bluuebunny/crossref_metadata_2025 huggingface dataset:
Mutations in the B.1.1.7 SARS-CoV-2 spike protein reduce receptor-binding affinity and induce a flexible link to the fusion peptide
Authors: Socher Eileen , Conrad Marcus , Heger Lukas , Paulsen Friedrich , Sticht Heinrich , Zunke Friederike , Arnold Philipp
Published: April 2021

The B.1.1.7 variant of the SARS-CoV-2 virus shows enhanced infectiousness over the wild type virus, leading to increasing patient numbers in affected areas. A number of single amino acid exchanges and deletions within the trimeric viral spike protein characterize this new SARS-CoV-2 variant. Crucial for viral entry into the host cell is the interaction of the spike protein with the cell surface receptor angiotensin-converting enzyme 2 (ACE2) as well as integration of the viral fusion peptide into the host membrane. Respective amino acid exchanges within the SARS-CoV-2 variant B.1.1.7 affect inter-monomeric contact sites within the spike protein (A570D and D614G) as well as the ACE2-receptor interface region (N501Y), which comprises the receptor-binding domain (RBD) of the viral spike protein. However, the molecular consequences of mutations within B.1.1.7 on spike protein dynamics and stability, the fusion peptide, and ACE2 binding are largely unknown. Here, molecular dynamics simulations comparing SARS-CoV-2 wild type with the B.1.1.7 variant revealed inter-trimeric contact rearrangements, altering the structural flexibility within the spike protein trimer. In addition to reduced flexibility in the N-terminal domain of the spike protein, we found increased flexibility in direct spatial proximity of the fusion peptide. This increase in flexibility is due to salt bridge rearrangements induced by the D614G mutation in B.1.1.7 found in pre- and post-cleavage state at the S2’ site. Our results also imply a reduced binding affinity for B.1.1.7 with ACE2, as the N501Y mutation restructures the RBD-ACE2 interface, significantly decreasing the linear interaction energy between the RBD and ACE2.

Our results demonstrate how mutations found within B.1.1.7 enlarge the flexibility around the fusion peptide and change the RBD-ACE2 interface, which, in combination, might explain the higher infectivity of B.1.1.7. We anticipate our findings to be starting points for in depth biochemical and cell biological analyses of B.1.1.7, but also other highly contagious SARS-CoV-2 variants, as many of them likewise exhibit a combination of the D614G and N501Y mutation.
Septin-microtubule association requires a MAP-like motif unique to Sept9 isoform 1 embedded into septin octamers
Authors: Kuzmić Mira , Linares Gerard Castro , Fialová Jindřiška Leischner , Iv François , Salaün Danièle , Llewellyn Alex , Gomes Maxime , Belhabib Mayssa , Liu Yuxiang , Asano Keisuke , Tachibana Taro , Koenderink Gijsje , Badache Ali , Mavrakis Manos , Verdier-Pinard Pascal
Published: April 2021

Septins, a family of GTP-binding proteins assembling into higher order structures, interface with the membrane, actin filaments and microtubules, which positions them as important regulators of cytoarchitecture. Septin 9 (Sept9), which is frequently overexpressed in tumors and mutated in hereditary neuralgic amyotrophy (HNA), mediates the binding of septins to microtubules, but the molecular determinants of this interaction remained uncertain. We demonstrate that a short MAP-like motif unique to Sept9 isoform 1 (Sept9_i1) drives septin octamer-microtubule interaction in cells andin vitroreconstitutions. Septin-microtubule association requires polymerizable septin octamers harboring Sept9_i1. Although outside of the MAP-like motif, HNA mutations abrogates this association, identifying a putative regulatory domain. Removal of this domain from Sept9_i1 sequesters septins on microtubules, promotes microtubule stability and alters actomyosin fiber distribution and tension. Thus, we identify key molecular determinants and potential regulatory roles of septin-microtubule interaction, paving the way to deciphering the mechanisms underlying septin associated pathologies.
Explainable Feature Extraction Using a Neural Network with non-Synaptic Memory for Hand-Written Digit Classification
Authors: Faghihi Faramarz , Alashwal Hany , Moustafa Ahmed A.
Published: April 2021

The human brain recognizes hand-written digits by extracting the features from a few training samples that compose the digit image including horizontal, vertical, and orthogonal lines as well as full or semi-circles. In this study, we present a novel brain-inspired method to extract such features from handwritten digits images in the MNIST database (Modified National Institute of Standards and Technology database). In this study, we developed an explainable feature extraction method for hand written digit classification in which the extracted information are stored inside the neurons as non-synaptic memory manner. For this purpose, a neural network with 10 single neurons was trained to extract features of training images (each neuron represents one digit class). Following that, the trained single neurons are used for the retrieval of information from test images in order to assign them to digit categories. The accuracy of the classification method of test set images is calculated for different number of training samples per digit. The method demonstrates 75 % accuracy using 0.016 % of the training data and maximally shows accuracy 86 % using one epoch of whole training data. The method as an understandable feature extraction method allows users to see how it works and why it does not perform well on some digit classes. To our knowledge, this is the first model that stores information inside single neurons (i.e., non-synaptic memory) instead of storing the information in synapses of connected layers. Due to enabling single neurons to compute individually, it is expected that such class of neural networks show higher performance compared to traditional neural networks used in complicated classification problems.
Rose Extract Treatment on the CD4+ T lymphocytes
Authors: Arokiaraj Mark Christopher , Menesson Eric
Published: April 2021

Background and Aims

To study the effect of rose extract on CD4+T lymphocytes, and assess the cytokines response after cell treatment. In our previous study on endothelial cells, the rose extract reduced the secretion of inflammatory markers significantly.

Methods

The red rose extract used in this study was prepared and stored until use at -20°C. T cells were seeded in 96-well plates at 313500 cells/well in 100μl of cell culture medium in duplicate, one half of the wells were used for biomarkers screening in the culture medium, and the other half for cytotoxicity assay. 24h after plating, the cells were treated in duplicate with 100μl of red rose extract diluted at 0.5%, 0.1%, 0.05%, 0.01% and 0.005% (v/v) in cell culture medium or with culture medium only as control for 72h. Some other wells were for untreated cells, and cells treated with rose extract at 0.005% for 48h incubation time. After 48h and 72h, the corresponding wells were used for the cytotoxicity assay and from the duplicate wells, the cell culture media were collected and stored at -80°C until the biomarkers screening assay.

Results

Cytotoxicity assay revealed insignificant changes. IFN-gamma, MCP-1, GRO, RANTES and TIMP, Angiopoietin 1 and MMP-9 were elevated. Except MMP-9 which had fold changes >2 other cytokines were minimally elevated at various concentrations and timing of rose extract treatment. None of the cytokines were less than 0.8-fold.

Conclusions

Unlike in the endothelial cells, there is mild elevation in few inflammatory markers on T lymphocytes treatment by rose extract. Further studies need to be performed to estimate the clinical relevance.
On the Analysis of Transcriptional Noise From RNA-sequencing Data
Authors: Vitting-Seerup Kristoffer
Published: April 2021

RNA-sequencing (RNA-seq) has revolutionized our understanding of molecular and cellular biology. A central cornerstone in the analysis of RNA-seq is the bioinformatic tools that quantify the data. To evaluate the efficacy of these tools, scientists rely heavily on simulation of RNA-seq. Recently Varabyouet al. took simulation of RNA-seq data to the next level by providing simulated data, that includes simulation of transcriptional noise. While this represents a significant step forward in our ability to perform realistic benchmarks of RNA-seq tools, the data provided by Varabyouet al. need refinement. In the following, I suggest a few improvements with a specific focus on splicing noise.

Preface

I wrote this paper intending to submit it as a Commentary on the Varabyouet al. 2020 Genome Research paper1, but apparently, Genome Research does not publish correspondence-type articles. That is why it is currently on BioRxiv. If you have suggestions about where this paper could potentially be published do not hesitate to contact me.
De novomutations in domestic cat are consistent with an effect of reproductive longevity on both the rate and spectrum of mutations
Authors: Wang Richard J. , Raveendran Muthuswamy , Alan Harris R. , Murphy William J. , Lyons Leslie A. , Rogers Jeffrey , Hahn Matthew W.
Published: April 2021

The mutation rate is a fundamental evolutionary parameter with direct and appreciable effects on the health and function of individuals. Here, we examine this important parameter in the domestic cat, a beloved companion animal as well as a valuable biomedical model. We estimate a mutation rate of 0.86 × 10-8per bp per generation for the domestic cat (at an average parental age of 3.8 years). We find evidence for a significant paternal age effect, with more mutations transmitted by older sires. Our analyses suggest that the cat and the human have accrued similar numbers of mutations in the germline before reaching sexual maturity. The per-generation mutation rate in the cat is 28% lower than what has been observed in humans, but is consistent with the shorter generation time in the cat. Using a model of reproductive longevity, which takes into account differences in the reproductive age and time to sexual maturity, we are able to explain much of the difference in per-generation rates between species. We further apply our reproductive longevity model in a novel analysis of mutation spectra and find that the spectrum for the cat resembles the human mutation spectrum at a younger age of reproduction. Together, these results implicate changes in life-history as a driver of mutation rate evolution between species. As the first direct observation of the paternal age effect outside of rodents and primates, our results also suggest a phenomenon that may be universal among mammals.
Preliminaryin silicoexperiments: Towards new cancer treatments?
Authors: Fliess Michel , Join Cédric , Moussa Kaouther , Djouadi Seddik M. , Alsager Mohamed
Published: April 2021

We present some “in silico” experiments to design combined chemo- and immunotherapy treatment schedules. We introduce a new framework by combining flatness-based control along with model-free control. The flatness property of the used mathematical model yields straightforward reference trajectories. They provide us with the nominal open-loop control inputs. Closing the loop via model-free control allows to deal with the uncertainties on the injected drug doses. Several numerical simulations illustrating different case studies are displayed. We show in particular that the considered health indicators are driven to the safe region, even for critical initial conditions. Furthermore, in some specific cases there is no need to inject chemotherapeutic agents.
Maize RAMOSA3 accumulates in nuclear condensates enriched in RNA POLYMERASE II isoforms during the establishment of axillary meristem determinacy
Authors: Demesa-Arevalo Edgar , Abraham-Juarez Maria Jazmin , Xu Xiaosa , Bartlett Madelaine , Jackson David
Published: April 2021

Brief Abstract

Maize meristem determinacy is regulated by Trehalose-6-Phosphate Phosphatase (TPP) metabolic enzymes RAMOSA3 and TPP4. However, this function is independent of their enzymatic activity, suggesting they have an unpredicted, or moonlighting function. Using whole-mount double immunolabeling and imaging processing, we investigated the co-localization of RA3 nuclear speckles with markers for transcription, chromatin state and splicing. We find evidence for RA3 co-localization with RNA POL II, a transcription marker, and not with markers for promoter chromatin remodeling or mRNA processing, suggesting a function of nuclear RA3 in mediating a transcriptional response during meristem determinacy.
Precise gene models using long-read sequencing reveal a unique poly(A) signal inGiardia lamblia
Authors: Bilodeau Danielle Y. , Sheridan Ryan M. , Balan Balu , Jex Aaron R. , Rissland Olivia S.
Published: April 2021

During pre-mRNA processing, the poly(A) signal is recognized by a protein complex that ensures precise cleavage and polyadenylation of the nascent transcript. The location of this cleavage event establishes the length and sequence of the 3′ UTR of an mRNA, thus determining much of its post-transcriptional fate. Here, using long-read sequencing, we characterize the polyadenylation signal and related sequences surroundingGiardia lambliacleavage sites for over 2600 genes. We find thatG. lambliauses a AGURAA poly(A) signal, which differs from the mammalian AAUAAA. We also describe howG. lamblialacks common auxiliary elements found in other eukaryotes, along with the proteins that recognize them. Further, we identify 133 genes that show evidence of alternative polyadenylation. These results suggest that despite pared down cleavage and polyadenylation machinery, 3′ end formation still appears to be an important regulatory step for gene expression inG. lamblia.
Integrative multi-omics analysis reveals conserved hierarchical mechanisms of FOXO3 pioneer-factor activity
Authors: Brown Abigail K. , Maybury-Lewis Sun Y. , Webb Ashley E.
Published: April 2021

FOXO transcription factors are critical for cellular homeostasis and have been implicated in longevity in several species. Yet how these factors directly affect aging, particularly in humans, is not well understood. Here, we take an integrated multi-omics approach to identify the chromatin-level mechanisms by which FOXO3 coordinates transcriptional programs. We find that FOXO3 functions as a pioneer factor in human cells, directly altering chromatin accessibility to regulate gene expression. Unexpectedly, FOXO3’s pioneer activity at many sites is achieved through a two-step process, in which chromatin accessibility is initially reduced, then transitions to an open conformation. The direct FOXO3 network comprises chromatin remodelers, including the SWI/SNF remodeling complex, which we find is functionally required for FOXO3 activity. We also identify a novel secondary network of activator protein-1 (AP-1) transcription factors deployed by FOXO3, which orchestrate a neuronal-specific subnetwork. Together, this hierarchical FOXO3 pioneer network regulates key cellular processes including metabolism, proteostasis, epigenetics and proliferation, which must be tightly controlled under changing conditions that accompany aging.
Inhibition of itch by neurokinin 1 receptor (Tacr1) -expressing ON cells in the rostral ventromedial medulla
Authors: Follansbee Taylor , Domocos Dan , Nguyen Eileen , Nguyen Amanda , Bountouvas Aristea , Velasquez Lauren , Carstens Mirela Iodi , Takanami Keiko , Ross Sarah E. , Carstens E.
Published: April 2021

The rostral ventromedial medulla (RVM) is important in descending modulation of spinal nociceptive transmission, but it is unclear if the RVM also modulates spinal pruriceptive transmission. RVM ON cells are activated by noxious algesic and pruritic stimuli and are pronociceptive. Many RVM-spinal projection neurons express the neurokinin-1 receptor (Tacr1), and ON-cells are excited by local administration of substance P (SP). We hypothesized that Tacr1-expressing RVM ON cells exert an inhibitory effect on itch opposite to their pronociceptive action. Intramedullary microinjection of SP significantly potentiated RVM ON cells and reduced pruritogen-evoked scratching while producing mild mechanical sensitization. Chemogenetic activation of RVM Tacr1-expressing RVM neurons also reduced acute pruritogen-evoked scratching. Optotagging experiments confirmed RVM Tacr1-expressing neurons to be ON cells. We conclude that Tacr1-expressing ON cells in RVM play a significant role in the modulation of pruriceptive transmission.
Single-cell atlas of human oral mucosa reveals a stromal-neutrophil axis regulating tissue immunity in health and inflammatory disease
Authors: Williams DW , Greenwell- Wild T , Brenchley L , Dutzan N , Overmiller A , Sawaya AP , Webb S , Martin D , Hajishengallis G , Divaris K , Morasso M , Haniffa M , Moutsopoulos NM
Published: April 2021

The oral mucosa remains an understudied barrier tissue rich in exposure to antigens, commensals and pathogens. Moreover, it is the tissue where one of the most prevalent human microbe-triggered inflammatory diseases, periodontitis, occurs. To understand this complex environment at the cellular level, we assemble herein a human single-cell transcriptome atlas of oral mucosal tissues in health and periodontitis. Our work reveals transcriptional diversity of stromal and immune cell populations, predicts intercellular communication and uncovers an altered immune responsiveness of stromal cells participating in tissue homeostasis and disease at the gingival mucosa. In health, we define unique populations ofCXCL1,2,8-expressing epithelial cells and fibroblasts mediating immune homeostasis primarily through the recruitment of neutrophils. In disease, we further observe stromal, particularly fibroblast hyper-responsiveness linked to recruitment of leukocytes and neutrophil populations. Ultimately, a stromal-neutrophil axis emerges as a key regulator of mucosal immunity. Pursuant to these findings, most Mendelian forms of periodontitis were shown to be linked to genetic mutations in neutrophil and select fibroblast-expressed genes. Moreover, we document previously unappreciated expression of known pattern- and damage-recognition receptors on stromal cell populations in the setting of periodontitis, suggesting avenues for triggering stromal responses. This comprehensive atlas offers an important reference for in-depth understanding of oral mucosal homeostasis and inflammation and reveals unique stromal–immune interactions implicated in tissue immunity.
Visualizing the organization and differentiation of the male-specific nervous system ofC. elegans
Authors: Tekieli Tessa , Yemini Eviatar , Nejatbakhsh Amin , Varol Erdem , Fernandez Robert W. , Masoudi Neda , Paninski Liam , Hobert Oliver
Published: April 2021

Sex differences in the brain are prevalent throughout the animal kingdom and particularly well appreciated in the nematodeC. elegans. While 294 neurons are shared between the two sexes, the nervous system of the male contains an additional 93 malespecific neurons, most of which have received very little attention so far. To make these neurons amenable for future study, we describe here how a multicolor, multipromoter reporter transgene, NeuroPAL, is capable of visualizing the distinct identities of all male specific neurons. We used this tool to visualize and characterize a number of features of the male-specific nervous system. We provide several proofs of concept for using NeuroPAL to identify the sites of expression ofgfp-taggedreporter genes. We demonstrate the usage of NeuroPAL for cellular fate analysis by analyzing the effect of removal of developmental patterning genes, including a HOX cluster gene (egl-5), a miRNA (lin-4) and a proneural gene (lin-32/Ato), on neuronal identity acquisition within the male-specific nervous system. We use NeuroPAL and its intrinsic cohort of more than 40 distinct differentiation markers to show that, even though male-specific neurons are generated throughout all four larval stages, they execute their terminal differentiation program in a coordinated manner in the fourth larval stage that is concomitant with male tale retraction. This wave of differentiation couples neuronal maturation programs with the appearance of sexual organs. We call this wave “just-in-time” differentiation by its analogy to the mechanism of “just-in-time” transcription of metabolic pathway genes.
Resurrecting self-cleaving mini-ribozymes from 40-million-year-old LINE-1 elements in human genome
Authors: Zhang Zhe , Xiong Peng , Wang Junfeng , Zhan Jian , Zhou Yaoqi
Published: April 2021

Long Interspersed Nuclear Element (LINE) retrotransposons play an important role in genomic innovation as well as genomic instability in many eukaryotes including human. Random insertions and extinction through mutational inactivation make them perfectly time-stamped “DNA fossils”. Here, we investigated the origin of a self-cleaving ribozyme in 5’ UTR of LINE-1. We showed that this ribozyme only requires 35 nucleotides for self-cleavage with a simple but previously unknown secondary-structure motif that was determined by deep mutational scanning and covariation analysis. Structure-based homology search revealed the existence of this mini-ribozyme in anthropoids but not in prosimians. In human, the most homologs of this mini-ribozyme were found in lineage L1PA6-10 but essential none in more recent L1PA1-2 or more ancient L1PA13-15. We resurrected mini-ribozymes according to consensus sequences and confirmed that mini-ribozymes were active in L1PA10 and L1PA8 but not in L1PA7 and more recent lineages. The result paints a consistent picture for the emergence of the active ribozyme around 40 million years ago, just before the divergence of the new world monkeys (Platyrrhini) and old-world monkeys (Catarrhini). The ribozyme, however, subsequently went extinct after L1PA7 emerged around 30 million years ago with a deleterious mutation. This work uncovers the rise and fall of the mini-LINE-1 ribozyme recorded in the “DNA fossils” of our own genome. More importantly, this ancient, naturally trans-cleaving ribozyme (after removing the non-functional stem loop) may find its modern usage in bioengineering and RNA-targeting therapeutics.
Elucidating the crosstalk between inflammation and DNA damage pathways in the pancreatic beta-cell through the diabetes susceptibility gene,TCF19
Authors: Yang Grace H. , Fontaine Danielle A. , Lodh Sukanya , Blumer Joseph T. , Roopra Avtar S. , Davis Dawn Belt
Published: April 2021

TCF19is a gene that is associated with both type 1 diabetes (T1DM) and type 2 diabetes (T2DM) in genome-wide association studies. Prior studies have demonstrated that TCF19 knockdown impairs β-cell proliferation and increases apoptosis. However, little is known about its role in diabetes pathogenesis or the effects of TCF19 gain-of-function. The aim of this study was to examine the impact of TCF19 overexpression in INS-1 β-cells on proliferation and gene expression. With TCF19 overexpression, there was an increase in nucleotide incorporation without any change in cell cycle gene expression, alluding to an alternate process of nucleotide incorporation. Analysis of RNAseq of TCF19 overexpressing cells revealed increased expression of several DNA damage response (DDR) genes, as well as a tightly linked set of genes involved in cell stress, immune system processes, and inflammation. This connectivity between DNA damage and inflammatory gene expression has not been well studied in the β-cell, and suggests a novel role for TCF19 in regulating these pathways. Future studies determining how TCF19 may modulate these pathways may provide potential targets for β-cell survival.
Antibody responses induced by trivalent inactivated influenza vaccine among pregnant and non-pregnant women in Thailand: a matched cohort study
Authors: Nakphook Sutthichai , Patumanond Jayanton , Shrestha Manash , Prasert Kriengkrai , Chittaganpitch Malinee , Mott Joshua A. , Praphasiri Prabda
Published: April 2021

Background

We compared influenza antibody titers among vaccinated and unvaccinated pregnant and non-pregnant women.

Methods

During 1st June – 30th September 2018, four groups of cohort participants - vaccinated pregnant, unvaccinated pregnant, vaccinated non-pregnant, and unvaccinated non-pregnant women were selected by matching age, gestational age, and the week of vaccination. Serum antibody titers against each strain of 2018 Southern Hemisphere inactivated trivalent influenza vaccine (IIV3) were assessed by hemagglutination inhibition (HI) assay on Day 0 (pre-vaccination) and Day 28 (one month post-vaccination) serum samples. Geometric mean titer (GMT), GMT ratio (GMR), seroconversion (defined as ≥4 fold increase in HI titer), and seroprotection (i.e. HI titer ≥1:40) were compared across the study groups using multilevel regression analyses, controlling for previous year vaccination from medical records and baseline antibody levels.

Results

A total of 132 participants were enrolled in the study (33 in each of the four study groups). The baseline GMTs were similar for influenza A(H1N1), A(H3N2), and B vaccine strains among all four groups (all p-values >0.05). After one month, both vaccinated groups had significantly higher GMT, GMR, seroconversion, and seroprotection than their unvaccinated controls (all p-values <0.05). The seroconversion rate was over 60% for any strain among the vaccinated groups, with the highest (88.8%) observed against A(H1N1) in the vaccinated pregnant group. Similarly, at least 75% of the vaccinated participants developed seroprotective antibody levels against all three strains; the highest seroprotection was found against A(H3N2) at 92.6% among vaccinated non-pregnant participants. Pregnant women had similar antibody responses (post-vaccination GMT, GMR, seroconversion, and seroprotection) to non-pregnant women for all three strains of IIV3 (all p>0.05).

Conclusions

The 2018 seasonal IIV3 was immunogenic against all three vaccine strains and pregnancy did not seem to alter the immune response to IIV3. These findings support the current influenza vaccination recommendations for pregnant women.
The MYB33, MYB65, and MYB101 transcription factors affect Arabidopsis and potato responses to drought by regulating the ABA signaling pathway
Authors: Wyrzykowska Anna , Bielewicz Dawid , Plewka Patrycja , Sołtys-Kalina Dorota , Wasilewicz-Flis Iwona , Marczewski Waldemar , Jarmolowski Artur , Szweykowska-Kulinska Zofia
Published: April 2021

Aims

Drought is a climate threat limiting crop production. Potato is one of the four most important food crops worldwide and is sensitive to water shortage. The CBP80 gene was shown to affect plant response to drought by regulating the level of microRNA159, and, consequently, the levels of the MYB33 and MYB101 transcription factors. (TF) Our studies aimed to show whether indeed the level of MYB33, MYB65, and MYB101 TFs affects plant response to water shortage.

Methods

Arabidopsis transgenic plants exhibiting downregulation and Arabidopsis and potato transgenic plants exhibiting overexpression of selected MYB TFs were obtained. Plants response to drought was mainly measured using relative water content (RWC) and stomata closure upon exogenous ABA.

Results

Three MYB TFs studied are involved in plant response to drought. When downregulated in Arabidopsis, the MYB33, MYB65 and MYB101 genes cause stomatal hyposensitivity to ABA, leading to reduced tolerance to drought. Transgenic Arabidopsis and potato plants overexpressing a mutated version of these genes with changed miR159 recognition site, show hypersensitivity to ABA and relatively high tolerance to drought conditions.

Conclusions

The MYB33, MYB65, and MYB101 genes are good be potential targets for innovative breeding to obtain crops with relatively high tolerance to drought.
Charting human subcortical maturation across the adult lifespan within vivo7 T MRI
Authors: Miletić Steven , Bazin Pierre-Louis , Isherwood Scott J. S. , Keuken Max C. , Alkemade Anneke , Forstmann Birte U.
Published: April 2021

The human subcortex comprises hundreds of unique structures. Subcortical functioning is crucial for behavior, and disrupted function is observed in common neurodegenerative diseases. Despite their importance, human subcortical structures continue to be difficult to studyin vivo. Here we provide a detailed account of 17 prominent subcortical structures, describing their approximate iron and myelin contents, morphometry, and their age-related changes across the normal adult lifespan. The results provide compelling insights into the heterogeneity and intricate age-related alterations of these structures. They also show that the locations of many structures shift across the lifespan, which is of direct relevance for the use of standard magnetic resonance imaging atlases. The results further our understanding of subcortical morphometry and neuroimaging properties, and of normal aging processes which ultimately can improve our understanding of neurodegeneration.
Rab10 regulates the sorting of internalised TrkB for retrograde axonal transport
Authors: Lazo Oscar M. , Schiavo Giampietro
Published: April 2021

Neurons process real-time information from axon terminals to coordinate gene expression, growth and plasticity. Input from distal axons is encoded as a stream of endocytic organelles, termed signalling endosomes, targeted to the soma. Formation of these organelles depends on target-derived molecules, such as brain-derived neurotrophic factor (BDNF), which is recognised by TrkB receptors on the plasma membrane, endocytosed and transported to the cell body along the microtubules network. Notwithstanding its neuropathological importance, the mechanism controlling the sorting of TrkB to signalling endosomes is currently unknown. In this work, we uncover the small GTPase Rab10 as critical for TrkB sorting and propagation of BDNF signalling from axon terminals to the soma. Our data demonstrate that Rab10 defines a novel class of axonal organelles, rapidly mobilised towards the axon terminal upon BDNF stimulation, enabling the axon to fine-tune retrograde signalling depending on BDNF availability at the synapse. These results help clarifying the neuroprotective phenotype recently associated to Rab10 polymorphisms and provide a new therapeutic target to halt neurodegeneration.
Myeloid and endothelial cells cooperate to promote hematopoietic stem cells expansion in the fetal niche
Authors: Cacialli Pietro , Mailhe Marie-Pierre , Golub Rachel , Bertrand Julien Y.
Published: April 2021

During embryonic development, very few hematopoietic stem cells (HSCs) are produced from the hemogenic endothelium, that will be expanded in a very specific niche. This fetal HSC niche comprises a complex and dynamic molecular network of interactions between multiple cell types, including endothelial cells (ECs) and mesenchymal stromal cells. It is known that functional changes in the hematopoietic niche, such as aging, vascular cell remodelling or inflammation can directly affect HSCs. Among all these inflammatory regulators, the eicosanoid prostaglandin E (PGE2) has been shown to be very important during embryonic life. However, the precise source of PGE2 in the embryo is still elusive. Here we show that all the genes involved in PGE2 synthesis and transport are expressed by distinct cells of the caudal hematopoietic tissue (CHT) in the zebrafish embryo and in the mouse fetal liver, suggesting that each cell type acts sequentially and collaboratively with the others to produce PGE2 and ultimately expand HSCs. Among these cells, we found myeloid cells (both neutrophils and macrophages) to be absolutely necessary, as they concur to the production of PGH2, the precursor of PGE2. To measure the impact of myeloid cells, we generated a genetic model of myeloid ablation, which caused a loss of HSCs in the CHT, that could be rescued by supplementing zebrafish embryos with PGE2 or PGH2. ECs expressed theslco2b1transporter to import PGH2, andptges3, the necessary enzyme to convert this latter into PGE2. Taken altogether, our data show that the triad composed of neutrophils, macrophages and ECs concurs to HSC expansion in the CHT.
CD95 expression in triple negative breast cancer blocks induction of an inflammatory state through differential regulation of NF-κB Signaling
Authors: Guégan Jean-Philippe , Pollet Justine , Ginestier Christophe , Charafe-Jauffret Emmanuelle , Peter Marcus E. , Legembre Patrick
Published: April 2021

CD95L is expressed by tumor-infiltrating lymphocytes to eliminate CD95-expressing tumor cells and thereby CD95 loss by tumor cells is often considered as a consequence of an immunoediting process. Nonetheless CD95 expression is maintained in most triple negative breast cancers (TNBCs), and we recently reported that CD95 loss in TNBC cells triggers the induction of a pro-inflammatory program promoting the recruitment of cytotoxic NK and CD8+ T-cells and impairing tumor growth. Using a comprehensive proteomic approach, we have identified two yet unknown CD95 interaction partners, Kip1 ubiquitination-promoting complex protein 2 (KPC2) and p65. KPC2 contributes to the partial degradation of p105 (NFκB1) and the subsequent generation of p50 homodimers, which transcriptionally represses pro-inflammatory NF-κB-driven gene expression. Mechanistically, KPC2 directly interacts with the C-terminal region of CD95 and links the receptor to RelA (p65) and KPC1, the catalytic subunit of the KPC complex that acts as E3 ubiquitin-protein ligase promoting the partial degradation of p105 into p50. Loss of CD95 in TNBC cells releases KPC2, limiting the formation of the NF-κB inhibitory homodimer complex (p50/p50), promoting NF-κB activation and the production of pro-inflammatory cytokines including CSF1, CSF2, CXCL1 and IL1 members, known to promote recruitment and differentiation of certain adaptive and innate immune effector cells.
Somite morphogenesis is required for axial blood vessel formation
Authors: Paulissen Eric , Palmisano Nicholas J. , Waxman Joshua , Martin Benjamin L.
Published: April 2021

Angioblasts that form the major axial blood vessels of the dorsal aorta and cardinal vein migrate towards the embryonic midline from distant lateral positions. Little is known about what controls the precise timing of angioblast migration and their final destination at the midline. Using zebrafish, we found that midline angioblast migration requires neighboring tissue rearrangements generated by somite morphogenesis. The somitic shape changes cause the adjacent notochord to separate from the underlying endoderm, creating a ventral midline cavity that provides a physical space for the angioblasts to migrate into. The anterior to posterior progression of midline angioblast migration is facilitated by retinoic acid induced anterior to posterior somite maturation and the subsequent progressive opening of the ventral midline cavity. Our work demonstrates a critical role for somite morphogenesis in organizing surrounding tissues to facilitate notochord positioning and angioblast migration, which is ultimately responsible for creating a functional cardiovascular system.

Summary statement

Retinoic acid induced somite morphogenesis generates a midline cavity that accommodates migrating angioblasts, which form the axial blood vessels.
Actuator model for spacecraft attitude control simulation
Authors: Zhang Chengxi , Wu Jin , Sun Ran , Wang Mingjiang , Ran Dechao
Published: April 2021

Purpose

The purpose of this paper is to study the general actuator modeling in spacecraft attitude control systems.

Design/methodology/approach

The proposed module in this paper provides various non-ideal factors such as the second-order dynamic time response, time-delay, bias torques, dead-zones and saturation. The actuator module can make the simulation as close to the practical situation as possible.

Findings

This paper presents a practical integrated module for the simulation of attitude control algorithms. Based on theoretical modeling, we give simulation modules and numerical examples. The proposed model can be directly used in spacecraft control simulation. Instead of considering only a few of them, it makes the simulation more convincing. Though it may not be perfect, it is better than totally ignoring the actuator dynamics.

Originality/value

The authors provide an integrated actuator model for spacecraft attitude control simulation, considering as many nonlinear factors as possible once time.
Optimization of profitability and liquidity for residential projects under debt and equity financing
Authors: Cevikcan Emre , Kose Yildiz
Published: April 2021

Purpose

An appropriate space allocation among different residence types gives higher profitability and liquidity for cash flow management in real estate projects for developers. Thereby, a balance between debt and equity should be kept for capital formation in developers where high level of cost, profit and risk exists. The purpose of this paper is to provide cash flow optimization under debt and equity financing while providing an appropriate space allocation of residence types via synchronous consideration of profitability and liquidity.

Design/methodology/approach

A novel optimization methodology that includes project financing, optimization and experimental design modules is proposed. The first module, project financing, considers the flexibility of utilizing one or both of debt financing and equity financing when making capital. The optimization module addresses space allocation among different residence types for a construction while maximizing profitability and liquidity using two mixed-integer linear programming models in a pre-emptive manner. The experimental design module assesses the effects of decisive parameters within the methodology via multivariate analysis of variance (MANOVA).

Findings

The proposed methodology is applied to a real-life residential project in Istanbul. The optimization module yielded 42.5% profitability via the first linear programming model and 2.2% trade-off between liquidity and profitability while minimizing the payback period by the second linear programming model. Meanwhile, MANOVA results showed that profit per square meter and sale rate trends are the most prominent factors considering their significant effects on net present value and payback period.

Originality/value

To the best knowledge of the author, related papers focused only on profitability under equity financing. Liquidity (as an objective) and equity financing (as a financing method) have not been handled. Hence, this paper not only performs profitability and liquidity-oriented cash flow optimization under debt and equity financing but also optimizes space allocation of residences for the first time.
Changing the layout of farmers markets can affect cross-contamination
Authors: Acosta Karla M. , Mohammad Zahra H. , Yu Heyao , Kirkwood Kristen , Gibson Kristen , Neal Jack A. , Sirsat Sujata A.
Published: April 2021

Purpose

The purpose of this study was to investigate whether the layout has an effect on cross-contaminations levels at farmers markets.

Design/methodology/approach

We used social cognitive theory's triadic reciprocity model to investigate how influencing the environment could change the behaviors of farmers’ market consumers and reduce the risk of microbial cross-contamination using a Fluorescent Compound (FC). For this purpose, a 3 × 2 experimental between-subject factorial design was utilized in this study: three farmers market layouts (i.e. U-shaped [U-S], L-shaped [L-S] and square-shaped [S–S]) and two different set-ups per market (i.e. produce and non-produce vendors completely separated, and alternating produce and non-produce vendors). FC was utilized to simulate microbial contamination on the participants (n = 54) hands. The participants were allowed to walk through the layout for 3 min and touch items after which a total of 475 swab samples were processed and recorded for absorbance levels.

Findings

The results indicated that the cross-contamination level of the U-S market was significantly lower (p < 0.001) than those of the L-S and S–S markets. The best market layout and set-up based on the average levels of simulated cross-contamination were the U-S market, particularly with the A set-up, where produce and non-produce booths were scattered.

Originality/value

This study is the first to use the quantification of FC to identify the impact of a farmers’ market layout/design on cross-contamination levels. These results can be used to provide guidance to market managers on layout and design from a safety standpoint to reduce the risk of cross-contamination.
Assessing the mediating effect of sustainable competitive advantage on the relationship between organisational innovativeness and firm performance
Authors: Çağlıyan Vural , Attar Melis , Abdul-Kareem Aleem
Published: April 2021

Purpose

This study aims to assess the mediating effect of sustainable competitive advantage (SCA) on the relationship between organisational innovativeness (OI) and performance of small- and medium-sized enterprises (SMEs) operating in Konya, Turkey.

Design/methodology/approach

A survey method is used to collect the necessary data for this research. A total of 264 respondents from 83 SMEs partook in the study. In choosing the sample size, both purposive sampling and simple random techniques are used. The data gathered are analysed using SPSS program and Hayes PROCESS macro v.3.4.1.

Findings

The results of the analyses reveal that OI has a statistically significant positive effect on SCA and firm performance (FP). Moreover, SCA is found to have a mediating effect on the relationship between OI and FP.

Practical implications

Policymakers and management of SMEs need to show great commitment to innovativeness and relate it to SCA to create superior customer value, thereby leading to a holistic and long-term FP.

Originality/value

This study brings to the fore empirical evidence on how SCA serves as a mediator between OI and FP. It also contributes to the literature by focusing on three distinct but related variables. The study makes theoretical contribution by highlighting the role of the resource-based theory in enhancing business performance and SCA through strategic internal resources and innovative activities.
Exploring the benefits and trade-offs of design standardization in capital projects
Authors: Choi Jin Ouk , Shrestha Binit Kumar , Kwak Young Hoon , Shane Jennifer
Published: April 2021

Purpose

Facility design standardization strategy has considerable advantages, highlighted by its widespread and consistent use in the shipbuilding and manufacturing industries. However, capital projects have failed to realize these benefits. The primary rationale behind this problem is the lack of proper understanding of design standardization, more specifically the benefits and equally importantly, the trade-offs of design standardization in capital projects. Therefore, this study highlights 13 benefits and six trade-offs of standardization in connection to design standardization, along with specific examples.

Design/methodology/approach

To achieve the study objectives, the researchers identified the most impactful benefits and trade-offs in terms of economic impact by surveying prominent players in the industry. Furthermore, the researchers examined 43 actual case projects (a case study) executed with the standardization strategy to evaluate the industry's status in terms of the levels of advantage achievement and disadvantage incurrence.

Findings

The results of this survey show that design once, reuse multiple times and design and procurement in advance are the most impactful benefits. Similarly, susceptible to changes in the market conditions is one of the top trade-offs that can be incurred in capital projects when implementing standardization. The results also highlight that design once, reuse multiple times is one of the most achieved benefits in standardized capital projects today, while cost of establishing the design standard is the most incurred trade-off.

Originality/value

This study provides important insight into how standardization strategy can be advantageous while also enriching the literature about pitfalls expected from standardization. Moreover, this study's results will help the industrial sector achieve higher levels of design standardization by providing a better understanding of the benefits and trade-offs of design standardization.
Battling COVID-19 with human resource management bundling
Authors: Adikaram Arosha S. , Naotunna N.P.G.S.I. , Priyankara H.P.R.
Published: April 2021

Purpose

This paper aims to present an empirically driven crisis management framework of complementary human resource management (HRM) bundles that can be utilized in simultaneously managing the health crisis, financial crisis and disruptions to business operations through lockdown and other government restrictions propelled by the COVID-19 pandemic.

Design/methodology/approach

The framework is developed employing qualitative methodology, drawing from the successful HRM practices adopted by 26 Sri Lankan companies in battling the many crises of COVID-19 and using the soft HRM approach as the theoretical basis.

Findings

The findings report a framework that consists of three key HRM bundles (health and safety bundle, cost-saving bundle and employee motivation and engagement bundle) entailing an array of inter-related, internally consistent, complementary and mutually reinforcing HRM practices and HRM activities. These HRM bundles and the HRM practices as well as the HRM activities therein, indicate how a softer approach to managing employees can be used during a crisis.

Practical implications

The framework will inform the HRPs of the HRM bundles, HRM practices and HRM activities that can be used to manage the multiple crises created by COVID-19 and other similar pandemics.

Originality/value

The study contributes to and expands the knowledge of HRM in crisis management generally and HRM in a global pandemic more specifically.
The role of strategic collaborations and relational capital in enhancing product performance – a moderated-mediated model
Authors: Prajogo Daniel , Mena Carlos , Chowdhury Mesbahuddin
Published: April 2021

Purpose

The purpose of this paper is to test the moderated-mediated model using a dataset drawn from 204 manufacturing firms in Australia, and Hayes' PROCESS macro software was used for analyzing the research model.

Design/methodology/approach

This study examines how firms can leverage the strategic value of their key supplier for improving their product performance by developing strategic collaborations with the key supplier as a mediating factor. Furthermore, it also seeks to understand the role that commitment plays in strategic relationships by testing how the mediating role of strategic collaboration is moderated by the level of buyer-suppliers relational capital.

Findings

The findings show that strategic collaborations mediate the relationship between the strategic value of key supplier and buyer's product performance, and the mediating effect is moderated by the relational capital between the buyer and the key supplier in such a way that the stronger the relational capital the stronger the indirect effect of strategic value of key supplier on buyer's product performance.

Practical implications

The findings show that firms could derive significant benefits from the strategic value of their key supplier in improving their product performance. However, the benefits can only be realized if firms can build successful strategic collaborations in the first place. At the same time, this study also demonstrates the importance of relational capital in terms of commitment and trust with the key supplier that influences the effectiveness of strategic collaborations in realizing the outcome of the collaborations.

Originality/value

This study addresses the gap in the literature by disentangling the complex relationship between a key supplier's strategic value and a buyer's product performance and the role that both collaboration and relational capital play in this relationship. By integrating strategic collaborations and relational capital of buyer-supplier relationships, this study not only confirms the links by testing key supplier's strategic value, strategic collaboration and product performance, but also extends the previous studies by incorporating the moderating role of relational capital as a contingent factor.