bluuebunny/crossref_metadata_2025 huggingface dataset:
In silico DNA codon optimization of the variant antigen-encoding genes of diverse strains of Nipah virus
Authors: Gupta Aeshna , Gangotia Disha , Vasdev Kavita , Mani Indra
Published: April 2021

Due to an increase in human and wildlife interaction, more and more zoonotic diseases are emerging. A prime example of this is the emergence of the Nipah virus (NiV). Due to high rate of mortality specifically in India and Bangladesh, there is an urgent need for accelerated research for NiV involving the development of vaccines or drugs. The genome of NiV consists of six genes (N, P, M, F, G and L) encoding yielding nucleoprotein, phosphoprotein, matrix, fusion, glycoprotein and large RNA polymerase. We have used these six genes for in silico assessment of DNA codon optimization inEscherichia coli. It was observed that the codon adaptation index (CAI) and GC content of the genes in optimized DNA were enhanced significantly as compared to wild-type strain. On an average, CAI and GC content of N gene in optimized DNA was enhanced by 2.3 (135.1%) and 1.2(9.9 %) fold respectively, while in P/V/C it was increased by 2.0 (98.3 %) and 1.1(7.8%) fold respectively. Further, the CAI and GC content in optimized DNA of M gene and F gene was enhanced by 2.0(99.0%) and 1.1(7.2%) fold respectively for gene M and 2.4(142.5 %), 1.2(15.4%) fold respectively for gene F. Gene G showed an increase of 2.1(114.8 %) fold for CAI, 1.1(11.2%) fold for GC content and gene L showed an increase of 2.4(143.7%) fold for CAI, 1.2(17.2%) fold for GC content. Our result demonstrates that the optimized genes could be useful for better expression in host without any truncated proteins and also useful for protein folding and function.
After-hyperpolarization promotes the firing of mitral cells through a voltage dependent modification of action potential threshold
Authors: Nicolas Fourcaud-Trocmé , Mickaël Zbili , Patricia Duchamp-Viret , Nicola Kuczewski
Published: April 2021

In the olfactory bulb (OB), mitral cells (MCs) display a spontaneous firing that is characterized by bursts of action potentials intermixed with silent periods. Burst firing frequency and duration are heterogeneous among MCs and increase with membrane depolarization. By using patch clamp recording on rat slices, we dissected out the intrinsic properties responsible of this activity. We showed that the threshold of action potential (AP) generation dynamically changes as a function of the trajectory of the membrane potential; becoming more negative when the membrane was hyperpolarized and having a recovering rate, inversely proportional to the membrane repolarization rate. Such variations appeared to be produced by changes in the inactivation state of voltage dependent Na+channels. Thus, the modification AP threshold favours the initiation of the burst following hyperpolarizing event such as negative membrane oscillations or inhibitory transmission. After the first AP, the following afterhyperpolarization (AHP) brought the threshold just below the membrane resting potential or within membrane oscillations and, as a consequence, the threshold was exceeded during the fast repolarization component of the AHP. In this way the fast AHP acts as a regenerative mechanism that sustains the firing. Bursts were stopped by the development of a slow repolarization component of the AHP. The AHP characteristics appeared as determining the bursting properties; AHP with larger amplitudes and faster repolarizations being associated with longer and higher frequency bursts. Thus, the increase of bursts length and frequency upon membrane depolarization would be attributable to the modifications of the AHP and of Na+channels inactivation.
Locomotion induced by medial septal glutamatergic neurons is linked to intrinsically generated persistent firing
Authors: Korvasová Karolína , Ludwig Felix , Kaneko Hiroshi , Sosulina Liudmila , Tetzlaff Tom , Remy Stefan , Mikulovic Sanja
Published: April 2021

Medial septal glutamatergic neurons are active during theta oscillations and locomotor activity. Prolonged optogenetic activation of medial septal glutamatergic neurons drives theta oscillations and locomotion for extended periods of time outlasting the stimulus duration. However, the cellular and circuit mechanisms supporting the maintenance of both theta oscillations and locomotion remain elusive. Specifically, it remains unclear whether the presence of theta oscillations is a necessary prerequisite for locomotion, and whether neuronal activity within the medial septum underlies its persistence. Here we show that a persistent theta oscillation can be induced by a brief transient activation of glutamatergic neurons. Moreover, persistent locomotion is initiated even if the theta oscillation is abolished by blocking synaptic transmission in the medial septum. We observe persistent spiking of medial septal neurons that outlasts the stimulus for several seconds, both in vivo and in vitro. This persistent activity is driven by intrinsic excitability of glutamatergic neurons.
Identifying Oscillatory Hyperconnectivity and Hypoconnectivity Networks in Major Depression Using Coupled Tensor Decomposition
Authors: Liu Wenya. , Wang Xiulin. , Xu Jing. , Chang Yi. , Hämäläinen Timo. , Cong Fengyu.
Published: April 2021

Previous researches demonstrate that major depression disorder (MDD) is associated with widespread network dysconnectivity, and the dynamics of functional connectivity networks are important to delineate the neural mechanisms of MDD. Cortical electroencephalography (EEG) oscillations act as coordinators to connect different brain regions, and various assemblies of oscillations can form different networks to support different cognitive tasks. Studies have demonstrated that the dysconnectivity of EEG oscillatory networks is related with MDD. In this study, we investigated the oscillatory hyperconnectivity and hypoconnectivity networks in MDD under a naturalistic and continuous stimuli condition of music listening. With the assumption that the healthy group and the MDD group share similar brain topology from the same stimuli and also retain individual brain topology for group differences, we applied the coupled nonnegative tensor decomposition algorithm on two adjacency tensors with the dimension of time × frequency × connectivity × subject, and imposed double-coupled constraints on spatial and spectral modes. The music-induced oscillatory networks were identified by a correlation analysis approach based on the permutation test between extracted temporal factors and musical features. We obtained three hyperconnectivity networks from the individual features of MDD and three hypoconnectivity networks from common features. The results demonstrated that the dysfunction of oscillation-modulated networks could affect the involvement in music perception for MDD patients. Those oscillatory dysconnectivity networks may provide promising references to reveal the pathoconnectomics of MDD and potential biomarkers for the diagnosis of MDD.
Rich and lazy learning of task representations in brains and neural networks
Authors: Flesch Timo , Juechems Keno , Dumbalska Tsvetomira , Saxe Andrew , Summerfield Christopher
Published: April 2021

How do neural populations code for multiple, potentially conflicting tasks? Here, we used computational simulations involving neural networks to define “lazy” and “rich” coding solutions to this multitasking problem, which trade off learning speed for robustness. During lazy learning the input dimensionality is expanded by random projections to the network hidden layer, whereas in rich learning hidden units acquire structured representations that privilege relevant over irrelevant features. For context-dependent decision-making, one rich solution is to project task representations onto low-dimensional and orthogonal manifolds. Using behavioural testing and neuroimaging in humans, and analysis of neural signals from macaque prefrontal cortex, we report evidence for neural coding patterns in biological brains whose dimensionality and neural geometry are consistent with the rich learning regime.
High nucleotide substitution rates associated with retrotransposon proliferation drive dynamic secretome evolution in smut pathogens
Authors: Depotter JRL , Ökmen B , Ebert MK , Beckers J , Jb Kruse , Thines M , Doehlemann G
Published: April 2021

Transposable elements (TEs) play a pivotal role in shaping diversity in eukaryotic genomes. The covered smut pathogen on barley,Ustilago hordei, encountered a recent genome expansion. Using long reads, we assembled genomes of 6U. hordeistrains and 3 sister species, to study this genome expansion. We found that larger genome sizes can mainly be attributed to a higher genome fraction of long terminal repeat retrotransposons (LTR-RTs). In the studied smut genomes, LTR-RTs fractions are the largest inU. hordeiand are positively correlated to the mating-type locus sizes, which is up to ∼560 kb inU. hordei. Furthermore, LTR-RTs were found to be associated with higher nucleotide substitution levels, as these higher levels occur more clustered in smut species with a recent LTR-RT proliferation. Moreover, genes in genome regions with higher nucleotide substitution levels generally reside closer to LTR-RTs than other genome regions. Genome regions with many nucleotide substitutions encountered an especially high fraction of CG substitutions, which is not observed for LTR-RT sequences. The high nucleotide substitution levels particularly accelerate the evolution of secretome genes, as their more flexible nature results that substitutions often lead to amino acid alterations.

Importance

Genomic alteration can be generated through various means, in which transposable elements (TEs) can play a pivotal role. Their mobility causes mutagenesis in itself and can disrupt the function of the sequences they insert into. Indirectly, they also impact genome evolution as their repetitive nature facilitates non-homologous recombination. Furthermore, TEs have been linked to specific epigenetic genome organizations. We report a recent TE proliferation in the genome of the barley covered smut fungus,Ustilago hordei.This proliferation is associated with a distinct nucleotide substitution regime that has a higher rate and a higher fraction of CG substitutions. This different regime shapes the evolution of genes in subjected genome regions. Our findings highlight that TEs may influence the error-rate of DNA polymerase in a hitherto unknown fashion.
Linking the dynamics of chromatin occupancy and transcription with predictive models
Authors: Tran Trung Q. , MacAlpine Heather K. , Tripuraneni Vinay , Mitra Sneha , MacAlpine David M. , Hartemink Alexander J.
Published: April 2021

Though the sequence of the genome within each eukaryotic cell is essentially fixed, it exists within a complex and changing chromatin state. This state is determined, in part, by the dynamic binding of proteins to the DNA. These proteins—including histones, transcription factors (TFs), and polymerases—interact with one another, the genome, and other molecules to allow the chromatin to adopt one of exceedingly many possible configurations. Understanding how changing chromatin configurations associate with transcription remains a fundamental research problem. We sought to characterize at high spatiotemporal resolution the dynamic interplay between transcription and chromatin in response to cadmium stress. Whereas gene regulatory responses to environmental stress in yeast have been studied, how the chromatin state changes and how those changes connect to gene regulation remain unexplored. By combining MNase-seq and RNA-seq data, we found chromatin signatures of transcriptional activation and repression involving both nucleosomal and TF-sized DNA-binding factors. Using these signatures, we identified associations between chromatin dynamics and transcriptional regulation, not only for known cadmium response genes, but across the entire genome, including antisense transcripts. Those associations allowed us to develop generalizable models that predict dynamic transcriptional responses on the basis of dynamic chromatin signatures.
The FEL in the SXL project at MAX IV
Authors: Qin Weilun , Curbis Francesca , Andersson Joel , Goryashko Vitaliy , Isaksson Lennart , Kyle Billy , Lindau Filip , Mansten Erik , Pop Mihai , Salén Peter , Tarawneh Hamed , Tavares Pedro F. , Thorin Sara , Vorozhtsov Alexey , Werin Sverker
Published: April 2021

In this paper the design of the free-electron laser (FEL) in the SXL (Soft X-ray Laser) project at the MAX IV Laboratory is presented. The target performance parameters originate in a science case put forward by Swedish users and the SXL FEL is foreseen to be driven by the existing MAX IV 3 GeV linac. The SXL project is planned to be realized in different stages and in this paper the focus is on Phase 1, where the basic operation mode for the FEL will be SASE (self-amplified spontaneous emission), with an emphasis on short pulses. Simulation results for two linac bunches (high and low charge) with different pulse duration are illustrated, as well as the performance for two-color/two-pulses mode and power enhancement through tapering. Besides standard SASE and optical klystron configurations, the FEL setup is also tailored to allow for advanced seeding schemes operations. Finally possible upgrades that will be implemented in a second phase of the project are discussed.
Full‐wave modelling of early‐time measurements in time‐domain electromagnetics: Consideration of coupling between Tx–Rx antennas and the ground
Authors: Finco Cécile , Schamper Cyril , Rejiba Fayçal , Cavalcante Fraga Luis H.
Published: April 2021

Early‐time measurements of time‐domain electromagnetics carry information of the near surface, and therefore, the interpretation of such measurements is important, particularly when utilizing small‐loop acquisition devices. However, these early‐time gates are often distorted by responses from the acquisition system itself, primarily caused by self‐transients associated with the transmission link composed of the transmitter and receiver loops and with the investigated medium electrical properties. Estimating all such potential couplings is crucial for interpreting early‐time measurements and gathering information on the near surface. In this study, a receptor loop made of 20 turns was built for this purpose. Field results and simulations were then compared, which shows how full‐wave finite‐difference method in the time‐domain simulations can be used to accurately calculate the impedance characteristics of time‐domain electromagnetics systems. All simulations were performed using finite‐difference time‐domain software based on a fully explicit three‐dimensional solver. First and second sets of simulations, respectively, were carried out in free space to compare the results to an alternate simulation method with equivalent lumped electrical circuits and on a homogeneous half‐space with varying electrical resistivities. The results were then used to improve the inversion of field data acquired on a test site in Garchy, France.
How do soil microbes exert impact on soil respiration and its temperature sensitivity?
Authors: Tong Di , Li Zhongwu , Xiao Haibing , Nie Xiaodong , Liu Chun , Zhou Mi
Published: April 2021

Understanding how soil microorganisms influence the direction and magnitude of soil carbon feedback to global warming is vital to predict future climate change. Although microbial activities are major contributors to soil respiration (RS) and its temperature sensitivity (Q10), the mechanisms underpinning microbial influence on RS and Q10 remain unclear. Coupling variation partitioning analysis (VPA), correlation analysis and multiple stepwise linear regression analysis, we illustrate that bacteria mainly affect RS and its temperature sensitivity (Q10) by shifting bacterial community composition (denoted by principal coordinates analysis). We also found that soil water content (SWC) and available nutrient (AN) were the factor key to changing bacterial community composition (P < 0.05). Co‐occurrence network demonstrated that Mod 0 ecological cluster composed of copiotrophic taxa groups was significantly associated with RS and Q10 (P < 0.01, R > 0.5), including Proteobacteria, Actinobacteria, and Bacteroidetes. Illuminating the mechanisms underpinning the influence of soil microbes on RS and Q10 values is fundamental to understanding mechanistic soil‐climate carbon cycles.
Need for speed: bacterial effector XopJ2 is associated with increased dispersal velocity of Xanthomonas perforans
Authors: Sharma Anuj , Timilsina Sujan , Abrahamian Peter , Minsavage Gerald V. , Colee James , Ojiambo Peter S. , Goss Erica M. , Vallad Gary E. , Jones Jeffrey B.
Published: April 2021

Bacterial spot caused by Xanthomonas perforans (Xp) is an economically important disease in tomato. Previous studies have shown that the recently isolated Xp strains have acquired and retained the effector gene, xopJ2, which has been reported to increase fitness of the pathogen in the field. To elucidate the fitness benefit of xopJ2, we quantified the effect of xopJ2 on the dispersal and evolution of Xp populations on tomato. We compared movement of two wild‐type Xp strains expressing xopJ2 to their respective xopJ2 mutants when co‐inoculated in the field. We developed a binary logistic model to predict the presence of Xp over spatial and temporal dimensions with or without xopJ2. Based on the model, wild‐type bacteria were dispersed approximately three times faster than the xopJ2 mutants. In a simulation experiment, the selective advantage due to increased dispersal velocity led to an increase in the frequency of xopJ2 gene in the Xp population and its apparent fixation within 10 to 12 cropping seasons of the tomato crop. Our results show that the presence of a single gene can affect the dispersal of a bacterial pathogen and significantly alter its population dynamics.
Fingermark ridge drift: Influencing factors of a not‐so‐rare aging phenomenon
Authors: De Alcaraz‐Fossoul Josep , Roberts Katherine A. , Johnson Cathy A. , Barrot Feixat Carme , Tully‐Doyle Ryan , Kammrath Brooke W.
Published: April 2021

Fingermark ridge drift is a random modification of (aged) fingermark patterns at a ridge scale. This phenomenon was previously proven to alter key elements used for identifications, such as the appearance of minutiae. Little is currently reported on the underlying factors contributing to its occurrence. The present study was designed to investigate further the variables of a previous study by including a total of 768 fingermarks from a male and female, two substrates (glazed ceramic tile and plastic), two distinct color powder developers (carbon black and titanium dioxide), three indoor lighting conditions (direct natural light, shade, and darkness), and two secretion types (sebaceous‐ and eccrine‐rich). Fingermarks were aged for 2–72 days, powdered, photographed, and drift detected by three independent observers. All aged fingermarks (672) were compared relative to fresh fingermarks (96), and ridge drift was observed in 42 of 672 (6%) fingermarks, while 168 (25%) were reported as indeterminate results. While ridge drift was detected in multiple fingermarks across all independent variables, statistical analysis using a multinomial logistics model showed that only powder type, secretion type, and the substrate indicated a significant correlation with increased incidences of this phenomenon. There was no significant correlation with the donor, time since deposition, or the environmental lighting conditions used. The highest incidence occurred when carbon black powder was used on a plastic substrate (>10%). The average observation of ridge drift is 6% of samples supporting that this phenomenon is not a rare event, particularly considering the conservative analysis approach implemented.
Balancing nutrients in a toxic environment: the challenge of eating
Authors: Wang Peng , Vassão Daniel G. , Raguschke Bettina , Furlong Michael J. , Zalucki Myron P.
Published: April 2021

Insect herbivores can regulate their food intake by mixing food sources with different nutrient content, but face the resulting challenge of ingesting various plant secondary metabolites. How insects deal with toxins in a complex nutrient environment is unclear. Here we investigated the influence of a classic plant secondary metabolite, allyl glucosinolate (sinigrin), and its hydrolyzed product allyl isothiocyanate (AITC), on the development of Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae) when fed on diets with different protein‐to‐carbohydrate (p : c) ratios. We also examined the effects of these toxins on larval biochemistry, by chemically analyzing the frass produced by insects feeding on the different diets. As expected, AITC had a greater negative effect than sinigrin on H. armigera life‐history traits. However, AITC at low concentration appeared to have a positive effect on some traits. Both sinigrin and AITC‐induced detoxification activity in the gut, and the reaction was related to diet protein concentration. High‐protein diets can provide the required free amino acid, especially cysteine, needed for the detoxification process. The nutrient content of the diet influences how plant secondary metabolites are handled, and the use of artificial diets in experiments investigating the metabolic fate of plant secondary compounds needs to be carefully evaluated.
Random drug testing in prisons: Does a little testing go a long way?
Authors: Nguyen Holly , Midgette Greg , Loughran Thomas , Zhang Yiwen
Published: April 2021

Research Summary

We investigated whether higher rates of random drug testing lower substance use among people who are incarcerated and improve prison safety. To answer this question, we estimated linear panel two‐way fixed effects models using naturally varying monthly rates of random drug testing across all Pennsylvania state prisons over a 45‐month period during 2016–2019. Overall, we find that the testing rate is not related to any of the variables we consider, including our key measure of interest, positive drug tests.

Policy Implications

Our analyses of historical monthly data find that higher levels of randomized testing did not yield more positive drug tests among incarcerated persons. Further and importantly, we did not find that lower testing rates was associated with negative consequences on other outcomes, suggesting that marginal increases in testing rates do not generate commensurate benefits. In this sense, our findings provide preliminary evidence that “a little testing goes a long way.” Replication and expansion of our study is required for stronger conclusions.
Evaluation of monitoring youth exposure to alcohol advertising on cable television, United States 2016–19
Authors: Ross Craig S. , Henehan Elizabeth R. , Alger Charlotte , White Laura F.
Published: April 2021

Background and aims

Exposure to alcohol advertising is associated with underage drinking, which contributes to adolescent morbidity and mortality. Alcohol advertisements are regulated by the alcohol industry. Our research team has published reports monitoring alcohol advertisers’ compliance with industry guidelines. In this study, we estimated: (1) changes in youth and adult exposure to alcohol advertisements on cable television from 2016–19 and (2) changes in youth exposure to types of non‐compliant advertising highlighted in monitoring reports over the same period.

Design

Interrupted time–series analysis using data from Nielsen US national television audience estimates, 2012–19.

Measures and methods

Outcome was advertising impressions (the total number of times an alcohol advertisement was viewed by youth or adults) by month. Non‐compliant exposure was impressions from advertisements that did not meet guidelines. Covariates were advertising spending in multiple media categories. Seasonal autoregressive integrated moving average models estimated trends in exposure before the publication of monitoring reports (2012–15 reference period) and during the monitoring period (2016–19). We compared the modeled exposure trend during the monitoring period to the reference period projected trend.

Setting

United States.

Participants

A total of 57 000 Nielsen panel households

Findings

Non‐compliant exposure declined 6158 [95% confidence interval (CI) = −11 406 to −911] million impressions, or −77.3% during the monitoring period compared with the reference period trend. Total youth exposure declined by 20 995 (CI = −34 701 to −7288) million impressions (27.0%). Non‐compliant exposure on programs, network dayparts and brands highlighted in monitoring reports declined by −82.4, −79.0 and −82.2%—more than other programs (−52.7%), network dayparts (−71.0%) or brands (143%). Adult exposure declined by 9.3%.

Conclusions

Publication of alcohol advertising monitoring reports appears to have been associated with a 27.0% decline in US youth exposure to alcohol advertising on cable television and a 77.3% decline in US youth exposure to non‐compliant alcohol advertising.
Prospective study of patient satisfaction with enhanced recovery after surgery (ERAS) protocol in the immediate post‐operative period in gynaecological oncology
Authors: Thangavel Dhivya , Gerges Bassem , Brand Alison
Published: April 2021

Background

Enhanced recovery after surgery (ERAS) is a multimodal protocol which aims to facilitate faster discharge from hospital and recovery after surgery by minimising physiological and physical stress on the body before, during and after surgery.

Aims

The aim of this study is to evaluate patient satisfaction while being managed with the ERAS pathway and to determine whether it is an acceptable model of care in this respect.

Materials and Methods

The study is an observational study of patient satisfaction in ERAS in gynaecological oncology. Patients who underwent laparoscopy or laparotomy for malignancy or suspected malignancy were asked to complete a validated questionnaire (EORTC IN‐PATSAT32) prior to discharge from hospital after surgery.

Results

There were 113 (75.33%) patients recruited out of 150 patients who were approached. There were 68 cases of laparotomy and 45 cases of laparoscopy. There were no statistically significant differences between baseline characteristics of responders and non‐responders in both the laparotomy and the laparoscopy group. Patients reported high levels of satisfaction, with a mean score for general satisfaction of 92.2 (SD 11.44 ± 1.387) in the laparotomy group and 92.4 (SD 10.69 ± 1.594) for the laparoscopy group.

Conclusions

The results of our study reflect high levels of patient satisfaction in both the laparotomy and laparoscopy groups. This could be attributed to a strong focus on discharge planning through a multi‐disciplinary approach, specifically addressing key aspects to recovery from initial consultation. The study reflects the successful implementation of an ERAS protocol with gynaecological oncological surgery in this unit.
The effect of saline versus air for cuff inflation on the incidence of high intra‐cuff pressure in paediatric MicroCuff® tracheal tubes: a randomised controlled trial
Authors: Armstrong J. , Jenner P. , Poulose S. , Moppett I. K.
Published: April 2021

The use of cuffed tracheal tubes in paediatric anaesthesia is now common. The use of nitrous oxide in anaesthesia risks excessive tracheal tube cuff pressures, as nitrous oxide can diffuse into the cuff during the course of surgery. The aim of this single‐centre, prospective, randomised controlled trial was to compare the effect of saline versus air for the inflation of tracheal tube cuffs on the incidence of excessive intra‐operative cuff pressure in children undergoing balanced anaesthesia with nitrous oxide. Children (age ≤ 16 y) were randomly allocated to receive either saline (saline group) or air (air group) to inflate the cuff of their tracheal tube. The pressure in the tracheal tube cuff was measured during surgery and brought down to the initial inflation level if it breached a safe limit (25 cmH2O). Post‐extubation adverse respiratory events were noted. Data from 48 patients (24 in each group), aged 4 months to 16 y, were analysed. The requirement for reduction in intra‐cuff pressure occurred in 1/24 patients in the saline group, compared with 16/24 patients in the air group (p < 0.001). The incidence of extubation‐related adverse events was similar in the saline and air groups (15/24 vs. 13/24, respectively; p = 0.770). The use of saline to inflate the cuff of paediatric cuffed tubes reduces the incidence of high intra‐cuff pressures during anaesthesia. This may provide a pragmatic extra safety barrier to help reduce the incidence of excessive tracheal cuff pressure when nitrous oxide is used during paediatric anaesthesia.
Pharmacological inhibition of USP30 activates tissue‐specific mitophagy
Authors: Luo Hongke , Krigman Judith , Zhang Ruohan , Yang Mingchong , Sun Nuo
Published: April 2021

Aim

Mitophagy is the regulated process that targets damaged or dysfunctional mitochondria for lysosomal‐mediated removal. This process is an essential element of mitochondrial quality control, and dysregulation of mitophagy may contribute to a host of diseases, most notably neurodegenerative conditions such as Parkinson's disease. Mitochondria targeted for mitophagic destruction are molecularly marked by the ubiquitination of several outer mitochondrial membrane (OMM) proteins. This ubiquitination is positively regulated, in part, by the mitochondrial‐targeted kinase PINK1 and the E3 ubiquitin ligase Parkin. In contrast, the reverse phenomenon, deubiquitination, removes ubiquitin from Parkin substrates embedded in the OMM proteins, antagonizing mitophagy. Recent evidence suggests that the mitochondrial deubiquitinase USP30 negatively regulates Parkin‐mediated mitophagy, providing opportunities to identify USP30 inhibitors and test for their effects in augmenting mitophagy. Here we will characterize a USP30 inhibitor and demonstrate how the pharmacological inhibition of USP30 can augment stress‐induced mitophagic flux.

Methods

We have conducted mitophagy and mitochondrial analyses in cultured cells. We have determined the plasma pharmacokinetics of the USP30 inhibitor in mice and conducted analyses using the mt‐Keima mice to measure in vivo mitophagy directly.

Results

The compound has minimal mitochondrial toxicity in cultured cells and is tolerated well in mice. Interestingly, we demonstrated tissue‐specific induction of mitophagy following USP30 pharmacological inhibition. In particular, pharmacological inhibition of USP30 induces a significant increase in cardiac mitophagy without detriment to cardiac function.

Conclusion

Our data support the evidence that USP30 inhibition may serve as a specific strategy to selectively increase mitophagic flux, allowing for the development of novel therapeutic approaches.
Finding meaning in unfair experiences: Using expressive writing to foster resilience and positive outcomes
Authors: Saldanha Maria Francisca , Barclay Laurie J.
Published: April 2021

Decades of research have demonstrated that experiencing workplace unfairness can result in profound negative consequences for employees. Integrating conservation of resources theory with meaning‐finding perspectives, we argue that engaging in meaning‐finding in the aftermath of unfairness can foster state resilience and promote positive outcomes. To promote meaning‐finding, we develop and test a new expressive writing intervention (i.e. a guided writing technique that facilitates the processing of negative experiences). Results indicate that the meaning‐finding expressive writing intervention is associated with higher resilience than traditional expressive writing. Moreover, resilience mediates the relationship between meaning‐finding (vs. traditional) expressive writing and willingness to reconcile, positive relationships with others, and life satisfaction. Theoretically, our findings highlight that engaging in meaning‐finding can transform aversive experiences into opportunities to foster resilience and positive outcomes. Practically, meaning‐finding expressive writing provides an effective, simple, and cost‐effective tool that can be used by employees and counseling programs to promote recovery.
Learning by making: A framework to revisit practices in a constructionist learning environment
Authors: Morado María Florencia , Melo Ayelén Eva , Jarman Angela
Published: April 2021

Makerspaces are collaborative workspaces where people construct their ideas using a variety of materials and tools ranging from no tech to high tech, where components can be moulded and transformed into different projects depending on each maker’s vision. Educational makerspaces allow educators to respond to the diverse interests of individual learners. This paper documents the learning of participants at an educational makerspace founded on constructionist principles. We analyse the characteristics of the Maker Movement and the features of an educational makerspace, identify learning dimensions, select a case, analyse field notes, photos and videos using an interpretivist paradigm and refine the practical framework guiding the facilitation of the case study discussed. Given that the investigators are also the facilitators of the activities, this framework allows an a posteriori analysis of the practices used to make learning visible.

Practitioner notes

What is already known about this topic

Makerspaces promote learning in STEM, developing 21st century skills such as effective communication and problem solving.

Makerspaces accommodate diverse students and their interests.

Makerspaces encourage DIY practices and design thinking.

What this paper adds

New dimensions for analysing what has been learned in a constructionist educational makerspace.

New indicators that illustrate the different dimensions of learning, which permit in‐depth analysis of specific practices and promote reflection.

A framework which can be applied in the analysis of learning in similar environments.

Recognition that constructionist makerspaces can enhance learning in all disciplines, moving beyond the limits of STEM or STEAM.

Implications for practice and/or policy

New ways to plan and execute activities in an educational makerspace and any constructionist education centre.

A reference for identifying and making visible learning inside educational makerspaces and any constructionist education centre.

Assurance of the quality of learning developed in educational makerspaces and any constructionist education centre.
Historical and new insights into pathogenesis of type 1 diabetes (2)
Authors: Wong F S , Tree T I
Published: April 2021

In this second and final part of the collection of articles for the Immunology of Diabetes Society review series on insights into pathogenesis of type 1 diabetes, we present two articles. The first of these covers a debate that took place in the Immunology of Diabetes Society meeting in London 2018, in which five investigators presented a case for specific immune cells/targets to be the ‘Achilles Heel of type 1 diabetes’. The second article presents further insights into the generation of post-translationally modified peptides. It focuses upon mechanisms and processes that lead to new potentially autoantigenic targets for CD8+ T cells, and complements the review of new hybrid peptide targets for CD4+ T cells in the first part of our series.
Weight‐based thyroid dosing vs fixed dosing during pregnancy for subclinical hypothyroidism: A retrospective cohort study
Authors: Bohlega Balsam , Zahedi Afshan , Tomlinson George , Feig Denice S.
Published: April 2021

Objective

Thyroid hormones play a crucial role in foetal growth and neurocognitive development. Our aim was to compare a weight‐based dosing method of starting thyroxine to a fixed‐dose method in newly diagnosed women with subclinical hypothyroidism during pregnancy.

Design

We performed a retrospective cohort study of consecutive women with newly diagnosed subclinical hypothyroidism during pregnancy seen at Mount Sinai Hospital and Women's College Hospital, Toronto, Canada 2015–2018.

Patients

We identified women that were treated based on pre‐pregnancy weight and those that were given a fixed dose of 50 mcg/day.

Measurements

The percent of women who reached the target TSH of <2.5 mIU/L within 4–8 weeks was compared using a chi‐squared test and a logistic regression model, adjusting for age, initial TSH and gestational age treatment was started.

Results

393 women were included: 252 treated using a fixed‐dose approach; 141 treated based on pre‐pregnancy weight. In the unadjusted analysis, there was no difference between the groups in the percentage of women in the target range within 4–8 weeks (89.6% in the fixed‐dose group vs 88.8% in the weight‐based group (p = .954)). However, after adjustment for between‐group differences in age, initial TSH and gestational age treatment was started, there was a significantly greater odds of achieving the target range using the weight‐based dosing (OR 4.26 (1.60–11.7), p = .004).

Conclusions

Treating women with newly diagnosed subclinical hypothyroidism during pregnancy with a weight‐based strategy increased the odds of reaching the target TSH range within 4–8 weeks. Clinicians caring for these women should consider this approach when starting treatment during pregnancy.
Combining payment for crop damages and reward for productivity to address wildlife conflict
Authors: Joshi Poorva , Dahanukar Neelesh , Bharade Shankar , Dethe Vijay , Dethe Smita , Bhandare Neha , Watve Milind
Published: April 2021

Conflict caused by wild herbivores damaging crops is an almost universal problem in conservation. We designed and implemented a game‐theory‐based system for supporting farmers whose crops were being heavily damaged by wild herbivores. In this community‐operated system, farmers self‐report their production, which is endorsed by neighboring farmers. The average deficit in production is compensated for by a payment that is directly proportional to the average deficit in production of the group and to the individual farmer's productivity. As a result, farmers are compensated for the average damage (support) and rewarded for individual productivity (reward) (i.e., support cum reward [SuR]). The design of the game is such that only honest reporting gives maximum returns. Farmers who underreport receive less payment because the SuR amount is proportionate to their self‐reported productivity. The endorsing farmers, in their own self‐interest, prevent overreporting. The system involves multiple game situations, the combined result of which is a stable strategy based on honesty and hard work. In 2 villages along the western boundary of Tadoba Andhari Tiger Reserve in central India, we tested the system with 75 farmers over 6 crop seasons. After a few initial attempts to cheat, honesty prevailed throughout the group. Average crop productivity increased 2.5‐fold, in spite of damage, owing to increased effort by farmers. Apart from wildlife conflict resolution, the model offers a promising alternative to crop insurance and a potential behavioral green revolution in agriculture.
Conducting conservation social science surveys online
Authors: Wardropper Chloe B. , Dayer Ashley A. , Goebel Madeline S. , Martin Victoria Y.
Published: April 2021

The coronavirus (COVID‐19) pandemic is affecting the environment and conservation research in fundamental ways. Many conservation social scientists are now administering survey questionnaires online, but they must do so while ensuring rigor in data collection. Further, they must address a suite of unique challenges, such as the increasing use of mobile devices by participants and avoiding bots or other survey fraud. We reviewed recent literature on online survey methods to examine the state of the field related to online data collection and dissemination. We illustrate the review with examples of key methodological decisions made during a recent national study of people who feed wild birds, in which survey respondents were recruited through an online panel and a sample generated via a project participant list. Conducting surveys online affords new opportunities for participant recruitment, design, and pilot testing. For instance, online survey panels can provide quick access to large and diverse samples of people. Based on the literature review and our own experiences, we suggest that to ensure high‐quality online surveys one should account for potential sampling and nonresponse error, design survey instruments for use on multiple devices, test the instrument, and use multiple protocols to identify data quality problems. We also suggest that research funders, journal editors, and policy makers can all play a role in ensuring high‐quality survey data are used to inform effective conservation programs and policies.
From connoisseur to the good manager. Perspectives in managerial curatorship from Canada and Brazil
Authors: Viau‐Courville Mathieu
Published: April 2021

Managerial curatorship developed mainly, though not exclusively, as a practice and museum model in so‐called society museums during the 1990s, particularly in French‐speaking Canada and later in parts of French‐speaking Europe. It was progressively adopted in other cultural and heritage organizations in Latin America and more recently in the UK and USA. This model involves professional project managers taking on certain curatorial tasks such as exhibition‐making. This intentional deconstruction of the traditional curatorship model originally envisioned a displacement, or in some cases, a complete removal of the traditional curator figure. This paper examines two cases of managerial curatorship: one in Canada (Musée de la civilisation, Quebec City, 1988) and one in Brazil (Museu da Pessoa, São Paulo, 1991). It then puts forth two arguments. First, that there should be more focus on developing healthy teamwork by concurrently investing in community participation and career development of key staff figures. The second argument is that encouraging creativity is key to maintaining the sustainability of such a model in the 21st century.
Akrasia and moral motivation
Authors: Shpall Sam
Published: April 2021

The motivation problem as normally conceived is a problem about explaining the special connection between moral judgment and motivation. This understanding of the problem has structured a great deal of thinking in contemporary metaethics and moral psychology. For example, claims about the special motivational import of moral judgment have figured as central premises in the most influential arguments for noncognitivism. But debates about moral motivation have eventuated in seemingly intractable disputes between internalists and externalists about, for example, the possibility of genuine amoralism. In this paper, I motivate a new way forward, which draws underappreciated insights from philosophical thinking about the irrationality of akrasia. One central lesson is that discussions of the motivation problem should move away from the focus on moral judgment specifically. A more controversial and radical proposal is that the traditional motivation problem can be dissolved. Contra externalists, there is one fundamental and necessary connection between judgment and motivation. But this connection—a connection between all things considered normative judgment and motivation in rational agents—in fact requires no special explanation at all.
Antiseizure medications and fetal nutrients: Effects on choline transporters in a human placental cell line
Authors: Tetro Nino , Moushaev Sonia , Shmuel Miri , Eyal Sara
Published: April 2021

Objective

Many nutrients essential to the fetus and for proper function of the placenta itself cannot freely diffuse across membrane barriers, and their transplacental transfer depends on transporters. Our previous studies provided evidence for altered expression of transporters for folic acid in trophoblasts exposed to antiseizure medications (ASMs). The goal of the current study was to explore the effects of older and newer ASMs on the expression and function of uptake transporters for choline, which interacts with folate at pathways for methyl group donation.

Methods

BeWo cells were incubated for 2 or 5 days with valproate (42, 83, or 166 µg/ml), carbamazepine (6 or 12 µg/ml), levetiracetam (10 or 30 µg/ml), lamotrigine (3 or 12 µg/ml), lacosamide (5, 10, or 20 µg/ml), or their vehicles (n = 6/treatment group). Quantitative polymerase chain reaction (PCR) analysis was utilized to study the effects of ASMs on the transcript levels of the choline transportersSLC44A1(CTL1) andSLC44A2(CTL2). Transporter protein expression in valproate‐treated cells was assessed by western blot analysis. Choline and acetylcholine were quantified in cell lysates by a choline/acetylcholine assay kit.

Results

Compared with controls, valproate and levetiracetam at high therapeutic concentrations (83 and 30 µg/ml, respectively) lowered choline transporter transcript levels by up to 42% and 26%, and total choline levels by 20% and 21%, respectively (p < .05). At 83 μg/ml, valproate additionally reduced CTL1 and CTL2 protein expression, by 39 ± 21% and 61 ± 13% (mean ± SD), respectively (p < .01). Carbamazepine reducedSLC44A1transcript levels, whereas lacosamide modestly decreased the expression ofSLC44A2. Lamotrigine did not alter choline transporter expression.

Significance

Antiseizure medications, particularly at high therapeutic concentrations, can interfere with the placental uptake of choline. In line with current knowledge from pregnancy registries and clinical studies, the present in vitro findings further support careful adjustment of maternal ASM doses during pregnancy.
Orthodox–Reformed Dialogue and the Ecumenical Recovery of Theosis
Authors: Mosser Carl
Published: April 2021

Agreement about theosis in Orthodox–Reformed dialogues played a small but strategic role in the ecumenical recovery of the patristic doctrine of deification and its emergence as a locus of Reformed theology. Ecumenical dialogue helped dispel the idea that theosis is a distinctively Orthodox doctrine incompatible with the Western tradition. This idea was first propounded in the 19th century by Albrecht Ritschl, Ferdinand Kattenbusch, Adolf von Harnack, and others associated with the Ritschlian school. It was later appropriated by émigré Orthodox scholars. Orthodox–Reformed dialogue helped correct this and other misconceptions about theosis. This began informally in correspondence between Thomas F. Torrance and Georges Florovsky and continued in formal dialogue meetings. Orthodox–Reformed dialogue also highlighted patristic ways of thinking about salvation that were not then prominent in Reformed theology. However, as the Reformed participants consulted the works of John Calvin, they realized that he shared those patristic ways of thinking. Today, Reformed theologians are eager contributors to the ecumenical recovery of theosis. They increasingly discuss theosis as a doctrine native to the Reformed tradition.