bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a novel rodent rapid serial visual presentation task reveals dissociable effects of stimulant vs non-stimulant treatments on attention
Authors: Benn Abigail , Robinson Emma S.J.
Published: October 2021

The rapid serial visual presentation (RSVP) task and continuous performance tasks (CPT) are used to assess attentional impairments in patients with psychiatric and neurological conditions. This study developed a novel touchscreen task for rats based on the structure of a human RSVP task and used pharmacological manipulations to investigate their effects on different performance measures. Normal animals were trained to respond to a target image and withhold responding to distractor images presented within a continuous sequence. In a second version of the task a false-alarm image was included so performance could be assessed relative to two types of non-target distractors. The effects of acute administration of the stimulant and non-stimulant treatments for ADHD (amphetamine and atomoxetine) were tested in both tasks. Methylphenidate, ketamine and nicotine were tested in the first task only. Amphetamine made animals more impulsive and decreased overall accuracy but increased accuracy when the target was presented early in the image sequence. Atomoxetine improved accuracy overall with a specific reduction in false-alarm responses and a shift in the attentional curve reflecting improved accuracy for targets later in the image sequence. However, atomoxetine also slowed responding and increased omissions. Ketamine, nicotine and methylphenidate had no specific effects at the doses tested. These results suggest that stimulant versus non-stimulant treatments have different effects on attention and impulsive behaviour in this rat version of an RSVP task. These results also suggest that RSVP-like tasks have the potential to be used to study attention in rodents.
The military as a neglected pathogen transmitter, from the 19th century to COVID-19: A systematic review
Authors: Chaufan Claudia , Dutescu Ilinca A. , Fekre Hanah , Marzabadi Saba , Noh K.J.
Published: October 2021

Background

The risk of outbreaks escalating into pandemics has soared with globalization. Therefore, understanding transmission mechanisms of infectious diseases has become critical to formulating global public health policy. This systematic review assessed evidence in the medical and public health literature for the military as a disease vector.

Methods

We searched 3 electronic databases without temporal restrictions. Two researchers independently extracted study data using a standardized form. Through team discussions, studies were grouped according to their type of transmission mechanism and direct quotes were extracted to generate themes and sub-themes. A content analysis was later performed and frequency distributions for each theme were generated.

Results

Of 6477 studies, 210 met our inclusion criteria and provided evidence, spanning over two centuries (1810 – 2020), for the military as a pathogen transmitter, within itself or between it and civilians. Biological mechanisms driving transmission included person-to-person transmission, contaminated food and water, vector-borne, and airborne routes. Contaminated food and/or water were the most common biological transmission route. Social mechanisms facilitating transmission included crowded living spaces, unhygienic conditions, strenuous working, training conditions, absent or inadequate vaccination programs, pressure from military leadership, poor compliance with public health advice, contractor mismanagement, high-risk behaviours, and occupation-specific freedom of movement. Living conditions were the most common social transmission mechanism, with young, low ranking military personnel repeatedly reported as the most affected group. Selected social mechanisms, such as employment-related freedom of movement, were unique to the military as a social institution. While few studies explicitly studied civilian populations, considerably more contained information that implied that civilians were likely impacted by outbreaks described in the military.

Conclusions

This study identified features of the military that pose a significant threat to global health, especially to civilian health in countries with substantial military presence or underdeveloped health systems. While biological transmission mechanisms are shared by other social groups, selected social transmission mechanisms are unique to the military. As an increasingly interconnected world faces the challenges of COVID-19 and future infectious diseases, the identified features of the military may exacerbate current and similar challenges and impair attempts to implement successful and equitable global public health policies.
Clinical implementation of a machine learning system to detect deteriorating patients reduces time to response and intervention
Authors: Brufau Santiago Romero , Rosenthal Jacob , Kautz Jordan , Storlie Curtis , Gaines Kim , Nagel Jill , VanDeusen Adam , Johnson Matthew , Hickman Joel , Hardin Dale , Schmidt Julie , Dankbar Gene , Huddleston Jeanne
Published: October 2021

Introduction

Acute physiological deterioration is a major contributor to in-hospital morbidity and mortality. Early detection and intervention of deteriorating patients is key to improving patient outcomes. Prior research has demonstrated the effectiveness of Early Warning Systems and other algorithmic approaches in automatically identifying these patients from passively monitoring vital signs.

Methods

In this work, we conduct a prospective pilot study of clinical deployment of the Mayo Clinic Bedside Patient Rescue (BPR) system using an escalating alerting logic enabled by machine learning. Among four units where the BPR system was deployed, time to response and time to intervention for deteriorating patients were significantly reduced relative to matched control units.

Results

In pilot units, time to response decreased by 35.4% (from 63.2 minutes to 40.8 minutes) and time to intervention decreased by 48.5% (from 106.3 minutes to 55.9 minutes). No significant differences were observed in counterbalance metrics of mortality, ICU transfer rate, and Rapid Response Team activation rate. Furthermore, the automated alerting system was well-received by clinicians participating in the pilot study, as assessed by survey.

Discussion

These results demonstrate a successful clinical deployment of a practice-changing machine learning alert system with demonstrable impact on improving patient care.
Strategic Leadership Coaching supports Young Executives decision-making
Authors: Heyns-Nell Charlene , Williams Kimberley Clare , Hume David John , Howells Fleur Margaret
Published: October 2021

Decision-making is central to daily function for executives in any organisation. Strategic leadership coaching (SLC) is an effective way to support complex decision-making, yet empirical neuroscientific data to support is lacking. The purpose of this study was to investigate the effects of SLC on young executive’s cortical arousal and their neural circuitry activation during the completion of computerized tasks which require activation of decision-making circuitry. We hypothesised SLC would improve cortical arousal when engaged with decision-making tasks, specifically increased electroencephalography (EEG) relative alpha band activity and improved neural circuitry engagement, measured as increased amplitude of event-related potential wave components. This study included thirty-one young male executives, of which eighteen underwent 8 sessions of SLC over two months. EEG records were collected thrice from those who underwent SLC (prior, post, and two months post), and twice from the control group (two months apart). The EEG recording session included completion of two decision-making tasks, an Iowa gambling task and Stroop colour-word conflict task. Finding, SLC increased alpha band activity over left frontal and central electrodes, and increased right parietal N170 amplitude and left parietal P300 amplitude. These findings support our hypothesis, as SLC improved cognitive cortical resources (enhanced alpha) which in turn permitted greater efficiency within decision-making circuitry (increased wave component amplitudes). This study provides the first and necessary neurobiological evidence to support and develop this line of research in SLC, and other forms of coaching, as it adds significant value.
Probiotic-guided CAR-T cells for universal solid tumor targeting
Authors: Vincent Rosa L. , Gurbatri Candice R. , Redenti Andrew , Coker Courtney , Arpaia Nicholas , Danino Tal
Published: October 2021

Synthetic biology enables the engineering of interactions between living medicines to overcome the specific limitations of any singular therapy. One major challenge of tumor-antigen targeting therapies like chimeric antigen receptor (CAR)-T cells is the identification of targetable antigens that are specifically and uniformly expressed on heterogenous solid tumors. In contrast, certain species of bacteria selectively colonize immune-privileged tumor cores and can be readily engineered as antigen-independent platforms for therapeutic delivery. Bridging these approaches, we develop a platform of probiotic-guided CAR-T cells (ProCARs), in which T cells are engineered to sense synthetic antigens (SA) that are produced and released by tumor-colonizing probiotic bacteria. We demonstrate increased CAR-T cell activation and tumor-cell lysis when SAs anchor to components of the extracellular matrix. Moreover, we show that ProCARs are intratumorally activated by probiotically-delivered SAs, receive further stimulation from bacterial TLR agonists, and are safe and effective in multiple xenograft models. This approach repurposes tumor-colonizing bacteria as beacons that guide the activity of engineered T cells, and in turn builds the foundation for communities of living medicines.
Methylome inheritance and enhancer dememorization reset an epigenetic gate safeguarding embryonic programs
Authors: Wu Xiaotong , Zhang Hongmei , Zhang Bingjie , Zhang Yu , Wang Qiuyan , Shen Weimin , Wu Xi , Li Lijia , Xia Weikun , Nakamura Ryohei , Liu Bofeng , Liu Feng , Takeda Hiroyuki , Meng Anming , Xie Wei
Published: October 2021

Drastic epigenetic reprogramming is essential to convert terminally-differentiated gametes to totipotent embryos. However, it remains puzzling why post-fertilization global DNA reprogramming occurs only in mammals but not in non-mammalian vertebrates. In zebrafish, global methylome inheritance is however accompanied by sweeping enhancer “dememorization” as they become fully methylated. By depleting maternal dnmt1 using oocyte microinjection in situ, we eliminated DNA methylation in zebrafish early embryos, which died around gastrulation with severe differentiation defects. Strikingly, methylation deficiency leads to extensive derepression of adult tissue-specific genes and CG-rich enhancers, which acquire ectopic TF binding and, unexpectedly, H3K4me3. By contrast, embryonic enhancers are generally CG-poor and evade DNA methylation repression. Hence, global DNA hypermethylation inheritance coupled with enhancer dememorization installs an epigenetic gate that safeguards embryonic programs and ensures temporally ordered gene expression. We propose that “enhancer dememorization” underlies and unifies distinct epigenetic reprogramming modes in early development between mammals and non-mammals.
Stably Accelerating Stiff Quantitative Systems Pharmacology Models: Continuous-Time Echo State Networks as Implicit Machine Learning
Authors: Anantharaman Ranjan , Abdelrehim Anas , Jain Anand , Pal Avik , Sharp Danny , Utkarsh  , Rackauckas Chris
Published: October 2021

Quantitative systems pharmacology (QsP) may need to change in order to accommodate machine learning (ML), but ML may need to change to work for QsP. Here we investigate the use of neural network surrogates of stiff QsP models. This technique reduces and accelerates QsP models by training ML approximations on simulations. We describe how common neural network methodologies, such as residual neural networks, recurrent neural networks, and physics/biologically-informed neural networks, are fundamentally related to explicit solvers of ordinary differential equations (ODEs). Similar to how explicit ODE solvers are unstable on stiff QsP models, we demonstrate how these ML architectures see similar training instabilities. To address this issue, we showcase methods from scientific machine learning (SciML) which combine techniques from mechanistic modeling with traditional deep learning. We describe the continuous-time echo state network (CTESN) as the implicit analogue of ML architectures and showcase its ability to accurately train and predict on these stiff models where other methods fail. We demonstrate the CTESN’s ability to surrogatize a production QsP model, a >1,000 ODE chemical reaction system from the SBML Biomodels repository, and a reaction-diffusion partial differential equation. We showcase the ability to accelerate QsP simulations by up to 56x against the optimized DifferentialEquations.jl solvers while achieving <5% relative error in all of the examples. This shows how incorporating the numerical properties of QsP methods into ML can improve the intersection, and thus presents a potential method for accelerating repeated calculations such as global sensitivity analysis and virtual populations.
Universal Ontogenetic Growth without Fitted Parameters: Implications for Life History Invariants & Population Growth
Authors: Escala Andrés
Published: October 2021

Since the work of Von Bertalanffy (1957), several models have been proposed that relate the ontogenetic scaling of energy assimilation and metabolism to growth, which are able to describe ontogenetic growth trajectories for living organisms and collapse them onto a single universal curve (West et al. 2001; Barnavar et al. 2002). Nevertheless, all these ontogenetic growth models critically depend on fitting parameters and on the allometric scaling of the metabolic rate. Using a new metabolic rate relation (Escala 2019) applied to a Bertalanffy-type ontogenetic growth equation, we find that ontogenetic growth can also be described by a universal growth curve for all studied species, but without the aid of any fitting parameters (i.e., no fitting procedure is performed on individual growth curves). We find that the inverse of the heart frequency fH, rescaled by the ratio of the specific energies for biomass creation and metabolism, defines the characteristic timescale for ontogenetic growth. Moreover, our model also predicts a generation time and lifespan that explain the origin of several ‘Life History Invariants’ (Charnov 1993) and predict that the Malthusian parameter should be inversely proportional to both the generation time and lifespan, in agreement with the data in the literature (Duncan et al. 1997; Dillingham et. al 2016; Hatton et al 2019). In our formalism, several critical timescales and rates (lifespan, generation time and intrinsic population growth rate) are all proportional to the heart frequency fH, and thus, their allometric scaling relations come directly from the allometry of the heart frequency, which is typically fH∝ M−0.25under basal conditions.
Short-Term Dairy Elimination and Reintroduction Minimally Perturbs the Gut Microbiota in Self-Reported Lactose Intolerant Adults
Authors: Smith Courtney J. , Dethlefsen Les , Gardner Christopher , Nguyen Linda , Feldman Marcus , Costello Elizabeth K. , Kolodny Oren , Relman David A.
Published: October 2021

One of the outstanding questions regarding the human gut microbiota is how interventions designed to manipulate the microbiota may influence host phenotypic traits. Here, we employed a dietary intervention to probe this question in the context of lactose intolerance. To assess the effects of dairy elimination and reintroduction on the microbiota and host phenotype, we paired fecal 16S rRNA amplicon sequencing with a clinical assay for lactose intolerance, the hydrogen breath test. We studied 12 self-reported mildly lactose intolerant adults, each with tri-weekly collection of fecal samples over a 12-week study period (2 weeks baseline, 4 weeks of dairy elimination, 6 weeks of gradual milk reintroduction) and a hydrogen breath test before and after each phase. We found that although none of the subjects experienced a change in clinically defined status of lactose intolerant or tolerant, most subjects were qualitatively better able to tolerate dairy products with minimal symptoms at the end of the study compared to their baseline. Like clinical status, gut microbiota also resisted modification. Although the mean fraction of the genus Bifidobacterium, a group known to metabolize lactose, increased slightly with dairy reintroduction (from 0.0125 to 0.0206; Wilcoxon P = 0.068), the overall structure of each subject’s gut microbiota remained highly individualized and largely stable. Our study is small, but it suggests the possibility of qualitatively improved tolerance in the absence of change in clinically defined tolerance nor major change in the gut microbiota.
STAG2 promotes the myelination transcriptional program in oligodendrocytes
Authors: Cheng Ningyan , Kanchwala Mohammed , Evers Bret M. , Xing Chao , Yu Hongtao
Published: October 2021

Cohesin folds chromosomes via DNA loop extrusion. Cohesin-mediated chromosome loops regulate transcription by shaping long-range enhancer-promoter interactions, among other mechanisms. Mutations of cohesin subunits and regulators cause human developmental diseases termed cohesinopathy. Vertebrate cohesin consists of SMC1, SMC3, RAD21, and either STAG1 or STAG2. To probe the physiological functions of cohesin, we created conditional knockout (cKO) mice with Stag2 deleted in the nervous system. Stag2 cKO mice exhibit growth retardation, neurological defects, and premature death, in part due to insufficient myelination of nerve fibers. Stag2 cKO oligodendrocytes exhibit delayed maturation and downregulation of myelination-related genes. Stag2 loss reduces promoter-anchored loops at downregulated genes in oligodendrocytes. Thus, STAG2-cohesin generates promoter-anchored loops at myelination-promoting genes to facilitate their transcription. Our study implicates defective myelination as a contributing factor to cohesinopathy and establishes oligodendrocytes as a relevant cell type to explore the mechanisms by which cohesin regulates transcription.
Multiple nutritional and gut microbial factors associated with allergic rhinitis: the Hitachi Health Study
Authors: Sahoyama Yukari , Hamazato Fumiaki , Shiozawa Manabu , Nakagawa Tohru , Suda Wataru , Ogata Yusuke , Hachiya Tsuyoshi , Kawakami Eiryo , Hattori Masahira
Published: October 2021

Several studies suggest the involvement of dietary habits and gut microbiome in allergic diseases. However, little is known about the nutritional and gut microbial factors associated with the risk of allergic rhinitis (AR). We recruited 186 apparently healthy workers with symptoms of AR and 106 controls at the Hitachi Health Care Center, Japan. The habitual consumption of 42 selected nutrients were examined using the brief-type self-administered diet history questionnaire. Faecal samples were collected and subjected to amplicon sequencing of the 16S ribosomal RNA gene hypervariable regions. Association analysis revealed that four nutrients (retinol, vitamin A, cryptoxanthin, and copper) were negatively associated with AR. Among 40 genera examined, relative abundance of Prevotella and Escherichia were associated with AR. Furthermore, significant statistical interactions were observed between retinol and Prevotella. The age- and sex-adjusted odds of AR were 25-fold lower in subjects with high retinol intake and high Prevotella abundance compared to subjects with low retinol intake and low Prevotella abundance. Our data provide insights into complex interplay between dietary nutrients, gut microbiome, and the development of AR.
RSV protects bystander cells against IAV infection by triggering secretion of type I and type III interferons
Authors: Czerkies Maciej , Kochańczyk Marek , Korwek Zbigniew , Prus Wiktor , Lipniacki Tomasz
Published: October 2021

We observed the interference between two prevalent respiratory viruses, respiratory syncytial virus (RSV) and influenza A virus (IAV, H1N1), and characterized its molecular underpinnings in alveolar epithelial cells (A549). We found that RSV induces higher interferon (IFN) β production than IAV and that IFNβ priming confers higher protection against infection with IAV than with RSV. Consequently, we focused on the sequential infection scheme: RSV-then-IAV. Using the A549 WT, IFNAR1 KO, IFNLR1 KO, and IFNAR1–IFNLR1 double KO cell lines we found that both IFNβ and IFNλ are necessary for maximum protection against subsequent infection. Immunostaining revealed that preinfection with RSV partitions the cell population into a subpopulation susceptible to subsequent infection with IAV and an IAV-proof subpopulation. Strikingly, the susceptible cells turned out to be those already compromised and efficiently expressing RSV, whereas the bystander, interferon-primed cells are resistant to IAV infection. Thus, the virus–virus exclusion at the cell population level is not realized through a direct competition for a shared ecological niche (single cell) but rather achieved with the involvement of specific cytokines induced within the host innate immune response.

Importance

The influenza A virus (IAV) and the respiratory syncytial virus (RSV) are common recurrent respiratory infectants, which show a relatively high coincidence. We demonstrated that preinfection with RSV partitions the cell population into a subpopulation susceptible to subsequent infection with IAV and an IAV-proof subpopulation. The susceptible cells are those already compromised and efficiently expressing RSV, whereas the bystander cells are resistant to IAV infection. The cross-protective effect critically depends on IFNβ and IFNλ signaling and thus ensues when the proportion of cells preinfected with RSV is relatively low yet sufficient to trigger a pervasive antiviral state in bystander cells. Our study suggests that mild, but not severe, respiratory infections may have a short-lasting protective role against more dangerous respiratory viruses, including SARS-CoV-2.
Dynamin-2 Phosphorylation as A Critical Regulatory Target of Bin1 and GSK3α for Endocytosis in Muscle
Authors: Laiman Jessica , Loh Julie , Tang Wei-Chun , Chuang Mei-Chun , Liu Hui-Kang , Chen Bi-Chang , Chang Yi-Cheng , Chuang Lee-Ming , Liu Ya-Wen
Published: October 2021

Tight regulation of endocytosis ensures accurate control of cellular signaling and membrane dynamics, which are crucial for tissue morphogenesis and functions. Mutations of Bin1 and dynamin-2 (Dyn2), proteins that generate membrane curvature and sever endocytic invaginations, respectively, cause progressive hereditary myopathy. Here, we show that Bin1 inhibits Dyn2 via direct interaction of its SRC Homology 3 (SH3) domain with the proline-rich domain (PRD) of Dyn2. Phosphorylation of S848 of Dyn2 by GSK3α, a kinase downstream of insulin signaling, relieves Dyn2 from the inhibition of Bin1 and promotes endocytosis in muscle. Mutations of Bin1 associated with centronuclear myopathy disrupt its inhibition of Dyn2, thereby exaggerating Dyn2 fission activity and causing excessive fragmentation of T-tubules in the muscle cells. Our work reveals how Bin1-Dyn2 interaction fine-tunes membrane remodeling at the molecular level, and lay the foundation for future exploration of endocytic regulation and hereditary muscle diseases.
CD47 cross-dressing by extracellular vesicles expressing CD47 inhibits phagocytosis without transmitting cell death signals
Authors: Li Yang , Wu Yan , Federzoni Elena A. , Wang Xiaodan , Dharmawan Andre , Hu Xiaoyi , Wang Hui , Hawley Robert J. , Stevens Sean , Sykes Megan , Yang Yong-Guang
Published: October 2021

Transgenic CD47 overexpression is an encouraging approach to ameliorating xenograft rejection and alloresponses to pluripotent stem cells, and the efficacy correlates with the level of CD47 expression. However, CD47, upon ligation, also transmits signals leading to cell dysfunction or death, raising a concern that overexpressing CD47 could be harmful. Here, we unveiled an alternative source of cell surface CD47. We showed that extracellular vesicles (EVs), including exosomes (Exos), released from normal or tumor cells overexpressing CD47 (transgenic or native) can induce efficient CD47 cross-dressing on pig or human cells. Like the autogenous CD47, CD47 cross-dressed on cell surfaces is capable of interacting with SIRPα to inhibit phagocytosis. However, ligation of the autogenous, but not cross-dressed, CD47 induced cell death. Thus, CD47 cross-dressing provides an alternative source of cell surface CD47 that may elicit its anti-phagocytic function without transmitting harmful signals to the cells. CD47 cross-dressing also suggests a previously unidentified mechanism for tumor-induced immunosuppression. Our findings should help to further optimize the CD47 transgenic approach that may improve outcomes by minimizing the harmful effects of CD47 overexpression.
Intercellular alignment of apical-basal polarity coordinates tissue homeostasis and growth
Authors: Gui Jinghua , Huang Yunxian , Myllymäki Satu-Marja , Mikkola Marja , Shimmi Osamu
Published: October 2021

Maintaining apicobasal polarity (ABP) is crucial for epithelial integrity and homeostasis during tissue development. Although recent studies have greatly advanced our understanding of intracellular mechanisms underlying ABP establishment, it remains largely unknown how the ABP is regulated at the tissue level. Here, we address intercellular mechanisms coordinating ABP using the Drosophila wing imaginal disc. By studying Scribble, a key ABP determinant, we show that ABP is regulated through intercellular alignment, which takes place either progressively or regressively in a context-dependent manner. Cells expressing wild type scribble progressively restore ABP in scribble hypomorphic mutant cells. In contrast, cells with conditional scribble knockdown instigate the regressive loss of polarity in abutting wild type cells. Our data reveal that genetic and physical interactions between Scribble, Septate junction complex and α-Catenin appear to be key for sustaining intercellular network of ABP. Taken together, our findings indicate that the intercellular relay of the status of ABP contributes to the robustness of polarity across the tissue.
Annotation of glycolysis, gluconeogenesis, and trehaloneogenesis pathways provide insight into carbohydrate metabolism in the Asian citrus psyllid
Authors: Tamayo Blessy , Kercher Kyle , Vosburg Chad , Massimino Crissy , Jernigan Margaryta R. , Hasan Denisse L. , Harper Douglas , Mathew Anuja , Adkins Samuel , Shippy Teresa , Hosmani Prashant S. , Flores-Gonzalez Mirella , Panitz Naftali , Mueller Lukas A. , Hunter Wayne B. , Benoit Joshua B. , Brown Susan J. , D’Elia Tom , Saha Surya
Published: October 2021

Citrus greening disease is caused by the pathogenCandidatusLiberibacter asiaticus, which is transmitted by the Asian citrus psyllid,Diaphorina citri. There is no curative treatment or significant prevention mechanism for this detrimental disease that causes continued economic losses from reduced citrus production. A high quality genome ofD. citriis being manually annotated to provide accurate gene models required to identify novel control targets and increase understanding of this pest. Here, we annotated genes involved in glycolysis, gluconeogenesis, and trehaloneogenesis in theD. citrigenome, as these are core metabolic pathways and suppression could reduce this pest. Specifically, twenty-five genes were identified and annotated in the glycolysis and gluconeogenesis pathways and seven genes for the trehaloneogenesis pathway. Comparative analysis showed that the glycolysis genes inD. citriare highly conserved compared to orthologs in other insect systems, but copy numbers vary inD. citri.

Expression levels of the annotated gene models were analyzed and several enzymes in the glycolysis pathway showed high expression in the thorax. This is consistent with the primary use of glucose by flight muscles located in the thorax. A few of the genes annotated inD. citrihave been targeted for gene knockdown as a proof of concept, for RNAi therapeutics. Thus, manual annotation of these core metabolic pathways provides accurate genomic foundations for developing gene-targeting therapeutics to reduceD. citri.
Natural history of a mouse model of X-linked myotubular myopathy
Authors: Sarikaya Ege , Volpatti Jonathan , Sabha Nesrin , Maani Nika , Gonorazky Hernan D. , Celik Alper , Onofre-Oliveira Paula , Dowling James J.
Published: October 2021

X-linked myotubular myopathy is a severe monogenetic disorder of the skeletal muscle caused by loss of expression/function mutations in theMTM1(myotubularin) gene. There is a growing understanding of the pathologic and molecular abnormalities associated with loss of MTM1, and emerging therapeutic strategies that are in the process of translation to patients. Much of these data have been uncovered through experimentation in pre-clinical animal models of the disease. The most widely used model is an Mtm1 gene knockout mouse line; this line faithfully recapitulates the salient genetic and pathologic features of the disease. Despite the advances in aspects of XLMTM, there remain many unknowns related to disease pathomechanisms and to understanding of MTM1’s function in normal muscle development, and a continued need for therapy identification and development. To address these barriers, and to lay the groundwork for future study, we performed a natural history study of the Mtm1 knockout mouse model of XLMTM. We show that certain molecular and pathologic changes precede overt phenotypic changes, while others, including abnormalities in triad structure, occur more coincident with muscle weakness in the mouse. In total, we provide a comprehensive longitudinal assessment of molecular and structural features of the murine XLMTM disease process.
Examining opioid withdrawal scoring and adaptation of global scoring systems to male and female C57BL/6J mice
Authors: Bravo Isabel , Bluitt Maya , McElligott Zoe
Published: October 2021

Opioid Use Disorder (OUD) is a chronic and relapsing psychiatric condition which is currently the leading cause of accidental death in the US. Symptoms of acute opioid withdrawal resemble a flu-like illness which is accompanied by a dysphoric state. Psychological comorbidities such as anxiety, depression, and disordered sleep can persist for months or years, well into the abstinence period. These symptoms are thought to drive further opioid intake in order to alleviate this unpleasant internal state. Many differences in OUD have been documented between male and female patients, with females at higher risk for relapse and overdose. This study sets out to characterize sex differences in symptoms and behavioral adaptations in mice during early withdrawal. Using our moderate dose, three-day precipitated withdrawal paradigm, we discovered significant effects of sex, time, and drug treatment on early withdrawal behaviors, locomotor activity, and gut motility in C57BL/6J mice. Here I will discuss previous methods of condensing behavioral phenotypes into one global withdrawal score, and propose a new methodology. This method increases the ability to detect nuanced effects and allows for more accurate translation across strain, sex, paradigm, and experimental context. Classification of opioid withdrawal-induced behavioral adaptations will allow for improved behavioral analysis of pharmacological manipulations, and investigations of brain circuitry involved in opioid withdrawal, as well as future screening of compounds with potential therapeutic benefit for the treatment of OUD.
Nipah virus Bangladesh infection elicits organ-specific innate and inflammatory responses in the marmoset model
Authors: Stevens Christian S. , Lowry Jake , Juelich Terry , Atkins Colm , Johnson Kendra , Smith Jennifer K. , Panis Maryline , Ikegami Tetsuro , tenOever Benjamin , Freiberg Alexander N. , Lee Benhur
Published: October 2021

The common marmoset (Callithrix jacchus) is increasingly recognized as an ideal non-human primate (NHP) at high-biocontainment due to its smaller size and relative ease of handling. Here, we evaluated the susceptibility and pathogenesis of Nipah virus Bangladesh strain (NiVB) infection in marmosets at biosafety level 4. Infection via the intranasal and intratracheal route resulted in fatal disease in all four infected marmosets. Three developed pulmonary edema and hemorrhage as well as multi-focal hemorrhagic lymphadenopathy, while one recapitulated neurologic clinical symptoms and cardiomyopathy on gross pathology. Organ-specific innate and inflammatory responses were characterized by RNA-seq in six different tissues from infected and control marmosets. Notably, a unique transcriptome was revealed in the brainstem of the marmoset exhibiting neurological symptoms. Our results provide a more comprehensive understanding of NiV pathogenesis in an accessible and novel NHP model, closely reflecting clinical disease as observed in NiV patients.
CsMYB4a from Camellia sinensis Regulates the Auxin Signaling Pathway by Interacting with CsIAA4
Authors: Ma Guo-Liang , Wu Ying-Ling , Jiang Chang-Juan , Chen Yi-Fan , Xing Da-Wei , Zhao Yue , Liu Ya-Jun , Xia Tao , Gao Li-Ping
Published: October 2021

Members of the R2R3-MYB4 subgroup are well-known negative regulatory transcription factors of phenylpropane and lignin pathways. In this study, we found that transgenic tobacco plants overexpressing a R2R3-MYB4 subgroup gene from Camellia sinensis (CsMYB4a) showed inhibited growth that was not regulated by phenylpropane and lignin pathways, and these plants exhibited altered sensitivity to synthetic auxin 1-naphthaleneacetic acid (α-NAA) treatment. An auxin/indole-3-acetic acid 4 (AUX/IAA4) gene from Camellia sinensis (CsIAA4) participating in the regulation of the auxin signal transduction pathway was screened from the yeast two-hybrid library with CsMYB4a as the bait protein, and tobacco plants overexpressing this gene showed a series of auxin-deficiency phenotypes, such as dwarfism, small leaves, reduced lateral roots, and a shorter primary root. CsIAA4 transgenic tobacco plants were less sensitive to exogenous α-NAA than control plants, which was consistent with the findings for CsMYB4a transgenic tobacco plants. The knockout of the endogenous NtIAA4 gene (a CsIAA4 homologous gene) in tobacco plants alleviated growth inhibition in CsMYB4a transgenic tobacco plants. Furthermore, protein–protein interaction experiments proved that domain II of CsIAA4 is the key motif for the interaction between CsIAA4 and CsMYB4a and that the degradation of CsIAA4 is prevented when CsMYB4a interacts with CsIAA4. In summary, our results suggest that CsMYB4a is a multifunctional transcription factor that regulates the auxin signaling pathway, phenylpropane and lignin pathways. This study provides new insights into the multiple functions of R2R3-MYB4 subgroup members as a group of well-known negative regulatory transcription factors.

One-sentence summary

CsMYB4a act as multifunctional transcription factor that regulates the auxin signaling pathway, phenylpropane and lignin pathways.
Molecular assembly of measles and Nipah virus: specific lipid binding drives conformational change and matrix polymerization
Authors: Norris Michael J. , Husby Monica L. , Kiosses William B. , Yin Jieyun , Rennick Linda J. , Heiner Anja , Harkins Stephanie , Pokhrel Rudramani , Schendel Sharon L. , Hastie Kathryn M. , Landeras-Bueno Sara , Salie Zhe Li , Lee Benhur , Chapagain Prem P. , Maisner Andrea , Duprex W Paul , Stahelin Robert V. , Saphire Erica Ollmann
Published: October 2021

Measles virus, Nipah virus, and multiple other paramyxoviruses cause disease outbreaks in humans and animals worldwide. The paramyxovirus matrix (M) protein mediates virion assembly and budding from host cell membranes. M is thus a key target for antivirals, but few high-resolution structures of paramyxovirus M are available, and we lack the clear understanding of how viral M proteins interact with membrane lipids to mediate viral assembly and egress needed to guide antiviral design. Here, we reveal that M proteins associate with phosphatidylserine and phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) at the plasma membrane. Using X-ray crystallography, electron microscopy, and molecular dynamics we demonstrate that PI(4,5)P2 binding induces conformational and electrostatic changes in the M protein surface that trigger membrane deformation, matrix layer polymerization, and virion assembly.
The edible seaweed Laminaria japonica contains cholesterol analogues that inhibit Lipid Peroxidation and Cyclooxygenase Enzymes
Authors: Lu Xingyu , Dissanayake Amila A. , Xiao Chuqiao , Gao Jie , Zhao Mouming , Nair Muraleedharan G.
Published: October 2021

In this study, 5 sterols were isolated and purified from Laminaria japonica, commonly known as edible brown seaweed, and their structures were identified based on detailed chemical methods and spectroscopic analyses. Spectroscopic analyses characterized 5 sterols as 29-Hydroperoxy-stigmasta-5,24(28)-dien-3β-ol, saringosterol (24-vinyl-cholest-5-ene-3β,24-diol), 24-methylenecholesterol, fucosterol (stigmasta-5,24-diene-3β-ol), and 24-Hydroperoxy-24-vinyl-cholesterol. The bioactivities of these sterols were tested using lipid peroxidation (LPO) and cyclooxygenase (COX-1 and −2) enzyme inhibitory assays. Fucosterol exhibited the highest COX-1 and −2 enzyme inhibitory activities at 59 and 47%, respectively. Saringosterol, 24-methylenecholesterol and fucosterol showed higher LPO inhibitory activity at >50% than the other compounds. In addition, the results of molecular docking revealed that the 5 sterols were located in different pocket of COX-1 and −2 and fucosterol with tetracyclic skeletons and olefin methine achieved the highest binding energy (−7.85 and −9.02 kcal/mol) through hydrophobic interactions and hydrogen bond. Our results confirm the presence of 5 sterols in L. japonica and its significant anti-inflammatory and antioxidant activity.

Graphical abstract

Highlights

Sterols 29-hydroperoxy-stigmasta-5,24(28)-dien-3β-ol and 24-hydroperoxy-24-vinyl-cholesterol are identified for the first time in L. japonica.

Saringosterol, 24-methylenecholesterol and fucosterol showed strong LPO inhibitory activity.

Fucosterol showed highest binding affinity for COX-1 and −2 enzymes through hydrophobic interactions.
RBFOX splicing factors contribute to a broad but selective recapitulation of peripheral tissue splicing patterns in the thymus
Authors: Jansen Kathrin , Shikama-Dorn Noriko , Attar Moustafa , Maio Stefano , Lopopolo Maria , Buck David , Holländer Georg A. , Sansom Stephen N.
Published: October 2021

Thymic epithelial cells (TEC) control the selection of a T cell repertoire reactive to pathogens but tolerant of self. This process is known to involve the promiscuous expression of virtually the entire protein-coding gene repertoire, but the extent to which TEC recapitulate peripheral isoforms, and the mechanisms by which they do so, remain largely unknown. We performed the first assembly-based transcriptomic census of transcript structures and splicing factor (SF) expression in mouse medullary TEC (mTEC) and 21 peripheral tissues. Mature mTEC expressed 60.1% of all protein-coding transcripts, more than was detected in any of the peripheral tissues. However, for genes with tissue-restricted expression, mTEC produced fewer isoforms than did the relevant peripheral tissues. Analysis of exon inclusion revealed an absence of brain-specific microexons in mTEC. We did not find unusual numbers of novel transcripts in TEC, and we show that Aire, the facilitator of promiscuous gene expression, promotes the generation of long “classical” transcripts (with 5′ and 3′ UTRs) but has only a limited impact on alternative splicing in mTEC. Comprehensive assessment of SF expression in mTEC identified a small set of nonpromiscuously expressed SF genes, among which we confirmed RBFOX to be present with AIRE in mTEC nuclei. Using a conditional loss-of-function approach, we show that Rbfox2 promotes mTEC development and regulates the alternative splicing of promiscuously expressed genes. These data indicate that TEC recommission a small number of peripheral SFs, including members of the RBFOX family, to generate a broad but selective representation of the peripheral splice isoform repertoire.
Sensory analysis and volatile compounds in Caiman latirostris meat in comparison with other traditional meats
Authors: Nepote Valeria , Lábaque Maria Carla , Quiroga Patricia Raquel , de Lujan Leiva Pamela Maria , Rey Paez Arley , Piña Carlos Ignacion , Simoncini Melina Soledad
Published: October 2021

Purpose

The aim of the paper is to compare consumer acceptance, sensory analysis and volatile compounds of caiman meat with regard to surubí fish and chicken meat.

Design/methodology/approach

Caiman tail, chicken thigh and surubí meats' cuts were cooked in a pan with little oil and salt. The affective tests of acceptance (9-points hedonic scale) and preference ranking were evaluated by 80 consumers. Sensory analysis carried out by eight trained panelists described attributes' intensities on an unstructured linear scale (0–150 mm). Volatile compounds were analysed by solid-phase micro-extraction and gas chromatography/mass spectrometry GC–MS.

Findings

Caiman meat had good acceptance values of 6–7 (“like slightly” to “like moderately”), being similarly preferred to surubí but less than chicken. The ratings of bitterness, hardness, fibrous appearance, fibrous texture and cohesiveness were higher and raw colour, characteristic flavour and oiliness were lower in caiman's meat than in the others. Caiman meat had lower juiciness than chicken but similar to surubí. Caiman showed lower levels of aldehydes than chicken, lower level of hydrocarbons and higher levels of acids and esters than the other meats. Alcohols, mainly found in caiman and chicken meat, were positively associated to aroma acceptance. Hydrocarbons, mainly found in surubí meat, were positively associated with the characteristic flavour and negatively correlated with aroma acceptance. Volatile composition of meats was related to their sensory attributes and consumer acceptance.

Originality/value

Given that caiman meat showed similar acceptance and preference to that of surubí, it could be considered a good quality meat, helping promote current programmes of sustainable use of natural resources.
Study of factors influencing apartment prices in Prishtina, Kosovo
Authors: Hoxha Visar , Hoxha Dhurata , Hoxha Jehona
Published: October 2021

Purpose

The purpose of this study is to identify which are the main factors influencing the apartment prices in Prishtina, the capital of Kosovo, during the period 2018–2020. The factors identified will be used by real estate developers and investors for better decision-making in apartment investments.

Design/methodology/approach

The research methodology is quantitative. The methodology analyzes 1,468 real estate transaction contracts of apartment buildings using a probability random sampling. The research methodology uses multiple regression analysis to identify whether the research model is significant in predicting apartment prices but also identify which are the main factors that influence the apartment prices in Prishtina, Kosovo.

Findings

The present study finds that location, size, floor, access to road and building quality affect apartment prices in Prishtina, whereas surprisingly access to green spaces and availability of parking spaces have no statistically significant effect on apartment prices in Kosovo.

Research limitations/implications

The study has great implications for the real estate developers in Prishtina, Kosovo showing how to improve their decision-making process in real estate investments to know which characteristics are most valued by investors for investment in new apartment buildings in Prishtina, Kosovo and local authorities in Prishtina, Kosovo to modernize the access to road infrastructure for its inhabitants and adopt building regulations that will enforce strict criteria as far as building quality is concerned.

Originality/value

The study is the first quantitative study that studies the factors influencing the apartment prices in Prishtina, Kosovo.
3D CAD model reconstruction and fast prototyping of rotational parts: a reverse engineering approach
Authors: Chowdary Boppana V. , Jaglal Deepak
Published: October 2021

Purpose

This paper aims to present a reverse engineering (RE) approach for three-dimensional (3D) model reconstruction and fast prototyping (FP) of broken chess pieces.

Design/methodology/approach

A case study involving a broken chess piece was selected to demonstrate the effectiveness of the proposed unconventional RE approach. Initially, a laser 3D scanner was used to acquire a (non-uniform rational B-spline) surface model of the object, which was then processed to develop a parametric computer aided design (CAD) model combined with geometric design and tolerancing (GD&T) technique for evaluation and then for FP of the part using a computer numerical controlled (CNC) machine.

Findings

The effectiveness of the proposed approach for reconstruction and FP of rotational parts was ascertained through a sample part. The study demonstrates non-contact data acquisition technologies such as 3D laser scanners together with RE systems can support to capture the entire part geometry that was broken/worn and developed quickly through the application of computer aided manufacturing principles and a CNC machine. The results indicate that design communication, customer involvement and FP can be efficiently accomplished by means of an integrated RE workflow combined with rapid product development tools and techniques.

Originality/value

This research established a RE approach for the acquisition of broken/worn part data and the development of parametric CAD models. Then, the developed 3D CAD model was inspected for accuracy by means of the GD&T approach and rapidly developed using a CNC machine. Further, the proposed RE led FP approach can provide solutions to similar industrial situations wherein agility in the product design and development process is necessary to produce physical samples and functional replacement parts for aging systems in a short turnaround time.
Learning from incidents: applying the 3-P model of workplace learning
Authors: Murphy Victoria L. , Littlejohn Allison , Rienties Bart
Published: October 2021

Purpose

Learning from incidents (LFI) is an organisational process that high-risk industries use following an accident or near-miss to prevent similar events. Literature on the topic has presented a fragmented conceptualisation of learning in this context. This paper aims to present a holistic taxonomy of the different aspects of LFI from the perspective of front-line staff.

Design/methodology/approach

The 3-P model of workplace learning was used to guide a thematic analysis of interview data from 45 participants, exploring learner factors, learning context, learning processes and learning products.

Findings

The analysis was used to create a taxonomy of 21 aspects of learning, grouped into themes using the 3-P model of workplace learning. Many of the aspects of learning reflected previous literature, such as the importance of open communication. The analysis additionally demonstrated the interconnected nature of organisational and individual level learning, as well as how formal resources are needed to support informal learning in this context.

Originality/value

This study presents a holistic taxonomy of LFI from the perspective of front-line staff, addressing a known challenge of LFI literature being fragmented. Additionally, it provides examples of how aspects of organisational learning would influence individual-level learning and vice versa, adding to the relatively sparse number of studies that have explored this aspect. Finally, the paper highlights how informal learning in contexts where workers continually need to make sense of unseen hazards depends on formal learning activities and resources.