bluuebunny/crossref_metadata_2025 huggingface dataset:
STEM: A Method for Mapping Single-cell and Spatial Transcriptomics Data with Transfer Learning
Authors: Hao Minsheng , Luo Erpai , Chen Yixin , Wu Yanhong , Li Chen , Chen Sijie , Gao Haoxiang , Bian Haiyang , Wei Lei , Zhang Xuegong
Published: September 2022

Profiling spatial variations of cellular composition and transcriptomic characteristics is important for understanding the physiology and pathology of tissues in health or diseases. Spatial transcriptomics (ST) data are powerful for depicting spatial gene expression but the currently dominating high-throughput technology is yet not at single-cell resolution. On the other hand, single-cell RNA-sequencing (SC) data provide high-throughput transcriptomic information at the single-cell level but lack spatial information. Integrating these two types of data would be ideal for revealing transcriptomic landscapes at single-cell resolution. We developed the method STEM (SpaTially aware EMbedding) for this purpose. It uses deep transfer learning to encode both ST and SC data into a unified spatially aware embedding space, and then uses the embeddings to infer the SC-ST mapping and predict pseudo-spatial adjacency between cells in the SC data. Semi-simulation and real data experiments verified that the embeddings preserved the spatial information and eliminated technical biases between SC and ST data. Besides, we can use attribution analysis in STEM to reveal genes whose expressions dominate spatial information. We applied STEM to data of human squamous cell carcinoma and of hepatic lobule to uncover the spatial localization of rare cell types data and reveal cell-type-specific gene expression variation along a spatial axis. STEM is a powerful tool for mapping SC and ST data to build single-cell level spatial transcriptomic landscapes, and can provide mechanistic insights into the spatial heterogeneity and microenvironments of tissues.
INSULIN-LIKE GROWTH FACTOR I REDUCES CORONARY ATHEROSCLEROSIS IN PIGS WITH FAMILIAL HYPERCHOLESTEROLEMIA
Authors: Sukhanov Sergiy , Higashi Yusuke , Yoshida Tadashi , Danchuk Svitlana , Alfortish Mitzi , Goodchild Traci , Scarborough Amy , Sharp Thomas , Jenkins James S. , Garcia Daniel , Ivey Jan , Tharp Darla L. , Schumacher Jeffrey , Rozenbaum Zach , Kolls Jay K. , Bowles Douglas , Lefer David , Delafontaine Patrice
Published: September 2022

Objective

Although murine models of coronary atherosclerotic disease (CAD) have been used extensively to determine mechanisms, limited new therapeutic options have emerged. Pigs with familial hypercholesterolemia (FH pigs) develop complex coronary atheromas that are almost identical to human lesions. We reported previously that insulin-like growth factor 1 (IGF-1) reduced aortic atherosclerosis and promoted features of stable plaque in a murine model. We tested IGF-1 effects in atherosclerotic FH pigs to consider use of IGF-1 to treat CAD in humans. FH pigs were administered with IGF-1 for 6 months. Atherosclerosis was quantified by serial intravascular ultrasound (IVUS) and histology, plaque composition - by immunohistochemistry. We used spatial transcriptomics (ST) analysis to identify global transcriptome changes in advanced plaque compartments and to obtain mechanistic insights into IGF-1 effects.

Results

IGF-1-injected FH pigs had 1.8-fold increase in total circulating IGF-1 levels compared to control. IGF-1 decreased relative coronary atheroma (IVUS) and lesion cross-sectional area (histology). IGF-1 induced vascular hypertrophy and reduced circulating triglycerides, markers of systemic oxidative stress and pro-atherogenic CXCL12 chemokine levels. IGF-1 increased fibrous cap thickness, and reduced necrotic core size, macrophage content, and cell apoptosis, changes consistent with promotion of a stable plaque phenotype. IGF-1 suppressed FOS/FOSB factors and gene expression of MMP9 and CXCL14 in plaque macrophages, suggesting possible involvement of these molecules in IGF-1’s effect on atherosclerosis.

Conclusions

IGF-1 reduced coronary plaque burden and promoted features of stable plaque in a pig model, providing support for consideration of clinical trials. ST profiling of plaques provided novel insights into potential mechanisms.
B lymphocytes in Treatment-Naïve Pediatric Lupus Patients are Epigenetically Distinct from Healthy Children
Authors: Hui-Yuen Joyce S , Jiang Kaiyu , Malkiel Susan , Eberhard B Anne , Walters Heather , Diamond Betty , Jarvis James N.
Published: September 2022

Background

Systemic lupus erythematosus (SLE) is a complex disease likely triggered by gene-environment interactions. We have shown that most of the SLE-associated haplotypes encompass genomic regions enriched for epigenetic marks associated with enhancer function in neutrophils, and T and B cells, suggesting that genetic risk is exerted through altered gene regulation. Data remain scarce on how epigenetic variance contributes to disease risk in pediatric SLE (pSLE). We aim to identify differences in epigenetically-regulated chromatin architecture in treatment-naïve pSLE patients compared to healthy children.

Methods

Using the assay for transposase-accessible chromatin with sequencing (ATACseq), we surveyed open chromatin in 8 treatment-naïve pSLE patients, with at least moderate disease severity, and 5 healthy children. We investigated whether regions of open chromatin unique to pSLE patients demonstrate enrichment for specific transcriptional regulators, using standard computational approaches to identify unique peaks and a false discovery rate of <0.05. Further analyses for differential transcription factor binding, histone modification enrichment, and variant calling were performed using multiple bioinformatics packages in R and Linux.

Results

There were 30,139 differentially accessible regions (DAR) identified unique to pSLE B cells, of which 64.3% are more accessible in pSLE than B cells from healthy children. Many of these DAR are found in distal, intergenic regions, and are enriched for enhancer histone marks (p=0.027). When we compared B cells from pSLE patients to those of untreated adults, we found more regions of inaccessible chromatin, and fewer DAR within 10-100kb of known SLE haplotypes. In pSLE B cells, 65.2% of the DAR are located within or near known SLE haplotypes. Further analysis revealed enrichment of several transcription factor binding motifs within these DAR that may regulate genes involved in the pro-inflammatory responses and cellular adhesion.

Conclusions

This is the first report describing differences in chromatin architecture between pSLE patients and healthy children. We demonstrate an epigenetically-distinct profile in pSLE B cells when compared to those from healthy children and adults with lupus, indicating that pSLE B cells are predisposed for disease onset and development. Increased chromatin accessibility in non-coding genomic regions controlling activation of inflammation and the immune response suggest that transcriptional dysregulation by regulatory elements that control B cell activation plays an important role in the pathogenesis of pSLE.
Neurophysiological basis of hemodynamic responses in the developing human brain before the time of normal birth
Authors: Poppe Tanya , Willers Moore Jucha , Rupawala Mohammed , Price Anthony N. , Godinez Felipe , Whitehead Kimberley , Dall’Orso Sofia , Edwards A. David , Fabrizi Lorenzo , Arichi Tomoki
Published: September 2022

Neurovascular coupling that links neural activity to localized increases in blood flow is essential both for brain function and to prevent tissue injury. In the healthy human brain, this underlies an association between the duration of EEG microstates, which represent coordinated and metastable activation of neuronal ensembles, and increases in hemodynamic activity. However, in early human life it is not clear whether neurovascular coupling is functional as the underlying physiological mechanisms may be too immature to effectively support it. Here, we combined MRI compatible robotics with simultaneous EEG and fMRI data acquisition in 13 preterm infants to assess whether the relationship between neural activity and hemodynamic responses is present in this critical period of early life. Passive sensorimotor stimulation elicited both a distinct sequence of four EEG microstates and a significant rise in the blood oxygen level dependent (BOLD) fMRI signal in the left primary sensorimotor cortex. Furthermore, EEG microstate duration was significantly related to BOLD response amplitude. These results suggest that effective neurovascular coupling is present in the human brain even before the normal time of birth and reveal a complex relationship between EEG and fMRI signals underpinned by patterns of activity across distinct neural ensembles.
Leaf traits predict water-use efficiency in U.S. Pacific Northwest grasslands under rain exclusion treatment
Authors: Dawson Hilary Rose , Maxwell Toby M. , Reed Paul B. , Bridgham Scott D. , Silva Lucas C. R.
Published: September 2022

Does drought stress in temperate grasslands alter the relationship between plant structure and function? Here we report data from an experiment focusing on growth form and species traits that affect the critical functions of water- and nutrient-use efficiency in prairie and pasture plant communities. A total of 139 individuals of 12 species (11 genera and four families) were sampled in replicated plots maintained for three years across a 520 km latitudinal gradient in the Pacific Northwest, USA. Rain exclusion did not alter the interspecific relationship between foliar traits and stoichiometry or intrinsic water-use efficiency. Rain exclusion reduced intrinsic water-use efficiency in grasses, an effect was primarily species-specific, although leaf morphology, life history strategy, and phylogenetic distance predicted intrinsic water-use efficiency for all twelve species when analyzed together. Variation in specific leaf area explained most of the variation in intrinsic water-use efficiency between different functional groups, with annual forbs and annual grasses at opposite ends of the resource-use spectrum. Our findings are consistent with expected trait-driven tradeoffs between productivity and resource-use efficiency, and provide insight into strategies for the sustainable use and conservation of temperate grasslands.

Plain language summary

Scientists have previously shown that plant leaf form (e.g., shape, width, size) has a predictable relationship to leaf function (e.g., how it can perform biological processes). When we deprive plants of water, does this relationship break down? We grew prairie and pasture plants at three sites in Oregon and Washington, USA, spanning a broad range of climate and water availability. At each site, we built shelters over half our plots to keep out some of the rain, reducing how much water our plants received. Leaf form-function relationships did not change between plots with more or less water. However, each species had a different water use efficiency and nutrient content, and some grasses had an unusual response, that is, they became less efficient at using water under less rain. Overall, we were pretty good at predicting water and nutrient use based on leaf form, whether plants were annual or perennial, and how related they were. Our findings match expectations about leaf structure-function relationships and people who manage temperate grasslands can use our results to decide which plants will work best for using and conserving their systems.

Key points

Foliar structure-function relationships did not change under experimental drought.

Leaf morphology, life history, and phylogenetics predicted resource-use for 12 species.
Selection leads to remarkable variability in the outcomes of hybridization across replicate hybrid zones
Authors: McFarlane S. Eryn , Jahner Joshua P. , Lindtke Dorothea , Buerkle C. Alex , Mandeville Elizabeth G.
Published: September 2022

Hybrid zones have been viewed as an opportunity to see speciation in action. When hybrid zones are replicated, it is assumed that if the same genetic incompatibilities are maintaining reproductive isolation across all instances of secondary contact, those incompatibilities should be identifiable by consistent patterns in the genome. In contrast, changes in allele frequencies due to genetic drift should be idiosyncratic for each hybrid zone. To test this assumption, we simulated 20 replicates of each of 12 hybrid zone scenarios with varied genetic incompatibilities, rates of migration, selection and different starting population size ratios of parental species. We found remarkable variability in the outcomes of hybridization in replicate hybrid zones, particularly with Bateson-Dobzhansky-Muller incompatibilities and strong selection. We found substantial differences among replicates in the overall genomic composition of individuals, including admixture proportions, inter-specific ancestry complement, and number of ancestry junctions. Additionally, we found substantial variation in genomic clines among replicates at focal loci, regardless of locus-specific selection. We conclude that processes other than selection are responsible for some consistent outcomes of hybridization, whereas selection on incompatibilities can lead to genomically widespread and highly variable outcomes. We highlight the challenge of mapping between pattern and process in hybrid zones and call attention to how selection against incompatibilities will commonly lead to variable outcomes. We hope that this study informs future research on replicate hybrid zones and encourages further development of statistical techniques, theoretical models, and exploration of additional axes of variation to understand reproductive isolation.
GPCRome-wide structural analysis of G-protein-coupling selectivity
Authors: Matic Marin , Miglionico Pasquale , Inoue Asuka , Raimondi Francesco
Published: September 2022

We present a comprehensive computational analysis of available 3D GPCR-G-protein complexes to inspect the structural determinants of G-protein-coupling selectivity.

Analysis of the residue contacts at interaction interfaces has revealed a network of secondary structure elements recapitulating known structural hallmarks determining G-protein-coupling specificity, including TM5, TM6 and ICLs. We coded interface contacts into generic-number fingerprints to reveal specific coupling-determinant positions. Clustering of Gs vs Gi complexes is best achieved when considering both GPCR and G-protein contacting residues rather than separated representations of the interaction partners, suggesting that coupling specificity emerges as contextual residue interactions at the interface. Interestingly, Gs-GPCR complexes contain a higher number of contacts than Gi/o-GPCR complexes, likely caused by overall higher conservation and structural constraint on the Gs interface. In contrast, Gi/o proteins adopt a wider number of alternative docking poses on cognate receptors, as assessed via structural alignments of representative 3D complexes.

Furthermore, binding energy calculations demonstrate that distinct structural properties of the complexes contribute to higher stability of Gs than Gi/o complexes. AlphaFold2 predictions of experimental binary complexes confirmed several of these structural features and allowed us to augment the structural coverage of poorly characterized complexes (e.g. G12/13).

We propose that the structural properties of different G-protein complexes, such as structural restraining of Gs compared to Gi/o ones, could be instrumental in fine-tuning their activation and downstream signaling mechanisms.

Highlights

-Comprehensive structural bioinformatics analysis of available GPCR-G-protein complexes captures common as well as group-specific structural features responsible of receptor-G-protein recognition

-Distinct contact patterns explain different docking modes of Gi/o vs Gs complexes, the latter being characterized by higher enrichment of characteristic contacts and lower structural variability suggestive of higher interface conservation.

-Structural hallmarks are associated with different estimated binding energies, which mainly discriminates Gs versus Gi/o couplings, but which also point to class-dependent differences (e.g. Class A vs Class B) in binding the same transducer (Gs)
High-accuracy protein model quality assessment using attention graph neural networks
Authors: Zhang Peidong , Xia Chunqiu , Shen Hong-Bin
Published: September 2022

Great improvement has been brought to protein tertiary structure prediction through deep learning. It is important but very challenging to accurately rank and score decoy structures predicted by different models. CASP14 results show that existing quality assessment (QA) approaches lag behind the development of protein structure prediction methods, where almost all existing QA models degrade in accuracy when the target is a decoy of high quality. How to give an accurate assessment to high-accuracy decoys is particularly useful with the available of accurate structure prediction methods. Here we propose a fast and effective single-model QA method, QATEN, which can evaluate decoys only by their topological characteristics and atomic types. Our model uses graph neural networks and attention mechanisms to evaluate global and amino acid level scores, and uses specific loss functions to constrain the network to focus more on high-precision decoys and high-precision protein domains. On the CASP14 evaluation decoys, QATEN performs better than other QA models under all correlation coefficients when targeting averageLDDT. QATEN shows promising performance when considering only high-accuracy decoys. Compared to the embedded evaluation modules of predictedCα-RMSD(pRMSD) in RosettaFold and predictedLDDT(pLDDT) in AlphaFold2, QATEN is complementary and capable of achieving better evaluation on some decoy structures generated by AlphaFold2 and RosettaFold themselves. These results suggest that the new QATEN approach can be used as a reliable independent assessment algorithm for high-accuracy protein structure decoys.
Gills, growth, and activity across fishes
Authors: Bigman Jennifer S. , Wegner Nicholas C. , Dulvy Nicholas K.
Published: September 2022

Life history theory argues that an organism’s maximum size and its corresponding growth rate have evolved to maximize lifetime reproductive output. The Gill Oxygen Limitation Theory suggests that in aquatic organisms, maximum size is instead constrained by the surface area of the gills, the primary site of gas exchange with the environment. A central prediction of this theory is a tight relationship among maximum size, growth, and gill surface area. Yet since this idea was first tested in the early 1980s, data availability has increased and analytical methods have advanced considerably. Here, we revisit this relationship with new data and a novel phylogenetic Bayesian multilevel modeling framework that allows us to understand how individual variation in gill surface area confers relationships of maximum size, growth, and gills across species. Specifically, we bring gill surface area into an allometric context and examine whether the gill surface area for a given body size (intercept) and the rate at which gill surface changes with size (slope), for a given species, explains growth performance -- an index integrating the life history tradeoff between growth and maximum size -- across fish species. Additionally, we assess whether variation in von Bertalanffy growth coefficients across species can be explained by gill surface area. Finally, we explore whether additional factors – here, activity and evolutionary history -- explain variation in maximum size and growth across species. Overall, we find that although a positive relationship exists among maximum size, growth, and gill surface area across fishes, it is weak. Additionally, gill surface area does not explain much variation in growth coefficients across species, especially for those that reach the same maximum size. However, we find that the activity level of a fish explains more variation in maximum size and growth across species compared to gill surface area. Our results support the idea that in fishes, growth and maximum size are not simply related to gill surface area, and that other covariates—both tractable (e.g., activity, metabolic rate, temperature) and less tractable (e.g., predation risk, resource availability, and variation)—appear to explain more variation in life history traits across species.
Mapping of the Classical Mutation rosette Highlights a Role for Calcium in Wound-induced Rooting
Authors: Modrego Abelardo , Pasternak Taras , Omary Moutasem , Albacete Alfonso , Cano Antonio , Pérez-Pérez José Manuel , Efroni Idan
Published: September 2022

Removal of the root system induces the formation of new roots from the remaining shoot. This process is primarily controlled by the phytohormone auxin which interacts with other signals in a yet unresolved manner. Here, we study the classical tomato mutation rosette (ro) which lacks shoot-borne roots. ro plants were severely inhibited in the formation of wound-induced roots and have reduced rates of auxin transport. We mapped ro to the tomato ortholog of the Arabidopsis thaliana BIG and the mammalians UBR4/p600. RO/BIG is a large protein of unknown biochemical function. In A. thaliana, BIG was implicated in the regulation of auxin transport and calcium homeostasis. We show that exogenous calcium inhibits wound-induced root formation in both tomato and A. thaliana ro/big mutants. Exogenous calcium antagonized the root-promoting effects of the auxin IAA, but not of 2,4-D, an auxin analog that is not recognized by the polar transport machinery, and accumulation of the auxin transporter PIN1 was sensitive to calcium levels in the ro/big mutants. Consistent with a role for calcium in mediating auxin transport, both ro/big mutants and calcium-treated wild-type plants were hypersensitive to treatment with polar auxin transport inhibitors. Subcellular localization of BIG suggests that like its mammalian ortholog, it is associated with the endoplasmic reticulum (ER). Analysis of subcellular morphology revealed that ro/big mutants exhibited disruption in cytoplasmic streaming. We suggest that RO/BIG maintain auxin flow by stabilizing PIN membrane localization, possibly by attenuating the inhibitory effect of Ca2+ on cytoplasmic streaming.
On the Geometry of Elementary Flux Modes
Authors: Wieder Frederik , Henk Martin , Bockmayr Alexander
Published: September 2022

Elementary flux modes (EFMs) play a prominent role in the constraint-based analysis of metabolic networks. They correspond to minimal functional units of the metabolic network at steady-state and as such have been studied for almost 30 years. The set of all EFMs in a metabolic network tends to be very large and may have exponential size in the number of reactions. Hence, there is a need to elucidate the structure of this set. Here we focus on geometric properties of EFMs. We analyze the distribution of EFMs in the face lattice of the steady-state flux cone of the metabolic network and show that EFMs in the relative interior of the cone occur only in very special cases. As a measure of complexity, we introduce the concept of the degree of an EFM, which is the dimension of the inclusionwise minimal face containing it. Geometric analysis can help to better understand the structure of the set of EFMs, which is important from both the mathematical and the biological viewpoint.
RNA cytometry of single-cells using semi-permeable microcapsules
Authors: Leonaviciene Greta , Mazutis Linas
Published: September 2022

Analytical tools for gene expression profiling of individual cells are critical for studying complex biological systems. However, the techniques enabling rapid measurements of gene expression on thousands of single-cells are lacking. Here, we report a high-throughput RNA cytometry for digital profiling of single-cells isolated in liquid droplets enveloped by a thin semi-permeable membrane (microcapsules). Due to selective permeability of the membrane, the desirable enzymes and reagents can be loaded, or replaced, in the microcapsule at any given step by simply changing the reaction buffer in which the microcapsules are dispersed. Therefore, complex molecular biology workflows can be readily adapted to conduct nucleic acid analysis on encapsulated mammalian cells, bacteria, or other biological species. The microcapsules support sequential multi-step enzymatic reactions, and remain intact under different biochemical conditions, freezing, thawing and thermocycling. Combining microcapsules with conventional FACS provides a high-throughput approach for conducting RNA cytometry of individual cells based on their digital gene expression signature.
Mechanical stimuli activate gene expression via a cell envelope stress sensing pathway
Authors: Harper Christine E. , Zhang Wenyao , Shin Jung-Ho , van Wijngaarden Ellen , Chou Emily , Lee Junsung , Wang Zhaohong , Dörr Tobias , Chen Peng , Hernandez Christopher J.
Published: September 2022

In tissues with mechanical function, the regulation of remodeling and repair processes is often controlled by mechanosensitive mechanisms; damage to the tissue structure is detected by changes in mechanical stress and strain, stimulating matrix synthesis and repair. While this mechanoregulatory feedback process is well recognized in animals and plants, it is not known whether such a process occurs in bacteria. InVibrio cholerae, antibiotic-induced damage to the load-bearing cell wall promotes increased signaling by the two-component system VxrAB, which stimulates cell wall synthesis. Here we show that changes in mechanical stress and strain within the cell envelope are sufficient to stimulate VxrAB signaling in the absence of antibiotics. We applied mechanical forces to individual bacteria using three distinct loading modalities: extrusion loading within a microfluidic device, compression, and hydrostatic pressure. In all three cases, VxrAB signaling, as indicated by a fluorescent protein reporter, was increased in cells submitted to greater magnitudes of mechanical loading, hence diverse forms of mechanical stimuli activate VxrAB signaling. Mechanosensitivity of VxrAB signaling was lost following removal of the VxrAB stimulating endopeptidase ShyA, suggesting that VxrAB may not be directly sensing mechanical forces, but instead relies on other factors including lytic enzymes in the periplasmic space. Our findings suggest that mechanical signals play an important role in regulating cell wall homeostasis in bacteria.

Significance Statement

Biological materials with mechanical function (bones, muscle, etc.) are often maintained through mechanosensitive mechanisms, in which damage-induced reductions in stiffness stimulate remodeling and repair processes that restore mechanical function. Here we show that a similar process can occur in bacteria. We find that mechanical stresses in the bacterial cell envelope (the primary load-bearing structure in bacteria) regulate signaling of a two-component system involved in cell wall synthesis. These findings suggest that the mechanical stress state within the cell envelope can contribute to cell wall homeostasis. Furthermore, these findings demonstrate the potential to use mechanical stimuli to regulate gene expression in bacteria.
Nicotinamide-N-methyltransferase is essential for SAM and 1-methylnicotinamide homeostasis in the AML12 hepatocyte cell line
Authors: Yoda Mayuko , Mizuno Rin , Izumi Yoshihiro , Takahashi Masatomo , Bamba Takeshi , Kawaoka Shinpei
Published: September 2022

Nicotinamide-N-methyltransferase (NNMT) is an enzyme that consumes S-adenosyl-methionine (SAM) and nicotinamide (NAM) to produce S-adenosyl-homocysteine (SAH) and 1-methylnicotinamide (MNAM). How much NNMT contributes to the quantity regulation of these four metabolites depends on whether NNMT is a major consumer or producer of these metabolites, which varies among various cellular contexts. Yet, whether NNMT critically regulates these metabolites in the AML12 hepatocyte cell line has been unexplored. To address this, we knock down Nnmt in AML12 cells and investigate the effects of Nnmt RNAi on metabolism and gene expression. We find that Nnmt RNAi accumulates SAM and SAH, whereas it reduces MNAM with NAM being unaltered. These results indicate that NNMT is a significant consumer of SAM and critical for MNAM production in this cell line. Moreover, transcriptome analyses reveal that altered SAM and MNAM homeostasis is accompanied by various detrimental molecular phenotypes, as exemplified by the down-regulations of lipogenic genes such as Srebf1. Consistent with this, oil-red O-staining experiments demonstrate the decrease of total lipids upon Nnmt RNAi. These results suggest that NNMT maintains proper SAM and MNAM homeostasis, providing an additional example where NNMT plays a critical role in regulating SAM and MNAM metabolism.
Physiological state matching in a pair bonded poison frog
Authors: Nowicki Jessica P. , Rodríguez Camilo , Lee Julia C. , Goolsby Billie C. , Yang Chen , Cleland Thomas A. , O’Connell Lauren A.
Published: September 2022

More than a century ago, Charles Darwin hypothesized that the empathy-like phenotype is a phylogenetically widespread phenomenon. This idea remains contentious, due to the challenges of empirically examining emotions, and few investigations among non-mammalian vertebrates. We provide support for Darwin’s hypothesis by discovering partial evidence for the most ancestral form of empathy, emotional contagion (i.e., matching another individual’s emotional state), in the pair bonding mimetic poison frog,Ranitomeya imitator. We found that male corticosterone, a physiological biomarker of stress, positively correlates with female partners in experimental and semi-natural conditions. This does not appear to coincide with behavioral state-matching. However, it is specific to female partners relative to familiar female non-partners, and is independent of effects that commonly confound studies on emotional contagion. Furthermore, this physiological state-matching is irrespective of partnership longevity or lifetime reproductive output. These results physiologically indicate socially selective emotional contagion in a monogamous amphibian, and paradigms that elicit coinciding neural and behavioral indicators and morphogenic co-variation are needed for further corroboration. Further studies on ancestral forms of empathy in non-mammalian vertebrates are warranted.
Dysregulation of Acid Ceramidase-mediated Sphingolipid Metabolism Contributes to Tumor Progression in Tuberous Sclerosis Complex
Authors: Astrinidis Aristotelis , Li Chenggang , Zhang Erik Y. , Zhao Xueheng , Zhao Shuyang , Guo Minzhe , Huang Rong , Zhang Alan G. , Kopras Elizabeth , Gupta Nishant , Smith Eric , Fugate Elizabeth , Lindquist Diana , Wikenheiser-Brokamp Kathryn , Setchell Kenneth D. , McCormack Francis x. , Xu Yan , Yu Jane J.
Published: September 2022

Tuberous Sclerosis Complex (TSC) is disorder of multi-system benign neoplasia in the brain, heart, kidneys and lungs. Lymphangioleiomyomatosis (LAM) is a progressive pulmonary disease affecting exclusively women. Both are caused by mutations inTSC1andTSC2, resulting in mTORC1 hyperactivation. Single cell RNA sequencing of LAM lungs identified activation of genes in the sphingolipid pathway. Independent validation studies showed that acid ceramidase (ASAH1) and dihydroceramide desaturase (DEGS1), key enzyme for regulating sphingolipid and ceramide metabolism, were significantly increased in TSC2-null cells, and their expression and activity were rapamycin-insensitive. TSC2 negatively regulated the biosynthesis of tumorigenic sphingolipids. Suppression of ASAH1 by shRNA or the inhibitor ARN14976 (17a) markedly decreased the viability of TSC2-null cells.In vivo, 17a significantly decreased the growth of Tsc2-null cell derived mouse xenografts. When combined with rapamycin, 17a more strongly inhibited the progression of renal cystadenomas inTsc2+/-mice than either agent alone, evaluated by pathology and MRI. Collectively, our studies identify a rapamycin-insensitive disorder of sphingolipid metabolism in TSC2-null cells and tumors and validate the novel hypothesis that TSC2 regulates sphingolipid production and action via ASAH1. Targeting aberrant sphingolipid metabolism pathways may have therapeutic value in TSC and LAM, and possibly in mTORC1-hyperactive neoplasms.
Cuticular wax, but not the cutin matrix, is renewed during the lifespan of Clusia rosea leaves 13CO2 labelling and gas exchange study
Authors: Kubásek Jiří , Kalistová Tereza , Janová Jitka , Askanbayeva Balzhan , Bednář Jan , Šantrůček Jiří
Published: September 2022

The plant cuticle, which aided the water-to-land transition of plants, provides various services to the plant surface, and its synthesis and maintenance represent substantial metabolic costs. Nevertheless, only limited information regarding cuticle dynamics is available.

We determined the composition and dynamics of Clusia rosea cuticular waxes and matrix using 13CO2 labelling, compound-specific and bulk isotope ratio mass spectrometry. Collodion was used for wax collection; gas exchange techniques were employed to test for any collodion effects on living leaves.

Cutin matrix (MX) area density did not vary between young and mature leaves and between leaf sides. Only young leaves incorporated new carbon into their MX. Collodion-based sampling discriminated between epicuticular (EW) and intracuticular wax (IW) effectively. EW differed in composition from IW. The newly synthetized wax was deposited in IW first and later in EW. Both young and mature leaves synthetized IW and EW; the faster dynamics in young leaves was not due to a faster synthesis rate but was the result of lower wax coverage. Longer-chain alkanes were deposited preferentially on the abaxial, stomatous leaf side, producing differences between leaf sides in wax composition.

We introduce a new, sensitive isotope labelling method and demonstrate that cuticular wax is renewed during leaf ontogeny of Clusia rosea. We discuss the ecophysiological significance of the new insights.
Accurate lattice parameters from 3D electron diffraction data. I. Optical distortions
Authors: Brázda Petr , Klementová Mariana , Krysiak Yaşar , Palatinus Lukáš
Published: September 2022

Determination of lattice parameters from 3D electron diffraction (3D ED) data measured in a transmission electron microscope is hampered by a number of effects that seriously limit the achievable accuracy. The distortion of the diffraction patterns by the optical elements of the microscope is often the most severe problem. A thorough analysis of a number of experimental datasets shows that, in addition to the well known distortions, namely barrel-pincushion, spiral and elliptical, an additional distortion, dubbed parabolic, may be observed in the data. In precession electron diffraction data, the parabolic distortion leads to excitation-error-dependent shift and splitting of reflections. All distortions except for the elliptical distortion can be determined together with lattice parameters from a single 3D ED data set. However, the parameters of the elliptical distortion cannot be determined uniquely due to correlations with the lattice parameters. They can be determined and corrected either by making use of the known Laue class of the crystal or by combining data from two or more crystals. The 3D ED data can yield lattice parameter ratios with an accuracy of about 0.1% and angles with an accuracy better than 0.03°.
The structure of succinyl-CoA synthetase bound to the succinyl-phosphate intermediate clarifies the catalytic mechanism of ATP-citrate lyase
Authors: Huang Ji , Fraser Marie E.
Published: September 2022

Succinyl-CoA synthetase (SCS) catalyzes a three-step reaction in the citric acid cycle with succinyl-phosphate proposed as a catalytic intermediate. However, there are no structural data to show the binding of succinyl-phosphate to SCS. Recently, the catalytic mechanism underlying acetyl-CoA production by ATP-citrate lyase (ACLY) has been debated. The enzyme belongs to the family of acyl-CoA synthetases (nucleoside diphosphate-forming) for which SCS is the prototype. It was postulated that the amino-terminal portion catalyzes the full reaction and the carboxy-terminal portion plays only an allosteric role. This interpretation was based on the partial loss of the catalytic activity of ACLY when Glu599 was mutated to Gln or Ala, and on the interpretation that the phospho-citryl-CoA intermediate was trapped in the 2.85 Å resolution structure from cryogenic electron microscopy (cryo-EM). To better resolve the structure of the intermediate bound to the E599Q mutant, the equivalent mutation, E105αQ, was made in human GTP-specific SCS. The structure of the E105αQ mutant shows succinyl-phosphate bound to the enzyme at 1.58 Å resolution when the mutant, after phosphorylation in solution by Mg2+-ATP, was crystallized in the presence of magnesium ions, succinate and desulfo-CoA. The E105αQ mutant is still active but has a specific activity that is 120-fold less than that of the wild-type enzyme, with apparent Michaelis constants for succinate and CoA that are 50-fold and 11-fold higher, respectively. Based on this high-resolution structure, the cryo-EM maps of the E599Q ACLY complex reported previously should have revealed the binding of citryl-phosphate and CoA and not phospho-citryl-CoA.
Structure of the Monkeypox virus profilin-like protein A42R reveals potential functional differences from cellular profilins
Authors: Minasov George , Inniss Nicole L. , Shuvalova Ludmilla , Anderson Wayne F. , Satchell Karla J. F.
Published: September 2022

The infectious disease human monkeypox is spreading rapidly in 2022, causing a global health crisis. The genomics of Monkeypox virus (MPXV) have been extensively analyzed and reported, although little is known about the virus-encoded proteome. In particular, there are no reported experimental MPXV protein structures other than computational models. Here, a 1.52 Å resolution X-ray structure of the MPXV protein A42R, the first MPXV-encoded protein with a known structure, is reported. A42R shows structural similarity to profilins, which are cellular proteins that are known to function in the regulation of actin cytoskeletal assembly. However, structural comparison of A42R with known members of the profilin family reveals critical differences that support prior biochemical findings that A42R only weakly binds actin and does not bind poly(L-proline). In addition, the analysis suggests that A42R may make distinct interactions with phosphatidylinositol lipids. Overall, the data suggest that the role of A42R in the replication of orthopoxviruses may not be readily determined by comparison to cellular profilins. Furthermore, these findings support the need for increased efforts to determine high-resolution structures of other MPXV proteins to inform physiological studies of the poxvirus infection cycle and to reveal potential new strategies to combat human monkeypox should this emerging infectious disease with pandemic potential become more common in the future.
Factors and obstacles determining the investments in continuing education and training of managers: the case of Bulgarian enterprises
Authors: Neycheva Mariya , Baltov Milen
Published: September 2022

Purpose

This study aims to examine internal and external factors as well as main obstacles to managers’/owners’ participation in education and training.

Design/methodology/approach

The sample comprises managers of 151 Bulgarian predominantly micro- and small-size enterprises. The data was gathered in 2020 through direct standardized interviews at the respondent’s workplace. This study uses quantitative estimation methods including binominal and multinominal logistic regression as well as nonparametric testing.

Findings

Regarding the findings in the relevant studies, the results confirm that the larger firm's size, the existence of human resource management strategy and practices as well as learning-oriented culture stimulate employer-financed management training. The lack of trainers with relevant need-specific expertise appears to be a major barrier. Additionally, the outputs highlight the role of other important determinants not being extensively discussed so far such as the level of development of the region in which the company operates, involvement in R&D and innovation activity as well as the issue of trust in trainer.

Practical implications

This study provides insights into (under)investments in continuing vocational training which might lead to practical implications for businesses, education and government policy in lifelong learning. Moreover, this study focuses on a country with one of the lowest participation rates in adult education across Europe which allows for a better understanding of similar examples.

Originality/value

To the best of the author’s knowledge, this is the first paper examining determinants of management training in Bulgaria and one of the few in the European context. It gives support to the existing literature but adds new findings as well.
Financial capability and informal bankruptcy: comparing student loan holders and non-holders
Authors: Yao Rui , Xiao Jing Jian
Published: September 2022

Purpose

The purpose of this study is to examine the association between financial capability and informal bankruptcy, especially among families in which the respondent and/or spouse borrowed student loans to fund their own education and families that did not have such loans.

Design/methodology/approach

US nationally representative data were employed. Three family types were used, families with student loans borrowed to fund respondent and/or spouse's education and education was completed (type 1 holders) or not completed (type 2 holders), and families that did not borrow student loans for respondent and/or spouse's education (non-holders). Informal bankruptcy was measured by being insolvent and late in debt payment for 60 or more days. Financial capability was measured by both an index and its various components. Multivariate logistic regressions were conducted to examine associations between financial capability and informal bankruptcy.

Findings

Generally, financial capability was negatively associated with informal bankruptcy, and student loan holders were more likely to be informally bankrupt than non-holders. However, such negative associations were statistically significant for type 1 holders and non-holders but insignificant for type 2 holders. Two desirable financial behaviors (information search and online banking) reduced the chance of informal bankruptcy for type 2 holders.

Research limitations/implications

First, cross-sectional data cannot establish a causal relationship. Second, findings using data from a single country may not be generalized to other countries.

Practical implications

Financial service professionals should help loan applicants evaluate the necessity of borrowing. Banking professionals can use the findings to develop products to meet different consumer needs. Financial educators should target different groups with different strategies in financial capability education. Policymakers should develop policies helping student loan holders complete education funded by student loans.

Originality/value

This study examines factors related to informal bankruptcy, providing insights to warning signs of bankruptcy. This study explores the potential effect of a new factor, financial capability, on informal bankruptcy, filling in a gap in the bankruptcy literature. This study recognizes differences in informal bankruptcy among various types of families and examines the different effects of financial capabilities on informal bankruptcy for different types of families.
Gender, STEM women and entrepreneurship: a review and future research directions
Authors: Treanor Lorna
Published: September 2022

Purpose

This invited paper aims to explore current knowledge and recent trends within published management research to illustrate the development and contribution of research on this topic and to outline promising future research directions.

Design/methodology/approach

A systematic literature review of 34 articles between January 2018 and August 2022 has been undertaken, which reflects the increased scholarly attention, in recent years, upon the topic of women entrepreneurs in the fields of science, technology, engineering and mathematics (STEM).

Findings

This review highlights that this topic remains under-explored and that recent research tends to explore STEM women's entrepreneurial activity in different country contexts. The opportunity exists to advance theoretical understandings of how gender is operationalised within gendered contexts and places.

Originality/value

This paper reviews research to date and offers suggested avenues for further research.
Ensuring resilience through fiscal responses to COVID-19; an empirical study of Mauritian micro small medium enterprises (MSMEs)
Authors: Beebeejaun Ambareen
Published: September 2022

Purpose

The official authorities have established several action plans including fiscal support measures to help micro, small and medium enterprises (MSMEs) counter the negative repercussions of COVID-19. In this regard, the purpose of this research is to critically assess the recent fiscal policies endeavoured by the Mauritian authorities in response to COVID-19, to assess the awareness and perception of some local MSMEs of these initiatives, to investigate the extent to which these MSMEs have benefited from them and also, to suggest recommendations to the Mauritian authorities on how to enhance the existing framework to ensure sustainable and equitable development.

Design/methodology/approach

This study has adopted both the quantitative and qualitative research methods. Primary data were obtained by conducting a survey of some Mauritian MSMEs, and secondary data were obtained by referring to laws and policy papers on the research topic. Some statistical tests were performed using SPSS software on the primary data to illustrate the research findings.

Findings

Despite the laudable initiatives, the survey conducted for this research demonstrates that MSMEs in Mauritius have a moderate awareness of these fiscal support measures. Furthermore, upon being asked whether they have availed of these tax incentives, again a moderate mean average was derived which implies that not all MSMEs have fully benefited from fiscal support to help them in countering the negative effects of COVID-19.

Originality/value

At present, this study will be amongst the first academic writings on the effectiveness of the fiscal measures undertaken by the Mauritian authorities to deal with issues entailed by the COVID-19. The study is carried out with the aim of combining a large amount of empirical, theoretical, and factual information that can be of use to various stakeholders and not only to academics.