bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulatory cross-talk supports resistance to Zn intoxication in Streptococcus
Authors: Sullivan Matthew J. , Goh Kelvin G. K. , Ulett Glen C.
Published: July 2021

Metals such as copper (Cu) and zinc (Zn) are important trace elements that can effect bacterial cell physiology but can also intoxicate bacteria at high concentrations. Discrete genetic systems for management of Cu and Zn efflux have been described in several bacteria pathogens, including streptococci. However, insight into molecular cross-talk between systems for Cu and Zn management in bacteria that drive metal detoxification, is limited. Here, we describe a biologically consequential cross-system effect of metal management in group B Streptococcus (GBS) governed by the Cu-responsive copY regulator in response to Zn. RNAseq analysis of wild-type (WT) and copY-deficient GBS exposed to metal stress revealed unique transcriptional links between the systems for Cu and Zn detoxification. We show that the Cu-sensing functions of CopY extend beyond Cu, and enable CopY to regulate Cu and Zn stress responses to effect genes involved in central cellular processes, including riboflavin synthesis. CopY also contributed to supporting GBS virulence in vivo following infection of mice. Identification of the Zn resistome of GBS using TraDIS revealed a suite of genes essential for GBS growth in metal stress. Several of the genes identified are novel to systems that support bacterial survival in metal stress, and represent a diversity of mechanisms of microbial metal homeostasis during cell stress. Overall, this study reveals a new and important mechanism of cross-system complexity driven by CopY in bacteria to regulate cell management of metal stress and survival.

Author Summary

Metals, such as Cu and Zn, can be used by the mammalian immune system to target bacterial pathogens, and consequently, bacteria have evolved discrete genetic systems that subvert this host-derived antimicrobial response. Systems for Cu and Zn homeostasis are well characterized, including the transcriptional control of sensing and responding to metal stress. Here we have discovered novel features of metal response sytems in Streptococcus that have major implications for pathogenesis and virulence. We show that Streptococcus resists Zn intoxication by utilizing a bona fide Cu regulator, CopY, to maintain cellular metal homeostasis, which enables the bacteria to survive stressful conditions. We identify new genes in Streptococcus that confer resistance to zinc intoxication, including several that have not previously been linked to metal ion homeostasis in any bacterium. The identification of cross-system metal management and new resistance mechanisms enhances our understanding of metal ion homeostasis in bacteria and its effect on pathogenesis.
CIGB-300 synthetic peptide, an antagonist of CK2 kinase activity, as a treatment for Covid-19. A computational biology approach
Authors: Miranda Jamilet , Bringas Ricardo , Fernández-de-Cossio Jorge , Perera Yasser
Published: July 2021

Drug repositioning became the first choice for treating Covid-19 patients due to the urgent need to deal with the pandemic. Similarities in the hijacking mechanisms used by SARS-CoV-2 and several type of cancer, suggest the repurposing of cancer drugs to treat Covid-19. CK2 kinase antagonists have been proposed for the treatment of cancer. A recent study in cells infected with SARS-CoV-2 virus found a significant CK2 kinase activity, and the use of a CK2 inhibitor showed antiviral responses. CIGB-300, originally designed as an anticancer peptide, is an antagonist of CK2 kinase activity that binds to CK2 phospho-acceptor sites. Recent preliminary results show an antiviral activity of CIGB-300 versus a surrogate model of coronavirus. Here we present a computational biology study that provides evidences at the molecular level of how CIGB-300 might interfere with SARS-CoV-2 life cycle inside infected human cells. First, from SARS-CoV studies, we infer the potential incidence of CIGB-300 in SARS-CoV-2 interference on immune response. Next, from the analysis of multiple Omics data, we propose the action of CIGB-300 since early stage of viral infections perturbing the virus hijacking of RNA splicing machinery. It was also predicted the interference of CIGB-300 in virus-host interactions responsible for the high infectivity and the particular immune response to SARS-CoV-2 infection. Further, we provide evidences of CIGB-300 attenuation of phenotypes related to muscle, bleeding, coagulation and respiratory disorders.
Synaptic Mechanisms of Top-Down Control in the Non-Lemniscal Inferior Colliculus
Authors: Oberle Hannah M. , Ford Alexander N. , Dileepkumar Deepak , Czarny Jordyn , Apostolides Pierre F.
Published: July 2021

Corticofugal projections to evolutionarily ancient, sub-cortical structures are ubiquitous across mammalian sensory systems. These “descending” pathways enable the neocortex to control ascending sensory representations in a predictive or feedback manner, but the underlying cellular mechanisms are poorly understood. Here we combine optogenetic approaches with in vivo and in vitro patch-clamp electrophysiology to study the projection from auditory cortex to the inferior colliculus (IC), a major descending auditory pathway that controls IC neuron feature selectivity, plasticity and auditory perceptual learning. Although individual auditory cortico-collicular synapses were generally weak, IC neurons often integrated inputs from multiple corticofugal axons that generated reliable, tonic depolarizations even during prolonged presynaptic activity. Latency measurements in vivo showed that descending signals reach the IC within 30 ms of sound onset, which in IC neurons corresponded to the peak of synaptic depolarizations evoked by short sounds. Activating ascending and descending pathways at latencies expected in vivo caused a NMDA receptor dependent, supra-linear EPSP summation, indicating that descending signals can non-linearly amplify IC neurons’ moment-to-moment acoustic responses. Our results shed light upon the synaptic bases of descending sensory control, and imply that heterosynaptic cooperativity contributes to the auditory cortico-collicular pathway’s role in plasticity and perceptual learning.
The Role of Biofilms, Bacterial Phenotypes, and Innate Immune Response in Mycobacterium avium Colonization to Infection
Authors: Weathered Catherine , Pennington Kelly , Escalante Patricio , Pienaar Elsje
Published: July 2021

Mycobacterium avium complex (MAC), is known for colonizing and infecting humans following inhalation of the bacteria. MAC pulmonary disease is notoriously difficult to treat and prone to recurrence. Both the incidence and prevalence MAC pulmonary disease have been increasing globally.

MAC is well known to form biofilms in the environment, and in vitro, these biofilms have been shown to aid MAC in epithelial cell invasion, protect MAC from phagocytosis, and cause premature apoptosis in macrophages. In vivo, the system of interactions between MAC, biofilms and host macrophages is complex, difficult to replicate in vitro and in animal models, has not been fully characterized. Here we present a three-dimensional agent-based model of a lung airway to help understand how these interactions evolve in the first 14 days post-bacterial inhalation. We parameterized the model using published data and performed uncertainty analysis to characterize outcomes and parameters’ effects on those outcomes.

Model results show diverse outcomes, including wide ranges of macrophage recruitment levels, and bacterial loads and phenotype distribution. Though most bacteria are phagocytosed by macrophages and remain intracellular, there are also many simulations in which extracellular bacteria continue to drive the colonization and infection. Initial parameters dictating host immune levels, bacterial loads introduced to the airway, and biofilm conditions have significant and lasting impacts on the course of these results. Additionally, though macrophage recruitment is key for suppressing bacterial loads, there is evidence of significant excess recruitment that fail to impact bacterial numbers. These results highlight a need and identify a path for further exploration into the inhalation events in MAC infection. Early infection dynamics could have lasting impacts on the development of nodular bronchiectatic or fibrocavitary disease as well as inform possible preventative and treatment intervention targeting biofilm-macrophage interactions.
Evaluating the feasibility and efficacy of a dual-modality nanoparticle contrast agent (Nanotrast-CF800) for image-guided sentinel lymph node mapping in the oral cavity of healthy dogs
Authors: Wan Jennifer , Oblak Michelle L. , Ram Ann S. , McKenna Charly , Singh Ameet , Nykamp Stephanie
Published: July 2021

A combination of pre- and intraoperative sentinel lymph node (SLN) mapping techniques has been suggested to optimize SLN detection. A novel liposomal nanoparticle, Nanotrast-CF800 (CF800), utilizes computed tomography lymphography (CTL) and near infrared fluorescence imaging (NIRF) for image-guided surgery and SLN mapping. This novel tracer agent has not been evaluated in companion animals. The objective of this study was to evaluate the feasibility and efficacy of CF800 for SLN mapping in the oral cavity of healthy dogs and to report any local adverse effects. Six healthy adult purpose-bred research dogs randomly received either 1 mL (group 1) or 2 mL (group 2) of CF800 injected into the submucosa at the level of the right canine maxillary tooth. CTL and percutaneous NIRF were performed at 1, 3, and 10 minutes, then 1, 2, 4, 7, and 10 days post-injection (p.i). Overall, both CTL and NIRF identified SLNs in all dogs. The overall peak mean contrast enhancement of the SLNs was 73.98 HU (range 63.45-86.27 HU) at 2 days p.i. Peak fluorescence of the SLN occurred at 1 day p.i. The agent was retained within the SLN for at least 7 days for CTL and 4 days for NIRF. No adverse effects were observed. Local administration of CF800 was simple and feasible for the detection of SLNs using CTL+NIRF in the head and neck of healthy dogs and was not associated with significant local adverse events.
Unraveling three-dimensional chromatin structural dynamics during spermatogonial differentiation
Authors: Zheng Yi , Zhang Lingkai , Jin Long , Zhang Pengfei , Li Fuyuan , Guo Ming , Gao Qiang , Zeng Yao , Li Mingzhou , Zeng Wenxian
Published: July 2021

Spermatogonial stem cells (SSCs) are able to undergo self-renewal and differentiation. Unlike the self-renewal that replenishes the SSC and progenitor pool, the differentiation is an irreversible process committed to meiosis. While the preparations for meiotic events in differentiating spermatogonia (Di-SG) are likely to be accompanied by alterations in chromatin structure, the three-dimensional (3D) chromatin architectural difference between SSCs and Di-SG, and the higher-order chromatin dynamics during spermatogonial differentiation, have not been systematically investigated. Here, we performed in situ high-throughput chromosome conformation capture (Hi-C), RNA-sequencing (RNA-seq) and chromatin immunoprecipitation-sequencing (ChIP-seq) analyses on porcine undifferentiated spermatogonia (Un-SG, which consist of SSCs and progenitors) and Di-SG. By integrating and analyzing these data, we identified that Di-SG exhibited increased disorder but weakened compartmentalization and topologically associating domains (TADs) in comparison with Un-SG, suggesting that diminished higher-order chromatin architecture in meiotic cells, as shown by recent reports, is preprogramed in Di-SG. Our data also revealed that A/B compartments and TADs were related to dynamic gene expression during spermatogonial differentiation. We further unraveled the contribution of promoter-enhancer interactions (PEIs) to pre-meiotic transcriptional regulation, which has not been accomplished in previous studies due to limited cell input and resolution. Together, our study uncovered the 3D chromatin structure of SSCs/progenitors and Di-SG, as well as the interplay between higher-order chromatin architecture and dynamic gene expression during spermatogonial differentiation, providing novel insights into the mechanisms for SSC self-renewal and differentiation and having implications for diagnosis and treatment of male sub-/infertility.
Selfish bacteria are active throughout the water column of the ocean
Authors: Giljan Greta , Brown Sarah , Lloyd C. Chad , Ghobrial Sherif , Amann Rudolf , Arnosti Carol
Published: July 2021

Heterotrophic bacteria use extracellular enzymes to hydrolyze high molecular weight (HMW) organic matter to low molecular weight (LMW) hydrolysis products that can be taken into the cell. These enzymes represent a considerable investment of carbon, nitrogen, and energy, yet the return on this investment is uncertain, since hydrolysis of a HMW substrate outside a cell yields LMW products that can be lost to diffusion and taken up by scavengers that do not produce extracellular enzymes1. However, an additional strategy of HMW organic matter utilization, ‘selfish’ uptake2, is used for polysaccharide degradation, and has recently been found to be widespread among bacterial communities in surface ocean waters3. During selfish uptake, polysaccharides are bound at the cell surface, initially hydrolyzed, and transported into the periplasmic space without loss of hydrolysis products2, thereby retaining hydrolysate for the selfish bacteria and reducing availability of LMW substrates to scavenging bacteria. Here we show that selfish bacteria are common not only in the sunlit upper ocean, where polysaccharides are freshly produced by phytoplankton, but also deeper in the oceanic water column, including in bottom waters at depths of more than 5,500 meters. Thus, the return on investment, and therefore also the supply of suitable polysaccharides, must be sufficient to maintain these organisms.
A manifold neural population code for space in hippocampal coactivity dynamics independent of place fields
Authors: Levy Eliott R.J. , Carrillo-Segura Simón , Park Eun Hye , Redman William T. , Hurtado José R. , Chung SueYeon , Fenton André A.
Published: July 2021

Hippocampus is comprised of ∼20% place cells, discharging in cell-specific locations (“place fields”), standardly interpreted as a dedicated neuronal code for space. However, place cell discharge is temporally unreliable across seconds and days, and place fields are multimodal, suggesting an alternative “ensemble cofiring” spatial code with manifold dynamics that does not require reliable spatial tuning. We evaluated these hypotheses using GCaMP6f and miniature microscopes to image mouse CA1 ensemble activity in two environments, across 3 weeks. Both place fields and ensemble coactivity relationships appear to “remap,” being distinct between, and (weakly) similar within environments. Decoding location as well as environment from 1-s ensemble location-specific discharge is effective and improves with experience. Decoding the environment (but not location) from cell-pair coactivity relationships is also effective and improves with experience, even after removing place tuning. Discriminating environments from 1-s ensemble coactivity relies crucially on the cells with the most anti-cofiring cell-pair relationships because ensemble activity is internally-organized on a low-dimensional manifold of non-linear cofiring relationships that intermittently reregisters to environments according to the anti-cofiring subpopulation activity.
Airborne environmental DNA metabarcoding for the monitoring of terrestrial insects - a proof of concept
Authors: Roger Fabian , Ghanavi Hamid , Danielsson Natalie , Wahlberg Niklas , Löndahl Jakob , Pettersson Lars B. , Andersson Georg K.S. , Olén Niklas Boke , Clough Yann
Published: July 2021

Biodiversity is in decline due to human land use, exploitation, and climate change. To be able to counteract this alarming trend it is paramount to closely monitor biodiversity at global scales. Because this is practically impossible with traditional methods, the last decade has seen a strong push for solutions. In aquatic ecosystems the monitoring of species from environmental DNA (eDNA) has emerged as one of the most powerful tools at our disposal but in terrestrial ecosystems the power of eDNA for monitoring has so far been hampered by the local scale of the samples. In this study we report the first attempt to detect insects from airborne eDNA. We compare our results to two traditional insect monitoring projects (1) using light trapping for moth monitoring and (2) transect counts for the monitoring of butterflies and wild bees. While we failed to detect many of the same species monitored with the traditional methods, airborne eDNA metabarcoding revealed DNA from from six classes of Arthropods, and twelve order of Insects - including representatives from all of the four largest orders: Diptera (flies), Lepidoptera (butterflies and moths), Coleoptera (beetles) and Hymenoptera (bees, wasps and ants). We also recovered DNA from nine species of vertebrates, including frogs, birds and mammals as well as from 12 other phyla. We suggest that airborne eDNA has the potential to become a powerful tool for terrestrial biodiversity monitoring, with many impactful applications including the monitoring of pests, invasive or endangered species or disease vectors.
Transcriptomic Analysis of Human Skin Wound Healing and Rejuvenation Following Ablative Fractional Laser Treatment
Authors: Sherrill Joseph D. , Finlay Deborah , Binder Robert L. , Robinson Michael K. , Wei Xingtao , Tiesman Jay P. , Flagler Michael J. , Loftus Jean M. , Kimball Alexa B. , Bascom Charles C. , Isfort Robert J.
Published: July 2021

Ablative fractional laser treatment is considered the gold standard for skin rejuvenation. In order to understand how fractional laser works to rejuvenate skin, we performed microarray profiling on skin biopsies to identify temporal and dose-response changes in gene expression following fractional laser treatment. The backs of 14 women were treated with ablative fractional laser (Fraxel®) and 4 mm punch biopsies were collected from an untreated site and at the treated sites 1, 3, 7, 14, 21 and 28 days after the single treatment. In addition, in order to understand the effect that multiple fractional laser treatments have on skin rejuvenation, several sites were treated sequentially with either 1, 2, 3, or 4 treatments (with 28 days between treatments) followed by the collection of 4 mm punch biopsies. RNA was extracted from the biopsies, analyzed using Affymetrix U219 chips and gene expression was compared between untreated and treated sites. We observed dramatic changes in gene expression as early as 1 day after fractional laser treatment with changes remaining elevated even after 1 month. Analysis of individual genes demonstrated significant and time related changes in inflammatory, epidermal, and dermal genes, with dermal genes linked to extracellular matrix formation changing at later time points following fractional laser treatment. When comparing the age-related changes in skin gene expression to those induced by fractional laser, it was observed that fractional laser treatment reverses many of the changes in the aging gene expression. Finally, multiple fractional laser treatments resulted in continued changes in gene expression, with many genes either differentially regulated or continuously upregulated with increasing number of treatments, indicating that maximal skin rejuvenation requires multiple fractional laser treatments. In conclusion, fractional laser treatment of skin activates several biological processes involved in wound healing and tissue regeneration, all of which significantly contribute to the rejuvenating effect of fractional laser treatment on aged skin.
Ultrastructural and functional analysis of extra-axonemal structures in trichomonads
Authors: Coceres Veronica M. , Iriarte Lucrecia S. , Miranda-Magalhães Abigail , de Andrade Thiago André Santos , de Miguel Natalia , Pereira-Neves Antonio
Published: July 2021

Trichomonas vaginalis and Tritrichomonas foetus are extracellular flagellated parasites that inhabit humans and other mammals, respectively. In addition to motility, flagella act in a variety of biological processes in different cell types; and extra-axonemal structures (EASs) has been described as fibrillar structures that provide mechanical support and act as metabolic, homeostatic and sensory platforms in many organisms. Here, we identified the presence of EASs forming prominent flagellar swellings in T. vaginalis and T. foetus and we observed that their formation was associated with the parasites adhesion on the host cells, fibronectin, and precationized surfaces; and parasite:parasite interaction. A high number of rosettes, clusters of intramembrane particles that has been proposed as sensorial structures, and microvesicles protruding from the membrane were observed in the EASs. The protein VPS32, a member of the ESCRT-III complex crucial for diverse membrane remodeling events, the pinching off and release of microvesicles, was found in the surface as well as in microvesicles protruding from EASs. Moreover, we demonstrated that overexpression of VPS32 protein induce EAS formation and increase parasite motility in semi-solid medium. These results provide valuable data about the role of the flagellar EASs in the cell-to-cell communication and pathogenesis of these extracellular parasites.
Recording and Manipulation of the Maternal Oxytocin Neural Activities in Mice
Authors: Yukinaga Hiroko , Hagihara Mitsue , Tsujimoto Kazuko , Chiang Hsiao-Ling , Kato Shigeki , Kobayashi Kazuto , Miyamichi Kazunari
Published: July 2021

Pulsatile release of the hormone oxytocin (OT) mediates uterine contraction during parturition and milk ejection during lactation1–3. These pulses are generated by unique activity patterns of the central neuroendocrine OT neurons located in the paraventricular and supraoptic hypothalamus. Classical studies have characterized putative OT neurons by in vivo extracellular recording techniques in rats and rabbits under anesthesia1, 4–7 or awake8–10. Due to technical limitations, however, the identity of OT neurons in these previous studies was speculative based on their electrophysiological characteristics and axonal projection to the posterior pituitary, not on OT gene expression. To pinpoint OT neural activities among other hypothalamic neurons that project to the pituitary11, 12 and make better use of cell-type-specific neuroscience toolkits13, a mouse model needs to be developed for studies of parturition and lactation. We herein introduce viral genetic approaches in mice to characterize the maternal activities of OT neurons by fiber photometry. During lactation, a sharp photometric peak of OT neurons appeared at approximately 520 s following simultaneous suckling stimuli from three pups. The amplitude of the peaks increased as the mother mice experienced lactation, irrespective of the age of the pups, suggesting the intrinsic plasticity of maternal OT neurons. Based on a mono-synaptic input map to OT neurons, we pharmacogenetically activated the inhibitory neurons in the bed nucleus of the stria terminalis and found suppression of the activities of OT neurons. Collectively, our study illuminates temporal dynamics in the maternal neural activities of OT neurons and identifies one of its modulatory circuits.

Highlights

- Pulsatile activities of genetically-defined OT neurons in mother mice were recorded in vivo.

- The maternal experience-dependent plasticity of the OT neural activities was found.

- Input-mapping of OT neurons in mother mice was performed by rabies-mediated trans-synaptic tracing.

- Photometric peaks of OT neurons were suppressed by the activation of BST inhibitory neurons.
Modular assembly of dynamic models in systems biology
Authors: Pan Michael , Gawthrop Peter J. , Cursons Joseph , Crampin Edmund J.
Published: July 2021

It is widely acknowledged that the construction of large-scale dynamic models in systems biology requires complex modelling problems to be broken up into more manageable pieces. To this end, both modelling and software frameworks are required to enable modular modelling. While there has been consistent progress in the development of software tools to enhance model reusability, there has been a relative lack of consideration for how underlying biophysical principles can be applied to this space. Bond graphs combine the aspects of both modularity and physics-based modelling. In this paper, we argue that bond graphs are compatible with recent developments in modularity and abstraction in systems biology, and are thus a desirable framework for constructing large-scale models. We use two examples to illustrate the utility of bond graphs in this context: a model of a mitogen-activated protein kinase (MAPK) cascade to illustrate the reusability of modules and a model of glycolysis to illustrate the ability to modify the model granularity.

Author summary

The biochemistry within a cell is complex, being composed of numerous biomolecules and reactions. In order to develop fully detailed mathematical models of cells, smaller submodels need to be constructed and connected together. Software and standards can assist in this endeavour, but challenges remain in ensuring submodels are both consistent with each other and consistent with the fundamental conservation laws of physics.

In this paper, we propose a new approach using bond graphs from engineering. In this approach, connections between models are defined using physical conservation laws. We show that this approach is compatible with current software approaches in the field, and can therefore be readily used to incorporate physical consistency into existing model integration methodologies. We illustrate the utility of this approach in streamlining the development of models for a signalling network (the MAPK cascade) and a metabolic network (the glycolysis pathway).

The advantage of this approach is that models can be developed in a scalable manner while also ensuring consistency with the laws of physics, enhancing the range of data available to train models. This approach can be used to quickly construct detailed and accurate models of cells, facilitating future advances in biotechnology and personalised medicine.
Novel modification by L/F-tRNA-protein transferase (LFTR) generates a Leu/N-degron ligand in Escherichia coli
Authors: Ottofuelling Ralf D. , Ninnis Robert L. , Truscott Kaye N. , Dougan David A.
Published: July 2021

The N-degron pathways are a set of proteolytic systems that relate the half-life of a protein to its N-terminal (Nt) residue. In Escherchia coli the principal N-degron pathway is known as the Leu/N-degron pathway of which an Nt Leu is a key feature of the degron. Although the physiological role of the Leu/N-degron pathway is currently unclear, many of the components of the pathway are well defined. Proteins degraded by this pathway contain an Nt degradation signal (N-degron) composed of an Nt primary destabilizing (Nd1) residue (Leu, Phe, Trp or Tyr) and an unstructured region which generally contains a hydrophobic element. Most N-degrons are generated from a pro-N-degron, either by endoproteolytic cleavage, or by enzymatic attachment of a Nd1 residue (Leu or Phe) to the N-terminus of a protein (or protein fragment) by the enzyme Leu/Phe tRNA protein transferase (LFTR) in a non-ribosomal manner. Regardless of the mode of generation, all Leu/N-degrons are recognized by ClpS and delivered to the ClpAP protease for degradation. To date, only two physiological Leu/N-degron bearing substrates have been verified, one of which (PATase) is modified by LFTR. In this study, we have examined the substrate proteome of LFTR during stationary phase. From this analysis, we have identified several additional physiological Leu/N-degron ligands, including AldB, which is modified by a previously undescribed activity of LFTR. Importantly, the novel specificity of LFTR was confirmed in vitro, using a range of model proteins. Our data shows that processing of the Nt-Met of AldB generates a novel substrate for LFTR. Importantly, the LFTR-dependent modification of T2-AldB is essential for its turnover by ClpAPS, in vitro. To further examine the acceptor specificity of LFTR, we performed a systematic analysis using a series of peptide arrays. These data reveal that the identity of the second residue modulates substrate conjugation with positively charged residues being favored and negatively charged and aromatic residues being disfavored. Collectively, these findings extend our understanding of LFTR specificity and the Leu/N-degron pathway in E. coli.
The relationships between structural organization, material properties, and loading conditions and the risk of fracture and fracture location in the femur
Authors: Bredbenner Todd L.
Published: July 2021

Increased risk of skeletal fractures due to bone mass loss is a major public health problem resulting in significant morbidity and mortality, particularly in the case of hip fractures. Current clinical methods based on two-dimensional measures of bone mineral density (areal BMD or aBMD) are often unable to identify individuals at risk of fracture. The underlying hypothesis of this study was that combinations of femur structural traits are different for those femurs that suffer a fragility fracture within the proximal region of the femur and those that sustain a fracture in either the subtrochanteric or midshaft region of the femur, resulting in an “atypical femur fracture”. Accordingly, the objective of this study was to determine the effects of varying combinations of structural traits, material properties, and loading conditions on femur stress response and the location of stress response variation using a validated parametric finite element model. Statistical shape and trait modelling of the femur was used to describe variability in the structural organization of a set of femurs in an efficient manner and the resulting description of structural variability was exploited to investigate how different mechanisms of fracture might occur, whether in the proximal region or in the subtrochanteric and midshaft region. In combination with parameters describing loading condition and material property variation, variation in structural organization is associated with regional increases in maximum principal stress and the percentage of bone expected to damage, and these increases are likely associated with increased fracture risk. The results of this study indicate that there are multiple pathways and combinations of descriptor variation that may result in increased fracture risk and that these pathways can lead to fracture in any region of the femur under both overload conditions, such as with sideways fall loading, and stance loading, which due to the repetitive nature may lead to the accumulation of fatigue damage within the bone and further impair bone condition and increased susceptibility to fracture.
The olfactory gating of visual preferences to human skin and colors in mosquitoes
Authors: San Alberto Diego Alonso , Rusch Claire , Zhan Yinpeng , Straw Andrew D. , Montell Craig , Riffell Jeffrey A.
Published: July 2021

Mosquitoes track odors, locate hosts, and find mates visually. The color of a food resource, such as a flower or warm-blooded host, can be dominated by long wavelengths of the visible light spectrum (green to red for humans) and is likely important for object recognition and localization. However, little is known about the hues that attract mosquitoes or how odor affects mosquito visual search behaviors. We used a real-time 3D tracking system and wind tunnel that allowed careful control of the olfactory and visual environment to quantify the behavior of more than 1.3 million mosquito trajectories. We found that CO2induces a strong attraction to specific hues, including those that humans perceive as cyan, orange, and red. Sensitivity to orange and red correlates with mosquitoes’ strong attraction to the color spectrum of human skin, which is dominated by these wavelengths. Attraction was eliminated by filtering the orange and red bands from the skin color spectrum and by introducing mutations targeting specific long-wavelength opsins or CO2detection. Collectively, our results show that odor is critical for mosquitoes’ wavelength preferences and that the mosquito visual system is a promising target for inhibiting their attraction to human hosts.
Extracellular mechanical forces drive endocardial cell volume decrease during cardiac valve morphogenesis
Authors: Vignes Hélène , Vagena-Pantoula Christina , Prakash Mangal , Norden Caren , Jug Florian , Vermot Julien
Published: July 2021

Organ morphogenesis involves dynamic changes of tissue properties at the cellular scale. In addition, cells need to adapt to their mechanical environment through mechanosensitive pathways. How mechanical cues influence cell behaviors during morphogenesis, however, remains poorly understood. Here we studied the influence of mechanical forces during the formation of the atrioventricular canal (AVC) where cardiac valves develop. We show that in zebrafish the AVC forms within a zone of tissue convergence between the atrium and the ventricle which is associated with increased activation of the actomyosin meshwork and endocardial cell orientation changes. We demonstrate that tissue convergence occurs with a major reduction of endocardial cell volume triggered by mechanical forces and the mechanosensitive channels TRPP2/TRPV4. In addition, we show that the extracellular matrix component hyaluronic acid controls cell volume changes. Together, our data suggest that cell volume change is a key cellular feature activated by mechanical forces during cardiovascular morphogenesis. This work further unravels how mechanical forces and extracellular matrix can influence tissue remodeling in developing organs.
Structural insights into the substrate-binding proteins Mce1A and Mce4A from Mycobacterium tuberculosis
Authors: Asthana Pooja , Singh Dhirendra , Pedersen Jan Skov , Hynönen Mikko J. , Sulu Ramita , Murthy Abhinandan V. , Laitaoja Mikko , Jänis Janne , Riley Lee W. , Venkatesan Rajaram
Published: July 2021

Mycobacterium tuberculosis (Mtb), which is responsible for more than a million deaths annually, uses lipids as the source of carbon and energy for its survival in the latent phase of infection. Mtb cannot synthesize all of the lipid molecules required for its growth and pathogenicity. Therefore, it relies on transporters such as the mammalian cell entry (Mce) complexes to import lipids from the host across the cell wall. Despite their importance for the survival and pathogenicity of Mtb, information on the structural properties of these proteins is not yet available. Each of the four Mce complexes in Mtb (Mce1–4) comprises six substrate-binding proteins (SBPs; MceA–F), each of which contains four conserved domains (N-terminal transmembrane, MCE, helical and C-terminal unstructured tail domains). Here, the properties of the various domains of Mtb Mce1A and Mce4A, which are involved in the import of mycolic/fatty acids and cholesterol, respectively, are reported. In the crystal structure of the MCE domain of Mce4A (MtMce4A39–140) a domain-swapped conformation is observed, whereas solution studies, including small-angle X-ray scattering (SAXS), indicate that all Mce1A and Mce4A domains are predominantly monomeric. Further, structural comparisons show interesting differences from the bacterial homologs MlaD, PqiB and LetB, which form homohexamers when assembled as functional transporter complexes. These data, and the fact that there are six SBPs in each Mtb mce operon, suggest that the MceA–F SBPs from Mce1–4 may form heterohexamers. Also, interestingly, the purification and SAXS analysis showed that the helical domains interact with the detergent micelle, suggesting that when assembled the helical domains of MceA–F may form a hydrophobic pore for lipid transport, as observed in EcPqiB. Overall, these data highlight the unique structural properties of the Mtb Mce SBPs.
Mg(H2O)2[TeO2(OH)4]: a polytypic structure with a two-mode disordered stacking arrangement
Authors: Stöger Berthold , Krüger Hannes , Weil Matthias
Published: July 2021

Crystals of the hydrous magnesium orthotellurate(VI) Mg(H2O)2[TeO2(OH)4] were grown by slow diffusion of an aqueous MgCl2 solution into a KOH/Te(OH)6 solution immobilized in gelatin. The crystal structure is built of sheets of nearly regular corner-sharing [MgO6] and [TeO6] octahedra. Half of the bridging O atoms are connected to disordered H atoms, which are located in rhomboidal voids (long and short diameters of ∼5.0 and ∼2.5 Å, respectively) of these layers. Moreover, the TeVI atom connects to two OH− ions and the MgII atom to two H2O molecules. The OH− ions and H2O molecules connect adjacent layers forming a disordered hydrogen-bonding network. In a given layer, an adjacent layer may be positioned in four ways, which can be characterized by one of two origin shifts and one of two orientations with respect to [100]. The crystals feature a disordered stacking arrangement, leading to rods of diffuse scattering in the diffraction pattern. The polytypism is explained by application of the order–disorder (OD) theory. Different refinement models are compared and the diffuse scattering is evaluated with structure factor calculations. The correlation coefficient of subsequent origin shifts is ∼ −0.33, whereas the orientation of the layers is essentially random. Determining the latter is particularly difficult owing to a small contribution to the diffraction pattern and virtually indistinguishable diffraction patterns for pairs of correlations with the same absolute value. On longer standing in a glass vial, an ordered polytype forms.
Democracy, accountability and audit: the creation of the UK NAO as a defence of liberty
Authors: Ferry Laurence , Midgley Henry
Published: July 2021

Purpose

The study focusses on explaining why advocates for reform to state audit in the United Kingdom (UK) in the early 1980s, focussed on improving the links between the new National Audit Office (NAO) and Parliament, rather than on traditional notions of audit independence. The study shows how this focus on the auditor's link to Parliament depends on a particular concept of liberty and relates this to the wider literature on the place of audit in democratic society.

Design/methodology/approach

Understanding the issue of independence of audit in protecting the liberties and rights of citizens needs addressed. In this article, the authors investigate the creation of audit independence in the UK in the National Audit Act (1983). To do so, the authors employ a neo-Roman concept of liberty to historical archives ranging from the late 1960s to 1983.

Findings

The study shows that advocates for audit reform in the UK from the 1960s to the 1980s were arguing for an extension to Parliament's power to hold the executive to account and that their focus was influential on the way that the new NAO was established. Using a neo-Roman concept of liberty, the authors show that they believed Parliamentary surveillance of the executive was necessary to secure liberty within the UK.

Research limitations/implications

The neo-Roman republican concept of liberty extends previous studies in considering the importance of audit for public accountability, the preservation of liberty and democracy.

Practical implications

Public sector audit can be a fundamentally democratic activity. Auditors should be alert to the constitutional importance of their work and see parliamentary accountability as a key objective.

Originality/value

The neo-Roman concept of liberty extends previous studies in considering the importance of audit for public accountability, preservation of liberty and democracy.
A network of circular economy villages: design guidelines for 21st century Garden Cities
Authors: Liaros Steven
Published: July 2021

Purpose

The purpose is to open the possibility for a research institute, perhaps in partnership with a local council and a major developer, to bring together skills necessary to prototype the CEV development model.

Design/methodology/approach

This paper advances the development of a hypothetical, systems-based approach to the design and development of smart rural villages – a network of circular economy villages (CEVs). The method is to assimilate visionary ideas from 20th century town planning literature related to decentralisation and the development of new towns in rural areas, identifying key design principles. The present trajectory of infrastructure design and emerging development models are then analysed to modernise the design principles for implementation in the 21st century.

Findings

The availability of localised, renewable energy micro-grids potentially makes CEVs feasible and affordable. The shift to remote work and movement of people to regional areas suggests that this may be a desirable development form. This can only be confirmed through the development of a pilot project as proof of concept.

Originality/value

The proposed CEV development model applies circular economy strategies to every aspect of the smart rural village development including financing, ownership, spatial planning, design and material selection.
New derivative-free iterative family having optimal convergence order sixteen and its applications
Authors: Kaur Manpreet , Kumar Sanjeev , Kansal Munish
Published: July 2021

Purpose

The purpose of the article is to construct a new class of higher-order iterative techniques for solving scalar nonlinear problems.

Design/methodology/approach

The scheme is generalized by using the power-mean notion. By applying Neville's interpolating technique, the methods are formulated into the derivative-free approaches. Further, to enhance the computational efficiency, the developed iterative methods have been extended to the methods with memory, with the aid of the self-accelerating parameter.

Findings

It is found that the presented family is optimal in terms of Kung and Traub conjecture as it evaluates only five functions in each iteration and attains convergence order sixteen. The proposed family is examined on some practical problems by modeling into nonlinear equations, such as chemical equilibrium problems, beam positioning problems, eigenvalue problems and fractional conversion in a chemical reactor. The obtained results confirm that the developed scheme works more adequately as compared to the existing methods from the literature. Furthermore, the basins of attraction of the different methods have been included to check the convergence in the complex plane.

Originality/value

The presented experiments show that the developed schemes are of great benefit to implement on real-life problems.
Cultivating social capital: an exploratory analysis of business postgraduates in Ghana
Authors: Ayentimi Desmond Tutu , Hinson Robert Ebo , Burgess John
Published: July 2021

Purpose

This paper, grounded on social capital and social networking theory, examines how postgraduate students in Ghana cultivate and utilise social resources towards career development.

Design/methodology/approach

Following a qualitative study design, the authors recruited and conducted interviews with postgraduate student-workers undertaking a two-year Master of Science in International Business.

Findings

There was an active engagement and consciously pre-plan mobilisation of social resources and utilisation of social resources among the postgraduates. Despite the diverse processes of social capital development identified, four important key themes emerged underpinning social capital mobilisation and utilisation: (1) the recognition of the importance of social capital acquisition, (2) the strong link between social capital and individual successes in employment and business opportunities, (3) the importance of the utilisation of social resources for emotional support and (4) the use of social capital to reinforce the individual social identity and recognition of an individual's worth.

Practical implications

The authors offer a theoretical and practical contribution with a frame of understanding by demonstrating that there is more to social capital than economic gain.

Social implications

Unlike the findings from prior research in Africa, the strong institutional and cultural conditions did not constrain the key force of education and employability as drivers in attainment and social positioning. This is an interesting and positive finding from the research, especially in terms of the importance of providing educational opportunities to overcome institutional and cultural barriers to workforce participation and career development.

Originality/value

Social networks contribute to career success, and while the participants used social networks that reinforced ethnic and religious bonds, there is the opportunity to develop networks through other identity processes, especially education. Formal education imparts more than formal skills and qualifications. It provides the opportunity to access networks that transcend personal identity such as ethnicity and to get support for career development.
What’s not to like about evidence-based management: a hyper-rational fad?
Authors: Hulpke John F. , Fronmueller Michael P.
Published: July 2021

Purpose

A topic currently receiving significant academic and practitioner attention is called evidence-based management. The purpose of this paper is to suggest that this approach is sometimes over-sold and may be a fad. Additionally, evidence-based management fails to fully recognize the importance of tacit knowledge, what Kahneman calls system 1. Evidence-based management does provide tools to better use what Kahneman calls system 2, rationality. Decision-makers need to take advantage of both rational and beyond rational processes.

Design/methodology/approach

This is an essay, it is not a report of a study. At this point in time, this paper needs thinking, reflection, pondering, more than a data-based study.

Findings

Advocates promote evidence-based management in part to help avoid fads, yet evidence-based management itself has many of the characteristics of a fad. Evidence-based management is based on an objective rational view of the world and suggests highly rational methods of decision-making. However, a rational fact-based might not give sufficient credit to instinct and feelings. Decision-makers should take into account facts, evidence, when making decisions, but not ignore intuition, hunches and feelings. This study is learning that decisions use a galaxy of approaches, with both cognitive and affective flexibility.

Research limitations/implications

As with any opinion-based paper, this lacks empirical support. Proponents ask us to believe in evidence-based management. Neither we, the authors of this paper, nor the proponents of evidence-based management can empirically support the ideas offered. An additional limitation is that the paper is written in one language, English. Translation into another language might yield different meanings.

Practical implications

There are advantages for scholars and practitioners to look at the best available evidence. There can be disadvantages in overlooking non-quantifiable factors.

Social implications

Those who use evidence-based management should also take into account feelings, ethics, aesthetics, creativity, for the betterment of society. To solve wicked problems one needs more than facts and rational analysis.

Originality/value

The overwhelming majority of those writing about evidence-based management are supporters. This study offers a different view. This paper brings new ideas and new thinking to both the extensive fad literature and the huge evidence-based management literature. Evidence-based management is discussed widely. Google Scholar lists more than two million papers in 2019, 2020 and 2021 on evidence-based management. Readers of this journal should critically evaluate this popular set of ideas.