , Jiang Junfeng , Sun Daoqi , Bai Zhonghu , Lu Xiaojie , Gong Fang
Published: May 2023

The inactivated vaccine CoronaVac is one of the most widely used COVID-19 vaccines globally. However, the longitudinal evolution of the immune response induced by CoronaVac remains elusive compared to other vaccine platforms. Here, we recruited 88 healthy individuals that received 3 doses of CoronaVac vaccine. We longitudinally evaluated their polyclonal and antigen-specific CD4+T cells and neutralizing antibody response after receiving each dose of vaccine for over 300 days. Both the 2ndand 3rddose of vaccination induced robust spike-specific neutralizing antibodies, with a 3rdvaccine further increased the overall magnitude of antibody response, and neutralization against Omicron sub-lineages B.1.1.529, BA.2, BA.4/BA.5 and BA.2.75.2. Spike-specific CD4+T cell and circulating T follicular helper (cTFH) cells were markedly increased by the 2ndand 3rddose of CoronaVac vaccine, accompanied with altered composition of functional cTFHcell subsets with distinct effector and memory potential. Additionally, cTFHcells are positively correlated with neutralizing antibody titers. Our results suggest that CoronaVac vaccine-induced spike-specific T cells are capable of supporting humoral immunity for long-term immune protection.
Spatial Multiomics Reveal the Role of Wnt Modulator, Dkk2, in Palatogenesis
Authors: Oliver Piña Jeremie , Raju Resmi , Roth Daniela M. , Winchester Emma Wentworth , Padilla Cameron , Iben James , Faucz Fabio R. , Cotney Justin L. , D’Souza Rena N.
Published: May 2023

Multiple genetic and environmental etiologies contribute to the pathogenesis of cleft palate, which constitutes the most common among the inherited disorders of the craniofacial complex. Insights into the molecular mechanisms regulating osteogenic differentiation and patterning in the palate during embryogenesis are limited and needed for the development of innovative diagnostics and cures. This study utilized thePax9-/-mouse model with a consistent phenotype of cleft secondary palate to investigate the role ofPax9in the process of palatal osteogenesis. While prior research had identified upregulation of Wnt pathway modulatorsDkk1andDkk2inPax9-/-palate mesenchyme, limitations of spatial resolution and technology restricted a more robust analysis. Here, data from single-nucleus transcriptomics and chromatin accessibility assays validated byin situhighly multiplex targeted single-cell spatial profiling technology suggest a distinct relationship betweenPax9+and osteogenic populations. Loss ofPax9results in spatially restricted osteogenic domains bounded byDkk2, which normally interfaces withPax9in the mesenchyme. These results suggest that Pax9-dependent Wnt signaling modulators influence osteogenic programming during palate formation, potentially contributing to the observed cleft palate phenotype.
A rapid workflow for neuron counting in combined light sheet microscopy and magnetic resonance histology
Authors: Tian Yuqi , Johnson G Allan , Williams Robert W , White Leonard
Published: May 2023

Information on regional variation in cell numbers and densities in the CNS provides critical insight into structure, function, and the progression of CNS diseases. However, variability can be real or can be a consequence of methods that do not account for technical biases, including morphologic deformations, errors in the application of cell type labels and boundaries of regions, errors of counting rules and sampling sites. We address these issues of by introducing a workflow that consists of the following steps: 1. Magnetic resonance histology (MRH) to establish the size, shape, and regional morphology of the mouse brain in situ. 2. Light-sheet microscopy (LSM) to selectively label all neurons or other cells in the entire brain without sectioning artifacts. 3. Register LSM volumes to MRH volumes to correct for dissection errors and morphological deformations. 4. Implement novel protocol for automated sampling and counting of cells in 3D LSM volumes. This workflow can analyze the cells density of one brain region in less than 1 min and is highly replicable to cortical and subcortical gray matter regions and structures throughout the brain. We report deformation-corrected neuron (NeuN) counts and neuronal density in 13 representative regions in 5 C57B6/6J and 2 BXD strains. The data represent the variability among cases for the same brain region and across regions within case. Our data are consistent with previous studies. We demonstrate the application of our workflow to a mouse model of aging. This workflow improves the accuracy of neuron counting and the assessment of neuronal density on a region-by-region basis, with broad applications in how genetics, environment, and development across the lifespan impact brain structure.
Rhythmic entrainment of saccadic eye-movements in macaque FEF
Authors: Shaverdi Yeganeh , Setarehdan Seyed Kamaledin , Treue Stefan , Esghaei Moein
Published: May 2023

Saccadic eye movements play a key role in gaining information about the surrounding environment. However, the neural mechanisms underlying the timing of these eye movements remain poorly understood. Here, we investigated the entrainment of saccadic eye movement by oscillatory neural activities in rhesus monkeys performing a visual foraging task. We found that saccades are phase-locked to beta LFP oscillations (16-22 Hz) in the frontal eye field (FEF), 100 ms before saccade onset, supporting a causal role of these oscillations in saccade timing. Furthermore, we show that the alignment between saccades and FEF LFPs varies, depending on the spatial relationship between the saccade target and the response field (RF) of neurons in the FEF. These findings suggest that the phase of the oscillatory neural activities determines the timing and direction of saccades.
SARS-CoV-2 infection leads to Tau pathological signature in neurons
Authors: Di Primio Cristina , Quaranta Paola , Mignanelli Marianna , Siano Giacomo , Bimbati Matteo , Piazza Carmen Rita , Spezia Piero Giorgio , Perrera Paola , Basolo Fulvio , Poma Anello Marcello , Costa Mario , Pistello Mauro , Cattaneo Antonino
Published: May 2023

Background

The coronavirus disease 19 (COVID-19) has represented an issue for global health since its outbreak in March 2020. It is now evident that the SARS-CoV-2 infection results in a wide range of long-term neurological symptoms and is worryingly associated with the aggravation of Alzheimer’s disease. Little is known about the molecular basis of these manifestations.

Methods

Several SARS-CoV-2 strain variants were used to infect SH-SY5Y neuroblastoma cells and K18-hACE C57BL/6J mice. The Tau phosphorylation profile and aggregation propensity upon infection were investigated using immunoblot and immunofluorescence on cellular extracts, subcellular fractions, and brain tissue. The viral proteins Spike, Nucleocapsid, and Membrane were overexpressed in SH-SY5Y cells and the direct effect on Tau phosphorylation was checked using immunoblot experiments.

Results

Upon infection, Tau is phosphorylated at several pathological epitopes associated with Alzheimer’s disease and other tauopathies. Moreover, this event increases Tau’s propensity to form insoluble aggregates and alters its subcellular localization.

Conclusions

Our data support the evidence that SARS-CoV-2 infection in the Central Nervous System triggers downstream effects altering Tau function, eventually leading to the impairment of neuronal function.
Acute effect of transcranial direct current stimulation (tDCS) on postural control of trained athletes: a randomized controlled trial
Authors: Giancatarina Mary , Grandperrin Yohan , Nicolier Magali , Gimenez Philippe , Vidal Chrystelle , Tio Gregory , Haffen Emmanuel , Bennabi Djamila , Grosprêtre Sidney
Published: May 2023

Transcranial direct current stimulation (tDCS) is used to modulate the brain function in targeted brain areas, and can acutely modulate motor control, such as postural control. While the acute effect of tDCS is well documented on patients, little is still known whether tDCS can alter the motor control of healthy populations with an already high level of motor skills. This study aimed to assess the acute effect of tDCS on postural control of trained athletes. Eighteen parkour practitioners, known for their good balance abilities, were tested on three occasions in the laboratory for each stimulation condition (2 mA ; 20 minutes) – primary motor cortex (M1), prefrontal cortex (dlPFC) and sham (placebo). Postural control was evaluated PRE and POST each stimulation by measuring Center of Pressure (CoP) displacements on a force platform during static conditions (bipedal and unipedal stance). Following M1 stimulation, significant decreases were observed in CoP area in unipedal (P=0.003) and bipedal (P<0.001) stances. As well, the CoP total length was significantly reduced in bipodal (P=0.005) as well as in unipedal stance (P<0.001), only after M1 stimulation. Relative pre-post changes observed after M1 stimulation were negatively correlated to experience in parkour only after unipedal stance (r=0.715, P<0.001), meaning that the more participants were trained the less tDCS was effective. No significant changes were noticed after sham and dlPFC stimulation. These results suggested that the modulation of gait performance in athletes following an acute intervention of tDCS is specific to the targeted brain region, and that more complex postures (such as unipedal stance) were more sensitive to the effect of tDCS according to the level of practice.
Single nuclei transcriptomics in human and non-human primate striatum implicates neuronal DNA damage and proinflammatory signaling in opioid use disorder
Authors: Phan BaDoi N. , Ray Madelyn H. , Xue Xiangning , Fu Chen , Fenster Robert J. , Kohut Stephen J. , Bergman Jack , Haber Suzanne N. , McCullough Kenneth M. , Fish Madeline K. , Glausier Jill R. , Su Qiao , Tipton Allison E. , Lewis David A. , Freyberg Zachary , Tseng George C. , Russek Shelley J. , Alekseyev Yuriy , Ressler Kerry J. , Seney Marianne L. , Pfenning Andreas R. , Logan Ryan W.
Published: May 2023

The striatum in the brain is involved in various behavioral functions, including reward, and disease processes, such as opioid use disorder (OUD). Further understanding of the role of striatal subregions in reward behaviors and their potential associations with OUD requires molecular identification of specific striatal cell types in human brain. The human striatum contains subregions based on different anatomical, functional, and physiological properties, with the dorsal striatum further divided into caudate and putamen. Both caudate and putamen are involved in altered reward processing, formation of habits, and development of negative affect states associated with OUD. Using single nuclei RNA-sequencing of human postmortem caudate and putamen, we identified canonical neuronal cell types in striatum (e.g.,dopamine receptor 1 or 2 expressing neurons, D1 or D2) and less abundant subpopulations, including D1/D2-hybrid neurons and multiple classes of interneurons. By comparing unaffected subjects to subjects with OUD, we found neuronal-specific differences in pathways related to neurodegeneration, interferon response, and DNA damage. DNA damage markers were also elevated in striatal neurons of rhesus macaques following chronic opioid administration. We also identified sex-dependent differences in the expression of stress-induced transcripts among astrocytes and oligodendrocytes from female subjects with OUD. Thus, we describe striatal cell types and leverage these data to gain insights into molecular alterations in human striatum associated with opioid addiction.
Decomposing bulk signals to reveal hidden information in processive enzyme reactions: A case study in mRNA translation
Authors: Haase Nadin , Christ Simon , Heinemann Dag , Rudorf Sophia
Published: May 2023

Processive enzymes, such as polymerases or ribosomes, are often studied in en-semble or bulk experiments through the monitoring of time-dependent signals, such as fluorescence time traces. However, ensemble signals are a superposition of the time traces of all molecules in the reaction and can exhibit less distinct features than individual single-molecule signals due to the stochasticity of biomolecular processes. Here, we demonstrate that under certain conditions, bulk signals from processive reactions can still be decomposed to reveal hidden information about individual reaction steps. Using mRNA translation as a case study for processive biochemical reactions, we explore the limits of least-squares approaches for ensemble fluorescence signal decomposition. Specifically, we show that decomposing a noisy ensemble signal generated by the translation of mRNAs containing more than a few codons represents an ill-posed problem, which can be addressed through Tikhonov regularization. Our findings can help to increase the information content extracted from bulk experiments, thereby expanding the range of these time- and cost-efficient methods.
MuSK-BMP signaling in adult muscle stem cells maintains quiescence and regulates myofiber size
Authors: Madigan Laura A. , Jaime Diego , Chen Isabella , Fallon Justin R.
Published: May 2023

A central question in adult stem cell biology is elucidating the signaling pathways regulating their dynamics and function in diverse physiological and age-related contexts. Muscle stem cells in adults (Satellite Cells; SCs) are generally quiescent but can activate and contribute to muscle repair and growth. Here we tested the role of the MuSK-BMP pathway in regulating adult SC quiescence by deletion of the BMP-binding MuSK Ig3 domain (‘ΔIg3-MuSK’). At 3 months of age SC and myonuclei numbers and myofiber size were comparable to WT. However, at 5 months of age SC density was decreased while myofiber size, myonuclear number and grip strength were increased - indicating that SCs had activated and productively fused into the myofibers over this interval. Transcriptomic analysis showed that SCs from uninjured ΔIg3-MuSK mice exhibit signatures of activation. Regeneration experiments showed that ΔIg3-MuSK SCs maintain full stem cell function. Expression of ΔIg3-MuSK in adult SCs was sufficient to break quiescence and increase myofiber size. We conclude that the MuSK-BMP pathway regulates SC quiescence and myofiber size in a cell autonomous, age-dependent manner. Targeting MuSK-BMP signaling in muscle stem cells thus emerges a therapeutic strategy for promoting muscle growth and function in the settings of injury, disease, and aging.

Highlights

MuSK, in its role as a BMP co-receptor, regulates adult muscle stem cell quiescence

The MuSK-BMP pathway acts cell autonomously

Increased muscle size and function with preservation of myonuclear density and stemness in mice with attenuated MuSK-BMP signaling
Repair oligodendrocytes demyelinating and disintegrating damaged axons after injury
Authors: Nocera Gianluigi , Vaquié Adrien , Hertzog Nadège , Steil Katharina , Duque Santiago Luis Cañón , Miedema Johannes , Bagin Cansu , Tevosian Margaryta , Lutz Beat , Sharifi-Aghili Azadeh , Hegner Katharina , Vollmer Doris , Bang Seokyoung , Lee Seung-Ryeol , Jeon Noo Li , Keyse Stephen M , López Sofía Raigón , Jacob Claire
Published: May 2023

After a spinal cord injury, axons fail to regrow, which results in permanent loss of function1. This is in contrast with peripheral axons that can regrow efficiently after injury2. These differences are partly due to the different plasticity of myelinating cells, Schwann cells and oligodendrocytes, in these two systems3. The molecular mechanisms underlying this different plasticity remain however poorly understood. Here, we show that the phosphatase Dusp64is a master inhibitor of oligodendrocyte plasticity after spinal cord injury. Dusp6 is rapidly downregulated in Schwann cells and upregulated in oligodendrocytes after axon injury. Simultaneously, the MAP kinases ERK1/2 are activated and the transcription factor c-Jun is upregulated in Schwann cells5,6, but not in oligodendrocytes. Ablation or inactivation of Dusp6 induces rapid ERK1/2 phosphorylation, c-Jun upregulation and filopodia formation in oligodendrocytes, leading to mechanically-induced, fast disintegration of distal ends of injured axons, myelin clearance and axonal regrowth. Together, our findings provide understanding of the mechanisms underlying the different plasticity of Schwann cells and oligodendrocytes after injury and a method to convert mature oligodendrocytes exhibiting inhibitory cues for axonal regrowth into repair oligodendrocytes reminiscent of repair Schwann cells. We show that repair oligodendrocytes successfully increase the compatibility of the spinal cord environment with axonal regrowth after injury, suggesting a potential use of repair oligodendrocytes as future therapeutic approach to treat spinal cord injuries.
Crystal structure of a three-tetrad, parallel, K+-stabilized human telomeric G-quadruplex at 1.35 Å resolution
Authors: Chen E. V. , Nicoludis J. M. , Powell B. M. , Li K. S. , Yatsunyk L. A.
Published: May 2023

The crystal structure of the G-rich human telomeric DNA Tel22 has been determined at 1.35 Å resolution in space group P6. Tel22 forms a non-canonical DNA structure called the G-quadruplex. The space group and unit-cell parameters are comparable to those in the crystal structures with PDB codes 6ip3 (1.40 Å resolution) and 1kf1 (2.15 Å resolution). The G-quadruplexes are highly similar in all of the structures. However, this structure of Tel22 displays clear density for polyethylene glycol and two potassium ions, which are located outside the ion channel in the G-quadruplex and play an important role in stabilizing the crystal contacts. In addition, 111 water molecules were identified (compared with 79 and 68 in PDB entries 6ip3 and 1kf1, respectively) that participate in intricate and extensive networks providing high stability to the G-quadruplex.
Exogenous trehalose application promotes survival by alleviating oxidative stress and affecting transcriptome in ethanol-stressed Wickerhamomyces anomalus
Authors: Li Yinfeng , Jiang Guilan , Long Hua , Liao Yifa , Huang Mingzheng , Yu Zhihai , Cheng Shuang , Wang Ying , Liu Xiaozhu
Published: May 2023

Purpose

Increased ethanol accumulation during ethanol fermentation generates stress in yeast cells, which finally reduces the fermentation performance and efficiency. Trehalose, a potential stress protectant, has been reported to regulate the response of yeast to diverse environmental stresses. This study aimed to explore how exogenous trehalose application affects the survival, transcriptome and antioxidant enzymes of Wickerhamomyces anomalus grown under ethanol stress conditions.

Design/methodology/approach

Exogenous trehalose was applied to the growth condition of W. anomalus, and optical densitometric method was used to detect contents of intracellular trehalose and MDA and activities of CAT and SOD. The survival was evaluated using spot analysis. Differentially expressed genes (DEGs) were identified through transcriptomics analysis.

Findings

The results showed that ethanol stress induced the accumulation of intracellular trehalose, with further exogenous trehalose application improving the survival and alleviating oxidative stress in ethanol-stressed W. anomalus. Transcriptomic results showed that trehalose has pleiotropic regulating effects on ethanol-stressed W. anomalus since most DEGs annotated to energy metabolism, amino acid metabolism, translation, folding, sorting and transport were affected post trehalose addition. Therefore, it is found that trehalose protected W. anomalus against ethanol stress, and these findings provide interesting insights into the mechanistic role of trehalose in improving ethanol stress tolerance of W. anomalus.

Originality/value

(1) Protective effect of exogenous trehalose addition on the survival of ethanol-stressed W. anomalus was proved. (2) Exogenous trehalose addition could partly alleviate oxidative stress induced by ethanol stress and affect transcriptome in W. anomalus.
Choice for sustainable meals at staff restaurants: influence of at-home food habits and food triggers
Authors: Debucquet Gervaise , Dugué Mélanie , Cardinal Mireille
Published: May 2023

Purpose

Collective catering sector is increasingly offering alternative and more sustainable food propositions, but their success rests on their reception by guests and changes induced in individual behaviors. The authors investigate food-change determinants by examining the relationship between food behavior at staff restaurants and at home.

Design/methodology/approach

In an experiment over four days conducted in three staff restaurants, the authors monitored the behavioral changes and motivations of guests (n = 599) offered choices between standard and sustainable options for meat, fish, dairy products, fruit-based desserts and a vegetarian dish. The calculation of a “sustainable consumption score,” based on actual consumption at a restaurant by a subsample (n = 160) of guests gives an indication of interest for sustainable options.

Findings

Higher overall choices were observed for vegetarian dishes and for the sustainable meat options rather than for the sustainable fish and desserts options, thus suggesting contrasted perceptions of the sustainable alternatives. The results revealed two profiles of consumers with contrasting scores. The “lower receptive guests” had lower commitment to sustainable food at home and at staff restaurants, while the “higher receptive guests” found in the intervention meaningful propositions for pursuing their existing at-home commitment.

Research limitations/implications

Long-term research would be required to verify whether repeated sustainable offers can break down deep-rooted choices and instill durable changes among consumers with lower commitment to sustainable food. This research contributes to the identification of some types of food that are more suitable for sustainable-oriented interventions.

Practical implications

Some food triggers are identified to further norm activation among the lower receptive profile of consumers.

Originality/value

By addressing continuities/discontinuities between at-home and at-restaurant consumption and mobilizing the “norm-activation” concept, the authors question the efficiency of sustainable food offers at work.
A study on implementing QFD (quality function deployment) in the construction of a commercial business center
Authors: Dara Sruthilaya
Published: May 2023

Purpose

This study aims to demonstrate how the process of quality function deployment (QFD) is used to identify the basic requirements of the customers in designing and executing the commercial business center.

Design/methodology/approach

This study was considered with the aim of determining the approach of QFD methodology used in the planning and designing of commercial business centers. The methodology used in the study is a customer-driven process that includes customer requirements in each and every aspect of the planning and designing of the project. The main focus of this study is to understand the requirements of the customers and to design and execute a commercial business project.

Findings

This study illustrates the quality requirements of the projects that benefit from the QFD process to obtain customer requirements for the planning and designing of commercial business centers. A case study is used to demonstrate the use of QFD process. This helps to explain the effective application of QFD in the planning and designing of business centers and similar constructions.

Research limitations/implications

The planning and designing of the commercial business center using the QFD process were challenging and hence it is limited to the design part. The strategic objectives are not taken into account while performing QFD in this case study and the risk of market research is lacking. House of quality (HOQ) can be too complicated at times; hence, the adaptability in the traditional QFD is lacking. Most of the work in the HOQ matrix is done through subjective evaluation. Therefore, this research is mostly useful for a single party responsible for all phases of the planning and designing of the project.

Originality/value

In the construction industry, the use of the QFD process for project performance analysis and application is restricted. As a result of the scarcity of studies on the planning and design of construction projects, this study on the planning and design of a construction project was inspired.
Nonlinear analysis of the semi-active particle damping vibration isolation system based on fractional-order theory
Authors: Xue Cheng , Xia Zhaowang , Lao Xingsheng , Yang Zhengqi
Published: May 2023

Purpose

The purpose of this study is to provide some references about applying the semi-active particle damper to enhance the stability of the pipe structure.

Design/methodology/approach

This paper establishes the dynamical models of semi-active particle damper based on traditional dynamical theory and fractional-order theory, respectively. The semi-active particle damping vibration isolation system applied in a pipe structure is proposed, and its analytical solution compared with G-L numerical solution is solved by the averaging method. The quantitative relationships of fractional-order parameters (a and kp) are confirmed and their influences on the amplitude-frequency response of the vibration isolation system are analyzed. A fixed point can be obtained from the amplitude-frequency response curve, and the optimal parameter used for improving the vibration reduction effect of semi-active particle damper can be calculated based on this point. The nonlinear phenomenon caused by nonlinear oscillators is also investigated.

Findings

The results show that the nonlinear stiffness parameter p will cause the jump phenomenon while p is close to 87; with the variation of nonlinear damping parameter μ, the pitchfork bifurcation phenomenon will occur with an unstable branch after the transient response; with the change of fractional-order coefficient kp, a segmented bifurcation phenomenon will happen, where an interval that kp between 18.5 and 21.5 has no bifurcation phenomenon.

Originality/value

This study establishes a mathematical model of the typical semi-active particle damping vibration isolation system according to fractional-order theory and researches its nonlinear characteristics.
Building students' attachment strength with higher education institutes using intangible resources: role of institutional branding
Authors: Khanna Kritika , Pandher Jagwinder Singh , Bedi Sarbjit Singh
Published: May 2023

Purpose

The present study has been carried out to study whether and how different aspects of brand management (brand identity, brand image and brand meaning) are instrumental in maintaining and enhancing attachment strength of students with higher education institutes (HEIs). Further, to understand what brand management aspect channels the impact of what branding driver on attachment strength in most effective manner.

Design/methodology/approach

The study analysed combined mediating effects as well as specific mediating effects to test the mediating role of brand management aspects.

Findings

The study reveals that brand image plays highest mediating role among all aspects of brand management. HEIs need to enhance service quality because brand image carries the highest influence of service quality on attachment strength. Similarly, brand identity carries the highest influence of heritage on attachment strength. Brand meaning carries the highest influence of competence and reputation on attachment strength.

Research limitations/implications

The present study, based on empirical research, has built the framework and mechanism for creating attachment strength utilising the intangible resources of HEIs through brand management. The present study examines how specific intangible resources exhibit varying influences on attachment strength via distinct brand management mediation effects.

Practical implications

The present study provides framework for designing branding strategies to build and channelise necessary intangible resources of branding for nourishing and nurturing attachment strength.

Originality/value

The present study contributes to scarce branding literature in context of HEIs. The study proposes role of HEI branding in developing students' attachment strength with their HEIs.