bluuebunny/crossref_metadata_2025 huggingface dataset:
Mapping potential malaria vector larval habitats for larval source management: Introduction to multi-model ensembling approaches
Authors: Zhou Guofa , Lee Ming-Chieh , Wang Xiaoming , Zhong Daibin , Yan Guiyun
Published: October 2022

Mosquito larval source management (LSM) is a viable supplement to the currently implemented first-line malaria control tools for use under certain conditions for malaria control and elimination. Implementation of larval source management requires a carefully designed strategy and effective planning. Identification and mapping of larval sources is a prerequisite. Ensemble modeling is increasingly used for prediction modeling, but it lacks standard procedures. We proposed a detailed framework to predict potential malaria vector larval habitats using ensemble modeling, which includes selection of models, ensembling method and predictors; evaluation of variable importance; prediction of potential larval habitats; and assessment of prediction uncertainty. The models were built and validated based on multi-site, multi-year field observations and climatic/environmental variables. Model performance was tested using independent multi-site, multi-year field observations. Overall, we found that the ensembled model predicted larval habitats with about 20% more accuracy than the average of the individual models ensembled. Key larval habitat predictors were elevation, geomorphon class, and precipitation 2 months prior. Mapped distributions of potential malaria vector larval habitats showed different prediction errors in different ecological settings. This is the first study to provide a detailed framework for the process of multi-model ensemble modeling. Mapping of potential habitats will be helpful in LSM planning.

Author’s summary

Mosquito larval source management (LSM) is a viable supplement to the currently implemented first-line malaria control tools. Implementation of LSM requires a carefully designed strategy and effective planning. Identification and mapping of larval sources is a prerequisite. Ensemble modeling is increasingly used for prediction modeling, but it lacks standard procedures. We proposed a detailed framework for such a process, including selection of models, ensembling methods and predictors; evaluation of variable importance; and assessment of prediction uncertainty. We used predictions of potential malaria vector larval habitats as an example to demonstrate how the procedure works, specifically, we used multi-site multi-year field observations to build and validate the model, and model performance was further tested using independent multi-site multi-year field observations – this training-validation-testing is often missing from previous studies. The proposed ensemble modeling procedure provides a framework for similar biological studies.
Effects of high pCO2 on snow crab embryos: Ocean acidification does not affect embryo development or larval hatching
Authors: Long William Christopher , Swiney Katherine , Foy Robert
Published: October 2022

Ocean acidification, a decrease in ocean pH due to absorption of anthropogenic CO2, has variable effects on different species. To examine the effects of decreased pH on snow crab (Chionoecetes opilio), a commercial species in Alaska, we reared ovigerous females in one of three treatments: ambient pH (~8.1), pH 7.8, and pH 7.5, through two annual reproductive cycles. Morphometric changes during development and hatching success were measured for embryos both years and calcification was measured for the adult females at the end of the 2-year experiment. Embryos and larvae analyzed in year one were from oocytes developed, fertilized, and extruded in situ, whereas embryos and larvae in year two were from oocytes developed, fertilized, and extruded under acidified conditions in the laboratory. Embryo morphology during development was unaffected by pH during both years. The number of successfully hatched live larvae was unaffected by pH treatment in both years. Embryo mortality was very low, hatching success high, and neither differed with treatment in either year. Percent calcium in adult females' carapaces did not differ among treatments at the end of the experiment. The results from this two-year study suggest that snow crabs are well adapted to projected ocean pH levels within the next 2 centuries, although other life-history stages still need to be examined for sensitivity.
A geometric approach to quantifying the neuromodulatory effects of persistent inward currents on single motor unit discharge patterns
Authors: Beauchamp James. A. , Pearcey Gregory E. P. , Khurram Obaid U. , Chardon Matthieu , Wang Curtis , Powers Randall K. , Dewald Julius P.A. , Heckman CJ.
Published: October 2022

Objective

All motor commands flow through motoneurons, which entrain control of their innervated muscle fibers, forming a motor unit (MU). Owing to the high fidelity of action potentials within MUs, their discharge profiles detail the organization of ionotropic excitatory/inhibitory as well as metabotropic neuromodulatory commands to motoneurons. Neuromodulatory inputs (e.g., norepinephrine, serotonin) enhance motoneuron excitability and facilitate persistent inward currents (PICs). PICs introduce quantifiable properties in MU discharge profiles by augmenting depolarizing currents upon activation (i.e., PIC amplification) and facilitating discharge at lower levels of excitatory input than required for recruitment (i.e., PIC prolongation). Approach: Here, we introduce a novel geometric approach to estimate neuromodulatory and inhibitory contributions to MU discharge through exploiting discharge non-linearities introduced by PIC amplification during time-varying linear tasks. In specific, we quantify the deviation from linear discharge (“brace height”) and the rate of change in discharge (i.e., acceleration slope, attenuation slope, angle). We further characterize these metrics on a simulated motoneuron pool with known excitatory, inhibitory, and neuromodulatory inputs and on human MUs (Tibialis Anterior: 1448, Medial Gastrocnemius: 2100, Soleus: 1062, First Dorsal Interosseus: 2296).

Main Result

In the simulated motor pool, we found brace height and attenuation slope to consistently indicate changes in neuromodulation and the pattern of inhibition (excitation-inhibition coupling), respectively, whereas the paired MU analysis (ΔF) was dependent on both neuromodulation and inhibition pattern. Furthermore, we provide estimates of these metrics in human MUs and show comparable variability in ΔF and brace height measures in MUs matched across multiple trials.

Significance

Spanning both datasets, we found brace height quantification to provide an intuitive method for achieving graded estimates of neuromodulatory and inhibitory drive to MUs on a single unit level. This complements common techniques and provides an avenue for decoupling changes in the level of neuromodulatory and pattern of inhibitory motor commands.
The striatum drives the ergogenic effects of caffeine
Authors: de Bem Alves Ana Cristina , Speck Ana Elisa , Resende Farias Hémelin , Martins Leo Meira , dos Santos Naiara Souza , Pannata Gabriela , Tavares Ana Paula , de Oliveira Jade , Tomé Ângelo R. , Cunha Rodrigo A. , Aguiar Aderbal S
Published: October 2022

Caffeine is one of the main ergogenic resources used in exercise and sports. Previously, we reported the ergogenic mechanism of caffeine through neuronal A2AR antagonism in the central nervous system [1]. We now demonstrate that the striatum rules the ergogenic effects of caffeine through neuroplasticity changes. Thirty-four Swiss (8-10 weeks, 47 ± 1.5 g) and twenty-four C57BL/6J (8-10 weeks, 23.9 ± 0.4 g) adult male mice were studied behaviorly and electrophysiologically using caffeine and energy metabolism was studied in SH-SY5Y cells. Systemic (15 mg/kg, i.p.) or striatal (bilateral, 15 μg) caffeine was psychostimulant in the open field (p< 0.05) and increased grip efficiency (p< 0.05). Caffeine also shifted long-term depression (LTD) to potentiation (LTP) in striatal slices and increased the mitochondrial mass (p< 0.05) and membrane potential (p< 0.05) in SH-SY5Y dopaminergic cells. Our results demonstrate the role of the striatum in the ergogenic effects of caffeine, with changes in neuroplasticity and mitochondrial metabolism.
Integrated global analysis in spider-flowers illuminates features underlying the evolution and maintenance of C4 photosynthesis
Authors: Zhao Wei , Li Jun , Sun Xingchao , Zheng Qiwei , Hua Wei , Liu Jun
Published: October 2022

The carbon concentrating mechanism—C4 photosynthesis—represents a classic example of convergent evolution. While how this important trait originated and evolved remains largely enigmatic. Here we present a high-quality chromosome-scale annotated genome assembly of the spider-flower Gynandropsis gynandra, a valuable leafy vegetable crop and medicinal plant that has also been recognized as an emerging C4 model species. Repetitive elements occupy up to 71.91% of its genome, and over half are LTR-RTs derived from recent bursts, contributing to genome size expansion. Strikingly, LTR-RT explosion also played a critical role in C4 evolution by altering expression features of photosynthesis-associated genes via preferential insertion in promoters. Synteny analysis in the Cleome genus unveils that an independent species-specific whole-genome duplication in G. gynandra, which we name Gg-α, occurred after divergence from its close relative C3 plant Tarenaya hassleriana. Integrated multi-omics profiling demonstrates that Gg-α, gene family expansion, recent LTR-RT amplification and more recent species-specific tandem duplication events have all facilitated the evolution of C4 photosynthesis, revealing uniqueness of C4 evolution in this lineage. Moreover, high leaf vein density and heat stress resilience are associated with shifted gene expression patterns. Altogether, this mode of C3-to-C4 transition yields new insights into evolutionary convergence of a complex plant trait.
Improving cell-type identification with Gaussian noise-augmented single-cell RNA-seq contrastive learning
Authors: Alsaggaf Ibrahim , Buchan Daniel , Wan Cen
Published: October 2022

Cell-type identification is an important task for single-cell RNA-seq (scRNA-seq) data analysis. In this work, we proposed a novel Gaussian noise augmented scRNA-seq contrastive learning framework (GsRCL) to learn a type of discriminative feature representations for cell-type prediction tasks. The experimental results suggest that the feature representations learned by GsRCL successfully improved the accuracy of cell-type prediction using scRNA-seq expression profiles.
Epigenetic CpG Duplex Marks Probed by an Evolved DNA Reader via a Well-Tempered Conformational Plasticity
Authors: Singh Himanshu , Das Chandan K. , Buchmuller Benjamin C. , Eppmann Simone , Schäfer Lars V. , Summerer Daniel , Linser Rasmus
Published: October 2022

5-methylcytosine (mC) and its TET-oxidized derivatives exist in CpG dyads of mammalian DNA and regulate cell fate, but how their individual combinations in the two strands of a CpG act as distinct regulatory signals is poorly understood. Readers that selectively recognize such novel “CpG duplex marks” could be versatile tools for studying their biological functions, but their design represents an unprecedented selectivity challenge. By mutational studies, NMR relaxation, and MD simulations, we here show that the selectivity of the first designer reader for an oxidized CpG duplex mark hinges on precisely tempered conformational plasticity of the scaffold adopted during directed evolution. Our observations reveal the critical aspect of defined motional features in this novel reader for affinity and specificity in the DNA/protein interaction, providing unexpected prospects for further design progress in this novel area of DNA recognition.
Subcortical coding of predictable and unsupervised sound-context associations
Authors: Chen Chi , Cruces-Solís Hugo , Ertman Alexandra , de Hoz Livia
Published: October 2022

Our environment is made of a myriad of stimuli present in combinations often patterned in predictable ways. For example, there is a strong association between where we are and the sounds we hear. Like so many environmental patterns, sound-context associations are learned implicitly, in an unsupervised manner, and are highly informative and predictive of normality. Yet, we know little about where and how unsupervised sound-context associations are coded in the brain. Here we measured plasticity in the auditory midbrain of mice living over days in a naturalistic environment designed to present sound-context associations with different degrees of predictability. Plasticity in the auditory midbrain, a hub of auditory input and multimodal feedback, developed over days and reflected learning of contextual information in a manner that depended on the predictability of the sound-context association and not on reinforcement. Plasticity took the form of broad frequency shifts in tuning in auditory midbrain neurons. These shifts were paralleled by an increase in response gain and correlated with an increase in neuronal frequency discrimination. Thus, the auditory midbrain codes for unsupervised predictable sound-context associations, revealing a subcortical engagement in the detection of contextual sounds. This detection might facilitate the processing of behaviorally relevant foreground information described to occur in cortical auditory structures.
NetLCP: An R package for prioritizing combinations of regulatory elements in the heterogeneous network with variant ‘switches’ detection
Authors: Ran Mingyu , Xu Jiankai
Published: October 2022

Numerous independent networks of regulatory elements, including lncRNA, circRNA and pathway, have been developed to crucial roles in computational systems biology. Crosstalks among those networks as a bridge to build and decode heterogeneous networks from multidimensional biological knowledge, aids to highlight regulatory elements. And combinations of regulatory elements (CREs) in the local area of heterogeneous network have been a hot issue due to its crucial role in biological processes. We introduce NetLCP, an R package with command and shiny-based GUI modes, for prioritizing CREs with variant ‘switches’ detection.

Availability and implementation

The NetLCP package and documentations are freely available at https://github.com/mortyran/NetLCP.

Supplementary information

Supplementary data are available online
Embracing fine-root system complexity to improve the predictive understanding of ecosystem functioning
Authors: Wang Bin , McCormack M. Luke , Ricciuto Daniel M. , Yang Xiaojuan , Iversen Colleen M.
Published: October 2022

Projecting the functioning of the biosphere requires a holistic consideration of whole-ecosystem processes. Although improving leaf and canopy processes has been the focus of ecosystem model development since the 1970s, the arbitrary homogenization of fine-root systems into a single pool is at odds with observations. This discrepancy has increased in the last two decades as accelerated conceptual and empirical advances have revealed functional differentiation and cooperation conferred by the hierarchical structure of fine-root orders and associations with mycorrhizal fungi in fine-root systems. To close this model-data gap, we propose a 3-pool structure comprising Transport and Absorptive fine roots with Mycorrhizal fungi (TAM) to model vertically resolved fine-root systems across organizational and spatial-temporal scales. A comparison of TAM to the single fine-root structure in a state-of-the-art Earth System Model using the ‘big-leaf’ approach demonstrates robust impacts on carbon cycling in temperate forests, lending further quantitative support to the empirical and theoretical basis for TAM. Strong support in both theory and practice therefore suggests a move beyond the useful but incorrect paradigm of single-pool homogenization, echoing a broad trend of embracing ecological complexities in terrestrial ecosystem modelling. Although challenges lay ahead towards realizing TAM in ecologically realistic demography models simulating emergent functioning from pattern and diversity, adoption of TAM by both modelers and empiricists holds promise to build a better predictive understanding of ecosystem functioning in the context of global change.
Microbiome network connectivity and composition linked to disease resistance in strawberry plants
Authors: Hassani M. Amine , Gonzalez Omar , Hunter Samuel S. , Holmes Gerald J. , Hewavitharana Shashika S. , Ivors Kelly , Lazcano Cristina
Published: October 2022

Plant recruit diverse microbial communities from the soil biota. Inter-microbial interactions and connectivity in the root microbiome could play essential roles in plant health by promoting resistance to soil-borne pathogens. Yet, understanding these interactions under field conditions is still scarce. Using a strawberry crop model, we characterized the prokaryotic and fungal communities in the rhizosphere and roots of three strawberry cultivars displaying varying resistance degrees to the soil-borne fungal pathogen Macrophomina phaseolina. We tested the hypothesis that resistant cultivars assemble distinct bacterial and fungal communities that foster microbial connectivity and mediate disease resistance. Our results show that the soil-borne pathogen, M. phaseolina, does not perturb the root microbiome of the strawberry cultivars. Microbiome comparative analysis indicated that the highly susceptible cultivar, Sweet Ann, assembles a distinct microbiome that shows reduced network connectivity, whereas more resistant cultivars were enriched in potential beneficial microbes and showed higher network connectivity. Collectively, these results suggest the role of plant genetic traits in the assembly of beneficial microbiome members. Our study reinforces the eminent role of the plant microbiome as trait of selection in breeding programs and stresses further understandings of the genetic and biological mechanisms that mediate microbiome assembly. Uncovering these mechanisms will be key for future plant breeding programs.
National Institutes of Health Research Project Grant Inflation 1998 to 2021
Authors: Lauer Michael , Wang Joy , Roychowdhury Deepshikha
Published: October 2022

We analyzed changes in total costs for National Institutes of Health (NIH) awarded Research Project Grants issued from 1998 to 2003. The NIH uses a data-driven price index – the Biomedical Research and Development Price Index (BRDPI) – to account for inflation based increases in grant costs. The BRDPI was higher than the general rate of inflation from 1998 until 2012; since then, the rate of inflation for NIH-funded research has been similar to the general rate of inflation. Despite increases in nominal costs, recent years have seen increases in the absolute numbers of RPG and R01 awards. Real (BRDPI-adjusted) average and median RPG costs increased during the NIH-doubling (1998 to 2003), but have remained relatively stable since. Of note, though, the degree of variation of RPG costs has changed over time, with more marked extremes observed on both higher and lower levels of cost. On both ends of the cost spectrum, the agency is funding a greater proportion of solicited projects, with nearly half of RPG money going towards solicited projects. After adjusting for potential confounders in a wholly non-parametric machine learning regression, we find no independent association of time with BRDPI-adjusted costs.
Multiplex HDR for Disease and Correction Modeling of SCID by CRISPR Genome Editing in Human HSPCs
Authors: Iancu Ortal , Allen Daniel , Knop Orli , Zehavi Yonathan , Breier Dor , Arbiv Adaya , Lev Atar , Lee Yu Nee , Beider Katia , Nagler Arnon , Somech Raz , Hendel Ayal
Published: October 2022

Severe combined immunodeficiency (SCID) is a group of monogenic primary immunodeficiencies caused by mutations in genes involved in the process of lymphocyte maturation and function. CRISPR-Cas9 gene editing of the patient’s own hematopoietic stem and progenitor cells (HSPCs) ex vivo could provide a therapeutic alternative to allogeneic hematopoietic stem cell transplantation (HSCT), the current gold standard for treatment of SCID. Using CRISPR-Cas9/rAAV6 gene-editing, we engineered genotypes in healthy donor (HD)-derived CD34+ HSPCs, thus eliminating the need for rare patient samples, to model both SCID and the therapeutic outcomes of gene-editing therapies for SCID via multiplexed homology directed repair (HDR). Firstly, we developed a SCID disease model via knock-out of both alleles of genes critical to the development of lymphocytes; and secondly, we established a knock-in/knock-out (KI-KO) strategy to develop a proof-of-concept single-allelic gene correction. Since SCID is a recessive disorder, correction of only one allele is enough to cure the patient. Based on these results, we performed gene correction of RAG2-SCID patient-derived CD34+ HSPCs that successfully developed into CD3+ T cells with diverse TCR repertoires in an in vitro T-cell differentiation (IVTD) platform. By using CRISPR-Cas9, multiplexed HDR, HD-derived CD34+ HSPCs, and an IVTD system we outline an approach for the study of human lymphopoiesis. We present both a way for researchers to determine the optimal configuration for CRISPR-Cas9 gene correction of SCID and other recessive blood disorders, and the feasibility of translating these techniques to perform gene correction in patient-derived CD34+ HSPCs.
Cerebellar degeneration impairs strategy discovery but not strategy recall
Authors: Tsay Jonathan S. , Schuck Lauren , Ivry Richard B.
Published: October 2022

The cerebellum is recognized to play a critical role in the automatic and implicit process by which movement errors are used to keep the sensorimotor system precisely calibrated. However, its role in other learning processes frequently engaged during sensorimotor adaptation tasks remains unclear. In the present study, we tested the performance of individuals with cerebellar degeneration on a variant of a visuomotor adaptation task in which learning requires the use of strategic re-aiming, a process that can nullify movement errors in a rapid and volitional manner. Our design allowed us to assess two components of this learning process, the discovery of an appropriate strategy and the recall of a learned strategy. Participants were exposed to a 60° visuomotor rotation twice, with the initial exposure block assessing strategy discovery and the re-exposure block assessing strategy recall. Compared to age-matched controls, individuals with cerebellar degeneration were slower to derive an appropriate aiming strategy in the initial Discovery block but exhibited similar recall of the aiming strategy during the Recall block. This dissociation underscores the multi-faceted contributions of the cerebellum to sensorimotor learning, highlighting one way in which this subcortical structure facilitates volitional action selection.
The methyltransferases METTL7A and METTL7B confer resistance to thiol-based histone deacetylase inhibitors
Authors: Robey Robert W. , Fitzsimmons Christina M. , Guiblet Wilfried M. , Frye William J.E. , González Dalmasy José M. , Wang Li , Russell Drake A. , Huff Lyn M. , Perciaccante Andrew J. , Ali-Rahmani Fatima , Lipsey Crystal C. , Wade Heidi M. , Mitchell Allison V. , Maligireddy Siddhardha S. , Terrero David , Butcher Donna , Edmondson Elijah F. , Jenkins Lisa M. , Nikitina Tatiana , Zhurkin Victor B. , Tiwari Amit K. , Piscopio Anthony D. , Totah Rheem A. , Bates Susan E. , Efsun Arda H. , Gottesman Michael M. , Batista Pedro J.
Published: October 2022

Histone deacetylase inhibitors (HDACis) are part of a growing class of epigenetic therapies used for the treatment of cancer. While elevated levels of the efflux pump P-gp are associated within vitroresistance to romidepsin, this mechanism does not translate to the clinic. We developed a romidepsin-resistant cell line with a resistance mechanism independent of P-gp function that acts upstream of the deacetylation process. We found that expression of the methyltransferase METTL7A is necessary for resistance, and that expression of METTL7A in naïve cells can drive resistance to thiol-containing HDACis. We demonstrate that METTL7A can methylate romidesinin vitroand that the ability of METTL7A to drive resistance to thiol-containing HDACis can be blocked by the methyltransferase inhibitor DCMB. Our data supports a model whereby exposure of cells to romidepsin selects for upregulation of the methyltransferase METTL7A, which in turn modifies the zinc-binding thiol, inactivating the drug.
Quantifying common and distinct information in single-cell multimodal data with Tilted-CCA
Authors: Lin Kevin Z. , Zhang Nancy R.
Published: October 2022

Multimodal single-cell technologies profile multiple modalities for each cell simultaneously and enable a more thorough characterization of cell populations alongside investigations into cross-modality relationships. Existing dimension-reduction methods for multimodal data focus on capturing the “union of information,” producing a lower-dimensional embedding that combines the information across modalities. While these tools are useful, we develop Tilted-CCA to quantify the “intersection and difference of information”, that is, a decomposition of a paired multimodal dataset into common axes of variation that is shared between both modalities and distinct axes of variation that is found only in one modality. Through examples, we show that Tilted-CCA enables meaningful visualization and quantification of the cross-modal information overlap. We also demonstrate the application of Tilted-CCA to two specific types of analyses. First, for single-cell experiments that jointly profile the transcriptome and surface antibody markers, we show how to use Tilted-CCA to design the target antibody panel to best complement the transcriptome. Second, for single-cell multiome data that jointly profiles transcriptome and chromatin accessibility, we show how to use the common embedding given by Tilted-CCA to identify development-informative genes and distinguish between transient versus terminal cell types.
The proto-oncogene c-Src phosphorylates cGAS to reduce DNA binding and activation
Authors: Dunker William , Zaver Shivam A , Howard Cameron J , Woodward Joshua J
Published: October 2022

cGMP-AMP synthase (cGAS) is a DNA sensor and responsible for inducing an anti-tumor immune response. Recent studies reveal cGAS is frequently inhibited in cancer, and therapeutic targets to promote anti-tumor cGAS function remain elusive. c-Src is a proto-oncogene tyrosine kinase and is expressed at elevated levels in numerous cancers. Here, we demonstrate that c-Src expression in tumors from various cancers negatively correlates with innate immune gene expression and patient survival. We determine that c-Src restricts cGAS signaling in human cell lines through c-Src small molecule inhibitors, depletion, and overexpression. cGAS and c-Src interact in cells and in vitro, while c-Src directly inhibits cGAS enzymatic activity and DNA binding in a kinase-dependent manner. c-Src phosphorylates cGAS, and inhibition of cGAS Y248 phosphorylation partially reduces c-Src inhibition. Collectively, our study demonstrates that cGAS anti-tumor signaling is hindered by the proto-oncogene c-Src and describes how cancer-associated proteins can regulate the innate immune system.
Inter-individual variation in human cortical cell type abundance and expression
Authors: Johansen Nelson , Somasundaram Saroja , Travaglini Kyle J. , Yanny Anna Marie , Shumyatcher Maya , Casper Tamara , Cobbs Charles , Dee Nick , Ellenbogen Richard , Ferreira Manuel , Goldy Jeff , Guzman Junitta , Gwinn Ryder , Hirschstein Daniel , Jorstad Nikolas L. , Keene C. Dirk , Ko Andrew , Levi Boaz P. , Ojemann Jeffrey G. , Pham Thanh , Shapovalova Nadiya , Silbergeld Daniel , Sulc Josef , Torkelson Amy , Tung Herman , Smith Kimberly , Lein Ed S. , Bakken Trygve E. , Hodge Rebecca D. , Miller Jeremy A.
Published: October 2022

Single cell transcriptomic studies have identified a conserved set of neocortical cell types from small post-mortem cohorts. We extend these efforts by assessing cell type variation across 75 adult individuals undergoing epilepsy and tumor surgeries. Nearly all nuclei map to one of 125 robust cell types identified in middle temporal gyrus, but with varied abundances and gene expression signatures across donors, particularly in deep layer glutamatergic neurons. A minority of variance is explainable by known factors including donor identity and small contributions from age, sex, ancestry, and disease state. Genomic variation was significantly associated with variable expression of 150-250 genes for most cell types. Thus, human individuals display a highly consistent cellular makeup, but with significant variation reflecting donor characteristics, disease condition, and genetic regulation.

One-Sentence Summary

Inter-individual variation in human cortex is greatest for deep layer excitatory neurons and largely unexplainable by known factors.
vamos: VNTR annotation using efficient motif sets
Authors: Ren Jingwen , Gu Bida , Chaisson Mark JP
Published: October 2022

Motivation

Roughly 3% of the human genome is composed of variable-number tandem repeats (VNTRs): tandemly repeated arrays of motifs at least six bases. These loci are highly polymorphic: over 61% of insertion and deletion variants at least 50 bases found from long-read assemblies are inside VNTRs. Furthermore, long-read assemblies reveal that VNTR loci are multiallelic, and can vary by both motif composition and copy number. Current approaches that define and merge variants based on alignment breakpoints do not capture this complexity of variation. A natural alternative approach is to instead define the motif composition of VNTR sequences from samples, and to detect differences based on comparisons of repeat composition. However, due to the complexity of VNTR sequences, it is difficult to establish a common reference set of motif sequences that may be used to describe variation in large sequencing studies.

Results

Here we present a method vamos: VNTR Annotation using efficient Motif Sets that for any VNTR locus selects a set of representative motifs from all motifs observed at that locus that may be used to encode VNTR sequences within a bounded edit distance of the original sequence. We use our method to characterize VNTR variation in 32 haplotype-resolved human genomes. In contrast to current studies that merge multi-allelic calls, we estimate an average of 3.1-4.0 alleles per locus.

Availability

github.com/chaissonlab/vamos, zenodo.org/record/7158427

Contact

mchaisso@usc.edu
CHK2 Regulates MUS81-EME2 Function in Response to Replication Stress and BRCA2 Deficiency
Authors: Malacaria Eva , Palma Anita , Rinalducci Sara , Franchitto Annapaola , Pichierri Pietro
Published: October 2022

MUS81 is a structure-specific endonuclease that processes DNA intermediates in mitosis and in S-phase following replication stress. MUS81 is crucial to cleave deprotected reversed forks in BRCA2-deficient cells. However, how MUS81 is regulated during replication stress in human cells remains unknown.

Our study reveals that CHK2 binds the MUS81-EME2 complex and positively regulates formation of DSBs upon replication stress or in the absence of BRCA2. The association with MUS81 occurs through the FHA domain of CHK2 and is disabled by the Li-Fraumeni-associated mutation I157T. The CHK2-MUS81-EME2 complex forms downstream fork reversal and degradation, and phosphorylation of MUS81 at CHK2-targeted sites is crucial to introduce DSBs at deprotected replication forks ensuring the replication fork recovery in BRCA2-deficient cells.

Collectively, our work sheds light into the regulation of the MUS81-EME2 complex and identifies a novel function of the ATM-CHK2 axis in the response to deprotected replication forks in the absence of BRCA2.
Hyperactive mTOR in Lung Mesenchyme Induces Endothelial Dysfunction and Pulmonary Vascular Remodeling
Authors: Lin Susan M. , Rue Ryan , Goel Akansha , Obraztsova Kseniya , Mukhitov Alexander R. , Vanka Kanth Swaroop , Smith Carly J. , Basil Maria C. , Ferguson Laura T. , Planer Joseph D. , Cantu Edward , Kwapiszewska Grazyna , Morrisey Edward E. , Evans Jillian F. , Krymskaya Vera P.
Published: October 2022

Pulmonary vascular remodeling is the key structural abnormality in pulmonary hypertension (PH). Mechanistic target of rapamycin (mTOR) has long been suspected to play a role in the development of pulmonary vascular remodeling. However, underlying cellular and molecular mechanisms leading to this pathophysiological condition remain incompletely understood. To elucidate the crosstalk between lung mesenchyme with activated mTOR and endothelial cells (ECs), we focused on a monogenic lung disease, pulmonary lymphangioleiomyomatosis (LAM). LAM is a progressive cystic lung disease caused by a mutational inactivation of tuberous sclerosis complex (TSC1/TSC2), which results in constitutive mTOR activation in mesenchymal LAM cells. ECs derived from LAM lung explants showed increased proliferation, migration, and defective angiogenesis compared to age- and sex-matched ECs from control human lung. In LAM cells, we found increased WNT2 ligand expression. We also identified corresponding Frizzled 4 (FZD) receptors on ECs isolated from distal LAM lung, suggesting cellular crosstalk between LAM cells and ECs. In endothelial-fibroblast cocultures, treatment of normal ECs with WNT2 ligands recapitulated LAM EC phenotype and morphology. We observed transcriptomic upregulation in metabolic, angiogenic and growth pathways in ECs of young mice, while 1-year-old Tsc2KO mice spontaneously developed pulmonary vascular remodeling with concurrent elevation in right ventricular systolic pressure. Our study demonstrates that LAM cells are not just a pathological mesenchymal cell state but a signaling hub that contributes to dysregulated cellular response in the surrounding vasculature, eventual pulmonary vascular remodeling and PH.
Coaxiality and perpendicularity prediction of saddle surface rotor based on deep belief networks
Authors: Sun Chuanzhi , Wang Yin Chu , Lu Qing , Liu Yongmeng , Tan Jiubin
Published: October 2022

Purpose

Aiming at the problem that the transmission mechanism of the assembly error of the multi-stage rotor with saddle surface type is not clear, the purpose of this paper is to propose a deep belief network to realize the prediction of the coaxiality and perpendicularity of the multi-stage rotor.

Design/methodology/approach

First, the surface type of the aero-engine rotor is classified. The rotor surface profile sampling data is converted into image structure data, and a rotor surface type classifier based on convolutional neural network is established. Then, for the saddle surface rotor, a prediction model of coaxiality and perpendicularity based on deep belief network is established. To verify the effectiveness of the coaxiality and perpendicularity prediction method proposed in this paper, a multi-stage rotor coaxiality and perpendicularity assembly measurement experiment is carried out.

Findings

The results of this paper show that the accuracy rate of face type classification using convolutional neural network is 99%, which meets the requirements of subsequent assembly process. For the 80 sets of test samples, the average errors of the coaxiality and perpendicularity of the deep belief network prediction method are 0.1 and 1.6 µm, respectively.

Originality/value

Therefore, the method proposed in this paper can be used not only for rotor surface classification but also to guide the assembly of aero-engine multi-stage rotors.
Rethinking digital construction: a study of BIM uptake capability in BIM infant construction industries
Authors: Adeniyi Onaopepo , Thurairajah Niraj , Leo-Olagbaye Feyisetan
Published: October 2022

Purpose

Practitioners have reported a minimal and non-use of building information modelling (BIM), especially in small and medium-sized organisations and BIM infant construction industries. This development calls for a reappraisal of organisations’ strength in capabilities required for BIM uptake towards the target of global construction digitalisation. This study aims to assess the BIM Level 2 uptake capability of organisations in a BIM infant construction industry and identify the underlying interactions between the capability criteria.

Design/methodology/approach

The study used a multivariable analysis of fifteen descriptors identified from the people, process, policy, finance and technology domain. Data collection was done in the BIM infant construction industry in Nigeria. Verification of the descriptors and an evaluation of BIM uptake capability in organisations was done. Seventy-three responses were received within the selected context, and data analysis was done with mean weighting and exploratory factor analysis. Maximum Likelihood extraction and Direct Oblimin rotation were used.

Findings

Factor analysis revealed three factors that explained 53.28% of the total variance in the BIM Level 2 uptake capability of construction organisations. The factors are workforce capacity and continuous development, an affinity for innovation and strength in physical and operational facilities.

Research limitations/implications

This study provides an overarching and insightful discussion on BIM uptake capability and construction digitalisation with evidence from a BIM-infant construction industry.

Practical implications

The findings of this study are a piece of valuable empirical evidence on Level 2 BIM uptake capability. This empirical situation analysis will inform the advocacy for the advancement of BIM and enhanced utilisation of building information. Evidence on the capability performance of the BIM infant industry has been revealed.

Originality/value

The outcome is expected to stir debate on the preparedness of organisations to further exploit the benefits of BIM in the BIM infant construction industry. Examination of the capability for a particular phase of BIM is scanty in the literature.
Converting commercial and industrial property into rented residential accommodation: development of a decision support tool
Authors: Taylor Kieran , Edwards David J. , Lai Joseph H.K. , Rillie Iain , Thwala Wellington Didibhuku , Shelbourn Mark
Published: October 2022

Purpose

This study aims to develop a decision-making tool that assesses the economic feasibility of converting commercial and industrial buildings into rented residential accommodation. This tool also enables developers to provide high-quality rented residential accommodation that contribute to the gentrification of formerly industrialised inner city or developed areas.

Design/methodology/approach

The overarching epistemological approach adopted used inductive reasoning and a postpositivist philosophical design to structure the research problem and devise new theories about the phenomena under investigation. From an operational perspective, a two-phase “waterfall” research approach was adopted. Phase one used extant literature to identify development factors and variables for consideration, risks posed and conversion appraisal criteria. Two case studies formed the basis of a cross comparative analysis, namely, a new build and conversion of a former industrial building into rented residential accommodation. Phase two identified development appraisal criteria, conducted a cost analysis and premised upon the findings, developed a decision support appraisal tool as a “proof of concept”.

Findings

The research combined key decision factors and variables that assist property developers when evaluating whether to convert commercial and industrial property into rented residential accommodation. The appraisal tool’s functionality was validated via a focus group discussion with senior property developers to ensure that assessment criteria and development weightings were appropriate. Feedback revealed that the tool was suitable for purpose and should now be adopted in practice and refined as appropriate and with usage.

Research limitations/implications

The appraisal tool presented could yield a far more accurate means of decision-making which, in turn, could ensure that predicted investment returns are received (thus reducing errors and lowering risk for investors). Future work is required to robustly test and validate the tool’s accuracy in practice. It is envisaged that future projects will provide a rich stream of data for such testing.

Originality/value

To the best of the authors’ knowledge, this work constitutes the first attempt to conceptualise a decision support tool for rented residential property development.
Priority setting for 2050 future images and policy agendas of the Republic of Korea: engaging the national assembly
Authors: Heo Jongho , Lee Chaejeong , Min Bogyeong
Published: October 2022

Purpose

This study aims to identify and prioritize preferable 2050 future images and the policy agendas of the Republic of Korea using a bottom-up approach, involving legislative staff of the National Assembly as well as experts from various fields.

Design/methodology/approach

The authors derived three future images from the future policy agendas selected by experts: society for growth of smart generations (GS), society for sustainability and safety (SS) and society for coexistence and diversity (CD). The survey conducted among legislative staff (n= 189) shows that the most preferred future image was SS. Then, the authors prioritized the policy agendas that aligned with future images using priority calculating methods.

Findings

The most prioritized policy agenda was “Social system for coexistence to resolve social conflict,” followed by “Social sustainability through tackling low birth rate.” The next was “Social integration policies to embrace diverse family composition” and “Responding to social change and knowledge transformation caused by artificial intelligence.” Among the top five rankings, two agendas from each SS and CD were selected.

Practical implications

To achieve the preferred future images, implementing policies related to sustainability, human rights and coexistence are necessary for continuous collaboration among stakeholders, especially those from the legislature.

Originality/value

This study presents a method of involving the National Assembly, which is a representative institution of the people and composed of various political parties, to set the national’s future vision and agenda from a long-term perspective.
Delivering remote therapy during the COVID-19 pandemic: a qualitative study with service users accessing a community personality disorder service
Authors: White Jasmin , Nillo Anne-Marie , Rowsell Kathryn , Roberts Victoria , Dudley-Hicks Duncan , Urbasch Michael , Cordwell John
Published: October 2022

Purpose

The purpose of this study is to qualitatively explore the views and opinions of service users accessing remote therapy through a community forensic personality disorder service during the COVID-19 pandemic.

Design/methodology/approach

A qualitative exploratory approach was adopted. Nine community forensic service users accessing virtual/telephone therapy through a community forensic mental health service were interviewed using semi-structed interviews. Data was analysed using Braun and Clarke (2006) thematic analysis techniques.

Findings

Analysis resulted in three overall themes: experience of communication in the therapeutic relationship; impacts of the change to remote working and making the best of what we have. A further seven subthemes were developed. A range of advantages and disadvantages to remote therapy were highlighted.

Research limitations/implications

This study was based on a small sample of service users accessing one community forensic service in England, and therefore caution should be taken when generalising the findings. All interviews were conducted remotely and thus may have only supported those who are able to engage in this way.

Practical implications

This paper has the potential to inform future remote therapy guidelines. Health services should consider keeping some elements of remote working and offering this as a choice to all service users.

Originality/value

This study is, to the best of the authors’ knowledge, the first study that attempts to explore the experiences of individuals accessing remote therapy within a forensic population who have personality disorders or traits.
Using resilience and passion to overcome bullying and lack of meaning at work: a pathway to change-oriented citizenship
Authors: De Clercq Dirk , Pereira Renato
Published: October 2022

Purpose

This study adds to human resource management research by addressing relevant questions about how and when employees' suffering from workplace bullying may direct them away from voluntary efforts to improve the organizational status quo. It postulates a mediating role of beliefs about work meaningfulness deprivation, as well as beneficial, moderating roles of two personal resources (resilience and passion for work) in this link.

Design/methodology/approach

The research hypotheses were tested with survey data collected among employees who work in the construction retail sector.

Findings

A critical reason that bullying victims refuse to exhibit change-oriented voluntarism is that they develop beliefs that their organization deprives them of meaningful work, which, as the authors theorize, enables them to protect their self-esteem resources. The extent to which employees can bounce back from challenging situations or feel passionate about work subdues this detrimental effect.

Practical implications

When employees feel upset about being bullied at work, their adverse work conditions may translate into work-related indifference (tarnished change-oriented citizenship), which then compromises employees' and the organization's ability to overcome the difficult situation. Managers should recognize how employees' personal resources can serve as protective shields against this risk.

Originality/value

This study details the detrimental role of demeaning workplace treatment in relation to employees' change-oriented organizational citizenship, as explained by their convictions that their organization operates in ways that make their work unimportant. It is mitigated by energy-enhancing personal resources.
Nicorandil mitigates amiodarone‐induced pulmonary toxicity and fibrosis in association with the inhibition of lung TGF‐β1/PI3K/Akt1‐p/mTOR axis in rats
Authors: Harb Inas , Ashour Hend , Rashed Laila A. , Mostafa Abeer , Samir Mai , Aboulhoda Basma Emad , El‐hanbuli Hala , Rashwan Eman , Mahmoud Heba
Published: October 2022

The long‐term side effect of the antiarrhythmic drug, amiodarone (AMIO), such as lung toxicity, remains a critical clinical issue. The previous knowledge denotes diverse antioxidant, anti‐inflammatory, and antifibrotic properties of the anti‐anginal drug, nicorandil (NI). Therefore, we aimed to investigate the possible protective effect of NI on pulmonary tissue remodelling following AMIO‐induced lung toxicity. The included rats were assigned into four equal groups (n = 8): (1) control, (2) control group that received NI 10 mg kg−1 day−1, (3) model group that received AMIO in a dose of 60 mg kg−1 day−1, and (4) treated group (AMIO‐NI) that were treated with AMIO plus NI as shown above. Drug administration continued for 10 weeks. AMIO resulted in deteriorated (p < 0.001) pulmonary functions accompanied by respiratory acidosis. AMIO showed an obvious histological injury score with intense collagen deposition, disturbed nitric oxide synthase enzymes (NOS/iNOS), and increased alpha smooth muscle actin expression. Furthermore, AMIO upregulated the transforming growth factor (TGF‐β1)/phosphoinositide‐3 kinase (PI3K)‐Akt1‐p/mammalian target of rapamycin (mTOR) axis, which determined the possible mechanism of AMIO on pulmonary remodelling. NI treatment significantly (p < 0.001) prevented the AMIO‐induced lung toxicity, as well as inhibited the TGF‐β1/PI3K/Akt1‐p/mTOR axis in the lung tissue of rats. The results were confirmed by an in‐vitro study.

Conclusion

The current results revealed that NI was effective in preserving the lung structure and functions. Amelioration of the oxidative stress and modulation of TGF‐β1/PI3K/Akt1‐p/mTOR have been achieved. This study suggests NI administration as a preventive therapy from the serious pulmonary fibrosis side effect of AMIO.