bluuebunny/crossref_metadata_2025 huggingface dataset:
Strain dependent structural effects and in vivo efficacy of enterovirus-D68 inhibitors
Authors: Lane Thomas , Fu Jianing , Sherry Barbara , Tarbet Bart , Hurst Brett L. , Riabova Olga , Kazakova Elena , Egorova Anna , Clarke Penny , Leser J. Smith , Frost Joshua , Rudy Michael , Tyler Ken , Klose Thomas , Kuhn Richard J. , Makarov Vadim , Ekins Sean
Published: December 2021

Acute flaccid myelitis (AFM) leads to loss of limb control in young children and is likely due to Enterovirus-D68 (EV-D68), for which there is no current treatment. We have developed a lead isoxazole-3-carboxamide analog of pleconaril (11526092) which displayed potent inhibition of the pleconaril-resistant CVB3-Woodruff (IC50 6-20 nM), EV-D68 (IC50 58 nM), and other enteroviruses. A mouse respiratory model of EV-D68 infection, in which pleconaril is inactive, showed decreased viremia of 3 log units as well as statistically significant 1 log reduction in lung titer reduction at day 5 after treatment with 11526092. A cryo-electron microscopy (cryo-EM) structure of EV-D68 in complex with 11526092 suggests that the increased potency may be due to additional hydrophobic interactions. Cryo-EM structures of 11526092 and pleconaril demonstrate destabilization of EV-D68 (MO strain) compared to the previously described stabilization of EV-D68 (Fermon strain) with pleconaril, illustrating clear strain dependent mechanisms of this molecule. 11526092 represents a more potent inhibitor in vitro with in vivo efficacy providing a potential future treatment for EV-D68 and AFM, suggesting an improvement over pleconaril for further optimization.

One-Sentence Summary

11526092 demonstrates protein destabilization, improved in vitro potency and in vivo efficacy when compared with pleconaril against EV-D68.
Arachnoid granulations may be protective against the development of shunt dependent chronic hydrocephalus after aneurysm subarachnoid hemorrhage
Authors: Almohaimede Khaled , Zaccagna Fulvio , Kumar Ashish , da Costa Leodante , Wong Erin , Heyn Chris , Kapadia Anish
Published: December 2021

Background and Purpose

Chronic hydrocephalus may develop as a sequela of aneurysmal subarachnoid hemorrhage, requiring long-term cerebrospinal fluid shunting. Several clinical predictors of chronic hydrocephalus and shunt dependence have been proposed. However, no anatomical predictors have been identified.

Materials and Methods

A retrospective cohort study was performed including 61 patients with aneurysmal subarachnoid hemorrhage. Clinical characteristics were noted for each patient including presentation World Federation of Neurosurgical Societies grade, modified Fischer grade, aneurysm characteristics, requirement for acute and chronic cerebrospinal fluid diversion, and 3-month modified Rankin scale. CT images were evaluated to determine the Evans’ index and to enumerate the number of arachnoid granulations. Association between the clinical characteristics with ventriculoperitoneal shunt insertion and the 3-month modified Rankin scale were assessed.

Results

The initial Evans’ index was positively associated with mFisher grade and age, but not the number of arachnoid granulations. 16.4 % patients required insertion of a ventriculoperitoneal shunt. The number of arachnoid granulations were a significant negative predictor of ventriculoperitoneal shunt insertion [OR: 0.251 (95% CI:0.073-0.862; P=0.028)]. There was significant difference in the number of arachnoid granulations between those with and without ventriculoperitoneal shunt (p=0.002). No patient with greater than 4 arachnoid granulations required a ventriculoperitoneal shunt, irrespective of severity of initial grade.

Conclusion

Arachnoid granulations may be protective against the development of shunt dependent chronic hydrocephalus after aneurysmal subarachnoid hemorrhage. This is irrespective of presenting hemorrhage severity. This is a potentially novel radiologic biomarker and anatomic predictor of shunt dependence.
Biological Aging of CNS-Resident Cells Alters the Clinical Course and Immunopathology of Autoimmune Demyelinating Disease
Authors: Atkinson Jeffrey R. , Jerome Andrew D. , Sas Andrew R. , Munie Ashley , Wang Cankun , Ma Anjun , Arnold W. David , Segal Benjamin M.
Published: December 2021

Biological aging is the strongest factor associated with the clinical phenotype of multiple sclerosis (MS). Relapsing remitting MS (RRMS) typically presents in the third or fourth decade, while the mean age of presentation of progressive MS (pMS) is 45 years old. Here we show that experimental autoimmune encephalomyelitis (EAE), induced by the adoptive transfer of encephalitogenic CD4+Th17 cells, is more severe, and less like to remit, in middle-aged compared with young adult mice. Donor T cells and neutrophils are more abundant, while B cells are relatively sparse, in central nervous system (CNS) infiltrates of the older mice. Experiments with reciprocal bone marrow chimeras demonstrate that radio-resistant, non-hematopoietic cells play a dominant role in shaping age-dependent features of the neuroinflammatory response, as well as the clinical course, during EAE. Reminiscent of pMS, EAE in middle-aged adoptive transfer recipients is characterized by widespread microglial activation. Microglia from older mice express a distinctive transcriptomic profile, suggestive of enhanced chemokine synthesis and antigen presentation. Collectively, our findings suggest that drugs that suppress microglial activation, and acquisition or expression of aging-associated properties, may be beneficial in the treatment of progressive forms of inflammatory demyelinating disease.
A New Paradigm for Investigating Real-World Social Behavior and its Neural Underpinnings
Authors: Alreja Arish , Ward Michael J. , Ma Qianli , Russ Brian E. , Bickel Stephan , Van Wouwe Nelleke C. , González-Martínez Jorge A. , Neimat Joseph S. , Abel Taylor J. , Bagić Anto , Parker Lisa S. , Richardson R. Mark , Schroeder Charles E. , Morency Louis–Philippe , Ghuman Avniel Singh
Published: December 2021

Eye tracking and other behavioral measurements collected from patient-participants in their hospital rooms afford a unique opportunity to study immersive natural behavior for basic and clinical translational research. We describe an immersive social and behavioral paradigm implemented in patients undergoing evaluation for surgical treatment of epilepsy, with electrodes implanted in the brain to determine the source of their seizures. Our studies entail collecting eye tracking with other behavioral and psychophysiological measurements from patient-participants during unscripted behavior, including social interactions with clinical staff, friends and family, in the hospital room. This approach affords a unique opportunity to study the neurobiology of natural social behavior, though it requires carefully addressing distinct logistical, technical, and ethical challenges. Collecting neurophysiological data synchronized to behavioral and psychophysiological measures helps us to study the relationship between behavior and physiology. Combining across these rich data sources while participants eat, read, converse with friends and family, etc., enables clinical-translational research aimed at understanding the participants’ disorders and clinician-patient interactions, as well as basic research into natural, real-world behavior. We discuss data acquisition, quality control, annotation, and analysis pipelines that are required for our studies. We also discuss the clinical, logistical, and ethical and privacy considerations critical to working in the hospital setting.
Super-immunity by broadly protective nanobodies to sarbecoviruses
Authors: Xiang Yufei , Huang Wei , Liu Hejun , Sang Zhe , Nambulli Sham , Tubiana Jérôme , Williams Kevin L , Duprex W Paul , Schneidman-Duhovny Dina , Wilson Ian A. , Taylor Derek J. , Shi Yi
Published: December 2021

Vaccine boosters and infection can facilitate the development of SARS-CoV-2 antibodies with improved potency and breadth. Here, we observed super-immunity in a camelid extensively immunized with the SARS-CoV-2 receptor-binding domain (RBD). We rapidly isolated a large repertoire of specific ultrahigh-affinity nanobodies that bind strongly to all known sarbecovirus clades using integrative proteomics. These pan-sarbecovirus nanobodies (psNbs) are highly effective against SARS-CoV and SARS-CoV-2 variants including the Omicron, with the best median neutralization potency at single-digit ng/ml. Structural determinations of 13 psNbs with the SARS-CoV-2 spike or RBD revealed five epitope classes, providing insights into the mechanisms and evolution of their broad activities. The highly evolved psNbs target small, flat, and flexible epitopes that contain over 75% of conserved RBD surface residues. Their potencies are strongly and negatively correlated with the distance of the epitopes to the receptor binding sites. A highly potent, inhalable and bispecific psNb (PiN-31) was developed. Our findings inform on the development of broadly protective vaccines and therapeutics.

One sentence summary

Successive immunization of SARS-CoV-2 RBD in a camelid enhanced the development of super-immunity and isolation and systematic characterization of a large repertoire of ultrahigh-affinity pan-sarbecovirus single-chain VHH antibodies to understand the evolution of this potent and broad immune response.
Biological characteristics of two mesenchymal stem cell lines isolated from the umbilical cord and adipose tissue of a neonatal common hippo (Hippopotamus amphibius)
Authors: Wei Jinpu , Dong Xiuxiu , Wang Bo , Wu Yajiang , Chen Wu , Hou Zhijun , Wang Chen , Wang Tao
Published: December 2021

Mesenchymal stem cells (MSCs) are multipotent adult stem cells and can be isolated from many tissues of the body. Due to their potentials to treat various diseases and be applied in animal breeding, MSCs have been isolated and identified regarding their biological properties. Common hippos (Hippopotamus amphibius) are a vulnerable species and yet the cryopreservation of their genetic materials is scare. In this study, we successfully established two MSC lines (UC-MSCs and AT-MSCs) from the umbilical cord and adipose tissue of a neonatal common hippo and comparatively described their features. Both UC-MSCs and AT-MSCs showed fibroblastoid morphology and could be continuously passaged for over 17 passages without dramatic signs of senescence. The cell cultures had normal chromosome composition, say, 17 pairs of autosomes and 1 pair of X chromosomes. UC-MSCs and AT-MSCs displayed similar gene expression profiles. They were positive for CD45, CD73, CD90 and CD105 and negative for HLA-DR. They demonstrated stemness maintenance by expression of classical stem cell markers. UC-MSCs and AT-MSCs manifested different differentiation potentials into other cell lineages. In summary, these two cell lines demonstrated the essential properties of mesenchymal stem cells and might play a role in the future research.
Stronger density-dependent growth of Japanese sardine with lower food availability: Comparison of growth and zooplankton biomass between a historical and current stock-increase period in the western North Pacific
Authors: Kamimura Yasuhiro , Tadokoro Kazuaki , Furuichi Sho , Yukami Ryuji
Published: December 2021

Density dependence is a fundamental concept for fish population dynamics. Although density-dependent growth and maturity among older juveniles and adults is important for regulating fish population size and for fisheries management, the mechanism of density dependence for marine fishes remains unclear. Here, we examined changes in Japanese sardine growth with increasing abundance beginning in the 2010s and how the current pattern of density-dependent growth differs from that of a previous stock-increase period from the 1970s to early 1980s. During the current period of increasing abundance, mean standard length has already dropped to the lowest level yet observed and growth has declined more sharply with increased abundance than in the 1970s and 1980s. Mesozooplankton biomass in July in the summer feeding grounds was also lower during the current period. Therefore, our results suggest that summer food availability in the western North Pacific controls the strength of density-dependent growth. A lower carrying capacity for Japanese sardine could account for the stronger density dependence of growth observed in the 2010s; this indicates that future Japanese sardine abundance might not increase as much as in the 1980s unless food availability improves.
DeepMHCII: A Novel Binding Core-Aware Deep Interaction Model for Accurate MHC II-peptide Binding Affinity Prediction
Authors: You Ronghui , Qu Wei , Mamitsuka Hiroshi , Zhu Shanfeng
Published: December 2021

Computationally predicting MHC-peptide binding affinity is an important problem in immunological bioinformatics. Recent cutting-edge deep learning-based methods for this problem are unable to achieve satisfactory performance for MHC class II molecules. This is because such methods generate the input by simply concatenating the two given sequences: (the estimated binding core of) a peptide and (the pseudo sequence of) an MHC class II molecule, ignoring the biological knowledge behind the interactions of the two molecules. We thus propose a binding core-aware deep learning-based model, DeepMHCII, with binding interaction convolution layer (BICL), which allows integrating all potential binding cores (in a given peptide) and the MHC pseudo (binding) sequence, through modeling the interaction with multiple convolutional kernels. Extensive empirical experiments with four large-scale datasets demonstrate that DeepMHCII significantly outperformed four state-of-the-art methods under numerous settings, such as five-fold cross-validation, leave one molecule out, validation with independent testing sets, and binding core prediction. All these results with visualization of the predicted binding cores indicate the effectiveness and importance of properly modeling biological facts in deep learning for high performance and knowledge discovery. DeepMHCII is publicly available at https://weilab.sjtu.edu.cn/DeepMHCII/.
Cryo-EM structures and binding of mouse and human ACE2 to SARS-CoV-2 variants of concern indicate that mutations enabling immune escape could expand host range
Authors: Ni Dongchun , Turelli Priscilla , Beckert Bertrand , Nazarov Sergey , Uchikawa Emiko , Myasnikov Alexander , Pojer Florence , Trono Didier , Stahlberg Henning , Lau Kelvin
Published: December 2021

Investigation of potential hosts of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is crucial to understanding future risks of spillover and spillback. SARS-CoV-2 has been reported to be transmitted from humans to various animals after requiring relatively few mutations.[1] There is significant interest in describing how the virus interacts with mice as they are well adapted to human environments, are used widely as infection models and can be infected.[2] Structural and binding data of the mouse ACE2 receptor with the Spike protein of newly identified SARS-CoV-2 variants are needed to better understand the impact of immune system evading mutations present in variants of concern (VOC). Previous studies have developed mouse-adapted variants and identified residues critical for binding to heterologous ACE2 receptors.[3,4] Here we report the cryo-EM structures of mouse ACE2 bound to trimeric Spike ectodomains of four different VOC: Beta, Omicron BA.1, Omicron BA.2.12.1 and Omicron BA.4/5. These variants represent the oldest to the newest variants known to bind the mouse ACE2 receptor. Our high-resolution structural data complemented with bio-layer interferometry (BLI) binding assays reveal a requirement for a combination of mutations in the Spike protein that enable binding to the mouse ACE2 receptor.

AUTHOR SUMMARY

The SARS-CoV-2 virus can infect different types of animals beyond humans. The virus uses its Spike protein on its surface to bind to cells. These cells have a protein called ACE2 that the Spike protein recognizes. Animals have slightly different ACE2 receptors compared to humans. Mice are widely used as a research animal and live in the same environments as humans so scientists are particularly interested. Understanding how Spike proteins binds to the mouse ACE2 receptor allows us to understand the impact of immune evading mutations found in new variants. We use a high resolution imaging technique called cryo-electron microscopy to look at how different Spike variants bind to the ACE2 receptor from mouse at a resolution where we can see the amino acids. We can see directly the individual amino acids and mutations on the Spike protein that interact with the mouse ACE2 receptor. Many of the mutations found in variants of concern also increase the strength of binding to the mouse ACE2 receptor. This result suggests that mutations in the Spike protein of future variants may have an additional effect in influencing how it binds to not only human ACE2 receptors but to mice and also different animals.
Dichotomous Feedback: A Signal Sequestration-based Feedback Mechanism for Biocontroller Design
Authors: Sootla Aivar , Delalez Nicolas , Alexis Emmanouil , Norman Arthur , Steel Harrison , Wadhams George H. , Papachristodoulou Antonis
Published: December 2021

We introduce a new design framework for implementing negative feedback regulation in Synthetic Biology, which we term ‘dichotomous feedback’. Our approach is different from current methods, in that it sequesters existing fluxes in the process to be controlled, and in this way takes advantage of the process’s architecture to design the control law. This signal sequestration mechanism appears in many natural biological systems and can potentially be easier to realise than ‘molecular sequestration’ and other comparison motifs that are nowadays common in biomolecular feedback control design. The loop is closed by linking the strength of signal sequestration to the process output. Our feedback regulation mechanism is motivated by two-component signalling systems, where we introduce a second response regulator competing with the natural response regulator thus sequestering kinase activity. Here, dichotomous feedback is established by increasing the concentration of the second response regulator as the level of the output of the natural process increases. Extensive analysis demonstrates how this type of feedback shapes the signal response, attenuates intrinsic noise while increasing robustness and reducing crosstalk.
Frontal cortical regulation of neurogenesis and cellular proliferation in the ventral subventricular zone
Authors: Naffaa Moawiah M , Khan Rehan R , Kuo Chay T. , Yin Henry H.
Published: December 2021

Neurogenesis and differentiation of the neural stem cells (NSCs) in the subventricular zone (SVZ) are controlled by cell-intrinsic molecular pathways that interact with extrinsic signaling cues. Here we identified a novel circuit that regulates neurogenesis and cellular proliferation in the lateral ventricle SVZ (LV-SVZ). Our results demonstrate direct glutamatergic inputs from the frontal cortex as well as local inhibitory interneurons, control the activity of distinctive cholinergic neurons in the subependymal zone (subep-ChAT+). In vivo optogenetic stimulation and inhibition in this circuit were sufficient to control local SVZ neurogenesis, LV NSCs proliferation, and SVZ cellular divisions in ventral SVZ. These findings shed light on local and distal neural circuit activity-dependent regulation of postnatal and adult SVZ neurogenesis and LV-SVZ cellular proliferation.
Booster vaccines protect hamsters with waning immunity from Delta VOC infection, disease, and transmission
Authors: Potts Kyle G. , Noyce Ryan S. , Gafuik Chris , John Cini M. , Todesco Hayley M. , De Heuvel Elaine , Favis Nicole , Kelly Margaret M. , Evans David H. , Mahoney Douglas J.
Published: December 2021

Waning immunity to COVID-19 vaccination is associated with increased risk of breakthrough infection, especially with highly transmissible variants of concern (VOC). Booster vaccination generates rapid immune recall in humans, which real-world observational studies suggest protects against VOC infection and associated disease, and modeling studies suggest could mitigate community spread. We directly tested the impact of booster vaccination on protection against Delta VOC infection, disease, and transmission to naïve cohorts in golden Syrian hamsters. Animals with waning immunity to bnt162b2 generated rapid immune recall and strong protection against upper- and lower-respiratory tract infection when boosted with bnt126b2, mRNA-1273 or AZD1222. Boosting with either mRNA vaccine generated moderate protection against lung inflammation and virus transmission to unvaccinated animals. Our data support booster vaccination as a tool to address emerging VOC in the COVID-19 pandemic.

One-Sentence Summary

A booster vaccine delivered 9 months after primary bnt162b2 vaccination protects hamsters from Delta VOC infection, disease, and transmission.
The origin of mouse extraembryonic endoderm stem cell lines
Authors: Lin Jiangwei
Published: December 2021

Mouse extraembryonic endoderm stem (XEN) cell lines can be derived from preimplantation embryos (pre-XEN) and postimplantation embryos (post-XEN). XEN cells share a gene expression profile and cell lineage potential with primitive endoderm (PrE) blastocysts. However, the cellular origin of XEN cells in embryos remains unclear. Here, we report that post-XEN cell lines are derived both from the extraembryonic endoderm and epiblasts of postimplantation embryos and that pre-XEN cell lines are derived both from PrE and epiblasts of blastocysts. Our strategy consisted of deriving post-XEN cells from clumps of epiblasts, parietal endoderm (PE) and visceral endoderm (VE) and deriving pre-XEN cell lines from single PrE and single epiblasts of blastocysts. Thus, XEN cell lines in the mouse embryo originate not only from PrE and PrE-derived lineages but also from epiblast and epiblast-derived lineages of blastocysts and postimplantation embryos.
Identification of Cell-Type-Specific Spatially Variable Genes Accounting for Excess Zeros
Authors: Yu Jinge , Luo Xiangyu
Published: December 2021

Spatial transcriptomic techniques can profile gene expressions while retaining the spatial information, thus offering unprecedented opportunities to explore the relationship between gene expression and spatial locations. The spatial relationship may vary across cell types, but there is a lack of statistical methods to identify cell-type-specific spatially variable (SV) genes by simultaneously modeling excess zeros and cell-type proportions. We develop a statistical approach CTSV to detect cell-type-specific SV genes. CTSV directly models spatial raw count data and considers zero-inflation as well as overdispersion using a zero-inflated negative binomial distribution. It then incorporates cell-type proportions and spatial effect functions in the zero-inflated negative binomial regression framework. The Rpackage pscl(Zeileis et al., 2008) is employed to fit the model. For robustness, a Cauchy combination rule is applied to integrate p-values from multiple choices of spatial effect functions. Simulation studies show that CTSV not only outperforms competing methods at the aggregated level but also achieves more power at the cell-type level. By analyzing pancreatic ductal adenocarcinoma spatial transcriptomic data, SV genes identified by CTSV reveal biological insights at the cell-type level. The R package of CTSV is available onhttps://github.com/jingeyu/CTSV.
HSP40 overexpression in pacemaker neurons protects against circadian dysfunction in aDrosophilamodel of Huntington’s Disease
Authors: Prakash Pavitra , Pradhan Arpit Kumar , Sheeba Vasu
Published: December 2021

Circadian disturbances are early features of neurodegenerative diseases, including Huntington’s Disease (HD), affecting the quality of life of patients and caregivers. Emerging evidence suggests that circadian decline feeds-forward to neurodegenerative symptoms, exacerbating them, highlighting a need for restoring circadian health. Therefore, we asked whether any of the known neurotoxic modifiers can suppress circadian dysfunction. We performed a screen of neurotoxicity-modifier genes to suppress circadian behavioural arrhythmicity in aDrosophilacircadian HD model. Notably, the molecular chaperones HSP40 and HSP70 (HeatShockProtein) emerged as significant suppressors in the circadian context, with HSP40 being the more potent mitigator of HD-induced deficits. Upon HSP40 overexpression in theDrosophilacircadian ventrolateral neurons (LNv), the behavioural rhythm rescue was associated with neuronal rescue of loss in circadian proteins from small LNv soma. Specifically, there was a restoration of the molecular clock protein Period and its oscillations in young flies and a long-lasting rescue of the output neuropeptide Pigment Dispersing Factor. Significantly, there was a reduction in the expanded Huntingtin inclusion load, concomitant with the appearance of a spot-like Huntingtin form. Thus, we provide evidence for the first time that implicates the neuroprotective chaperone HSP40 incircadian rehabilitation. Given the importance of proteostasis and circadian health in neurodegenerative diseases, the involvement of molecular chaperones in circadian maintenance has broader therapeutic implications.

Summary Statement

This study shows, for the first time, a neuroprotective role of chaperone HSP40 in overcoming circadian dysfunction associated with Huntington’s Disease in aDrosophilamodel
Fast and specific enrichment of cancer-related exosomes by DNA-nanoweight-assisted centrifugation
Authors: Lu Zhangwei , shi Ye , Ma Yuxuan , Jia Bin , Li Xintong , Li Zhe
Published: December 2021

Exosomes are nanoscale membrane vesicles actively released by cells and play an important role in the diagnosis of cancer-related diseases. However, it is challenging to efficiently enrich exosomes from extracellular fluids. In this work, we used DNA-tetrahedron as a nanoweight during centrifugation to precisely enrich tumor exosomes from a complex biological environment. Two different DNA tetrahedral nanostructures (DTAs), each carrying a specific aptamer for exosome biomarker recognition, were incubated with clinical samples simultaneously. One DTA triggered the cross-linking of multiple target exosomes, and therefore enabled low-speed and fast centrifugation for enrichment. The other DTA further narrowed down the target exosome subtype and initiated a hybridization chain reaction (HCR) for sensitive signal amplification. The method enabled the detection of 180 MCF-7-derived exosomes per microliter and 560 HepG2-derived exosomes per microliter, with 1000-fold higher sensitivity than conventional ELISA. This easy-to-operate method can enrich exosomes with excellent specificity and therefore will be appealing in biomedical research and clinical diagnosis.
Mapping prion pathology in mice using quantitative imaging: an MRI study
Authors: Demetriou Eleni , Tachrount Mohamed , Ellis Matthew , Linehan Jackie , Brandner Sebastian , Collinge John , Mead Simon , Shmueli Karin , Farrow Mark , Golay Xavier
Published: December 2021

Human prion diseases are fatal neurodegenerative disorders which cause cognitive impairment and neurological deficits. Additional measures of tissue status are necessary for improving the sensitivity and specificity of clinical diagnosis as in many cases clinical forms of prion disease are commonly mistaken for other forms of dementia. To that effect, we developed a set of quantitative magnetic resonance-based tools, including magnetic resonance spectroscopy (MRS), magnetization transfer ratio (MTR) and quantitative T1 and T2 imaging to study the course of the disease in an animal model of prion disease. Using in vivo MTR, significant changes were detected in the cortex and thalamus of late-stage prion -infected mice as compared to littermates. In addition, we found a significant increase of MTR in thalamus and cortex of 80 dpi healthy mice when compared with 160 dpi healthy mice suggestive of changes occurring during the development of the brain. Using quantitative T2 mapping, significantly higher values were measured in thalamus of prion mice at all stages of the disease (T2=40ms) while T1 was found to be significantly higher in cortex (T1=1.89s) and hippocampus, albeit only in late-stage prion mice as compared to aged-matched controls (T1=1.67s). Using quantitative MRS significant changes were detected in glutamate (Glu) and myo-inositol (Ins) at all stages of prion disease when compared with the control group. NAA, Cr, Lactate and Lipids were only found to be significantly different at early and late stages of the disease while Taurine (Tau) was only significantly increased in the asymptomatic stage without any significant change at early and late stages of the disease. These changes in MRI and MRS signals, which precede clinical signs of disease, could provide insights into the pathogenesis of this disease and may enable early detection of pathology.
FastCAT accelerates absolute quantification of proteins by using multiple short non-purified chimeric standards
Authors: Rzagalinski Ignacy , Bogdanova Aliona , Raghuraman Bharath Kumar , Geertsma Eric R. , Hersemann Lena , Ziemssen Tjalf , Shevchenko Andrej
Published: December 2021

Absolute (molar) quantification of clinically relevant proteins determines their reference values in liquid and solid biopsies. FastCAT (for Fast-track QconCAT) method employs multiple short (<50 kDa) stable-isotope labeled chimeric proteins (CPs) composed of concatenated quantotypic (Q-) peptides representing the quantified proteins. Each CP also comprises scrambled sequences of reference (R-) peptides that relate its abundance to a single protein standard (BSA). FastCAT not only alleviates the need in purifying CP or using SDS-PAGE, but also improves the accuracy, precision and dynamic range of the absolute quantification by grouping Q-peptides according to the expected abundance of target proteins. We benchmarked FastCAT against the reference method of MS Western and tested it in the direct molar quantification of neurological markers in the human cerebrospinal fluid at the low ng/mL level.
Benchmarking small-variant genotyping in polyploids
Authors: Cooke Daniel P. , Wedge David C. , Lunter Gerton
Published: December 2021

Genotyping from sequencing is the basis of emerging strategies in the molecular breeding of polyploid plants. However, compared with the situation for diploids, in which genotyping accuracies are confidently determined with comprehensive benchmarks, polyploids have been neglected; there are no benchmarks measuring genotyping error rates for small variants using real sequencing reads. We previously introduced a variant calling method, Octopus, that accurately calls germline variants in diploids and somatic mutations in tumors. Here, we evaluate Octopus and other popular tools on whole-genome tetraploid and hexaploid data sets created using in silico mixtures of diploid Genome in a Bottle (GIAB) samples. We find that genotyping errors are abundant for typical sequencing depths but that Octopus makes 25% fewer errors than other methods on average. We supplement our benchmarks with concordance analysis in real autotriploid banana data sets.
Affordable housing in urban India: a review of critical success factors (CSFs) addressing housing adequacy with affordability for the urban poor
Authors: Agarwal Shagun , Singh Tribhuvan Pratap , Bajaj Deepak , Pant Vimal
Published: December 2021

Purpose

This paper aims to focus on the housing situation in Indian cities and the various stakeholders involved in the housing sector. This study addresses the conflict in expectations of the supply and demand side of the housing and establishes the factors crucial to making housing successful for all the stakeholders, essential for sustainable urban development.

Design/methodology/approach

This paper is developed using the content analysis of preceding independent reviews on housing sustainability by authors across the globe, a review of the current housing situation in Indian cities and a Pilot study of the desired qualitative aspects of housing by the consumer group.

Findings

This paper identifies the challenges and constraints of the various stakeholders involved in the housing sector. A comprehensive list of all the parameters, both qualitative and quantitative, essential for successful housing implementation, focused on the preferences of the demand side, also referred to as the “Critical Success Factors (CSFs)” is generated. The results advocate a strict consideration and integration of these CSFs with the housing policies for all future housing projects.

Research limitations/implications

Most of the studies conducted in the past have reviewed the housing situation in India from the perspective of the government authorities and the initiatives undertaken by them to improve the housing crisis. However, a gap exists in achieving a balanced understanding of the supply-side constraints, with the demand-side expectations from the housing. Focusing only on the supply without adequately understanding the consumption can only lead to further chaos in the already turbulent housing situation.

Originality/value

To the best of author’s knowledge, this is among the first attempts to address the housing scenario in urban centers of India, simultaneously from the perspective of both the demand side and the supply side of the housing, giving additional impetus to the expectations of the demand side which are often ignored. This study becomes more relevant in the ongoing pandemic situation to be able to provide appropriate and acceptable housing solutions to all.
Tertiary wavelet model based automatic epilepsy classification system
Authors: Jaglan Satyender , Dhull Sanjeev Kumar , Singh Krishna Kant
Published: December 2021

Purpose

This work proposes a tertiary wavelet model based automatic epilepsy classification system using electroencephalogram (EEG) signals.

Design/methodology/approach

In this paper, a three-stage system has been proposed for automated classification of epilepsy signals. In the first stage, a tertiary wavelet model uses the orthonormal M-band wavelet transform. This model decomposes EEG signals into three bands of different frequencies. In the second stage, the decomposed EEG signals are analyzed to find novel statistical features. The statistical values of the features are demonstrated using multi-parameters graph comparing normal and epileptic signals. In the last stage, the features are inputted to different conventional classifiers that classify pre-ictal, inter-ictal (epileptic with seizure-free interval) and ictal (seizure) EEG segments.

Findings

For the proposed system the performance of five different classifiers, namely, KNN, DT, XGBoost, SVM and RF is evaluated for the University of BONN data set using different performance parameters. It is observed that RF classifier gives the best performance among the above said classifiers, with an average accuracy of 99.47%.

Originality/value

Epilepsy is a neurological condition in which two or more spontaneous seizures occur repeatedly. EEG signals are widely used and it is an important method for detecting epilepsy. EEG signals contain information about the brain's electrical activity. Clinicians manually examine the EEG waveforms to detect epileptic anomalies, which is a time-consuming and error-prone process. An automated epilepsy classification system is proposed in this paper based on combination of signal processing (tertiary wavelet model) and novel features-based classification using the EEG signals.
Contextual factors moderating the impact of strategic management accounting on competitive advantage
Authors: Oyewo Babajide
Published: December 2021

Purpose

This study investigates the influence of six interrelated contextual factors, namely organisational structure, quality of information technology, business strategy in terms of deliberate strategy-formulation, market orientation, market competition and perceived environmental uncertainty (PEU), on the usage intensity of innovative management accounting techniques commonly referred to as strategic management accounting (SMA); the impact of SMA usage on competitive advantage; and the moderating influence of the contextual factors on the relationship between SMA usage and competitive advantage.

Design/methodology/approach

Survey data were obtained through a structured questionnaire from publicly listed manufacturing companies on the main board of the Nigerian Stock Exchange (NSE). Ordinary least squares (OLS) regression and moderated regression were used to analyse data. Both exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were used to examine the validity and reliability of variables as first and second order of analysis. Structural equation modelling (SEM) (maximum likelihood estimation method) was applied to assess the robustness of result.

Findings

Market orientation and deliberate strategy-formulation emerged as significant determinants of SMA usage intensity. Although there is a significant relationship between SMA usage and competitive advantage, the strength of the relationship is moderate. Organisational structure, deliberate strategy-formulation and PEU significantly moderate the relationship between SMA usage and competitive advantage.

Research limitations/implications

The emergence of deliberate strategy-formulation, as both a significant predictor of SMA usage intensity and as the strongest moderator of the relationship between SMA usage and competitive advantage, establish that it is organisations that take a proactive approach to strategy issues that may derive the most benefit from SMA utilisation.

Practical implications

The result from this study brings to fore the need to involve management accountants in strategy-formulation and implementation in order to leverage their competence in deploying SMA techniques to enhance organisational competitiveness.

Originality/value

The current study is the first, to the researcher's knowledge, to specifically examine interrelated contextual factors distinctively affecting SMA usage and organisational competitiveness in a developing country. Whilst these six factors have been stressed as important determinants of the adoption of innovative management accounting techniques, the study provides empirical evidence on the extent to which they exert on SMA. The study presents empirical evidence on the relevance of market orientation—a construct which has surprisingly received little research attention in management accounting literature—as a variable which could affect the adoption of management accounting innovation.
Everyday genocide: femicide, transicide and the responsibility to protect
Authors: Standish Katerina
Published: December 2021

Purpose

The purpose of this paper is to establish a conceptual connection between gender-based violence (GBV) and genocide. Victims of gendercide, such as femicide and transicide, should be eligible for protections assigned to victims of genocide, including the Responsibility to Protect (R2P).

Design/methodology/approach

This study examines genocide, gendercide, femicide, transicide and the R2P doctrine to formulate a platform of engagement from which to argue the alignment and congruence of genocide with gendercide. Using a content analysis of the United Nations High Commission for Refugees definition of GBV, and Article II of the Genocide Convention (GC) five “directive” facets are examined, namely, identity, physical violence, psychological violence, oppressive violence and repressive violence.

Findings

Expressions of physical violence, psychological violence, oppressive violence and repressive violence reflected similarity, whereas the GCs omit sex and gender as facets of identity group inclusion. The only variation is the encapsulation of identity factors included in the acts of harm.

Practical implications

The elevation of gendercide to the status of genocide would permit us the leverage to make it not only illegal to permit gendercide – internationally or in-country – but make it illegal not to intervene, too.

Social implications

Deliberate harm based on sex and gender are crimes against people because of their real or perceived group membership, and as such, should be included in genocide theory and prevention.

Originality/value

This study explores a new conceptual basis for addressing gendercidal violence nationally to include sex and gender victim groups typically excluded from formal parameters of inclusion and address due to limitations in Article II. The analysis of genocide alongside GBV may inform scholars and activists in the aim to end gendered violence.
Policy barriers to sustainable construction practice in the Nigerian construction industry: an exploratory factor analysis
Authors: Babalola Ayotunde , Harinarain Nishani
Published: December 2021

Purpose

Sustainable construction practice is structured on regulatory and non-regulatory policies in developed and most developing countries. With the gradual uptake of sustainability concerns in the construction industry, this paper aims to identify the strategic need for clear-cut policies to improve sustainable construction practice. Previous studies have harped on the need for regulatory and industrial/organisational policies on improving sustainable construction practice within the Nigerian construction industry.

Design/methodology/approach

A questionnaire survey was used to evaluate the perspectives of construction professionals on the policy barriers for sustainable construction practice in Nigeria, and 46 policy barriers were identified. A total of 249 questionnaires were returned and useable for analysis.

Findings

Factor analysis revealed four clusters in the policy barriers to sustainable construction practice in the following order of significance: implementation strategies for sustainable construction practice, owners/client inputs for sustainable construction practice, stakeholder’s policy barriers and governmental and regulatory policy barriers.

Practical implications

Mitigating the identified barriers through effective policies will require adequate inputs from all relevant policymaking stakeholders and ensure improved sustainable construction practice among stakeholders and policymakers in the industry. This will in turn set a high standard and promote the practice of sustainable construction.

Originality/value

This study goes a step further in identifying the policy issues needed to ensure a smooth implementation of sustainable construction practice. The research findings will serve as a guide for policymakers in developing countries that through mitigation of the identified barriers, sustainable construction practice will be promoted.
Digital technologies and the balance between control and empowerment in performance management
Authors: Korsen Eirik Bådsvik Hamre , Holmemo Marte Daae-Qvale , Ingvaldsen Jonas A.
Published: December 2021

Purpose

This paper aims to explore how manufacturing organisations’ performance measurement and management (PMM) systems are evolving when digital technologies (DTs) are deployed. It focusses on the operational level, asking whether DTs are used to promote command-and-control or empowerment-oriented performance management.

Design/methodology/approach

The findings are based on a single case study from a department of a Norwegian electrochemical plant. The department recently implemented a performance measurement system (PMS) supported by DTs to capture, analyse and visualise close-to-real-time performance data on individuals and teams. The authors analysed both the management practices associated with the new PMS and how those related to other PMM-subsystems in the organisation.

Findings

When seen in isolation, the new PMS was used to promote empowerment and operators reported a significant increase in perceived psychological empowerment. However, other parts of the organisation’s PMM system remained control-oriented, so that the overall balance between control and empowerment remained stable.

Practical implications

New PMSs might be added to support local needs and create arenas for empowerment without disturbing the overall balance in the PMM system.

Originality/value

Building on the insights from the case study, the authors propose that DTs may be deployed to promote both command-and-control and empowerment within different PMM subsystems in the same organisation. Hence, the deployment of DTs is likely to have contradictory effects, which are best understood through a “system of systems” perspective on PMMs.
The auditing profession and the key audit matter reporting requirement
Authors: Mihret Dessalegn Getie , Kansal Monika , Muttakin Mohammad Badrul , Rana Tarek
Published: December 2021

Purpose

This study aims to examine the setting of International Standards on Auditing (ISA) 701 on disclosing key audit matters (KAMs) to explore the role of standard setting in maintaining or reconstituting the relationship of the auditing profession with preparers and users of financial reports.

Design/methodology/approach

This study draws on concepts from the sociology of the professions literature and the regulatory space metaphor. Data comprises comment letters and other documents pertaining to the setting of ISA 701.

Findings

The study shows that the KAM reporting requirement is part of the ongoing re-calibration of the regulatory arrangements governing auditing, which started in the early 2000s. This study interprets standard setting as a site for negotiating the relationships between linked ecologies in the audit regulatory space, namely, the auditing profession, preparers of financial statements and users of audited reports. This study identifies three processes involved in setting ISA 701, namely, reconstitution of the rules governing auditors’ reports as a link between the three ecologies, preserving boundaries between the auditing profession and preparers and negotiation aimed at balancing competing interests of the interrelated ecologies.

Originality/value

The study offers insights into the role of regulatory rule setting as a central medium through which the adaptive relationship of the profession with its environment is negotiated.
Class Composition, Labour's Strategy and the Politics of Work
Authors: Thompson Paul , Pitts Frederick Harry , Ingold Jo , Cruddas Jon
Published: December 2021

This article locates the emergence of new thinking on the left around work, age and assets within the lineage of ‘class composition’ analysis arising from the autonomist movement in mid‐twentieth century Italy. With reference to contemporary debates around electoral and political strategy within the Labour Party, the article critically appraises the potential applicability of this extra‐parliamentary ‘militant methodology’ for the present day identification of ontologically and epistemologically privileged class actors and political subjects in a first past the post parliamentary system. Noting the resemblance of such approaches to the orthodox Marxist ‘gravedigger thesis’, which reads off from economic relations the existence of agents of social transformation, the article argues that this analytical and strategic framing represents a flawed approach for Labour and the wider left. Other approaches are needed to navigate successfully the pluralist construction of consent through coalition building and compromise on which parliamentary politics rests.
Women, Land and Property, Then and Now: An Afterword
Authors: McDonagh Briony
Published: December 2021

The papers in this special issue make an important contribution to a growing body of work, exploring not only the ways gender and property were co‐constituted in Britain and the British colonies in the long eighteenth century but also the sources scholars must work with in uncovering women's lives and experiences. In this afterword, I explore some of the possibilities and prospects for developing research in this area, highlighting new directions and themes, as well as teasing out some of the wider implications of this persuasive and fascinating collection.