bluuebunny/crossref_metadata_2025 huggingface dataset:
Diversity of carbapenem-resistant Acinetobacter baumannii and bacteriophage-mediated spread of the Oxa23 carbapenemase
Authors: Abouelfetouh Alaa , Mattock Jennifer , Turner Dann , Li Erica , Evans Benjamin A.
Published: February 2022

Carbapenem-resistant

Acinetobacter baumannii

are prevalent in low- and middle-income countries such as Egypt, but little is known about the molecular epidemiology and mechanisms of resistance in these settings. Here, we characterize carbapenem-resistant

A. baumannii

from Alexandria, Egypt, and place it in a regional context. Fifty-four carbapenem-resistant isolates from Alexandria Main University Hospital (AMUH), Alexandria, Egypt, collected between 2010 and 2015 were genome sequenced using Illumina technology. Genomes were de novo assembled and annotated. Genomes for 36 isolates from the Middle East region were downloaded from GenBank. The core-gene compliment was determined using Roary, and analyses of recombination were performed in Gubbins. Multilocus sequence typing (MLST) sequence type (ST) and antibiotic-resistance genes were identified. The majority of Egyptian isolates belonged to one of three major clades, corresponding to Pasteur MLST clonal complex (CCPAS) 1, CCPAS2 and STPAS158. Strains belonging to STPAS158 have been reported almost exclusively from North Africa, the Middle East and Pakistan, and may represent a region-specific lineage. All isolates carried an oxa23 gene, six carried bla
NDM-1 and one carried bla
NDM-2. The oxa23 gene was located on a variety of different mobile elements, with Tn2006 predominant in CCPAS2 strains, and Tn2008 predominant in other lineages. Of particular concern, in 8 of the 13 CCPAS1 strains, the oxa23 gene was located in a temperate bacteriophage phiOXA, previously identified only once before in a CCPAS1 clone from the USA military. The carbapenem-resistant

A. baumannii

population in AMUH is very diverse, and indicates an endemic circulating population, including a region-specific lineage. A major mechanism for oxa23 dissemination in CCPAS1 isolates appears to be a bacteriophage, presenting new concerns about the ability of these carbapenemases to spread throughout the bacterial population.
The Age-Related Probability of Dying from COVID-19 among Those Infected: A Relative Survival Analysis
Authors: Swanson David A. , Poston Dudley , Krantz Steven G. , Rao Arni S.R. Srinivasa
Published: February 2022

Background

COVID-19 was first identified in Wuhan, the capital city of the province of Hubei in China. Due to the presentation of multiple symptoms at the same time, it is clinically important to understand the probability of dying from COVID-19 vs. the probability of dying from other causes.

Methods

Using data collected in Hubei that identified by age those who died of COVID-19 or its sequelae among the infected, we constructed a life table showing the conditional probability of dying at age x from COVID-19 and its sequela among those infected. Following the relative survival perspective, we also computed corresponding data for China that matched the format of the life table we constructed from the Hubei study. We then formed ratios of the 10-year conditional portability of dying at age x from COVID-19 for the Hubei COVID-19 victims to the ten-year conditional probability of dying at age x from all non-COVID-19 causes for those not infected by COVID-19 in China as a whole.

Findings

At every age, the conditional probability of dying from COVID-19 among those infected in Hubei is higher than the conditional probability of dying from all non-COVID-19 causes for China as a whole. Following a general age-related mortality pattern, the conditional probability of dying from COVID-19 from age 20 onward increases monotonically for those who are infected. Relative to the probability of dying in China from all other causes for those not infected, however, it declines monotonically from age 20 to age 70.

Interpretation

At younger ages the relative conditional probability of dying from CVOD-19 among the infected is substantially higher than it is for those infected who dying of all other causes and while staying higher at all ages, it declines monotonically with age. The monotonic decline in the ratio from age 20 to age 70 is a result of the age-related increase in the probability of dying from one or more of a number of competing causes, which, in the case at hand is manifested in the fact that non-COVID-19 deaths in China among the uninfected were generally increasing at a faster age-related rate than were the COVID-19 deaths to the infected in Hubei.
Heightened NLRP3 inflammasome activation is associated with aging and CMML diseases severity
Authors: Andina Nicola , de Meuron Louise , Schnegg-Kaufmann Annatina Sarah , Ansermet Camille , Bomaci Giuseppe , Keller Nino , Porret Naomi , Angelillo-Scherrer Anne , Bonadies Nicolas , Allam Ramanjaneyulu
Published: February 2022

Aging causes chronic low-grade inflammation known as inflamm-aging. It is a risk factor for chronic myelomonocytic leukemia (CMML), a hematological malignancy that is most prevalent in older people. Recent studies suggest a critical role for the NLRP3 inflammasome in inflamm-aging. However, the mechanisms involved in NLRP3 activation in aging and its involvement in CMML progression are not fully understood. Here, we report that aging increases interleukin-1β production upon NLRP3 activation in human CD14+ monocytes. Interestingly, we found that Toll-like receptor (TLR) 1/2 agonist Pam3Cysk4 directly activates NLRP3 inflammasome without the requirement of second activation signal in monocytes from older but not from younger healthy donors. Further, we observed a dichotomous response to NLRP3 inflammasome activation in monocytes from CMML patients. Intriguingly, CMML patients with heightened NLRP3 activation showed increased treatment dependency and disease severity. Collectively, our results suggest that aging causes increased sensitivity to NLRP3 inflammasome activation at cellular level, which may explain increased inflammation and immune dysregulation in older individuals. Furthermore, NLRP3 inflammasome activation was dysregulated in CMML and positively correlated with disease severity.
Ornithine Lipid is a Partial TLR4 Agonist and NLRP3 Activator
Authors: Pizzuto Malvina , Hurtado-Navarro Laura , Molina-Lopez Cristina , Soubhye Jalal , Gelbcke Michel , Rodriguez-Lopez Silvia , Ruysschaert Jean-Marie , Schroder Kate , Pelegrin Pablo
Published: February 2022

Myeloid cells recognise Gram-negative bacterial lipopolysaccharides (LPS). LPS recognition triggers inflammatory reactions through Toll-like receptor 4 (TLR4) and primes the cells for inflammasome activation. In phosphate-depleted environments, bacteria cannot produce LPS. Instead, they increase their synthesis of ornithine lipid (OL), which is constitutively present in some pathogenic Gram-negative and -positive bacteria but absent in commensals. OL is implicated in bacterial pathogenicity, but the mechanism is unclear. Using primary murine macrophages and human peripheral blood mononuclear cells, we identify OL as a partial TLR4 agonist and an NLRP3 inflammasome activator. For this, OL directly activates TLR4 and indirectly activates NLRP3 in a potassium-efflux-dependent manner. OL also upregulates the expression of NLRP3 and pro-IL-1β and induces cytokine secretion in primed and unprimed cells. By contrast, in the presence of LPS, OL functions as a partial TLR4 antagonist; LPS-induced TLR4 activation and inflammasome priming are inhibited by OL, leading to reduced TNF and IL-1β secretion. We thus suggest that in phosphate-depleted environments, OL replaces LPS bacterial immunogenicity while constitutively present OL may allow bacteria to escape immune surveillance.
Lactate Transport and Signaling Mediated by AMD3100 Ameliorates Astrocyte Pathology and Remyelination Without Additional Extension of SOD1G93A Mice’ Life-Span
Authors: Rabinovich-Nikitin Inna , Solomon Beka
Published: February 2022

Background

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons accompanied by the accumulation of the morphologically and functionally altered glial cells. Reactive astrocytes and microglia secrete pro-inflammatory mediators and contribute to disease progression. Notably, oligodendrocyte functions are disrupted in ALS, including trophic support, myelination, and oligodendrocyte differentiation. ALS patients and mutant SOD1 mice models display reduced levels of myelin basic protein (MBP) and monocarboxylate transporter 1 (MCT1) contributing to impairment of oligodendrocyte function. Lactate, an active metabolite capable of moving into or out of cells, acts as a signaling molecule, transported exclusively by monocarboxylate transporters (MCTs). We showed previously, that AMD3100 increases the lactate transporter MCT1 in an animal models of Alzheimer’s disease (AD) and ALS.

Methods and Results

AMD3100 is a reversible antagonist of CXCR4, and therefore inhibits the CXCR4/CXCL12 axis. AMD3100 was shown to have beneficial effects on extension of SOD1G93A mice’ life-span and enabling migration of hematopoietic stem cells (HSPCs) from bone marrow to periphery. The low content of lactate and transporters in SOD1G93A mice model led us to propose a combined treatment with AMD3100 and exogeneous L-lactate.

Conclusions

The combined treatment attenuated neuroinflammation and remyelination but did not have a significant extension of SOD1G93A mice’ life-span compared with AMD3100 treatment alone.
Making sense of disorder: Investigating intrinsically disordered proteins in the tardigrade proteome via a computational approach
Authors: Lowe Nora E. , Chang Roger L.
Published: February 2022

Tardigrades, also known as water bears, are a phylum of microscopic metazoans with the extraordinary ability to endure environmental extremes. When threatened by suboptimal habitat conditions, these creatures enter a suspended animation-like state called cryptobiosis, in which metabolism is diminished, similar to hibernation. In this state, tardigrades benefit from enhanced extremotolerance, withstanding dehydration efficiently for years at a time in a type of cryptobiosis called anhydrobiosis. Recent studies have demonstrated that the tardigrade proteome is at the heart of cryptobiosis. Principally, intrinsically disordered proteins (IDPs) and tardigrade-specific intrinsically disordered proteins (TDPs) are known to help protect cell function in the absence of water. Importantly, TDPs have been successfully expressed in cells of other species experimentally, even protecting human tissue against stressin vitro. However, previous work has failed to address how to strategically identify TDPs in the tardigrade proteome holistically. The overarching purpose of this current study, consequently, was to generate a list of IDPs/TDPs associated with tardigrade cryptobiosis that are high-priority for further investigation. Firstly, a novel database containing 44,836 tardigrade proteins from 338 different species was constructed to consolidate and standardize publicly available data. Secondly, a support vector machine (SVM) was created to sort the newly constructed database entries on the binary basis of disorder (i.e., IDP versus non-IDP). Features of this model draw from disorder metrics and literature curation, correctly classifying 160 of the 171 training set proteins (~93.6%). Of the 5,415 putative IDPs/TDPs our SVM identified, we present 82 (30 having confident subclass prediction and 52 having experimental detection in previous studies). Subsequently, the role each protein might play in tardigrade resilience is discussed. By and large, this supervised machine learning classifier represents a promising new approach for identifying IDPs/TDPs, opening doors to harness the tardigrade’s remarkable faculties for biomaterial preservation, genetic engineering, astrobiological research, and ultimately, the benefit of humankind.
CRISPR/Cas9 gene editing uncovers the role of CTR1 and ROS1 in melon fruit ripening and epigenetic regulation
Authors: Giordano Andrea , Domingo Miguel Santo , Quadrana Leandro , Pujol Marta , Martín-Hernández Ana Montserrat , Garcia-Mas Jordi
Published: February 2022

Melon (Cucumis melo L.) has emerged as an alternative model to study fruit ripening due to the coexistence of climacteric and non-climacteric varieties. The previous characterization of a major QTL ETHQV8.1 sufficient to trigger climacteric ripening in a non-climacteric background allowed the identification within the QTL interval of a negative regulator of ripening CmCTR1-like (MELO3C024518), and a putative DNA demethylase CmROS1 (MELO3C024516), the orthologue of DML2, a DNA demethylase regulating fruit ripening in tomato. To understand the role of these genes in climacteric ripening, we generated homozygous CRISPR knockout mutants of CmCTR1-like and CmROS1 in a climacteric genetic background. The climacteric behavior was altered in both loss-of-function mutants in two summer seasons with an advanced ethylene production profile compared to the climacteric wild type, suggesting a role of both genes in climacteric ripening in melon. Single cytosine methylome analyses of the CmROS1 knockout mutant revealed DNA methylation changes in the promoter regions of key ripening genes as ACS1, ETR1 and ACO1, and ripening associated-transcription factors as NAC-NOR, RIN and CNR, suggesting the importance of CmROS1-mediated DNA demethylation for triggering fruit ripening in melon.
Enrichment of specific GABAergic neuronal types in the mouse perirhinal cortex
Authors: Nigro Maximiliano José , Kjelsberg Kasper , Convertino Laura , Nair Rajeevkumar Raveendran , Witter Menno P.
Published: February 2022

GABAergic neurons represent 10-15% of the neuronal population of the cortex but exert a powerful control over information flow in cortical circuits. GABAergic neurons show an extraordinary diversity in their morphology, physiology, molecular markers and connectivity. This diversity allows GABAergic neurons to participate in a wide variety of microcircuit motifs. The diversity of GABAergic neurons has been shown to be conserved across cortical regions. The GABAergic population can be broadly divided in three major classes parvalbumin, somatostatin and 5HT3aR groups. The largest GABAergic class in the cortex is represented by the parvalbumin-expressing fast-spiking neurons, which provide powerful somatic inhibition to their postsynaptic targets. Recently, the density of parvalbumin-expressing neurons has been shown to be lower in associative areas of the mouse cortex, including the perirhinal cortex, as compared to sensory and motor areas. In the present study we investigated whether this reduction in parvalbumin-expressing neurons leads to a decreased GABAergic population, or to an enrichment of other GABAergic cell-types. We found that the GABAergic population of the perirhinal cortex is comparable to that of a primary sensory area, and it is enriched of neurons belonging to the 5HT3aR group. We also demonstrate that, despite the low density of parvalbumin-expressing neurons, the perirhinal cortex contains a comparable population of fast-spiking neurons, most of which do not express parvalbumin. Our results demonstrate a yet uncharacterized diversity within the fast-spiking population across cortical regions.
A critical test of deep convolutional neural networks’ ability to capture recurrent processing in the brain using visual masking
Authors: Loke Jessica , Seijdel Noor , Snoek Lukas , van der Meer Matthew , van de Klundert Ron , Quispel Eva , Cappaert Natalie , Scholte H. Steven
Published: February 2022

Recurrent processing is a crucial feature in human visual processing supporting perceptual grouping, figure-ground segmentation, and recognition under challenging conditions. There is a clear need to incorporate recurrent processing in deep convolutional neural networks (DCNNs) but the computations underlying recurrent processing remain unclear. In this paper, we tested a form of recurrence in deep residual networks (ResNets) to capture recurrent processing signals in the human brain. Though ResNets are feedforward networks, they approximate an excitatory additive form of recurrence. Essentially, this form of recurrence consists of repeating excitatory activations in response to a static stimulus. Here, we used ResNets of varying depths (reflecting varying levels of recurrent processing) to explain electroencephalography (EEG) activity within a visual masking paradigm. Sixty-two humans and fifty artificial agents (10 ResNet models of depths - 4, 6, 10, 18 and 34) completed an object categorization task. We show that deeper networks (ResNet-10, 18 and 34) explained more variance in brain activity compared to shallower networks (ResNet-4 and 6). Furthermore, all ResNets captured differences in brain activity between unmasked and masked trials, with differences starting at ∼98ms (from stimulus onset). These early differences indicated that EEG activity reflected ‘pure’ feedforward signals only briefly (up to ∼98ms). After ∼98ms, deeper networks showed a significant increase in explained variance which peaks at ∼200ms, but only within unmasked trials, not masked trials. In summary, we provided clear evidence that excitatory additive recurrent processing in ResNets captures some of the recurrent processing in humans.

Significance statement

The challenge of modeling recurrent processes is not trivial and the operationalization of recurrent processing is highly contested. In this paper, we tested the ability of deep residual networks (ResNets) to explain recurrent processes in the human brain. Though ResNets are feedforward networks, they have been shown to equate operations in recurrent neural networks. In this study, we show that deeper networks explained more variance in brain activity than shallower networks. However, all networks still performed far from the noise ceiling. Thus, we conclude that recurrent processing in ResNets captures a form of recurrent processing in humans though other types of recurrent processing (inhibition, multiplicative) that are not present in current regular deep neural networks (alexnet, cornet, resnet) are necessary for building better visual models.
Genetic liability to bipolar disorder and body mass index: A bidirectional two-sample mendelian randomization study
Authors: Byg Lars Meinertz , Speed Maria , Speed Doug , Østergaard Søren Dinesen
Published: February 2022

Objectives

Bipolar disorder is associated with increased body mass index (BMI), but it remains undetermined if this association is causal and, if so, in which direction it goes. Here, we sought to answer these questions using bidirectional two-sample Mendelian Randomization, a method from genetic epidemiology that uses data from genome-wide association studies (GWAS) to examine whether a risk factor is causal for an outcome.

Methods

We used summary statistics from GWAS of bipolar disorder and BMI conducted using data collected by the Psychiatric Genomics Consortium and the UK Biobank, respectively. The genetic instrument for bipolar disorder contained 53 SNPs and explained 0.5% of phenotypic variance, while the genetic instrument for BMI contained 517 SNPs and explained 7.1% of phenotypic variance.

Results

We found that a two-fold increase in the genetic liability to bipolar disorder causes a 0.6 (kg/m2) reduction in BMI, which is statistically significant (P=0.009), and predominantly driven by reduced fat mass. Conversely, we found no evidence that BMI causes changes in the risk of developing bipolar disorder (P=0.59).

Conclusion

The findings of this study indicate that the increased BMI observed among individuals with bipolar disorder is not a direct consequence of genetic liability to bipolar disorder, but more likely represents the sum of downstream correlates of manifest bipolar disorder, such as side effects of pharmacological treatment, poor diet and sedentary lifestyle, that are all modifiable and could potentially be targeted as part of clinical management.
Neuronal RNA granules are ribosome complexes stalled at the pre-translocation state
Authors: Kipper Kalle , Mansour Abbas , Pulk Arto
Published: February 2022

The polarized cell morphology of neurons dictates many neuronal processes, including the axodendridic transport of specific mRNAs and subsequent translation. mRNAs together with ribosomes and RNA-binding proteins form RNA granules that are targeted to axodendrites for localized translation in neurons. It has been established that localized protein synthesis in neurons is essential for long-term memory formation, synaptic plasticity, and neurodegeneration. We have used proteomics and electron microscopy to characterize neuronal RNA granules (nRNAg) isolated from rat brain tissues or human neuroblastoma. We show that ribosome containing RNA granules are morula-like structures when visualized by electron microscopy. Crosslinking-coupled mass-spectrometry identified potential G3BP2 binding site on the ribosome near the eIF3d-binding site on the 40S ribosomal subunit. We used cryo-EM to resolve the structure of the ribosome-component of nRNAg. The cryo-EM reveals that ribosomes in the nRNAg are stalled at the elongation state where tRNA’s are in the hybrid A/P and P/E site, and resemble the pre-translocation state ribosomes. We also describe a new kind of principal motion of the ribosome, which we call the rocking motion.
Circadian disruption enhances HSF1 signaling and tumorigenesis in Kras-driven lung cancer
Authors: Pariollaud Marie , Ibrahim Lara H. , Irizarry Emanuel , Mello Rebecca M. , Chan Alanna B. , Altman Brian J. , Shaw Reuben J. , Bollong Michael J. , Wiseman R. Luke , Lamia Katja A.
Published: February 2022

Disrupted circadian rhythmicity is a prominent feature of modern society and has been designated as a probable carcinogen by the World Health Organization. However, the biological mechanisms that connect circadian disruption and cancer risk remain largely undefined. We demonstrate that exposure to chronic circadian disruption (chronic jetlag, CJL) increases tumor burden in a mouse model of KRAS-driven lung cancer. Molecular characterization of tumors and tumor-bearing lung tissues revealed that CJL enhances the expression of heat shock factor 1 (HSF1) target genes. Consistently, exposure to CJL disrupted the highly rhythmic nuclear trafficking of HSF1 in the lung, resulting in an enhanced accumulation of HSF1 in the nucleus. HSF1 has been shown to promote tumorigenesis in other systems, and we find that pharmacological inhibition of HSF1 reduces the growth of KRAS-mutant human lung cancer cells. These findings implicate HSF1 as a molecular link between circadian disruption and enhanced tumorigenesis.
Pseudotime analysis reveals novel regulatory factors for multigenic onset and monogenic transition of odorant receptor expression
Authors: Hussainy Mohammad , Korsching Sigrun I. , Tresch Achim
Published: February 2022

During their maturation from horizontal basal stem cells, olfactory sensory neurons (OSNs) are known to select exactly one out of hundreds of olfactory receptors (ORs) and express it on their surface, a process called monogenic selection. Monogenic expression is preceded by a multigenic phase during which several OR genes are expressed in a single OSN. Here, we perform pseudotime analysis of a single cell RNA-Seq dataset of murine olfactory epithelium to precisely align the multigenic and monogenic expression phases with the cell types occurring during OSN differentiation. In combination with motif analysis of OR gene cluster-associated enhancer regions, we identify known and novel transcription (co-)factors (Ebf1, Lhx2, Ldb1, Fos and Sspp2) and chromatin remodelers (Kdm1a, Eed and Zmynd8) associated with OR expression. The inferred temporal order of their activity suggests novel mechanisms contributing to multigenic OR expression and monogenic selection.
Acyl-ghrelin attenuates neurochemical and motor deficits in the 6-OHDA model of Parkinson’s disease
Authors: Rees Daniel , Johnson Amy L. , Lelos Mariah , Smith Gaynor , Roberts Luke D. , Phelps Lindsay , Dunnett Stephen B. , Morgan Alwena H , Brown Rowan M , Wells Timothy , Davies Jeffrey S.
Published: February 2022

The feeding-related hormone, acyl-ghrelin, protects dopamine neurons in murine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-based models of experimental Parkinson’s disease (PD). However, the potential protective effect of acyl-ghrelin on substantia nigra pars compacta (SNpc) dopaminergic neurones and consequent behavioural correlates in the more widely used 6-hydroxydopamine (6-OHDA) rat medial forebrain bundle (MFB) lesion model of PD are unknown. To address this question, acyl-ghrelin levels were raised directly by mini-pump infusion for 7-days prior to unilateral injection of 6-OHDA into the MFB with assessment of amphetamine–induced rotations on days 27 and 35, and immunohistochemical analysis of dopaminergic neurone survival. While acyl-ghrelin treatment was insufficient to elevate food intake or body weight, it attenuated amphetamine-induced circling behaviour and SNpc dopamine neurone loss induced by 6-OHDA. These data support the notion that elevating circulating acyl-ghrelin may be a valuable approach to slow or impair progression of neurone loss in PD.

Highlights

Acyl-ghrelin attenuates SNpc dopamine cell loss in rat 6-OHDA-lesion model of PD

Acyl-ghrelin attenuates motor deficits in rat 6-OHDA-lesion model of PD
Single-cell atlas of epithelial and stromal cell heterogeneity by lobe and strain in the mouse prostate
Authors: Graham Mindy K , Chikarmane Roshan , Wang Rulin , Vaghasia Ajay , Gupta Anuj , Zheng Qizhi , Wodu Bulouere , Pan Xin , Castagna Nicole , Liu Jianyong , Meyers Jennifer , Skaist Alyza , Wheelan Sarah , Simons Brian W , Bieberich Charles , Nelson William G , DeWeese Theodore L , De Marzo Angelo M , Yegnasubramanian Srinivasan
Published: February 2022

Evaluating the complex interplay of cell types in the tissue microenvironment is critical to understanding the origin and progression of diseases in the prostate and potential opportunities for intervention. Mouse models are an essential tool to investigate the molecular and cell-type-specific contributions of prostate disease at an organismal level. While there are well-documented differences in the extent, timing, and nature of disease development in various genetically engineered mouse models in different mouse strains and prostate lobes within each mouse strain, yet, the underlying molecular phenotypic differences in cell types across mouse strains and prostate lobes are incompletely understood. To address this, we examined the single-cell transcriptomes of individual mouse prostate lobes from two commonly used mouse strains, FVB/NJ and C57BL/6J. Data dimensionality reduction and clustering analysis revealed that basal and luminal cells possessed strain-specific transcriptomic differences, with luminal cells also displaying marked lobe-specific differences. Additionally, three rare populations of epithelial cells clustered independently of strain and lobe: one population of luminal cells expressing Foxi1 and components of the vacuolar ATPase proton pump (Atp6v0d2andAtp6v1g3), another population expressing Psca and other stem cell-associated genes (Ly6a/Sca-1, Tacstd2/Trop-2), and a neuroendocrine population expressingChga, Chgb, andSyp. In contrast, stromal cell clusters, including fibroblasts, smooth muscle cells, endothelial cells, pericytes, and immune cell types, were conserved across strain and lobe, clustering largely by cell type and not by strain or lobe. One notable exception to this was the identification of two distinct fibroblast populations that we term subglandular fibroblasts and interstitial fibroblasts based on their strikingly distinct spatial distribution in the mouse prostate. Altogether, these data provide a practical reference of the transcriptional profiles of mouse prostate from two commonly used mouse strains and across all four prostate lobes.
Common signatures of differential microRNA expression in Parkinson’s and Alzheimer’s disease brains
Authors: Dobricic Valerija , Schilling Marcel , Farkas Ildiko , Gveric Djordje O , Schulz Jessica , Middleton Lefkos , Gentleman Steve , Parkkinen Laura , Bertram Lars , Lill Christina M.
Published: February 2022

Background

Dysregulation of microRNA (miRNA)-mediated gene expression has been implicated in the pathogenesis and course of many neurodegenerative diseases including Parkinson’s disease (PD). However, the functionally relevant miRNAs remain largely unknown. Previous meta-analyses on differential miRNA expression data inpost-mortemPD brains have highlighted several miRNAs showing consistent and statistically significant effects. However, these meta-analyses were based on exceedingly small sample sizes.

Methods

In this study, we quantified the expression of the four most compelling PD candidate miRNAs from these meta-analyses in the superior temporal gyrus (STG) of one of the largest case-controlpost-mortembrain datasets available (261 samples), thereby quadruplicating previously investigated sample sizes. Furthermore, we probed for common differential miRNA expression signatures with Alzheimer’s disease (AD) by also analyzing these miRNAs inpost-mortemSTG of 190 AD patients and controls and by testing six top AD miRNAs in the PD brains.

Results

Of all ten analyzed miRNAs, PD candidate miRNA homo sapiens (hsa-) miR-132-3p showed evidence for differential expression in both PD (p=4.89E-06) and AD (p=3.20E-24), and AD miRNAs hsa-miR-132-5p (p=4.52E-06) and hsa-miR-129-5p (p=0.0379) showed evidence for differential expression in PD. Combining these novel data with previously published data substantially improved the statistical support (α=3.85E-03 using Bonferroni correction) of the corresponding meta-analyses clearly and compellingly implicating these miRNAs in both PD and AD. Furthermore, hsa-miR-132-3p/-5p (but not hsa-miR-129-5p) showed association with neuropathological Braak PD staging (p=3.51E-03/p=0.0117), suggesting that these miRNAs may play a role in α-synuclein aggregation beyond the early disease phase.

Conclusions

Our study represents the largest independent assessment of recently highlighted candidate brain miRNAs in PD and ADpost-mortembrain samples, to date. Our results implicate hsa-miR-132-3p/-5p and hsa-miR-129-5p to be differentially expressed in both PD and AD brains, potentially pinpointing shared pathogenic mechanisms across these neurodegenerative diseases.
Single-cell transcriptomics of dynamic cell behaviors
Authors: Kwok Sheldon J.J. , Montoro Daniel T. , Haber Adam L. , Yun Seok-Hyun , Vinarsky Vladimir
Published: February 2022

Despite advances in spatial transcriptomics, the molecular profiling of dynamic behaviors of cells in their native environment remains a major challenge. We present a method, termed behavioral transcriptomics, that allows us to couple physiological behaviors of single cells in an intact tissue to deep molecular profiling of individual cells. This method enabled us to establish a novel molecular signature for a striking migratory cellular behavior following tissue injury.
A second DNA binding site on RFC facilitates clamp loading at gapped or nicked DNA
Authors: Liu Xingchen , Gaubitz Christl , Pajak Joshua , Kelch Brian A
Published: February 2022

Clamp loaders place circular sliding clamp proteins onto DNA so that clamp-binding partner proteins can synthesize, scan, and repair the genome. DNA with nicks or small single-stranded gaps are common clamp-loading targets in DNA repair, yet these substrates would be sterically blocked given the known mechanism for binding of primer-template DNA. Here, we report the discovery of a second DNA binding site in the yeast clamp loader Replication Factor C (RFC) that aids in binding to nicked or gapped DNA. This DNA binding site is on the external surface and is only accessible in the open conformation of RFC. Initial DNA binding at this site thus provides access to the primary DNA binding site in the central chamber. Furthermore, we identify that this site can partially unwind DNA to create an extended single-stranded gap for DNA binding in RFC’s central chamber and subsequent ATPase activation. Finally, we show that deletion of the BRCT domain, a major component of the external DNA binding site, results in defective yeast growth in the presence of DNA damage where nicked or gapped DNA intermediates occur. We propose that RFC’s external DNA binding site acts to enhance DNA binding and clamp loading, particularly at DNA architectures typically found in DNA repair.
CMTR1 is recruited to transcription start sites and promotes ribosomal protein and histone gene expression in embryonic stem cells
Authors: Liang Shang , Silva Joana Clara , Suska Olga , Lukoszek Radoslaw , Almohammed Rajaei , Cowling Victoria H
Published: February 2022

CMTR1 (cap methyltransferase 1) catalyses methylation of the first transcribed nucleotide of RNAPII transcripts (N1 2’-O-Me), creating part of the mammalian RNA cap structure. In addition to marking RNA as self, N1 2’-O-Me has ill-defined roles in RNA expression and translation. Here we investigated the gene specificity of CMTR1 and its impact on RNA expression in embryonic stem cells. Using chromatin immunoprecipitation, CMTR1 was found to bind to transcription start sites (TSS) correlating with RNAPII levels, predominantly binding at histone genes and ribosomal protein (RP) genes. Repression of CMTR1 expression resulted in repression of RNAPII binding at the TSS and repression of RNA expression, particularly of histone and RP genes. In correlation with regulation of histones and RP genes, CMTR1 repression resulted in repression of translation and induction of DNA replication stress and damage. Indicating a direct role for CMTR1 in transcription, addition of recombinant CMTR1 to purified nuclei increased transcription of the histone and RP genes. CMTR1 was found to be upregulated during neural differentiation and there was an enhanced requirement for CMTR1 for gene expression and proliferation during this process. We highlight the distinct roles of the cap methyltransferases RNMT and CMTR1 in target gene expression and differentiation.
CDK11 Promotes Centromeric Transcription to Maintain Centromeric Cohesion during Mitosis
Authors: Zhang Qian , Chen Yujue , Teng Zhen , Lin Zhen , Liu Hong
Published: February 2022

Actively-transcribing RNA polymerase (RNAP)II is remained on centromeres to maintain centromeric cohesion during mitosis although it is largely released from chromosome arms. This pool of RNAPII plays an important role in centromere functions. However, the mechanism of RNAPII retention on mitotic centromeres is poorly understood. We here demonstrate that Cdk11 depletion-induced centromeric cohesion defects are largely independent of Bub1. We further show that Cdk11 depletion and expression of its kinase-dead version significantly reduce both RNAPII and elongating RNAPII (pSer2) levels on centromeres, and also decrease centromeric transcription without altering the protein expression of cohesin and cohesion-regulators. Interestingly, enhanced centromeric transcription by THZ1 treatment or overexpression of CENP-B DNA-binding domain completely rescues Cdk11-depletion defects. These results suggest that Cdk11 promotes centromeric cohesion through facilitating centromeric transcription. Mechanistically, Cdk11 binds and phosphorylates RNAPII to promote transcription. Furthermore, mitosis-specific degradation of G2/M Cdk11-p58 recapitulates Cdk11-depletion defects. Altogether, our findings establish Cdk11 as an important regulator of centromeric transcription and as part of the mechanism for retaining RNAPII on centromeres during mitosis.
Exploring the effectiveness of word embedding based deep learning model for improving email classification
Authors: Asudani Deepak Suresh , Nagwani Naresh Kumar , Singh Pradeep
Published: February 2022

Purpose

Classifying emails as ham or spam based on their content is essential. Determining the semantic and syntactic meaning of words and putting them in a high-dimensional feature vector form for processing is the most difficult challenge in email categorization. The purpose of this paper is to examine the effectiveness of the pre-trained embedding model for the classification of emails using deep learning classifiers such as the long short-term memory (LSTM) model and convolutional neural network (CNN) model.

Design/methodology/approach

In this paper, global vectors (GloVe) and Bidirectional Encoder Representations Transformers (BERT) pre-trained word embedding are used to identify relationships between words, which helps to classify emails into their relevant categories using machine learning and deep learning models. Two benchmark datasets, SpamAssassin and Enron, are used in the experimentation.

Findings

In the first set of experiments, machine learning classifiers, the support vector machine (SVM) model, perform better than other machine learning methodologies. The second set of experiments compares the deep learning model performance without embedding, GloVe and BERT embedding. The experiments show that GloVe embedding can be helpful for faster execution with better performance on large-sized datasets.

Originality/value

The experiment reveals that the CNN model with GloVe embedding gives slightly better accuracy than the model with BERT embedding and traditional machine learning algorithms to classify an email as ham or spam. It is concluded that the word embedding models improve email classifiers accuracy.
Evaluating the demographic scenario of gated communities in Dammam metropolitan area, kingdom of Saudi Arabia
Authors: AlQahtany Ali
Published: February 2022

Purpose

The purpose of this paper is to assess the nature of gated communities in the Kingdom of Saudi Arabia (KSA) focusing on the experiences of residents from different gated communities in the Dammam Metropolitan Area (DMA). It seeks to assess the socio-economic background of such communities and find out why people choose to live in gated communities and their perceptions of such housing patterns.

Design/methodology/approach

The questionnaire survey technique was used in this study to achieve the main purpose. The study used the triangulation method, which includes both qualitative and quantitative techniques as the most appropriate approach to be adopted. Qualitative data was analyzed using content analysis, while statistical analysis was performed to analyze quantitative data.

Findings

The findings of the study highlight that although gated communities are physically closed by walls and gates, it is distinguished by good social relations not only among their residents but even with the external surroundings, which makes these communities more attractive. Of course, this contrasts to some extent with the prevailing thinking that such communities live in a state of social isolation.

Research limitations/implications

The ideas of people who live outside gated communities are very important, however, it was not explored in this study due to time limitations. So, future research could focus on citizens’ perceptions of this type of urban settlement.

Originality/value

To the best of the author’s knowledge, this is the first study assessing the nature of gated communities in KSA by focusing on the experiences of residents of different gated communities in DMA. Only a few studies have been done in this regard, so this research paper was conducted to bridge this research gap and build upon the literature.
Online teaching during COVID-19 crisis: the role of technostress and emotional dissonance on online teaching exhaustion and teaching staff productivity
Authors: Dahabiyeh Laila , Najjar Mohammad S. , Wang Gongtai
Published: February 2022

Purpose

Amid the coronavirus disease 2019 (COVID-19) pandemic, higher education institutions (HEI) all over the world have transitioned to online teaching. The purpose of this study is to examine the impact of technostress and negative emotional dissonance on online teaching exhaustion and teaching staff productivity.

Design/methodology/approach

Survey methodology was used to collect data from faculty members in Jordanian universities. A total of 217 responses were analyzed to test the research model.

Findings

The research findings reveal that technostress creators have various impact on online teaching exhaustion and teaching staff productivity. Negative emotional dissonance has positive impact on both online teaching exhaustion and teaching staff productivity. Further, online teaching exhaustion is negatively associated with teaching staff productivity.

Research limitations/implications

This research extends prior literature on technostress by examining the phenomenon in abnormal conditions (during a crisis). It further integrates technostress theory with emotional dissonance theory to better understand the impact of technostress creators on individual teaching staff productivity while catering for the interactional nature of teaching which is captured through emotional dissonance theory.

Practical implications

The research offers valuable insights for HEI and policymakers on how to support teaching staff and identifies strategies that should facilitate a smooth delivery of online education.

Originality/value

Unlike prior research that have examined technostress under normal operational conditions, this research examines the impact of technostress during a crisis. This study shows that technostress creators vary in their impact. Moreover, this study integrates technostress theory with emotional dissonance theory. While technostress theory captures the impact of technostress creators on individual teaching staff productivity, emotional dissonance theory captures the dynamic nature of the teaching process that involves interactions among teachers and students.
Optimization of maintenance strategies for steam boiler system using reliability-centered maintenance (RCM) model – A case study from Indian textile industries
Authors: Patil Suyog Subhash , Bewoor Anand K.
Published: February 2022

Purpose

This study focuses on the application of reliability-centered maintenance (RCM) to a textile industry steam boiler. The study aims to demonstrate the development and application of RCM to a steam boiler used in the textile industry.

Design/methodology/approach

RCM is a structured process that develops maintenance activities needed on physical resources in their operational environment to realize their inherent reliability by logically incorporating an appropriate mixture of reactive, preventive, condition-based and proactive maintenance methods. A detailed analysis of the RCM approach is presented to develop preventive maintenance (PM) program and improve the reliability and availability of the steam boiler system.

Findings

The research reveals that the identification of PM tasks is a good indicator of the PM program's efficiency and can serve as an important maintenance-related downtime source. It is also discovered that the majority of maintenance programs that claim to be proactive are, in fact, reactive. This article also shows how RCM may be successfully implemented to any system, resulting in increased system reliability.

Research limitations/implications

The paper focuses on a pilot study of the development and implementation of the RCM technique to a textile industry steam boiler. It is suggested that the developed RCM model can be applied to the entire plant.

Originality/value

The paper presents a comprehensive RCM model framework as well as an RCM decision framework, providing maintenance managers and engineers with a step-by-step approach to RCM implementation. The proposed framework is significant in that it may be utilized for both qualitative and quantitative analysis at the same time.
Examining instructional practices in news media literacy: shifts in instruction and co-construction
Authors: Spikes Michael A. , Rapp David N.
Published: February 2022

Purpose

As technology enables the rapid spread of mis- and disinformation, a critical challenge for scholars and practitioners involves building student’s news media literacy (NML), a subset of media literacy education centered around journalism. This paper aims to offer a case study of secondary civics classrooms that use NML lessons and current events in their curricula, providing an empirical account of teaching techniques being used to support students' dispositions and practices.

Design/methodology/approach

This multiple case study investigates three secondary classes taught by two teachers. Data collection methods included observations, field notes and interviews with the teachers. Discourse and actions were analyzed by probing the participant structures and means of classroom management.

Findings

The findings highlight instructional techniques used by both teachers which consisted of instructionist and constructivist approaches, with informative shifts observed between the two. The teachers used instructionist methods when transmitting declarative knowledge (such as key definitions), and constructivist methods when working with students to consider more abstract concepts and developing news stories.

Originality/value

The demand for NML and associated pedagogy is increasing given awareness of the rapid spread and problematic influence of mis-and disinformation. There is a critical need for describing teachers’ implementations of these pedagogies, given calls for enacting NML into public policy despite limited awareness of the ways they actually unfold in classrooms. The current project shows how instructionist and constructivist frames prove helpful for understanding instructional practices, and for contemplating anticipated designs of NML pedagogy in classrooms.
ESG and corporate credit spreads
Authors: Barth Florian , Hübel Benjamin , Scholz Hendrik
Published: February 2022

Purpose

The authors investigate the implications of environmental, social and governance (ESG) practices of firms for the pricing of their credit default swaps (CDS). In doing so, the authors compare European and US firms and consider nonlinear and indirect effects. This complements the previous literature focusing on linear and direct effects using bond yields and credit ratings of US firms.

Design/methodology/approach

For this purpose, the authors apply fixed effects regressions on a comprehensive panel data set of US and European firms. Further, nonlinear and indirect effects are investigated utilizing quantile regressions and a path analysis.

Findings

The evidence indicates that higher ESG ratings mitigate credit risks of US and European firms from 2007 to 2019. The risk mitigation effect is U-shaped across ESG quantiles, which is consistent with opposing effects of growing stakeholder influence capacity and diminishing marginal returns on ESG investments. The authors further reveal a mediating indirect volatility channel that substantially amplifies the direct effect of ESG on credit risk. A one-standard-deviation improvement in ESG ratings is estimated to reduce CDS spreads of low, medium and high ESG firms by approximately 4%, 8% and 3%, respectively.

Originality/value

This is the first study to examine whether credit markets reflect regional differences between Europe and the US with regard to the ESG-CDS-relationship. In addition, this paper contributes to the existing literature by investigating differences in the response of CDS spreads across ESG quantiles and to study potential indirect channels connecting ESG and CDS spreads using structural credit risk variables.