bluuebunny/crossref_metadata_2025 huggingface dataset:
Demographically explicit scans for barriers to gene flow using gIMble
Authors: Laetsch Dominik R , Bisschop Gertjan , Martin Simon H , Aeschbacher Simon , Setter Derek , Lohse Konrad
Published: October 2022

Identifying regions of the genome that act as barriers to gene flow between recently diverged taxa has remained challenging given the many evolutionary forces that generate variation in genetic diversity and divergence along the genome, and the stochastic nature of this variation. Progress has been impeded by a conceptual and methodological divide between analyses that infer the demographic history of speciation and genome scans aimed at identifying locally maladaptive alleles i.e. genomic barriers to gene flow. Here we implement genomewide IM blockwise likelihood estimation (gIMble), a composite likelihood approach for the quantification of barriers, that bridges this divide. This analytic framework captures background selection and selection against barriers in a model of isolation with migration (IM) as heterogeneity in effective population size (Ne) and effective migration rate (me), respectively. Variation in both effective demographic parameters is estimated in sliding windows via pre-computed likelihood grids.gIMbleincludes modules for pre-processing/filtering of genomic data and performing parametric bootstraps using coalescent simulations. To demonstrate the new approach, we analyse data from a well-studied pair of sister species of tropical butterflies with a known history of post-divergence gene flow:Heliconius melpomeneandH. cydno. Our analyses uncover both large-effect barrier loci (including well-known wing-pattern genes) and a genome-wide signal of a polygenic barrier architecture.

Author summary

As a fundamental process generating biological diversity, speciation involves the evolution of reproductive isolation and thus the build-up of barriers to genetic exchange among organismal groups. While population genomic data are arguably the only source of information we have about most recent speciation events, the way such data are analysed remains depressingly superficial: population genomic studies of speciation are phrased either as scans for outliers of genetic differentiation, or are based on models of neutral evolution under the constraint of a single genome-wide demography. Here we introduce a new statistical framework calledgIMbleto estimate the effective rate of gene flow and the effective population sizes along the genome from population genomic data. By capturing genome-wide variation in these two effective demographic parameters,gIMbledisentangles the genomic footprints of different modes of selection and provides a direct quantification of the species barrier. To illustrate this framework, we analyse a classic speciation genomic dataset fromHeliconiusbutterflies. We show that barriers to gene flow in this system include both large effect loci – most, but not all, of which were known from functional work – as well as a genome-wide signature of weak-effect polygenic barriers.
RAPTOR: A Five-Safes approach to a secure, cloud native and serverless genomics data repository
Authors: Shih Chih Chuan , Chen Jieqi , Lee Ai Shan , Bertin Nicolas , Hebrard Maxime , Khor Chiea Chuen , Li Zheng , Juan Tan Joanna Hui , Meah Wee Yang , Peh Su Qin , Mok Shi Qi , Sim Kar Seng , Liu Jianjun , Wang Ling , Wong Eleanor , Li Jingmei , Tin Aung , Cheng Ching-Yu , Heng Chew-Kiat , Yuan Jian-Min , Koh Woon-Puay , Saw Seang Mei , Friedlander Yechiel , Sim Xueling , Chai Jin Fang , Chong Yap Seng , Davila Sonia , Goh Liuh Ling , Lee Eng Sing , Wong Tien Yin , Karnani Neerja , Leong Khai Pang , Yeo Khung Keong , Chambers John C , Chi Lim Su , Mong Goh Rick Siow , Tan Patrick , Dorajoo Rajkumar
Published: October 2022

Genomic researchers are increasingly utilizing commercial cloud platforms (CCPs) to manage their data and analytics needs. Commercial clouds allow researchers to grow their storage and analytics capacity on demand, keeping pace with expanding project data footprints and enabling researchers to avoid large capital expenditures while paying only for IT capacity consumed by their project. Cloud computing also allows researchers to overcome common network and storage bottlenecks encountered when combining or re-analysing large datasets. However, cloud computing presents a new set of challenges. Without adequate security controls, the risk of unauthorised access may be higher for data stored on the cloud. In addition, regulators are increasingly mandating data access patterns and specific security protocols on the storage and use of genomic data to safeguard rights of the study participants. While CCPs provide tools for security and regulatory compliance, utilising these tools to build the necessary controls required for cloud solutions is not trivial as such skill sets are not commonly found in a genomics lab. The Research Assets Provisioning and Tracking Online Repository (RAPTOR) by the Genome Institute of Singapore is a cloud native genomics data repository and analytics platform focusing on security and regulatory compliance. Using a “five-safes” framework (Safe Purpose, Safe People, Safe Settings, Safe Data and Safe Output), RAPTOR provides security and governance controls to data contributors and users leveraging cloud computing for sharing and analysis of large genomic datasets without the risk of security breaches or running afoul of regulations. RAPTOR can also enable data federation with other genomic data repositories using GA4GH community-defined standards, allowing researchers to boost the statistical power of their work and overcome geographic and ancestry limitations of data sets
Clarifying Microbial Nitrous Oxide Reduction Under Aerobic Conditions: Tolerant, Intolerant, and Sensitive
Authors: Wang Zhiyue , Vishwanathan Nisha , Kowaliczko Sophie , Ishii Satoshi
Published: October 2022

One of the major challenges for the bioremediation application of microbial N2O reduction is its oxygen sensitivity. While a few strains were reported capable of reducing N2O under aerobic conditions, the N2O reduction kinetics of phylogenetically diverse N2O reducers are not well understood. Here we analyzed and compared the kinetics of Clade I and Clade II N2O-reducing bacteria in the presence or absence of O2by using a whole-cell assay with N2O and O2microsensors. Among the seven strains tested, N2O reduction ofStutzerimonas stutzeriTR2 and ZoBell were not inhibited by oxygen (i.e., oxygen tolerant).Paracoccus denitrificans, Azospirillum brasilense, andGemmatimonas aurantiacareduced N2O in the presence of O2but slower than in the absence of O2(i.e., oxygen sensitive). N2O reduction ofPseudomonas aeruginosaandDechloromonas aromaticadid not occur when O2was present (i.e., oxygen intolerant). Amino acid sequences and predicted structures of NosZ were highly similar among these strains, whereas oxygen-tolerant N2O reducers had higher oxygen consumption rates. The results suggest that the mechanism of O2tolerance is not directly related to NosZ structure but rather related to the scavenging of O2in the cells and/or accessory proteins encoded by thenoscluster.

IMPORTANCE

Some bacteria can reduce N2O in the presence of O2, whereas others cannot. It is unclear whether this trait of aerobic N2O reduction is related to the phylogeny and structure of N2O reductase. The understanding of aerobic N2O reduction is critical in guiding emission control, due to the common concurrence of N2O and O2in natural and engineered systems. This study provided the N2O reduction kinetics of various bacteria under aerobic and anaerobic conditions and classified the bacteria into oxygen-tolerant, -sensitive, and -intolerant N2O reducers. Oxygen-tolerant N2O reducers rapidly consumed O2, which could help maintain the low O2concentration in the cells and keep their N2O reductase active. These findings are important and useful when selecting N2O reducers for bioremediation applications.
Acquisition of a large virulence plasmid (pINV) promoted temperature-dependent virulence and global dispersal of O96:H19 enteroinvasiveEscherichia coli
Authors: Miles Sydney L. , Torraca Vincenzo , Dyson Zoe A. , López-Jiménez Ana Teresa , Foster-Nyarko Ebenezer , Jenkins Claire , Holt Kathryn E. , Mostowy Serge
Published: October 2022

EnteroinvasiveEscherichia coli(EIEC) andShigellaare closely related agents of bacillary dysentery. It is widely viewed that EIEC andShigellaspecies evolved fromE. colivia independent acquisitions of a large virulence plasmid (pINV) encoding a type three secretion system (T3SS). Sequence Type (ST)99 O96:H19E. coliis an emergent clone of EIEC responsible for recent outbreaks in Europe and South America. Here, we reconstruct the evolutionary history of ST99E. coliusing BactDating, revealing distinct phylogenomic clusters of pINV-positive and -negative isolates. To study the impact of pINV acquisition on the virulence of this clone, we developed an EIEC-zebrafish infection model showing that virulence of ST99 EIEC is thermoregulated. Strikingly, zebrafish infection using the oldest available pINV-negative isolate reveals a separate, temperature-independent mechanism of virulence, indicating that ST99 non-EIEC strains were virulent before pINV acquisition. Taken together, these results suggest that an already pathogenicE. coliacquired pINV and that virulence of ST99 isolates became thermoregulated once pINV was acquired.

Importance

EnteroinvasiveEscherichia coli(EIEC) andShigellaare etiological agents of bacillary dysentery. Sequence Type (ST)99 is an emergent clone of EIEC hypothesised to cause human disease by the recent acquisition of pINV, a large plasmid encoding a type three secretion system (T3SS) that confers the ability to invade human cells. Here, using phylogenomic reconstruction and zebrafish larvae infection, we show that the virulence of ST99 EIEC isolates is highly dependent on temperature, while pINV-negative isolates encode a separate temperature-independent mechanism of virulence. These results highlight that ST99 non-EIEC isolates may have been virulent before pINV acquisition and highlight an important role for pINV acquisition in the emergence of ST99 EIEC in humans, allowing wider dissemination across Europe and South America.
Multiscale Hybrid Fabrication: Volumetric Printing Meets Two-Photon Ablation
Authors: Rizzo Riccardo , Ruetsche Dominic , Liu Hao , Chansoria Parth , Wang Anny , Hasenauer Amelia , Zenobi-Wong Marcy
Published: October 2022

The vascular tree spans length scales from centimeter to micrometer. Engineering multiscale vasculature, in particular from millimeter vessels to micrometer-size capillaries, represents an unmet challenge and may require the convergence of two or more printing modalities. Leveraging the great advances in light-based biofabrication, we herein introduce a hybrid strategy to tackle this challenge. By combining volumetric printing (VP) and high-resolution two-photon ablation (2PA), we demonstrate the possibility to create complex multiscale organotypic perfusable models with features ranging from mesoscale (VP) to microscale (2PA). To successfully combine these two methods, we first eliminated micrometer-size defects generated during VP process. Due to optical modulation instability of the laser source and selffocusing phenomenon that occurs when the light triggers the photoresin crosslinking, VP printed constructs feature micrometer-size filaments and channels. By optical tuning the refractive index of the photoresin, we demonstrate defect-free VP that can then be combined with 2PA. To facilitate the 2PA process and meet VP requirements, we introduce a purely protein-based photoclick photoresin combining gelatin-norbornene and gelatin-thiol. By optimizing defect-free VP and 2PA processes, we finally demonstrate the possibility to generate complex 3D vasculature-like constructs with features ranging from ~400 μm of VP to ~2 μm of 2PA. This hybrid strategy opens new possibilities to better recapitulate microtissues vasculature and complex architectures, with particular potential for microfluidics and organ/tissue-on-a-chip technologies.
Assessing the impacts of various factors related to identification, conservation, biogenesis, and function on circular RNA reliability
Authors: Chuang Trees-Juen , Chiang Tai-Wei , Chen Chia-Ying
Published: October 2022

Circular RNAs (circRNAs) are non-polyadenylated RNAs with a continuous loop structure characterized by a non-co-linear back-splice junction (BSJ). While dozens of computational tools have been developed and identified millions of circRNA candidates in diverse species, it remains a major challenge for determining circRNA reliability due to various types of false positives. Here, we systematically assess the impacts of numerous factors related to identification, conservation, biogenesis, and function on circRNA reliability by comparisons of circRNA expression from mock (total RNAs) and the corresponding co-linear/polyadenylated RNA-depleted datasets based on three different RNA treatment approaches. Eight important indicators of circRNA reliability are determined. The relative contribution to variability explained analyses further reveal that the relative importance of these factors in affecting circRNA reliability is conservation level of circRNA > full-length circular sequences > supporting BSJ read count > both BSJ donor and acceptor splice sites at the same co-linear transcript isoforms > both BSJ donor and acceptor splice sites at the annotated exon boundaries > BSJs detected by multiple tools > supporting functional features > both BSJ donor and acceptor splice sites undergoing alternative splicing. By extracting RT-independent circRNAs, circRNAs passing multiple experimental validations, and database-specific circRNAs, we showed the additive effects of these important factors in determining circRNA reliability. This study thus provides a useful guideline and an important resource for selecting high-confidence circRNAs for further investigations.
A multi-enhancer hub at theEts1locus controls T cell differentiation and allergic inflammation through 3D genome topology
Authors: Chandra Aditi , Yoon Sora , Michieletto Michael F. , Goldman Naomi , Ferrari Emily K. , Fasolino Maria , Joannas Leonel , Kee Barbara L. , Henao-Mejia Jorge , Vahedi Golnaz
Published: October 2022

Multi-enhancer hubs are spatial clusters of enhancers which have been recently characterized across numerous developmental programs. Yet, the functional relevance of these three-dimensional (3D) structures is poorly understood. Here we show that the multiplicity of enhancers interacting with the transcription factorEts1is essential to control the precise expression level of this gene in response to cellular cues, and the failure to do so can lead to allergic diseases. Focusing on T cells as a model, we identified a highly connected multi-enhancer hub at theEts1locus, comprising a noncoding regulatory element that is a hotspot for sequence variation associated with allergic diseases. We deleted this hotspot and found that the multi-enhancer connectivity is dispensable for T cell development but required for CD4+T helper (Th1) differentiation in response to changes in the cytokine milieu. Mice lacking this hotspot are thus protected from Th1-mediated colitis but demonstrate an overt allergic response to house dust mites, a T cell-mediated response which is dampened by Th1 cells. Mechanistically, the multi-enhancer hub controls the expression level ofEts1that is dispensable for the active enhancer landscape but required for the Th1-specific genome topology through recruitment of CTCF. Together, we establish a paradigm for the functional and mechanistic relevance of multi-enhancer hubs controlling cellular competence to respond specifically to an inductive cue.
Variation in thermal physiology can drive the temperature-dependence of microbial community richness
Authors: Clegg Tom , Pawar Samraat
Published: October 2022

Predicting how species diversity changes along environmental gradients is an enduring problem in ecology. Current theories cannot explain the observation that microbial taxonomic richness can show positive, unimodal, as well as negative diversity-temperature gradients. Here we derive a general empirically-grounded theory that can explain this phenomenon by linking microbial species richness in local communities to variation in their temperature-driven competitive interaction and growth rates. It predicts that richness depends on variation in shape of the thermal performance curves of these metabolic traits across species in the community. Specifically, the shape of the microbial community temperature-richness relationship depends on how the strength of competition across the community and the degree of variation in growth rates changes across temperature. These in turn can be predicted from the variation in thermal performance across the community. We show that empirical variation in the thermal performance curves of metabolic traits across extant bacterial taxa is indeed sufficient to generate the variety of community-level temperature-richness responses observed in the real world. Our results provide a new mechanism that can help explain temperature-diversity gradients in microbial communities, and provide a quantitative framework for interlinking variation in the thermal physiology of microbial species to their community-level diversity.
Dissecting the functional contributions of different neuronal subtypes in the dorsal striatum to perseverative behaviour in ephrin-A2/A5-/-mice
Authors: Tomar Maitri , Rodger Jennifer , Moretti Jessica
Published: October 2022

Overreliance on habit is linked with disorders such as drug addiction and obsessive-compulsive disorder and there is increasing interest in the use of repetitive transcranial magnetic stimulation (rTMS) to alter neuronal activity in the relevant pathways and reduce relapse or accelerated shift towards habit formation. Here we studied the brains of ephrin-A2A5-/-mice, which previously showed perseverative behaviour in progressive-ratio tasks, associated with low cellular activity in nucleus accumbens. We investigated if rTMS treatment had altered the hierarchical recruitment of brain regions from ventral to dorsal striatum associated with abnormal habit formation in these mice.

Brain sections of mice that underwent progressive-ratio tasks with and without low intensity rTMS (LI-rTMS) were taken from a previous study. We take advantage of the previous characterisation of perseverative behaviour to investigate the contribution of different neuronal subtypes and striatal regions. Striatal regions were stained for neuronal activation with c-Fos and for medium spiny neurons with DARPP32. Qualitative analysis was carried out for other neuronal subtypes in the striatum - GABAergic, parvalbumin-expressing and cholinergic interneurons.

Contrary to our hypothesis, we found neuronal activity in ephrin-A2A5-/-mice still reflected goal-directed behaviour. However, we saw that the dorsolateral striatum contributed more to total striatal activity in untreated ephrin-A2/A5-/-mice. This supported our hypothesis that ephrin-A2/A5-/-mice have greater c-Fos activity in habit-associated striatal regions. LI-rTMS in ephrin-A2A5-/-mice also appeared to delay the shift from goal-directed to habitual behaviour as suggested by increased activation in dorsomedial striatum and nucleus accumbens.
Autism-related behavioral phenotypes of threeCamk2amutant mouse lines with reduced CaMKIIα expression and/or activity
Authors: Thomas Jessica R. , Spiess Keeley L. , Colbran Roger J.
Published: October 2022

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a key modulator of excitatory synaptic transmission, gene expression, learning and memory. Mutations in theCAMK2Agene, which encodes CaMKIIα and is highly expressed in multiple regions in the forebrain, have been recently linked to neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). Our lab generated and characterized a knock-in (KI) mutant mouse with a glutamate-183 to valine (E183V) CaMKIIα mutation detected in several children diagnosed with ASD or ID. The E183V mutation reduces CaMKIIα activity and expression levels but the contributions of these two changes to the ASD-related behavioral phenotypes of these mice are unclear. Therefore, we performed side-by-side comparisons of the behavioral phenotypes of CaMKIIα E183V-KI mice with two other mutant mouse lines with either a complete loss of CaMKIIα expression (CaMKIIα Null mice) or reduced kinase activity (due to a threonine-286 to alanine mutation that abrogates autophosphorylation at this site) with no significant change in expression levels (CaMKIIα T286A-KI mice). In all three lines, homozygous mutant mice displayed increased stereotypic jumping behavior and hyperactivity, without alterations in anxiety or social interactions. Interestingly, homozygous mutant mice in all three lines also displayed a substantial reduction in tactile sensitivity using the Von Frey filament test. Together, these data suggest that reductions of either CaMKIIα expression or activity in mice disrupted normal motor and sensory functions.
Variability of wheel running behavior in mice is dependent on housing, sex, and genetic background
Authors: Kanold-Tso Zara , Plenz Dietmar
Published: October 2022

Environmental enrichment (EE) has been increasingly used to enhance and support the physiological fitness and natural behavior of research animals. For mice, which are known to be highly active nocturnal animals that live in large social groups, the introduction of running wheels is a particularly promising approach in EE. When wheels are introduced to their home cage, mice increase their nocturnal locomotion activity by orders of magnitude. However, little is known about how mice share such a readily adopted EE. Here, we studied wheel running in single-housed and group-housed mice. We hypothesized that group-housed mice will compete over the scarce resource of a running wheel leading to a change in overall wheel usage compared to single-housed mice that have exclusive wheel access. We measured wheel locomotion in two strains of single-housed and group-housed mice over multiple 24h periods at sub-second temporal resolution using a custom-designed data acquisition system. We observed both sex- and housing-specific differences in wheel usage. In single-housed C57Bl/6 mice, mice ran at consistent speeds and females ran larger distances. In group housing, periods of slow locomotion speeds as well as speed transitions emerged with fewer breaks in wheel usage. This group effect was less pronounced in a genetic mouse model (parvalbumin-Cre on C57Bl/6 background).

Our results demonstrate a change in wheel usage during group housing which supports competition over EE resources while enhancing overall locomotion in mice.
Protein aggregation and calcium dysregulation are the earliest hallmarks of synucleinopathy in human midbrain dopaminergic neurons
Authors: Virdi Gurvir S , Choi Minee L , Evans James R , Yao Zhi , Athauda Dilan , Strohbuecker Stephanie , Wernick Anna I , Alrashidi Haya , Melandri Daniela , Perez-Lloret Jimena , Angelova Plamena R , Sylantyev Sergiy , Eaton Simon , Heales Simon , Kunath Tilo , Horrocks Mathew H , Abramov Andrey Y , Patani Rickie , Gandhi Sonia
Published: October 2022

Mutations in theSNCAgene cause autosomal dominant Parkinson’s disease (PD), with progressive loss of dopaminergic neurons in the substantia nigra, and accumulation of aggregates of α-synuclein. However, the sequence of molecular events that proceed from theSNCAmutation during development, to its end stage pathology is unknown. Utilising human induced pluripotent stem cells (hiPSCs) withSNCAmutations, we resolved the temporal sequence of pathophysiological events that occur during neuronal differentiation in order to discover the early, and likely causative, events in synucleinopathies. We adapted a small molecule-based protocol that generates highly enriched midbrain dopaminergic (mDA) neurons (>80%). We characterised their molecular identity using single-cell RNA sequencing and their functional identity through the synthesis and secretion of dopamine, the ability to generate action potentials, and form functional synapses and networks. RNA velocity analyses confirmed the developmental transcriptomic trajectory of midbrain neural precursors into mDA neurons using our approach, and identified key driver genes in mDA neuronal development. To characterise the synucleinopathy, we adopted super-resolution methods to determine the number, size and structure of aggregates inSNCA-mutant mDA neurons. At one week of differentiation, prior to maturation to mDA neurons of molecular and functional identity, we demonstrate the formation of small aggregates; specifically, β-sheet rich oligomeric aggregates, inSNCA-mutant midbrain immature neurons. The aggregation progresses over time to accumulate phosphorylated aggregates, and later fibrillar aggregates. When the midbrain neurons were functional, we observed evidence of impaired physiological calcium signalling, with raised basal calcium, and impairments in cytosolic and mitochondrial calcium efflux. Once midbrain identity fully developed,SNCA-mutant neurons exhibited bioenergetic impairments, mitochondrial dysfunction and oxidative stress. During the maturation of mDA neurons, upregulation of mitophagy and autophagy occured, and ultimately these multiple cellular stresses lead to an increase in cell death by six weeks post-differentiation. Our differentiation paradigm generates an efficient model for studying disease mechanisms in PD, and highlights that protein misfolding to generate intraneuronal oligomers is one of the earliest critical events driving disease in human neurons, rather than a late-stage hallmark of the disease.
The gene expression landscape of the human locus coeruleus revealed by single-nucleus and spatially-resolved transcriptomics
Authors: Weber Lukas M. , Divecha Heena R. , Tran Matthew N. , Kwon Sang Ho , Spangler Abby , Montgomery Kelsey D. , Tippani Madhavi , Bharadwaj Rahul , Kleinman Joel E. , Page Stephanie C. , Hyde Thomas M. , Collado-Torres Leonardo , Maynard Kristen R. , Martinowich Keri , Hicks Stephanie C.
Published: October 2022

Norepinephrine (NE) neurons in the locus coeruleus (LC) make long-range projections throughout the central nervous system, playing critical roles in arousal and mood, as well as various components of cognition including attention, learning, and memory. The LC-NE system is also implicated in multiple neurological and neuropsychiatric disorders. Importantly, LC-NE neurons are highly sensitive to degeneration in both Alzheimer’s and Parkinson’s disease. Despite the clinical importance of the brain region and the prominent role of LC-NE neurons in a variety of brain and behavioral functions, a detailed molecular characterization of the LC is lacking. Here, we used a combination of spatially-resolved transcriptomics and single-nucleus RNA-sequencing to characterize the molecular landscape of the LC region and the transcriptomic profile of LC-NE neurons in the human brain. We provide a freely accessible resource of these data in web-accessible and downloadable formats.
GDAP1 binds 4-hydroxynonenal, the toxic end-product of lipid peroxidation, using its GST-like binding pocket
Authors: Googins Matthew R. , Brown Maya , Woghiren-Afegbua Aigbirhemwen O , Kiselyov Kirill I. , VanDemark Andrew P.
Published: October 2022

GDAP1 (Ganglioside-induced differentiation-associated protein 1) is a novel member of the GST superfamily of detoxifying enzymes that is anchored to the outer mitochondrial membrane. GDAP1 mutations and changes in expression levels result in the inherited neuropathy Charcot-Marie-Tooth (CMT) disease, types 2K, 4A and 4H. GDAP1 activity has been associated with many mitochondrial functions however direct molecular interactions underpinning these connections have remained elusive. Here we establish that GDAP1 can bind 4-hydroxynonenal (4HNE), a toxic end-product of lipid peroxidation. 4HNE binding requires the α-loop, a large sequence motif that is inserted within the substrate recognition domain and is unique to GDAP1. In human cells, GDAP1 overexpression plays a cytoprotective role against oxidative stress. This effect is lost upon deletion of the α-loop. Lastly, we demonstrate that a CMT-causing mutant that destabilizes α-loop positioning also results in a decrease in 4HNE binding affinity. Together these results establish 4HNE as the biological ligand for GDAP1, provide mechanistic insight into 4HNE binding, and demonstrate that altered 4HNE recognition is the likely mechanism underlying CMT-causing mutants such as T157P near the 4HNE binding site.
Amygdalostriatal transition zone neurons encode sustained valence to direct conditioned behaviors
Authors: Mills Fergil , Lee Christopher R. , Howe James R. , Li Hao , Shao Shan , Keisler Maria N. , Lemieux Mackenzie E. , Taschbach Felix H. , Keyes Laurel R. , Borio Matilde , Chen Hannah S. , Patel Reesha R. , Gross Alexa L. , Delahanty Jeremy , Cazares Christian , Maree Liezl , Wichmann Romy , Pereira Talmo D. , Benna Marcus K. , Root Cory M. , Tye Kay M.
Published: October 2022

In order to respond appropriately to threats in the environment, the brain must rapidly determine whether a stimulus is important and whether it is positive or negative, and then use that information to direct behavioral responses. Neurons in the amygdala have long been implicated in valence encoding and in fear responses to threatening stimuli, but show transient firing responses in response to these stimuli that do not match the timescales of associated behavioral responses. For decades, there has been a logical gap in how behavioral responses could be mediated without an ensemble representation of the internal state of valence that has rapid onset, high signal-to-noise, and is sustained for the duration of the behavioral state. Here, we present the amygdalostriatal transition zone (ASt) as a missing piece of this highly conserved process that is of paramount importance for survival, which does exactly this: represents an internal state (e.g. fear) that can be expressed in multiple motor outputs (e.g. freezing or escape). The ASt is anatomically positioned as a “shortcut” to connect the corticolimbic system (important for evaluation) with the basal ganglia (important for action selection) with the inputs of the amygdala and the outputs of the striatum – ideally poised for evaluating and responding to environmental threats. Fromin vivocellular resolution recordings that include both electrophysiology and calcium imaging, we find that ASt neurons are unique in that they are sparse coding, extremely high signal-to-noise, and also maintain a sustained response for negative valence stimuli for the duration of the defensive behavior – a rare but essential combination. We further show that photostimulation of the ASt is sufficient to drive freezing and avoidance behaviors. Using single-nucleus RNA sequencing andin situRNA labelling we generate a comprehensive profile of cell types and gene expression in the ASt, and find the ASt is genetically distinct from adjacent striatal and amygdalar structures. We also find that the ASt has a greater proportion of neurons expressingDrd2than neurons expressingDrd1a, a unique feature compared to other regions of the striatum. Usingin vivocalcium imaging, we show that that thisDrd2+population robustly encodes stimuli of negative valence, and in loss-of-function experiments find that optogenetic inhibition ofDrd2+ASt neurons causes a striking reduction in cue-conditioned fear responses. Together, our findings identify the ASt as a previously-unappreciated critical missing link for encoding learned associations and directing ongoing behavior.
Assessment of construction professionals' awareness of the smart building concepts in the Nigerian construction industry
Authors: Ejidike Cyril Chinonso , Mewomo Modupe Cecilia , Anugwo Iruka Chijindu
Published: October 2022

Purpose

The current movement toward digitisation has promoted the adoption of smart building technology globally. Despite its advantages, its usage in developing countries such as Nigeria is still very low. Therefore, the purpose of this paper is to investigate construction professionals' awareness of smart building concepts (SBCs) in the Nigerian construction industry and identify the parameters by which SBCs can be measured.

Design/methodology/approach

A quantitative survey was carried out using a questionnaire to gather relevant data in the study area. This paper was conducted on 363 registered construction professionals in the Nigerian construction industry. The collected data were analysed using descriptive statistics and Kruskal–Wallis H test analysis.

Findings

This paper indicated that the majority of Nigerian construction professionals are aware of SBCs. Furthermore, the Kruskal–Wallis H test shows no significant difference between the awareness level of the various construction professionals. This paper further revealed energy management systems, IT network connectivity, safety and security management systems and building automation systems as the most significant parameters in which SBCs can be measured.

Practical implications

This paper identified significant parameters influencing SBCs awareness in the Nigerian construction industry. These parameters can be integrated into the building during the design stage and can be incorporated into the policymaking process of construction firms to promote the awareness of SBCs and encourage practices related to construction sustainability.

Originality/value

This paper provides empirical evidence on the awareness of SBCs among construction professionals and significant parameters influencing awareness in the Nigerian construction industry.
Female economic empowerment through tourism training in the United Arab Emirates
Authors: Vij Mohit , Upadhya Amitabh , Agha Kakul , Begum Vazeerjaan , Kashmoola Basma Waleed , Senior John Roy
Published: October 2022

Purpose

The issue of female economic empowerment in the Middle East and the North Africa region (MENA) has attracted significant attention; however, its potential in the tourism sector has not been fully explored. This study aims to identify the steps involved in conceptualizing, designing, and conducting a customized tourism training program to economically empower women in the United Arab Emirates (UAE).

Design/methodology/approach

Grounded in stakeholder theory and using a triangulation method of data analysis, the study is an outcome of mixed-method research. The data were collected through focus group interviews, personal interviews and a survey involving women stakeholders from public and private sectors.

Findings

The study revealed that the desired components for tourist guide training among Emirati women include career paths, ways to seek support from family, entrepreneurial and leadership skills development, and destination knowledge.

Originality/value

The study provides theoretical and practical implications for a systematic training approach undertaken by a destination management organization (DMO) in liaison with other stakeholders. The study recommends a series of phases to scientifically design and conduct tourism training in order to empower women.
EDUCATION REFORM AND FINANCIALIZATION: Making the Fiscal Crisis of the Schools
Authors: Farmer Stephanie , Weber Rachel
Published: October 2022

Our fiscal analysis of Chicago Public Schools (CPS) from 1990 to 2018 contributes to a growing scholarship on the financialization of urban governance. We advance the concept of ‘recursive austerity’ to show how devolution and cuts at higher scales push local governments into the hands of both growth and debt machines. The use of short‐term and variable‐rate debt to pay for capital projects causes entrepreneurial and austerity strategies to chafe against their limitations and contradictions, which begets more austerity and structural dependence on credit markets. Faced with deficits, CPS undertook crippling austerity measures, such as staffing cuts, pension holidays and school closures, which disproportionately harmed Black students, households, teachers and neighborhoods. We explain how CPS moved from a voluntary high‐leverage strategy to finance capital projects to endemic debt dependency, characterized by habitual borrowing to refinance old loans and sustain operations. We argue that CPS's debt trap and recurring budget ‘crises’ are the outcomes of the fiscal management decisions it made with investment banks and the City of Chicago, and not only the result of secular trends such as declining enrollments.
Renewable Governance: Good for the Environment?
Authors: DYCK ALEXANDER , LINS KARL V. , ROTH LUKAS , TOWNER MITCH , WAGNER HANNES F.
Published: October 2022

We conjecture that board renewal mechanisms—those substantive enough to renew the thinking of the board—are required before investors can address the mismatch between their preferences regarding environmental sustainability and what insiders at firms are actually doing. We identify the adoption of majority voting for directors and the introduction of a female director as two corporate governance mechanisms potentially strong enough to renew a board's thinking on sustainability. Using a sample of 3,293 firms from 41 countries, along with quasi‐exogenous shocks to board renewal mechanisms in Canada and France, we find that both board renewal mechanisms are associated with significantly higher future environmental performance. Further tests provide suggestive evidence that board renewal is more strongly associated with environmental performance in settings with better institutions and more motivated institutional investors. These results suggest the importance of board renewal for alignment of firm policies with investor preferences around the world.
Situational factors and police use of force across micro‐time intervals: A video systematic social observation and panel regression analysis
Authors: Piza Eric L. , Connealy Nathan T. , Sytsma Victoria A. , Chillar Vijay F.
Published: October 2022

The current study analyzes police use of force as a series of time‐bound transactions between officers, civilians, and bystanders. The research begins with a systematic social observation of use‐of‐force events recorded on police body‐worn cameras in Newark, New Jersey. Researchers measure the occurrence and time stamps for numerous participant physical and verbal behaviors. Data are converted into a longitudinal panel format measuring all observed behaviors in 5‐second intervals. Panel logistic regression models estimate the effect of each behavior on use of force in immediate and subsequent temporal periods. Findings indicate certain variables influence use of force at a distinct point in time, whereas others exert influence on use of force across multiple time periods. The most influential variables relate to authority maintenance theoretical constructs. This finding supports prior perspectives arguing that police use of force largely results from officer attempts to maintain constant authority over civilians during face‐to‐face encounters. Nonetheless, a range of additional variables reflecting procedural justice, civilian resistance, and bystander presence significantly affect when police use force during civilian encounters. Results provide nuance to theoretical frameworks considering use of force as resulting from the interplay between officer and civilian actions and reactions.
Anaesthesia related mortality data at a Tertiary Pediatric Hospital in Western Australia
Authors: Hauser Neil D. , Sommerfield Aine , Drake‐Brockman Thomas F. E. , Slevin Lliana , Chambers Neil A. , Bergesio Riccardo , Christiansen Elaine , von Ungern‐Sternberg Britta S.
Published: October 2022

Background

Anaesthesia related mortality in paediatrics is rare. There are limited data describing paediatric anaesthesia related mortality. This study determined the anaesthesia related mortality at a Tertiary Paediatric Hospital in Western Australia.

Methods

A retrospective cohort study of children under‐18 years of age, that died within 30‐days of undergoing anaesthesia at Princess Margaret Hospital (PMH), between 01 January 2001 and 31 March 2015. A senior panel of clinicians reviewed each death to determine whether the death was (i) due wholly to the provision of anaesthesia (ii) due partly to the provision of anaesthesia or (iii) if death was related to the underlying pathology of the patient and anaesthesia was not contributory. Anaesthesia related mortality, 24‐h and 30‐day mortality as well as predictors of mortality were determined.

Results

A total of 154,538 anaesthetic events were recorded. There were 198 deaths within 30‐days of anaesthesia. Anaesthesia attributable mortality was 0.19/10,000 with all anaesthesia deaths occuring in patients undergoing cardiothoracic surgery. The 24‐h and 30‐day all‐cause mortality rate was 3.43/10,000 (95% CI 2.57–4.49) and 9.38/10,000 (95% CI 7.92–11.04), respectively. Overall mortality was 12.34/10,000 (95% CI 11.09–14.73) Age less than 1‐year, cardiac surgery, emergency surgery and higher ASA score were all significant predictors of mortality.

Conclusion

Paediatric anaesthesia related mortality as reflected in this retrospective cohort study is uncommon. Significant risk factors were determined as predictors of mortality.
Implementation of video laryngoscopes and the development in airway management strategy and prevalence of difficult tracheal intubation: A national cohort study
Authors: Lundstrøm Lars Hyldborg , Nørskov Anders K. , Kjeldgaard Line D. , Wetterslev Jørn , Rosenstock Charlotte V.
Published: October 2022

Background

We aimed to determine the development in the use of video laryngoscopy over a 9‐year period, and its possible impact on airway planning and management.

Methods

We retrieved 822,259 records of tracheal intubations recorded from 2008 to 2016 in the Danish Anaesthesia Database. The circumstances regarding pre‐operative airway assessment, the scheduled airway management plan and the actual airway management concerning video laryngoscopy were reported for each year of observation. Further, the association between year of observation and various airway management related outcomes was evaluated by multivariate logistic regression.

Results

There was a significant increase in airway management with ‘advanced technique successfully used within two attempts’ from 2.7% in 2008 to 15.5% in 2016 (p < .0001). This predominantly reflects use of video laryngoscopy. The prevalence of tracheal intubations ‘scheduled for video laryngoscopy’ increased from 3.5% in 2008 to 10.6% in 2016 (p < .0001). We found a significant increase in the prevalence of anticipated difficulties with intubations by direct laryngoscopy from 1.8% in 2008 to 5.2% in 2016 (p < .0001). The prevalence of failed tracheal intubations decreased from 0.14% in 2008 to 0.05% in 2016 (p < .0001).

Conclusion

From 2008 to 2016, a period of massive implementation of video laryngoscopes, a significant change in airway management behaviour was recorded. Increasingly, video laryngoscopy is becoming a first‐choice device for both acute and routine airway management. Most importantly, the data showed a noticeable reduction in failed intubation over the time of observation.
A CDH23 missense variant in Beauceron dogs with non‐syndromic deafness
Authors: Abitbol Marie , Jagannathan Vidhya , Lopez Marie , Courtin Ambre , Dufaure de Citres Caroline , Gache Vincent , Leeb Tosso
Published: October 2022

Congenital coat‐colour‐related deafness is common among certain canine breeds especially those exhibiting extreme white spotting or merle patterning. We identified a non‐syndromic deafness in Beauceron dogs characterised by a bilateral hearing loss in puppies that is not linked to coat colour. Pedigree analysis suggested an autosomal recessive transmission. By combining homozygosity mapping with whole genome sequencing and variant filtering in affected dogs we identified a CDH23:c.700C>T variant. The variant, located in the CHD23 (cadherin related 23) gene, was predicted to induce a CDH23:p.(Pro234Ser) change in the protein. Proline‐234 of CDH23 protein is highly conserved across different vertebrate species. In silico tools predicted the CDH23:p.(Pro234Ser) change to be deleterious. CDH23 encodes a calcium‐dependent transmembrane glycoprotein localised near the tips of hair‐cell stereocilia in the mammalian inner ear. Intact function of these cilia is mandatory for the transformation of the acoustical wave into a neurological signal, leading to sensorineural deafness when impaired. By genotyping a cohort of 90 control Beauceron dogs sampled in France, we found a 3.3% carrier frequency. The CDH23:c.[700C>T] allele is easily detectable with a genetic test to avoid at‐risk matings.
Contextual reference price in choice experiments
Authors: Lim Kar Ho , Hu Wuyang
Published: October 2022

A reference price depends on the context of purchase. For prices in preference elicitation experiments to be interpreted by respondents exactly as prices in real purchases, a condition must be met: Contextual reference prices in experiments and real purchases must equal. Using a choice experiment, we found that the willingness to pay estimates tend to be smaller when the respondents are reminded about their self‐reported reference price of the product. This shows that the equality of reference price between experiments and real purchases may not hold. Thus, willingness to pay estimated from a choice experiment may only be contextually specific to its setting. The theory of contextual reference price may offer a fresh perspective on hypothetical bias, and it may be useful in refining choice experiments.
Adapting an organ‐on‐chip device to study the effect of fetal sex and maternal race/ethnicity on preterm birth related intraamniotic inflammation leading to fetal neuroinflammation
Authors: Richardson Lauren S. , Emezienna Nkechinyere , Burd Irina , Taylor Brandie D. , Peltier Morgan R. , Han Arum , Menon Ramkumar
Published: October 2022

Problem

Fetal neuroinflammation has been linked to preterm birth‐related intraamniotic infection and inflammation; However, the contribution of fetal sex and maternal race/ethnicity is unknown. To determine if fetal sex and maternal race/ethnicity influence neuroinflammation, an organ‐on‐chip (OOC) model were established under normal or pathologic conditions utilizing amniotic fluid.

Method of study

OOC is composed of two‐cell culture chambers connected by Type IV collagen‐coated microchannels. Human fetal astroglia (SVGp12) and microglia (HMC3) were co‐cultured at an 80:20 ratio in the inner chamber. The outer chamber contained amniotic fluid (AF) from male and female fetuses of White Hispanic (WH) and African‐American (AA) pregnant women with or without lipopolysaccharide (LPS‐100 ng/ml) and incubated for 48 h. Glial migration (brightfield microscopy), activation (Immunocytochemistry), and cytokine production (Luminex assays) were quantified and compared (N = 4 for each category of sex and race/ethnicity).

Results

In a pooled analysis, AF+LPS did not induce glial activation or inflammatory changes compared to AF alone. When stratified by sex, male AF+LPS promoted significant glial activation (high CD11b:p < 0.05; low Iba1:p < 0.01) compared to male AF without LPS; however, this was not associated with changes in pro‐inflammatory cytokines. When stratified by race/ethnicity, AF+LPS induced glial activation in both groups, but a differential increase in pro‐inflammatory cytokines was seen between WH and AA AF (WH‐interleukin‐1β: p < 0.05; AA‐interleukin‐8: p < 0.01).

Conclusion

This OOC model of fetal neuroinflammation has determined that race/ethnicity differences do exist for perinatal brain injury. The fetal sex of neonates was not a determining factor of susceptibility to intraamniotic inflammation leading to neuroinflammation.