bluuebunny/crossref_metadata_2025 huggingface dataset:
Progeny counter mechanism in malaria parasites is linked to extracellular resources
Authors: Stürmer Vanessa S. , Stopper Sophie , Binder Patrick , Klemmer Anja , Becker Nils B. , Guizetti Julien
Published: January 2023

Malaria is caused by the rapid proliferation ofPlasmodiumparasites in patients and disease severity correlates with the number of infected red blood cells in circulation. Parasite multiplication within red blood cells is called schizogony and occurs through an atypical multinucleated cell division mode. The mechanisms regulating the number of daughter cells produced by a single progenitor are poorly understood. We investigated underlying regulatory principles by quantifying nuclear multiplication dynamics inPlasmodium falciparumandknowlesiusing super-resolution time-lapse microscopy. This revealed that the number of daughter cells was statistically independent of the duration of the nuclear division phase, which confirms that a counter mechanism, rather than a timer, regulates multiplication.P. falciparumcell volume at the start of nuclear division correlated with the final number of daughter cells. As schizogony progressed, the nucleocytoplasmic volume ratio, which has been found to be constant in all eukaryotes characterized so far, increased significantly, possibly to accommodate the exponentially multiplying nuclei. Depleting nutrients by dilution of culture medium caused parasites to produce less merozoites and reduced proliferation but did not affect cell volume or total nuclear volume at the end of schizogony. Our findings suggest that the counter mechanism implicated in malaria parasite proliferation integrates extracellular resource status to modify progeny number during blood stage infection.
Source Localization Using Recursively Applied and Projected MUSIC with Flexible Extent Estimation
Authors: Hecker Lukas , Tebartz van Elst Ludger , Kornmeier Jürgen
Published: January 2023

1

Magneto- and electroencephalography (M/EEG) are widespread techniques to measure neural activityin-vivoat a high temporal resolution but low spatial resolution. Locating the neural sources underlying the M/EEG poses an inverse problem, which is ill-posed. We developed a new method based on Recursive Application of Multiple Signal Classification (MUSIC). Our proposed method is able to recover not only the locations but, in contrast to other inverse solutions, also the extent of active brain regions flexibly (FLEX-MUSIC). This is achieved by allowing it to search not only for single dipoles but also dipole clusters of increasing extent to find the best fit during each recursion. FLEX-MUSIC achieved the highest accuracy for both single dipole and extended sources compared to all other methods tested. Remarkably, FLEX-MUSIC was capable to accurately estimate the level of sparsity in the source space (r= 0.82), whereas all other approaches tested failed to do so (r≤ 0.18). The average computation time of FLEX-MUSIC was considerably lower compared to a popular Bayesian approach and comparable to that of another recursive MUSIC approach and eLORETA. FLEX-MUSIC produces only few errors and was capable to reliably estimate the extent of sources. The accuracy and low computation time of FLEX-MUSIC renders it an improved technique to solve M/EEG inverse problems both in neuroscience research and potentially in pre-surgery diagnostic in epilepsy.
Whole transcriptome profiling of placental pathobiology in SARS-CoV-2 pregnancies identifies placental dysfunction signatures
Authors: Stylianou Nataly , Sebina Ismail , Matigian Nicholas , Monkman James , Doehler Hadeel , Röhl Joan , Allenby Mark , Nam Andy , Pan Liuliu , Rockstroh Anja , Sadeghirad Habib , Chung Kimberly , Sobanski Thais , O’Byrne Ken , Ana Clara Simoes Florido Almeida , Rebutini Patricia Zadorosnei , Machado-Souza Cleber , Stonoga Emanuele Therezinha Schueda , Warkiani Majid E , Salomon Carlos , Short Kirsty , McClements Lana , de Noronha Lucia , Huang Ruby , Belz Gabrielle T. , Souza-Fonseca-Guimaraes Fernando , Clifton Vicki , Kulasinghe Arutha
Published: January 2023

Objectives

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus infection in pregnancy is associated with higher incidence of placental dysfunction, referred to by a few studies as a “preeclampsia-like syndrome”. However, the mechanisms underpinning SARS-CoV-2-induced placental malfunction are still unclear. Here, we investigated whether the transcriptional architecture of the placenta is altered in response to SARS-CoV-2 infection.

Methods

We utilized whole-transcriptome, digital spatial profiling, to examine gene expression patterns in placental tissues from participants who contracted SARS-CoV-2 in the third trimester of their pregnancy (n=7) and those collected prior to the start of the coronavirus disease 2019 (COVID-19) pandemic (n=9).

Results

Through comprehensive spatial transcriptomic analyses of the trophoblast and villous core stromal cell subpopulations in the placenta, we identified signatures associated with hypoxia and placental dysfunction during SARS-CoV-2 infection in pregnancy. Notably, genes associated with vasodilation (NOS3), oxidative stress (GDF15,CRH), and preeclampsia (FLT1, EGFR, KISS1, PAPPA2),were enriched with SARS-CoV-2. Pathways related to increased nutrient uptake, vascular tension, hypertension, and inflammation, were also enriched in SARS-CoV-2 samples compared to uninfected controls.

Conclusions

Our findings demonstrate the utility of spatially resolved transcriptomic analysis in defining the underlying pathogenic mechanisms of SARS-CoV-2 in pregnancy, particularly its role in placental dysfunction. Furthermore, this study highlights the significance of digital spatial profiling in mapping the intricate crosstalk between trophoblasts and villous core stromal cells, thus shedding light on pathways associated with placental dysfunction in pregnancies with SARS-CoV-2 infection.

Graphical abstract

In this study, using spatial digital profiling transcriptomic approaches, we demonstrate that SARS-CoV-2 infection in pregnancy disrupts optimal placental function by altering the genomic architecture of trophoblasts and villous core stromal cells.
Dopamine neurons encode trial-by-trial subjective reward value in an auction-like task
Authors: Hill Daniel F. , Hickman Robert W. , Al-Mohammad Alaa , Stasiak Arkadiusz , Schultz Wolfram
Published: January 2023

The dopamine reward prediction error signal is known to be subjective but has so far only been assessed in aggregate choices. However, personal choices fluctuate across trials and thus reflect the instantaneous subjective reward value. In the well-established Becker-DeGroot-Marschak (BDM) auction-like mechanism, participants are encouraged to place bids that accurately reveal their instantaneous subjective reward value; inaccurate bidding results in suboptimal reward (‘incentive compatibility’). In our experiment, male rhesus monkeys became experienced over several years to place accurate BDM bids for juice rewards without specific external constraints. Their bids for physically identical rewards varied trial by trial and increased overall for larger rewards. In these highly experienced animals, responses of midbrain dopamine neurons followed the trial-by-trial variations of bids despite constant, explicitly predicted reward amounts. Inversely, dopamine responses were similar with similar bids for different physical reward amounts. Support Vector Regression demonstrated accurate prediction of the animals’ bids by as few as twenty dopamine neurons. Thus, the phasic dopamine reward signal reflects instantaneous subjective reward value.
DISCOVER-EEG: an open, fully automated EEG pipeline for biomarker discovery in clinical neuroscience
Authors: Gil Ávila Cristina , Bott Felix S. , Tiemann Laura , Hohn Vanessa D. , May Elisabeth S. , Nickel Moritz M. , Zebhauser Paul Theo , Gross Joachim , Ploner Markus
Published: January 2023

Biomarker discovery in neurological and psychiatric disorders critically depends on reproducible and transparent methods applied to large-scale datasets. Electroencephalography (EEG) is a promising tool for identifying biomarkers. However, recording, preprocessing, and analysis of EEG data is time-consuming and researcher- dependent. Therefore, we developed DISCOVER-EEG, an open and fully automated pipeline that enables easy and fast preprocessing, analysis, and visualization of resting state EEG data. Data in the Brain Imaging Data Structure (BIDS) standard are automatically preprocessed, and physiologically meaningful features of brain function (including oscillatory power, connectivity, and network characteristics) are extracted and visualized using two open-source and widely used Matlab toolboxes (EEGLAB and FieldTrip). We tested the pipeline in two large, openly available datasets, the LEMON dataset, containing 213 EEG recordings of healthy participants, and the TDBRAIN dataset, containing 1274 EEG recordings, mainly from patients with a psychiatric condition. Additionally, we performed an exploratory analysis of the LEMON dataset that could inspire biomarkers of healthy aging. Thus, the DISCOVER-EEG pipeline facilitates the aggregation, reuse, and analysis of large EEG datasets, promoting open and reproducible research on brain function.
Signaling in microbial communities with open boundaries
Authors: Winkle James J. , Saha Soutick , Essman Joseph , Bennett Matthew R. , Ott William , Josic Kresimir R , Mugler Andrew
Published: January 2023

Microbial communities such as swarms or biofilms often form at the interfaces of solid substrates and open fluid flows. At the same time, in laboratory environments these communities are commonly studied using microfluidic devices with media flows and open boundaries. Extracellular signaling within these communities is therefore subject to different constraints than signaling within classic, closed-boundary systems such as developing embryos or tissues, yet is understudied by comparison. Here, we use mathematical modeling to show how advective-diffusive boundary flows and population geometry impact cell-cell signaling in monolayer microbial communities. We reveal conditions where the intercellular signaling lengthscale depends solely on the population geometry and not on diffusion or degradation, as commonly expected. We further demonstrate that diffusive coupling with the boundary flow can produce signal gradients within an isogenic population, even when there is no flow within the population. We use our theory to provide new insights into the signaling mechanisms of published experimental results, and we make several experimentally verifiable predictions. Our research highlights the importance of carefully evaluating boundary dynamics and environmental geometry when modeling microbial cell-cell signaling and informs the study of cell behaviors in both natural and synthetic systems.
Prediction Analysis of Preterm Neonates Mortality using Machine Learning Algorithms via Python Programming
Authors: Monfared Vahid , Hashemi Afkham
Published: January 2023

Prediction analysis of preterm neonate mortality is necessary and significant for benchmarking and evaluating healthcare services in Hospitals and other medical centers. Application of artificial intelligence and machine learning models, which is a hot topic in medicine/healthcare and engineering, may improve physicians’ skill to predict the preterm neonatal deaths. The main purpose of this research article is to introduce a preterm neonatal mortality risk prediction by means of machine learning/ML predictive models to survive infants using supervised ML models if possible. Moreover, this paper presents some effective parameters and features which affect to survive the infants directly. It means, the obtained model has an accuracy of about 91.5% to predict the status of infant after delivery. After recognizing the critical status for an infant, physicians and other healthcare personnel can help to infant for possible surviving using special medical NICU cares. It has been tried to get some suitable models with high accuracy and comparing the results. In a word, a survival prediction analysis of preterm neonate mortality has been carried out using machine learning methods via Python programming (possible surviving infants after delivery in the hospital).
PPAR-γ is a promising therapeutic target for memory deficits induced by early alcohol exposure
Authors: Garcia-Baos Alba , Pastor Antoni , Gallego-Landin Ines , de la Torre Rafael , Sanz Ferran , Valverde Olga
Published: January 2023

Background

Patients diagnosed with fetal alcohol spectrum disorder (FASD) show persistent cognitive disabilities, including memory deficits. However, the neurobiological substrates of these deficits remain unclear. Here, we studied the participation of the expanded endocannabinoid system (ECS), which is known to be affected by alcohol in other life periods, and it is involved in memory impairments of neurodevelopmental disorders.

Methods

C57BL/6 female mice were exposed to a time-limited access to either water or alcohol to model prenatal and lactation alcohol exposure (PLAE). The expanded ECS was analyzed in the prefrontal cortex and the hippocampus of the offspring at post-partum day (PD) 25 and 70. Then, memory performance was tested after the repeated administration (from PD25 to PD34) of: i) URB597, to increase N-acylethanolamines (NAEs), and GW9662, a peroxisome proliferator-activated receptor gamma (PPAR-γ) antagonist; ii) pioglitazone, a PPAR-γ agonist. Finally, we used a viral approach to upregulate astrocytic PPAR-γ in the hippocampus to restore memory deficits.

Results

We report that PLAE causes a hippocampal reduction of NAEs and PPAR-γ at PD25. Moreover, URB597 suppresses PLAE-induced memory deficits through PPAR-γ, since its effects are prevented by GW9662. Direct PPAR-γ activation, using pioglitazone, also ameliorates memory impairments. Lastly, we demonstrate that the upregulation of PPAR-γ in hippocampal astrocytes is sufficient to rescue PLAE-induced memory deficits.

Conclusion

Our data reveal a bidirectional link between memory deficits and expanded ECS alterations in the context of early alcohol exposure. Furthermore, we proved that PPAR-γ in hippocampal astrocytes represents a specific therapeutic target for memory deficits in FASD.
Cytotrophoblast cells are selectively permissive and favor Zika virus, but no other related flavivirus, invasion to the placental stroma
Authors: Viettri Mercedes , Caraballo Gerson , Sanchez Ma. Elena , Espejel-Nuñez Aurora , Betanzos Abigail , Ortiz-Navarrete Vianney , Estrada-Gutierrez Guadalupe , Nava Porfirio , Ludert Juan E.
Published: January 2023

BACKGROUND

Zika virus (ZIKV) is highly teratogenic, in contrast with dengue virus (DENV) or the yellow fever virus vaccine (YFV-17D). The mechanisms employed by ZIKV to cross the placenta need to be elucidated.

METHODS

Parallel infections with ZIKV, DENV and YFV-17D were compared in terms of efficiency, activation of mTOR pathways and cytokine secretion profile in human cytotrophoblastic HTR8 cells (CTB), and monocytic U937 cells, differentiated to M2 macrophages (M2-MØ).

RESULTS

In CTB, ZIKV replication was significantly more efficient than DENV or YFV-17D. In M2-MØ, ZIKV replication continued to be more efficient, although differences between strains were reduced. Significantly greater activation of Phospho-S6r and Phospho-AKT/Ser473 fractions in CTB infected with ZIKV than with DENV or YFV-17D, was observed. CTB treated with the mTOR inhibitors rapamycin or AZD8055, showed a 20-fold-reduction in ZIKV yield, versus 5 and 3.5-fold for DENV and YFV-17D, respectively. Finally, we detected that ZIKV infection, but not DENV or YFV-17D, efficiently inhibited the interferon response of CTB cells.

CONCLUSIONS

These results suggest that CTB cells are permissive and act favoring ZIKV entry into the placental stroma, over DENV and YFV-17D and that the mTOR complex is a switch that enhances the replication of ZIKV in CTB cells.
Cryo-EM structure of DNA polymerase θ helicase domain in complex with inhibitor novobiocin
Authors: Guo Hanbo , Wang YanXia , Mao Jun , Zhao Huimin , He Yuntong , Hu Yuandong , Li Jing , Liu Yujie , Guan Zheng , Guo Allen , Ni Xiaodan , Zhang Fengying , Heng Jie
Published: January 2023

DNA double-strand breaks (DSBs) are highly toxic lesions that occur during the cellular metabolic process. DNA Polymerase theta (Polθ) is an error-prone polymerase that has been implicated in the repair of chromosome breaks, recovery of broken replication forks, and translesion synthesis. The inhibition of Polθ activity has been implicated in killing HR-deficient tumor cellsin vitroandin vivo. We present the first biochemical evidence that the antibiotics novobiocin (NVB) noncompetitively inhibit ATP hydrolysis by the ATPase domain of the Polθ helicase domain (Polθ-HLD). We report the Cryo-EM structure of apo dimeric Polθ helicase domain (Polθ-HLD), and the first inhibitor occupied Polθ-HLD structure. Our structure identifies a non-canonical novobiocin binding pocket, distinct from the canonical site that partially overlaps with the ATP in the ATPase domain. Comparison with the homolog helicase Hel308-DNA duplex complex suggests that the novobiocin competitively binds to a triangle hub on the DNA translocation pathway and blocks the ssDNA binding and translocation. Furthermore, the first dimeric structure of Polθ-HLD also provides a structural framework for revealing the microhomology-mediated end-joining mechanism. Our results demonstrate that the inhibitor-occupied structure combined with rational, structure-based drug design will undoubtedly accelerate the discovery of potent inhibitors with better efficacy and target selectivity to human Polθ.
Lipopolysaccharide integrity primes bacterial sensitivity to a cell wall-degrading intermicrobial toxin
Authors: Trotta Kristine L , Hayes Beth M , Schneider Johannes P , Wang Jing , Todor Horia , Grimes Patrick Rockefeller , Zhao Ziyi , Hatleberg William L , Silvis Melanie R , Kim Rachel , Koo Byoung Mo , Basler Marek , Chou Seemay
Published: January 2023

Gram-negative bacteria can antagonize neighboring microbes using a type VI secretion system (T6SS) to deliver toxins that target different essential cellular features. Despite the conserved nature of these targets, T6SS potency can vary across recipient species. To understand the molecular basis of intrinsic T6SS susceptibility, we screened for essentialEscherichia coligenes that affect its survival when antagonized by a cell wall-degrading T6SS toxin fromPseudomonas aeruginosa, Tae1. We revealed genes associated with both the cell wall and a separate layer of the cell envelope, surface lipopolysaccharide, that modulate Tae1 toxicityin vivo. Disruption of lipopolysaccharide synthesis providedEscherichia coli (Eco)with novel resistance to Tae1, despite significant cell wall degradation. These data suggest that Tae1 toxicity is determined not only by direct substrate damage, but also by indirect cell envelope homeostasis activities. We also found that Tae1-resistantEcoexhibited reduced cell wall synthesis and overall slowed growth, suggesting that reactive cell envelope maintenance pathways could promote, not prevent, self-lysis. Together, our study highlights the consequences of co-regulating essential pathways on recipient fitness during interbacterial competition, and how antibacterial toxins leverage cellular vulnerabilities that are both direct and indirect to their specific targetsin vivo.
4CAC: 4-class classifier of metagenome contigs using machine learning and assembly graphs
Authors: Pu Lianrong , Shamir Ron
Published: January 2023

Microbial communities usually harbor a mix of bacteria, archaea, plasmids, viruses, and microeukaryotes. Within these communities, viruses, plasmids, and microeukaryotes coexist in relatively low abundance, yet they engage in intricate interactions with bacteria. Moreover, viruses and plasmids, as mobile genetic elements, play important roles in horizontal gene transfer and the development of antibiotic resistance within microbial populations. However, due to the difficulty of identifying viruses, plasmids, and microeukaryotes in microbial communities, our understanding of these minor classes lags behind that of bacteria and archaea. Recently, several classifiers have been developed to separate one or two minor classes from bacteria and archaea in metagenome assemblies, but none can classify all of the four classes simultaneously. Moreover, existing classifiers have low precision on minor classes. Here, we developed a classifier called 4CAC that is able to identify viruses, plasmids, microeukaryotes, and prokaryotes simultaneously from metagenome assemblies. 4CAC generates an initial four-way classification using several sequence length-adjusted XGBoost models and further improves the classification using the assembly graph. Evaluation on simulated and real metagenome datasets demonstrates that 4CAC substantially outperforms existing classifiers and combinations thereof on short reads. On long reads, it also shows an advantage unless the abundance of the minor classes is very low. 4CAC runs 1-2 orders of magnitude faster than the other classifiers. The 4CAC software is available athttps://github.com/Shamir-Lab/4CAC.
Keratinocytes coordinate inflammatory responses and regulate development of secondary lymphedema
Authors: Park Hyeung Ju , Kataru Raghu P. , Shin Jinyeon , García Nores Gabriela D. , Encarnacion Elizabeth M. , Klang Mark G. , Riedel Elyn , Coriddi Michelle , Dayan Joseph H. , Mehrara Babak J.
Published: January 2023

Epidermal changes are histological hallmarks of secondary lymphedema, but it is unknown if keratinocytes contribute to its pathophysiology. Using clinical lymphedema specimens and mouse models, we show that keratinocytes play a primary role in lymphedema development by producing T-helper 2 (Th2) -inducing cytokines. Specifically, we find that keratinocyte proliferation and expression of protease-activated receptor 2 (PAR2) are early responses following lymphatic injury and regulate the expression of Th2-inducing cytokines, migration of Langerhans cells, and skin infiltration of Th2-differentiated T cells. Furthermore, inhibition of PAR2 activation with a small molecule inhibitor or the proliferation inhibitor teriflunomide (TF) prevents activation of keratinocytes stimulated with lymphedema fluid. Finally, topical TF is highly effective for decreasing swelling, fibrosis, and inflammation in a preclinical mouse model. Our findings suggest that lymphedema is a chronic inflammatory skin disease, and topically targeting keratinocyte activation may be a clinically effective therapy for this condition.
Anoctamin 10/TMEM16K mediates convergent extension and tubulogenesis during notochord formation in the early chordateCiona intestinalis
Authors: Liang Zonglai , Dondorp Daniel Christiaan , Chatzigeorgiou Marios
Published: January 2023

During embryonic development, cells are organized into complex tissues and organs. A highly conserved organ shape across metazoans is the epithelial tube. Tube morphogenesis is a complex multistep process where the molecular mechanisms underlying the diversity of cell behaviors such as convergent extension, cell elongation, and lumen formation are still intensely studied. Here, using genome editing and quantitative imaging in the early chordateCiona intestinaliswe show that Ano10/Tmem16k, a member of the evolutionarily ancient family of transmembrane proteins called Anoctamin/TMEM16 is required for convergent extension, lumen expansion and connection during notochord morphogenesis. In addition, we find that loss of Cii.Ano10/Tmem16k hampers cell behavior and cytoskeletal organization during tubulogenesis. In vivo Ca2+imaging revealed that genetic ablation of Cii.Ano10/Tmem16k hinders the ability of notochord cells to regulate bioelectrical signaling. Finally, we use electrophysiological recordings and a scramblase assay in tissue culture to demonstrate that Cii.Ano10/Tmem16k likely acts as an ion channel but not as a phospholipid scramblase. More generally, this work provides insights into the pre-vertebrate functions of Anoctamins and raises the possibility that Anoctamin/Tmem16 family members have an evolutionarily conserved role in tube morphogenesis.
Fine scale sampling reveals spatial heterogeneity of rhizosphere microbiome in youngBrachypodiumplants
Authors: Acharya Shwetha M. , Yee Mon Oo , Diamond Spencer , Andeer Peter F. , Baig Nameera F. , Aladesanmi Omolara T. , Northen Trent R. , Banfield Jillian F. , Chakraborty Romy
Published: January 2023

For a deeper and comprehensive understanding of the diversity, composition and function of rhizosphere microbiomes, we need to focus at the scale of individual roots in standardized growth containers. Root exudation patterns are known to vary across distinct parts of the root giving rise to spatially distinct microbial niches. To address this, we analyzed microbial community from two spatially distinct zones of the primary root (the tip vs. the base) inBrachypodium distachyon, grown in natural soil using standardized fabricated ecosystems known as EcoFABs as well as in more conventional pot and tubes. 16S rRNA based community analysis showed a stronger rhizosphere effect in the root base vs. bulk soil compared to the root tips vs. bulk soil, resulting in an enrichment of Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria, few OTUs belonging to less characterized lineages such as Verrucomicrobia and Acidobacteria. While the microbial community distributions are similar across growth containers, the EcoFAB displayed higher replicate reproducibility. Genome-resolved and bulk metagenomics revealed that genes associated with transcriptional regulation, transport of nutrients and catabolic enzymes indicating active metabolism, biofilm formation and root colonization were enriched in root tips. On the other hand, genes associated with nutrient-limitation and environmental stress were prominent in the bulk soil compared to the root tips, implying the presence of easily available, labile carbon and nutrients in the rhizosphere relative to bulk soil. Such insights into the relationships between root structure, exudation and microbial communities are critical for developing understanding of plant-microbe interactions.
Incorporating metabolic activity, taxonomy and community structure to improve microbiome-based predictive models for host phenotype prediction
Authors: Monshizadeh Mahsa , Ye Yuzhen
Published: January 2023

We developed MicroKPNN, a prior-knowledge guided interpretable neural network for microbiomebased human host phenotype prediction. The prior-knowledge used in MicroKPNN includes the metabolic activities of different bacterial species, phylogenetic relationships, and bacterial community structure. Application of MicroKPNN to seven gut microbiome datasets (involving five different human diseases including inflammatory bowel disease, type 2 diabetes, liver cirrhosis, colorectal cancer, and obesity) shows that incorporation of the prior knowledge helped improve the microbiome-based host phenotype prediction. MicroKPNN outperformed fully-connected neural network based approaches in all seven cases, with the most improvement of accuracy in the prediction of type 2 diabetes. MicroKPNN outperformed a recently developed deep-learning based approach DeepMicro, which selects the best combination of autoencoder and machine learning approach to make predictions, in six out of the seven cases. More importantly, we showed that MicroKPNN provides a way for interpretation of the predictive models. Our results suggested that the metabolic potential of the bacterial species contributed more than the two other sources of prior knowledge. MicroKPNN is publicly available athttps://github.com/mgtools/MicroKPNN.
Impact of acquisition and modeling parameters on test-retest reproducibility of edited GABA+
Authors: Hupfeld Kathleen E. , Zöllner Helge J. , Hui Steve C. N. , Song Yulu , Murali-Manohar Saipavitra , Yedavalli Vivek , Oeltzschner Georg , Prisciandaro James J. , Edden Richard A. E.
Published: January 2023

Literature values for within-subject test-retest reproducibility of gamma-aminobutyric acid (GABA), measured with edited magnetic resonance spectroscopy (MRS), vary widely. Reasons for this variation remain unclear. Here we tested whether sequence complexity (two-experiment MEGA-PRESS versus four-experiment HERMES), editing pulse duration (14 versus 20 ms), scanner frequency drift (interleaved water referencing (IWR) turned ON versus OFF), and linear combination modeling variations (three different co-edited macromolecule models and 0.55 versus 0.4 ppm spline baseline knot spacing) affected the within-subject coefficient of variation of GABA + macromolecules (GABA+). We collected edited MRS data from the dorsal anterior cingulate cortex from 20 participants (30.8 ± 9.5 years; 10 males). Test and retest scans were separated by removing the participant from the scanner for 5-10 minutes. Each acquisition consisted of two MEGA-PRESS and two HERMES sequences with editing pulse durations of 14 and 20 ms (referred to here as: MEGA-14, MEGA-20, HERMES-14, and HERMES-20; all TE = 80 ms, 224 averages). Reproducibility did not consistently differ for MEGA-PRESS compared with HERMES or for 14 compared with 20 ms editing pulses. A composite model of the 0.9 and 3 ppm macromolecules (particularly for HERMES) and sparser (0.55 compared with 0.4 ppm) spline baseline knot spacing yielded generally better test-retest reproducibility for GABA+. Replicating our prior results, linear combination modeling in Osprey compared with simple peak fitting in Gannet resulted in substantially better test-retest reproducibility. These results highlight the importance of model selection for edited MRS studies of GABA+, particularly for clinical studies which focus on individual patient differences in GABA+ or changes following an intervention.
Conformational free-energy landscapes of a Na+/Ca2+exchanger explain its alternating-access mechanism and functional specificity
Authors: Marinelli Fabrizio , Faraldo-Gómez José D.
Published: January 2023

Secondary-active transporters catalyze the movement of myriad substances across all cellular membranes, typically against opposing concentration gradients, and without consuming any ATP. To do so, these proteins employ an intriguing structural mechanism evolved to be activated only upon recognition or release of the transported species. We examine this self-regulated mechanism using a homolog of the cardiac Na+/Ca2+exchanger as a model system. Using advanced computer simulations, we map out the complete functional cycle of this transporter, including unknown conformations that we validate against existing experimental data. Calculated free-energy landscapes reveal why this transporter functions as an antiporter rather than a symporter, why it specifically exchanges Na+and Ca2+, and why the stoichiometry of this exchange is exactly 3:1. We also rationalize why the protein does not exchange H+for either Ca2+or Na+, despite being able to bind H+and its high similarity with H+/Ca2+exchangers. Interestingly, the nature of this transporter is not explained by its primary structural states, known as inward- and outward-open conformations; instead, the defining factor is the feasibility of conformational intermediates between those states, wherein access pathways leading to the substrate binding sites become simultaneously occluded from both sides of the membrane. This analysis offers a physically-coherent, broadly transferable route to understand the emergence of function from structure among secondary-active membrane transporters.

Significance

The class of membrane proteins known as secondary-active transporters mediate a wide range of critical cellular processes, including nutrient uptake, transmembrane signaling, and resistance to cytotoxic compounds, like human-made drugs. A detailed understanding of their molecular mechanisms is therefore of interest not only from a fundamental standpoint, but also because it will facilitate the design of inhibitors or stimulators that may be used as therapeutic agents. This study provides a conceptual mechanistic framework, grounded on statistical thermodynamics, that bridges the specific physiological function of these proteins and their molecular structure. While the study is focused on a particular subclass of transporters involved in cardiac physiology and cellular Ca2+homeostasis, we envisage our conclusions will be broadly applicable.
Direct observation of coordinated assembly of individual native centromeric nucleosomes
Authors: Popchock Andrew R. , Larson Joshua D. , Dubrulle Julien , Asbury Charles L. , Biggins Sue
Published: January 2023

Eukaryotic chromosome segregation requires the kinetochore, a megadalton-sized machine that forms on specialized centromeric chromatin containing CENP-A, a histone H3 variant. CENP-A deposition requires a chaperone protein HJURP that targets it to the centromere, but it has remained unclear whether HJURP has additional functions beyond CENP-A targeting and why high AT DNA content, which disfavors nucleosome assembly, is widely conserved at centromeres. To overcome the difficulties of studying nucleosome formation in vivo, we developed a microscopy assay that enables direct observation of de novo centromeric nucleosome recruitment and maintenance with single molecule resolution. Using this assay, we discover that CENP-A can arrive at centromeres without its dedicated centromere-specific chaperone HJURP, but stable incorporation depends on HJURP and additional DNA-binding proteins of the inner kinetochore. We also show that homopolymer AT runs in the yeast centromeres are essential for efficient CENP-A deposition. Together, our findings reveal requirements for stable nucleosome formation and provide a foundation for further studies of the assembly and dynamics of native kinetochore complexes.
SOS2 regulates the threshold of mutantEGFR-dependent oncogenesis
Authors: Theard Patricia L. , Linke Amanda J. , Sealover Nancy E. , Daley Brianna R. , Yang Johnny , Cox Katherine , Kortum Robert L
Published: January 2023

Son of Sevenless 1 and 2 (SOS1 and SOS2) are RAS guanine nucleotide exchange factors (RasGEFs) that mediate physiologic and pathologic RTK-dependent RAS activation. Here, we show that SOS2 modulates the threshold of epidermal growth factor receptor (EGFR) signaling to regulate the efficacy of and resistance to the EGFR-TKI osimertinib in lung adenocarcinoma (LUAD).SOS2deletion sensitizedEGFR-mutated cells to perturbations in EGFR signaling caused by reduced serum and/or osimertinib treatment to inhibit PI3K/AKT pathway activation, oncogenic transformation, and survival. Bypass RTK reactivation of PI3K/AKT signaling represents a common resistance mechanism to EGFR-TKIs;SOS2KO reduced PI3K/AKT reactivation to limit osimertinib resistance. In a forced HGF/MET-driven bypass model,SOS2KO inhibited HGF-stimulated PI3K signaling to block HGF-driven osimertinib resistance. Using a long termin situresistance assay, a majority of osimertinib resistant cultures exhibited a hybrid epithelial/mesenchymal phenotype associated with reactivated RTK/AKT signaling. In contrast, RTK/AKT-dependent osimertinib resistance was markedly reduced bySOS2deletion; the fewSOS2KO cultures that became osimertinib resistant primarily underwent non-RTK dependent EMT. Since bypass RTK reactivation and/or tertiaryEGFRmutations represent the majority of osimertinib-resistant cancers, these data suggest that targeting SOS2 has the potential to eliminate the majority of osimertinib resistance.

One sentence summary

SOS2 modulates the threshold of EGFR-PI3K signaling to regulate the efficacy of and resistance to osimertinib.
A spatial analysis of the robustness of the private kill abattoir network in the UK: proof-of-concept study
Authors: Franks Jeremy R. , Hepburn Jessica , Peden Rachel S.E.
Published: January 2023

Purpose

This study aims to explore the impacts of long-term trends in the closure of abattoir businesses in the UK on the robustness of the network of abattoirs which provides private kill services.

Design/methodology/approach

This proof-of-concept study uses responses from a farmer and an abattoir survey in a spatial analysis to help visualise the private kill network. Monte Carlo simulation is used to estimate the impacts of possible further closures of private kill abattoirs on the robustness of the private kill network.

Findings

In August 2020, 18% of the area of the UK was more than 45 km from a private kill abattoir, 21% was serviced by one, 14% by two and 47% by three or more abattoirs. After randomly removing 9 and 18% of private kill abattoirs, to reflect the current trend in the closure of private kill abattoirs, the area of the UK more than 45 km from a private kill service and the areas with one and two providers increased, whilst the area with three or more providers decreased for each scenario. This approach, therefore, can be used to quantify the network's resilience to further closures.

Research limitations/implications

The additional information that would be needed to allow this approach to help policymakers identify strategically valuable abattoir businesses is discussed.

Originality/value

No other national or international study has attempted to quantify the robustness of the network of private kill abattoirs.
The role of social media marketing activities in driving self–brand connection and user engagement behavior on Instagram: a moderation–mediation approach
Authors: Ibrahim Blend , Aljarah Ahmad
Published: January 2023

Purpose

This study explores central questions related to the connection between social media marketing activities (SMMAs), user engagement and the self-brand connection of restaurant Instagram pages. The study examines the mediating role of user engagement between SMMAs and self–brand connections. Also, this study explores the connection between SMMAs and user engagement through the moderating role of gender and trust.

Design/methodology/approach

A convenience sample method was employed to collect data from customers (18–24 years old). A structural equation modeling approach and PROCESS macro were applied based on 298 online questionnaires completed by customers who follow restaurant Instagram pages. The mediating effect for user engagement and the moderating effect for gender and trust were performed.

Findings

The findings revealed that SMMAs have a significant positive influence on self–brand connection and user engagement. Further, user engagement acts as a mediator between SMMAs and self–brand connection. The results illustrate the importance of SMMAs in enhancing user engagement in light of gender and trust.

Practical implications

This paper presents significant managerial implications for restaurant businesses about how SMMAs can effectively enhance user engagement behavior and self–brand connection on Instagram pages.

Originality/value

This research developed a theoretical model to understand how SMMAs might enhance user engagement in the restaurant industry by invoking gender and trust as moderating variables in the relationship between SMMAs and user engagement. This paper offers new theoretical and practical contributions that add value to social media marketing (SMM) literature by testing the moderated–mediation model of these constructs in the hospitality sector.
Digital ethnicity affordances: from a liability to an asset in immigrant entrepreneurship
Authors: Evansluong Quang , Grip Lena , Karayianni Eva
Published: January 2023

Purpose

This paper aims to understand how immigrant entrepreneurs use digital opportunities to overcome the liability of newness and foreignness and how an immigrant's ethnicity can be digitally performed as an asset in business.

Design/methodology/approach

The study adopts an inductive multiple case study approach using social media content. The data consist of over 3,500 posts, images and screenshots from Facebook, Instagram and the webpages of seven successful Vietnamese restaurants in Sweden. Grounded content analysis was conducted using NVivo.

Findings

The findings suggest that digitalising ethnic artifacts can mediate and facilitate three digital performances that together can turn ethnicity from a liability to an asset: (i) preserving performance through digital ethnicising, (ii) embracing performance through digital generativitising and (iii) appropriating performance through digital fusionising. The results support the introduction of a conceptual framework depicting the interwoven duality of horizontal and vertical boundary blurring, in which the former takes place between the offline and online spaces of immigrant businesses, and the latter occurs between the home and host country attachment of the immigrant businesses.

Originality/value

This study responds to calls for understanding how immigrant entrepreneurs can overcome the liability of foreignness. It offers a fresh look at ethnicity, which has been seen in a negative light in the field of immigrant entrepreneurship. This study illuminates that ethnicity can be used as a resource in immigrant entrepreneurship, specifically through the use of digital artifacts and digital platforms.
The sustainable development of rural-to-urban food supply chains in developing nations
Authors: Hoang Trang , Bell John , Hiep Pham Hung , Autry Chad W.
Published: January 2023

Purpose

This paper explores how firms develop and mature sustainable supply chains (SSCs) in developing nations (DNs). The primitive resources, infrastructures and understanding of SSCs in DNs often hinder both the ability of SSCs to mature and their effectiveness in delivering environmental, social and economic goals. The purpose of this paper is to address these issues.

Design/methodology/approach

Through the supply chain life cycle (SCLC) lens, the authors analyzed an embedded case study of a Vietnamese end-to-end food supply chain (using 32 semi-structured interviews and archival data) and interviewed senior leadership of three other food companies in early 2019. A post hoc study including five reinterviews in the same Vietnamese case company's supply chain also further validated the study in 2021.

Findings

The authors’ analyses reveal that changes in DN stakeholders' behaviors can quickly move firms' SSCs along the SCLC closer toward a mature stage, in which firms and their network stakeholders can create more sustainable value. They also identify strategies for firms to consider when developing their SSCs to activate these behavioral changes.

Originality/value

While many authors discuss SSCs' benefits for the environment and society, few assess how firms can design and operate SSCs effectively given the limited resources, infrastructures and SSC knowledge in DNs. This paper offers a compelling framework focusing on engaging various DNs' stakeholders to understand the life cycle of SSCs in less developed countries, in order to accelerate DNs' firms through early development toward a more SSC.
Pressures, power relationships and governance mechanisms: a multi-tier supply chain approach
Authors: Gemente Giovanni Beccari , da Silva Andrea Lago , da Silva Eliciane Maria , Costa Flavio Henrique
Published: January 2023

Purpose

To do this, the authors carried out a systematic literature review to answer three questions: (RQ1) Which external pressures affect an FC and its suppliers in an MSC? (RQ2) What influences power relationships between an FC and its suppliers for MSC compliance? and (RQ3) Which governance mechanisms support an FC to achieve compliance for managing its MSC?

Design/methodology/approach

This research aims to identify how external pressures affect chain agents to achieve compliance and implement governance mechanisms and analyzes the influence of the power relationship between FC and their suppliers.

Findings

The results identify how external pressures from different stakeholders act on FC and FT and ST suppliers. A combination of contractual governance mechanisms (auditing, certification, assessment, code of conduct and monitoring) with relational ones (third-party, cooperation) is identified, facilitating compliance between agents. Furthermore, different power relationships (power position, level of resources and institutional distance) that influence the implementation of governance mechanisms are explored.

Research limitations/implications

This article comprised only a systematic literature review and content analysis. Carrying out empirical research, covering the theme of this article, is the next step, which is being completed and will be discussed in due course in another publication.

Practical implications

The results can help professionals of the FC to understand their role in multi-tier supply chain (MSC), the external pressures exerted and the governance mechanisms that can be implemented to achieve compliance.

Originality/value

This article develops three relevant issues constantly addressed in MSC, which have not yet been combined to understand the management of multi-tier suppliers.
Multidimensional poverty in Brazil's north region
Authors: Rosa Samanda Silva da , Bagolin Izete Pengo , Ávila Rodrigo Peres de
Published: January 2023

Purpose

This article aims to analyse the spatial and temporal evolution of multidimensional poverty in Brazil's North Region and its relationship with territorial, economic and population dynamics.

Design/methodology/approach

A multidimensional poverty index (MPI) was calculated using the Alkire-Foster method and a spatial econometric model was estimated. The data come from population censuses conducted by the Brazilian Institute of Geography and Statistics (IBGE) for the years 1991, 2000 and 2010.

Findings

The results show a decrease in multidimensional poverty over the period analysed. However, they show this reduction occurred in a heterogeneous way in time and space, with emphasis on microregions in which, despite a reduction in the rate, the percentage of the population considered multidimensionally poor remained high during the 30 years of the study.

Research limitations/implications

The quality of available data.

Practical implications

It is possible to point out that public policies focused on improving infrastructure in medium-sized locations tend to have two positive effects: first, making production and consumption more accessible and sustainable for local communities, given that currently the cost of transport and logistics are factors that hinder socioeconomic development; second, to reduce the pressure of demand that this population of small and medium-sized locations exerts on public services currently offered only in larger locations. Although the logic of concentrating most public services in the largest cities makes sense in terms of economic efficiency, the particularities of the northern region and the recognition of its environmental importance point to the need for incentives for more spatially distributed economic activity.

Social implications

From the paper results, it is possible to think about more local public policies which are able to improve people's lifes without to damage the environment.

Originality/value

This is the first study on multidimensional poverty that covers the entire North region of Brazil (Amazon region) and that contemplates both the temporal and spatial dynamics of poverty.

Peer review

The peer review history for this article is available at: https://publons.com/publon/10.1108/IJSE-11-2021-0699.