bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of physical inactivity and tobacco use on mortality and morbidity in revascularized patients with peripheral arterial disease: A nationwide cohort study
Authors: Cha Seungwoo , Grace Sherry L , Han Kyungdo , Kim Bongseong , Paik Nam-Jong , Kim Won-Seok
Published: May 2021

Importance

Physical activity (PA) and tobacco use are key health behaviours in patients with peripheral arterial disease (PAD). Limited studies are available on effects of those behaviours in PAD after revascularization, including Asian countries where tobacco use is high.

Objective

To investigate the effects of PA and tobacco use on adverse clinical outcomes in patients with PAD after revascularization.

Design

Retrospective cohort study

Setting

Population-based study using the Korean National Health Insurance Service (NHIS) database

Participants

Patients who had received revascularization for PAD between 2010-2015 were included. They were categorized as active or inactive based on the number of days per week they engaged in PA and as current or non-tobacco users (self-report).

Exposures

PA and tobacco use.

Main outcomes

The primary outcome was all-cause mortality. Secondary outcomes included major adverse outcome (a composite of all-cause mortality, myocardial infarction, and stroke) and major adverse limb event (MALE, a composite of amputation and recurrent revascularization).

Results

The cohort comprised 8324 patients (mean age, 64.7 years; 76.9% male). Among them, 32.7% were inactive and 26.4% were tobacco users. Active patients had significantly better outcomes than inactive patients [all-cause mortality adjusted hazard ratio (adjHR) = 0.766 (0.685 – 0.855), major adverse outcome adjHR = 0.795 (0.719 – 0.878), MALE adjHR = 0.858 (0.773 – 0.953)]. Tobacco users had significantly poorer outcomes than non-users [all-cause mortality adjHR = 1.279 (1.124 – 1.456), major adverse outcome adjHR = 1.263 (1.124 – 1.418), MALE adjHR = 1.291 (1.143 – 1.458)].

Conclusions and Relevance

Even after receiving revascularization for PAD, a sizable proportion of patients were inactive and used tobacco, leading to adverse clinical outcomes. These modifiable risk factors are systematically addressed in cardiac rehabilitation; in line with current guideline recommendations, more needs to be done to ensure cardiac rehabilitation participation in patients with PAD.
A Predictive Modelling Framework for COVID-19 Transmission to Inform the Management of Mass Events
Authors: Donnat Claire , Bunbury Freddy , Kreindler Jack , Filippidis Filippos T. , El-Osta Austen , Esko Tõnu , Harris Matthew
Published: May 2021

Modelling COVID-19 transmission at live events and public gatherings is essential to evaluate and control the probability of subsequent outbreaks. Model estimates can be used to inform event organizers about the possibility of super-spreading and the predicted efficacy of safety protocols, as well as to communicate to participants their personalised risk so that they may choose whether to attend. Yet, despite the fast-growing body of literature on COVID transmission dynamics, current risk models either neglect contextual information on vaccination rates or disease prevalence or do not attempt to quantitatively model transmission, thus limiting their potential to provide insightful estimates. This paper attempts to bridge this gap by providing informative risk metrics for live public events, along with a measure of their associated uncertainty. Starting with a thorough review of the literature and building upon existing models, our approach ties together three main components: (a) reliable modelling of the number of infectious cases at the time of the event, (b) evaluation of the efficiency of pre-event screening and risk mitigation protocols, and (c) modelling the transmission dynamics during the event. We demonstrate how uncertainty in the input parameters can be included in the model using Monte Carlo simulations. We discuss the underlying assumptions and limitations of our approach and implications for policy around live events management.
Impact of an environmental epidemiology board game on knowledge, experience, and attitudes among children: A pilot study
Authors: Pranic Shelly Melissa , Batinovic Tina
Published: May 2021

Children are especially vulnerable to environmental harms, thus increasing their knowledge about risk factors caused by environmental exposures, in addition to epidemiology by providing practical experiences through a non-computer based educational game in environmental epidemiology may lead to more promising behavioral outcomes. Because no educational game exists in environmental epidemiology, we augmented an existing epidemiology game by adding an environmental health theme, involving practical decision-making and problem solving in environmental epidemiology. A cross-sectional survey assessed the game's impact, on children's knowledge, experience, and attitudes regarding environmental health, and experience and attitudes toward epidemiology following game exposure in 2016. Participants from Croatia had a median age of 11.5 years with interquartile range (IQR) 11-13. The majority of children indicated they had learned a lot about the environmental health concepts newly added to an existing epidemiology game. Our modified game offers interactive and practical examples, which may facilitate teaching environmental epidemiology to elementary school students.
Adherence and sustainability of interventions informing optimal control against COVID-19 pandemic
Authors: Di Domenico Laura , Sabbatini Chiara E. , Boëlle Pierre-Yves , Poletto Chiara , Crépey Pascal , Paireau Juliette , Cauchemez Simon , Beck François , Noel Harold , Lévy-Bruhl Daniel , Colizza Vittoria
Published: May 2021

After one year of stop-and-go COVID-19 mitigation, some European countries still experience sustained viral circulation due to the B.1.1.7 variant. As the prospect of phasing out this stage through vaccination draws closer, it is critical to balance the efficacy of long-lasting interventions and their impact on the quality of life. Focusing on the current situation in France, we show that moderate interventions require a much longer time to achieve the same result as high intensity lockdowns, with the additional risk of deteriorating control as adherence wanes. Integrating intensity and duration of social distancing in a data-driven “distress” index, we show that shorter strict lockdowns are largely more performant than longer moderate lockdowns, for similar intermediate distress and infringement on individual freedom. Our study shows that favoring milder interventions over more stringent short approaches on the basis of perceived acceptability could be detrimental in the long term, especially with waning adherence.
Risk of COVID-19 variant importation – How useful are travel control measures?
Authors: Arino Julien , Boëlle Pierre-Yves , Milliken Evan , Portet Stéphanie
Published: May 2021

We consider models for the importation of a new variant COVID-19 strain in a location already seeing propagation of a resident variant. By distinguishing contaminations generated by imported cases from those originating in the community, we are able to evaluate the contribution of importations to the dynamics of the disease in a community. We find that after an initial seeding, the role of importations becomes marginal compared to that of community-based propagation. We also evaluate the role of two travel control measures, quarantine and travel interruptions. We conclude that quarantine is an efficacious way of lowering importation rates, while travel interruptions have the potential to delay the consequences of importations but need to be applied within a very tight time window following the initial emergence of the variant.
Cerebrospinal Fluid and Plasma Procalcitonin for the Diagnosis of Neonatal Bacterial Meningitis
Authors: Dutta Sourabh , Sachdeva Naresh , Sanger Vilay , Pal Arnab , Ray Pallab
Published: May 2021

Objective

To determine accuracy of cerebro-spinal fluid (CSF) procalcitonin (PCT) to diagnose neonatal bacterial meningitis (NBM) among septic neonates and compare with other index tests.

Design

Prospective, cross-sectional, single-gate study

Setting

Level-3 neonatal unit

Patients

Neonates with suspected sepsis undergoing lumbar puncture

Index tests

CSF PCT, leukocyte count and biochemistry; plasma PCT and CSF:plasma PCT ratio

Reference standards

“Definite meningitis” defined by positive CSF culture and/or gram stain and/or broad-based primer 16S rDNA polymerase chain reaction. “Definite or probable meningitis” defined by definite meningitis or probable meningitis (based on cytochemistry cut-offs).

Results

Of 216 eligible neonates, 18 had “definite meningitis” and 37 “definite or probable meningitis”. Median (Q1, Q3) CSF PCT level was higher in “definite meningitis” compared to “no definite meningitis” [0.429 (0.123, 1.300) vs. 0.181 (0.119, 0.286) ng/ml respectively, p=0.028]. Likewise, it was higher in “definite or probable meningitis” compared to no meningitis [0.245 (0.136, 0.675) vs. 0.170 (0.116, 0.28), p=0.01]. The area under ROC curve (AUC) of CSF PCT level for definite meningitis was 0.656 and for “definite or probable meningitis” 0.635. Paired comparisons of AUC of CSF PCT with other index tests were not significant. Based on a priori cut-off of 0.2 ng/ml, CSF PCT level had a sensitivity (95% CI) of 67% (50, 80), specificity 58% (54, 61), LR+ 1.6 (1.1, 2.0) and LR- 0.6 (0.3, 0.9).

Conclusions

Higher values of CSF PCT are associated with NBM. CSF PCT cannot reliably discriminate between meningitis and no meningitis and is not superior to other CSF tests.
Lung Epithelial Cells Can Produce Antibodies Participating In Adaptive Humoral Immune Responses
Authors: Gao Erya , Shao Wenwei , Zhang Chi , Yu Meng , Dai Hui , Fan Tianrui , Zhu Zhu , Xu Weiyan , Huang Jing , Zhang Youhui , Qin Zhihai , Qiu Xiaoyan
Published: May 2021

It is generally believed that the main source of antibodies is B lymphocytes. In this study, our results first revealed that B cell-deficient mice could not produce antibodies specific for TI-Ags; however, mice with B cell deficiency could produce TD-Ag-specific antibodies, although antibody production was delayed compared with that in BALB/c mice after primary TD-Ag challenge. Subsequently, we identified that mouse lung epithelial cells could produce and secrete Ig, including IgM, IgA or IgG, which could display TD-Ag-specific antibody activity. Notably, the production of TD-Ag-specific antibodies by lung epithelial cells was found to be dependent on CD4+ T cells but not CD8+ T cells. Our findings indicate for the first time that B cells are not the only source of TD-Ag-specific antibodies but are essential for rapid TD-Ag-specific antibody production by non-B cells. This discovery may reveal a new mechanism for the production of specific antibodies.
Height, but not binding epitope, affects the potency of synthetic TCR agonists
Authors: Wilhelm Kiera B. , Morita Shumpei , McAffee Darren B. , Kim Sungi , O’Dair Mark K. , Groves Jay T.
Published: May 2021

Under physiological conditions, peptide-MHC (pMHC) molecules can trigger T-cell receptors (TCRs) as monovalent ligands that are sparsely distributed on the plasma membrane of an antigen-presenting cell. TCR can also be activated by artificial clustering, such as with pMHC tetramers or antibodies; however, these strategies circumvent many of the natural ligand discrimination mechanisms of the T cell and can elicit non-physiological signaling activity. We have recently introduced a synthetic TCR agonist composed of an anti-TCRβ Fab’ antibody fragment covalently bound to a DNA oligonucleotide, which serves as a membrane anchor. This Fab’-DNA ligand efficiently activates TCR as a monomer when membrane-associated and exhibits a potency and activation profile resembling agonist pMHC. In this report, we explore the geometric requirements for effective TCR triggering and cellular activation by Fab’-DNA ligands. We find that T cells are insensitive to the ligand binding epitope on the TCR complex, but that length of the DNA tether is important. Increasing the intermembrane distance spanned by Fab’-DNA:TCR complexes decreases TCR triggering efficiency and T cell activation potency, consistent with the kinetic-segregation model of TCR triggering. These results establish design parameters for construction of synthetic TCR agonists that are able to activate polyclonal T cell populations, such as T cells from a human patient, in a similar manner as the native pMHC ligand.

STATEMENT OF SIGNIFICANCE

We report geometric requirements for potent T cell activation by synthetic TCR ligands that mimic biophysical properties of the native pMHC ligand, but have the additional ability to activate polyclonal T cell populations. We find that increasing the space between apposed membranes at TCR binding events decreases ligand potency, but that changing the ligand’s binding epitope on the TCR has essentially no effect. The observed decrease in potency with increased ligand height is attributed to the longer ligands’ attenuated ability to trigger TCR at binding events.
High-Throughput Measurement and Machine Learning-Based Prediction of Collision Cross Sections for Drugs and Drug Metabolites
Authors: Ross Dylan H. , Seguin Ryan P. , Krinsky Allison M. , Xu Libin
Published: May 2021

Drug metabolite identification is a bottleneck of drug metabolism studies. Ion mobility-mass spectrometry (IM-MS) enables the measurement of collision cross section (CCS), a unique physical property related to an ion’s gas-phase size and shape, which can be used to increase the confidence in the identification of unknowns. A current limitation to the application of IM-MS to the identification of drug metabolites is the lack of reference CCS values. In this work, we present the production of a large-scale database of drug and drug metabolite CCS values, assembled using high-throughputin vitrodrug metabolite generation and a rapid IM-MS analysis with automated data processing. Subsequently, we used this database to train a machine learning-based CCS prediction model, employing a combination of conventional 2D molecular descriptors and novel 3D descriptors. This novel prediction model enables the prediction of different CCS values for different protomers, conformers, and positional isomers for the first time.
Genes responsible for avoiding attack of a beetle, relating to the duration of death feigning
Authors: Tanaka Keisuke , Sasaki Ken , Matsumura Kentarou , Yajima Shunsuke , Miyatake Takahisa
Published: May 2021

Predator avoidance is an important behavior that affects the degree of adaptation of organisms. We compared the DNA variation of one of the predator-avoidance behaviors, the recently extensively studied “death-feigning behavior,” between the long strain bred for feigning death for a long time and the short strain bred for feigning death for a short time. To clarify how the difference in DNA sequences between the long and short strains corresponds to the physiological characteristics of the death-feigning duration at the transcriptome level, we performed comprehensive and comparative analyses of gene variants inTribolium castaneumstrains using DNA-re-sequence. The duration of death feigning involves many gene pathways, including caffeine metabolism, tyrosine metabolism, tryptophan metabolism, metabolism of xenobiotics by cytochrome P450, longevity regulating pathways, and circadian rhythm. Artificial selection based on the duration of death feigning results in the preservation of variants of genes in these pathways in the long strain. When an animal wake up from a near-death experience is closely related to its success in avoiding predation. This study suggests that many metabolic pathways and related genes may be involved in the decision-making process of anti-predator animal behavior by forming a network in addition to the tyrosine metabolic system, including dopamine, revealed in previous studies.
Time-resolved scanning ion conductance microscopy for three-dimensional tracking of nanoscale cell surface dynamics
Authors: Leitao Samuel M. , Drake Barney , Pinjusic Katarina , Pierrat Xavier , Navikas Vytautas , Nievergelt Adrian P. , Brillard Charlène , Djekic Denis , Radenovic Aleksandra , Persat Alex , Constam Daniel B. , Anders Jens , Fantner Georg E.
Published: May 2021

Nanocharacterization plays a vital role in understanding the complex nanoscale organization of cells and organelles. Understanding cellular function requires high-resolution information about how the cellular structures evolve over time. A number of techniques exist to resolve static nanoscale structure of cells in great detail (super-resolution optical microscopy1, EM2, AFM3). However, time-resolved imaging techniques tend to either have lower resolution, are limited to small areas, or cause damage to the cells thereby preventing long-term time-lapse studies. Scanning probe microscopy methods such as atomic force microscopy (AFM) combine high-resolution imaging with the ability to image living cells in physiological conditions. The mechanical contact between the tip and the sample, however, deforms the cell surface, disturbs the native state, and prohibits long-term time-lapse imaging. Here, we develop a scanning ion conductance microscope (SICM) for high-speed and long-term nanoscale imaging. By utilizing recent advances in nanopositioning4, nanopore fabrication5, microelectronics6, and controls engineering7 we developed a microscopy method that can resolve spatiotemporally diverse three-dimenional processes on the cell membrane at sub-5nm axial resolution. We tracked dynamic changes in live cell morphology with nanometer details and temporal ranges of sub-second to days, imagining diverse processes ranging from endocytosis, micropinocytosis, and mitosis, to bacterial infection and cell differentiation in cancer cells. This technique enables a detailed look at membrane events and may offer insights into cell-cell interactions for infection, immunology, and cancer research.
Distant water industrial fishing in developing countries: A case study of Madagascar
Authors: White Easton R. , Baker-Médard Merrill , Vakhitova Valeriia , Farquhar Samantha , Ramaharitra Tendro Tondrasoa
Published: May 2021

As industrial vessels continue to expand in both extractive capacity and spatial range, concerns have grown over foreign industrial fishing occurring within the marine territories of developing countries, both legally and illegally. Madagascar’s status as a “least developed country”, coupled with its high marine biodiversity, makes its waters particularly susceptible to fishing by distant water fishing nations (DWFNs). However, given constraints in management and research, it is unclear how foreign industrial fishing, both legal via foreign agreements and illegal, may impact local marine resources that many coastal communities depend on for food security, cultural meaning and livelihoods. We used satellite-derived fishing effort data from 2012-2020, via Global Fishing Watch, to analyze industrial fishing effort occurring within Madagascar’s Exclusive Economic Zone (EEZ). We documented 907,643 hours of industrial fishing within the Madagascar EEZ across 277 vessels from 17 different countries. We found that Taiwanease vessels (39.8%) using drifting longlines and Malagasy (17.2% shrimp trawlers were the most prevalent. Fishing effort was highly seasonal (68% of effort between October and February) and increased with higher global fish prices and the Indian Ocean Dipole, which is a measure of regional water temperature cycles. We also found a number of instances (17.6% of the fishing effort for 170,726 total hours) of foreign fishing vessels operating close to shore and within a number of marine protected areas. These results highlight the need for increased transparency surrounding foreign fishing agreements and unauthorized fishing within the waters of developing countries. Increases in industrial fishing effort and encroachment into near-shore areas has the potential to severely threaten current sustainable fisheries management initiatives by conservation organizations and coastal communities.

Highlights

Distant water fishing nations dominated fishing efforts within Madagascar’s EEZ.

Longlining by foreign nations was the dominant fishing mode and increased from October-February.

Malagasy vessels focused on trawling for shrimp.

Fishing effort increased during positive Indian Ocean Dipoles and with higher fish prices.

Distant water fishing nations frequently fished close to shore and sometimes within MPAs.
Stable choice coding during changes of mind
Authors: Boyd-Meredith J Tyler , Piet Alex T , Dennis Emily Jane , Hady Ahmed El , Brody Carlos D
Published: May 2021

How do we choose the best action in a constantly-changing environment? Many natural decisions unfold in dynamic environments where newer observations carry better information about the present state of the world. Recent work has shown that rats can learn to optimally discount old evidence, updating their provisional decision when the environmental state changes. Provisional decisions are thought to be represented in the Frontal Orienting Fields (FOF), but this has only been tested in static environments where the provisional and final decisions are not easily dissociated. Here, we characterize the representation of accumulated evidence in rat FOF during decision-making in a dynamic environment. We find that FOF encodes evidence throughout decision formation with a temporal gain modulation that rises until the period when the animal may need to act. Using a behavioral model to predict the timing of changes of mind revealed that FOF neurons respond rapidly to these events, representing the new provisional decisions in their firing rates. Our results suggest that the FOF represents provisional decisions even in dynamic, uncertain environments, allowing for rapid motor execution when it is time to act.
Photoperiodic Flowering Response of Essential Oil, Grain, and Fiber Hemp (Cannabis sativaL.) Cultivars
Authors: Zhang Mengzi , Anderson Steven L. , Brym Zachary , Pearson Brian J.
Published: May 2021

Cultivation of hemp (Cannabis sativaL.) in tropical and subtropical regions can be challenging if flowering behavior of a given cultivar is unknown, poorly understood, or not accurately selected for the photoperiod. Identifying cultivars adapted to local environmental conditions is key to optimizing hemp vegetative and flowering performance. We investigated the effects of varying light cycles in regulating extension growth and flowering response of 15 essential oil and 12 fiber/grain hemp cultivars both in indoors and outdoors. Plants were subjected to eleven photoperiods in the controlled rooms ranging from 12 h to 18 h, and natural day length in the field. The critical photoperiod threshold was identified for seven essential oil cultivars and two fiber/grain cultivars. ‘Cherry Wine-CC’, ‘PUMA-3’, and ‘PUMA-4’ had the shortest critical day length between 13 h 45 min and 14 h. The flowering of essential oil cultivars was generally delayed by 1 to 2 d when photoperiod exceeded 13 h compared to 12 h, and flowering was further delayed by 7 to 8 d when photoperiod exceed 14 h. In fiber/grain cultivars, flowering was generally delayed by 1 to 3 d when day length exceeded 14 h. Flowering for most essential oil cultivars was delayed by 5 to 13 d under 14 h photoperiod compared to 13 h 45 min, suggesting a photoperiod difference as little as 15 min can significantly influence the floral initiation of some essential oil cultivars. Cultivars represented by the same name but acquired from different sources can perform differently under the same environmental conditions, suggesting genetic variation among cultivars with the same name. Average days to flower of fiber/grain cultivars was correlated with reported cultivar origin with faster flowering occurring among northern cultivars when compared to southern cultivars. Plant height generally increased as the day length increased in essential oil cultivars but was not affected in fiber/grain cultivars. In addition, civil twilight of approximately 2 µmol·m-2·s-1was discovered to be biologically effective in regulating hemp flowering. Collectively, we conclude that most of the essential oil cultivars and some southern fiber/grain cultivars tested express suitable photoperiods for tropical and sub-tropical region cultivation.
The FDA-approved drug apremilast suppresses alcohol intake: clinical and pre-clinical validation
Authors: Grigsby Kolter B. , Mangieri Regina A. , Roberts Amanda J. , Lopez Marcelo F. , Tran Alexander , Firsick Evan J. , Townsley Kayla G. , Beneze Alan , Bess Jessica , Eisenstein Toby K. , Meissler Joseph J. , Light John M. , Miller Jenny , Quello Susan , Shadan Farhad , Skinner Michael , Aziz Heather C. , Metten Pamela , Morissett Richard A. , Crabbe John C. , Roberto Marisa , Becker Howard C. , Mason Barbara J. , Ozburn Angela R.
Published: May 2021

Treatment options for Alcohol Use Disorders (AUD) have minimally advanced since 2004, while the annual deaths and economic toll have become alarmingly high. Bringing potential therapeutics beyond the bench and into the clinic for AUD requires rigorous pharmacological screening across molecular, behavioral, pre-clinical, and clinical studies in neuroscience. The repurposing of FDA-approved compounds is an effective and expedited means of screening pharmacotherapies for AUD. Here, we demonstrate that apremilast, a phosphodiesterase type 4 inhibitor that is FDA approved for psoriasis and psoriatic arthritis, reduces binge-like alcohol intake and behavioral measures of motivation in unique, preclinical genetic risk models for drinking to intoxication and reduces excessive alcohol drinking in models of stress-facilitated drinking and alcohol dependence. In a double blind, placebo-controlled human laboratory study in non-treatment seeking individuals with AUD, apremilast significantly reduced the number of drinks per day. Lastly, using site-directed drug infusions and electrophysiology we determined that apremilast may act by increasing neural activity in the nucleus accumbens, an important alcohol-related brain region, to reduce alcohol intake in mice. These results demonstrate that apremilast reduces excessive alcohol drinking across a spectrum of AUD severity and support its importance as a potential therapeutic for AUD.
Novel Object Detection and Multiplexed Motion Representation in Retinal Bipolar Cells
Authors: Gaynes John A. , Budoff Samuel A. , Grybko Michael J. , Hunt Joshua B. , Poleg-Polsky Alon
Published: May 2021

Antagonistic interactions between the center and surround receptive field (RF) components lie at the heart of the computations performed in the visual system. Center-surround RFs are thought to enhance responses to spatial contrasts (i.e., edges), but how they contribute to motion processing is unknown. Here, we addressed this question in retinal bipolar cells, the first visual neuron with classic center-surround interactions. We found that bipolar glutamate release emphasizes objects that emerge in the RF; their responses to continuous motion are smaller, slower, and cannot be predicted by signals elicited by stationary stimuli. The alteration in signal dynamics induced by novel objects dwarfs the enhancement of spatial edges and can be explained by priming of RF surround during continuous motion. These findings echo the salience of human visual perception and demonstrate an unappreciated capacity of the center-surround architecture to facilitate novel object detection and multiplexed encoding of distinct sensory modalities.
Gastrin producing syngeneic mesenchymal stem cells protect non-obese diabetic mice from type 1 diabetes
Authors: Gaudreau Marie-Claude , Gudi Radhika R. , Li Gongbo , Johnson Benjamin M. , Vasu Chenthamarakshan
Published: May 2021

Progressive destruction of pancreatic islet β-cells by immune cells is a primary feature of type 1 diabetes (T1D) and therapies that can restore the functional β-cell mass are needed to alleviate disease progression. Here, we report the use of mesenchymal stromal/stem cells (MSCs) for the production and delivery of Gastrin, a peptide-hormone which is produced by intestinal cells and fetal islets and can increase β-Cell mass, to promote protection from T1D. A single injection of syngeneic MSCs that were engineered to express Gastrin (Gastrin-MSCs) caused a significant delay in hyperglycemia in non-obese diabetic (NOD) mice compared to engineered control-MSCs. Similar treatment of early-hyperglycemic mice caused the restoration of euglycemia for a considerable duration, and these therapeutic effects were associated with protection of, and/or higher frequencies of, insulin producing islets and less severe insulitis. While the overall immune cell phenotype was not affected profoundly upon treatment using Gastrin-MSCs or upon in vitro culture, pancreatic lymph node cells from Gastrin-MSC treated mice, upon ex vivo challenge with self-antigen, showed a Th2 and Th17 bias, and diminished the diabetogenic property in NOD-Rag1deficient mice suggesting a disease protective immune modulation under Gastrin-MSC treatment associated protection from hyperglycemia. Overall, this study shows the potential of production and delivery of Gastrin in vivo, by MSCs, in protecting insulin producing β-cells and ameliorating the disease progression in T1D.
Markov state models from hierarchical density-based assignment
Authors: Mitxelena Ion , López Xabier , de Sancho David
Published: May 2021

Markov state models (MSMs) have become one of the preferred methods for the analysis and interpretation of molecular dynamics (MD) simulations of conformational transitions in biopolymers. While there is great variation in terms of implementation, a well-defined workflow involving multiple steps is often adopted. Typically, molecular coordinates are first subjected to dimensionality reduction and then clustered into small “microstates”, which are subsequently lumped into “macrostates” using the information from the slowest eigenmodes. However, the microstate dynamics is often non-Markovian and long lag times are required to converge the MSM. Here we propose a variation on this typical workflow, taking advantage of hierarchical density-based clustering. When applied to simulation data, this type of clustering separates high population regions of conformational space from others that are rarely visited. In this way, density-based clustering naturally implements assignment of the data based on transitions between metastable states. As a result, the state definition becomes more consistent with the assumption of Markovianity and the timescales of the slow dynamics of the system are recovered more effectively. We present results of this simplified workflow for a model potential and MD simulations of the alanine dipeptide and the FiP35 WW domain.
Insularity forcing on plant persistence strategies in edaphic island systems
Authors: Conti Luisa , Méndez-Castro Francisco E. , Chytrý Milan , Götzenberger Lars , Hájek Michal , Horsák Michal , Jiménez-Alfaro Borja , Klimešová Jitka , Zelený David , Ottaviani Gianluigi
Published: May 2021

Aim

Trait-based approaches are increasingly implemented in island biogeography, providing key insights into the eco-evolutionary dynamics of insular systems. However, what determines persistence of plant species once they have arrived and established in an island remains largely unexplored. Here, we examined links between non-acquisitive persistence strategies and insularity across three terrestrial edaphic island systems, hypothesising that insularity promotes strategies for local persistence.

Location

Europe: Western Carpathians, Moravia, and Cantabrian Range.

Time period

Present.

Major taxa studied

Vascular plants.

Methods

For each system, we used linear models at the island scale to test whether persistence-related plant trait patterns (average trait values and diversity) depend on three insularity metrics (island size, isolation and target effect). We focused on patterns of edaphic island specialists because, in contrast to matrix-derived species, their presence is confined to the edaphic islands.

Results

We found that insularity metrics explained large proportions in the variation of the average and diversity of persistence-related traits of edaphic island specialists. Insularity was associated with a decline in the proportion of island specialists that have clonal abilities, yet it affected trait values of specialists towards enhanced abilities to persist locally (e.g. more extensive lateral spread) while reducing trait variability. Higher degrees of insularity within the systems were translated to stronger effects on functional trait patterns.

Main conclusions

Insularity affects plant species diversity, distribution and forms in terrestrial island-like systems, similarly as it is assumed for true islands. Insularity – measured using a single (island size, isolation) or combined (target effect) predictors – may operate selecting for enhanced and less diverse persistence strategies. Ultimately, this process, which we call insularity forcing, operates as a selective process to promote species ability to avoid local extinction and to persist on terrestrial islands.
Optimizing Parameters for Using the Parallel Auditory Brainstem Response (pABR) to Quickly Estimate Hearing Thresholds
Authors: Polonenko Melissa J , Maddox Ross K
Published: May 2021

Objectives

Timely assessments are critical to providing early intervention and better hearing and spoken language outcomes for children with hearing loss. To facilitate faster diagnostic hearing assessments in infants, the authors developed the parallel auditory brainstem response (pABR), which presents randomly timed trains of tone pips at five frequencies to each ear simultaneously. The pABR yields high-quality waveforms that are similar to the standard, single-frequency serial ABR but in a fraction of the recording time. While well-documented for standard ABRs, it is yet unknown how presentation rate and level interact to affect responses collected in parallel. Furthermore, the stimuli are yet to be calibrated to perceptual thresholds. Therefore, this study aimed to determine the optimal range of parameters for the pABR and to establish the normative stimulus level correction values for the ABR stimuli.

Design

Two experiments were completed, each with a group of 20 adults (18 – 35 years old) with normal hearing thresholds (≤ 20 dB HL) from 250 to 8000 Hz. First, pABR electroencephalographic (EEG) responses were recorded for six stimulation rates and two intensities. The changes in component wave V amplitude and latency were analyzed, as well as the time required for all responses to reach a criterion signal-to-noise ratio of 0 dB. Second, behavioral thresholds were measured for pure tones and for the pABR stimuli at each rate to determine the correction factors that relate the stimulus level in dB peSPL to perceptual thresholds in dB nHL.

Results

The pABR showed some adaptation with increased stimulation rate. A wide range of rates yielded robust responses in under 15 minutes, but 40 Hz was the optimal singular presentation rate. Extending the analysis window to include later components of the response offered further time-saving advantages for the temporally broader responses to low frequency tone pips. The perceptual thresholds to pABR stimuli changed subtly with rate, giving a relatively similar set of correction factors to convert the level of the pABR stimuli from dB peSPL to dB nHL.

Conclusions

The optimal stimulation rate for the pABR is 40 Hz, but using multiple rates may prove useful. Perceptual thresholds that subtly change across rate allow for a testing paradigm that easily transitions between rates, which may be useful for quickly estimating thresholds for different configurations of hearing loss. These optimized parameters facilitate expediency and effectiveness of the pABR to estimate hearing thresholds in a clinical setting.

Highlights

The pABR yields robust responses across stimulus rates and intensities.

The optimal rate is 40 Hz, but using multiple rates may prove useful.

The pABR shows some adaptation with increased stimulation rate.

Extended analysis windows improve response detection for low stimulus frequencies.

Behavioral thresholds subtly change across pABR rate, giving similar dB nHL values.
Force profile of the two-handed hardstyle kettlebell swing performed by an RKC-certified instructor
Authors: Meigh Neil J. , Hing Wayne A. , Schram Ben , Keogh Justin W.L.
Published: May 2021

Background

The effects of hardstyle kettlebell training are increasingly cited in strength and conditioning research, yet reference data from a proficient swing is scarce. The aim of this exploratory study was to investigate the force profile of a two-handed hardstyle swing performed by a Russian Kettlebell Challenge (RKC) instructor.

Methods

The subject is a 44-year-old male, body mass 75.6 kg, height 173.5 cm, with six years of regular hardstyle training experience. Two-handed hardstyle swings were performed with a series of incremental mass kettlebells (8-68 kg). Ground reaction force (GRFs) was obtained from a floor-mounted force platform. Force-time curves (FTCs), peak force, forward force, rate of force development (RFD) and swing cadence were investigated.

Results

Data revealed the FTC of a proficient swing is highly consistent and dominated by a single force peak (mean SD = 47 N), with a profile that remained largely unchanged to 24 kg. Pearson correlation analysis revealed a very strong positive correlation in peak force with kettlebell mass (r = 0.95), which increased disproportionately from the lightest to heaviest kettlebells; net peak force increased from 8.36 ± 0.75 N.kg-1 (0.85 × BW) to 12.82 ± 0.39 N.kg-1 (1.3× BW). There was a strong negative correlation between RFD and kettlebell mass (r = 0.82) that decreased from 39.2 N.s-1.kg-1 to 21.5 N.s-1.kg-1. There was a very strong positive correlation in forward ground reaction force with kettlebell mass (r = 0.99), expressed as a ratio of vertical ground reaction, that increased from 0.092 (9.2%) to 0.205 (20.5%). Swing cadence exceeded 40 swings per minute (SPM) with all kettlebells.

Conclusion

Our findings challenge some of the popular beliefs of the hardstyle kettlebell swing. Consistent with hardstyle practice, and previous kinematic analysis of expert and novice, force-time curves show a characteristic single large force peak, differentiating passive from active shoulder flexion. Ground reaction force did not increase proportionate to kettlebell mass, with a magnitude of forward force smaller than described in practice. These results could be useful for coaches and trainers wanting to improve athletic performance, and healthcare providers using the kettlebell swing for therapeutic purposes. Findings from this study were used to inform the BELL Trial, a pragmatic controlled trial of kettlebell training with older adults. www.anzctr.org.au ACTRN12619001177145.
Expression of GRINA Correlates with Prognosis in Human Cancers: A Pan-cancer Analysis
Authors: Islam S. M. Riazul , Saha Subbroto Kumar , El-Sappagh Shaker , Tariq Faisal , Das Joydeep , Afzal Muhammad , Cho Ssang-Goo
Published: May 2021

GRINA is an emerging target for cancer therapy. However, the role of GRINA expression and its correlation with cancer patient survival has not been comprehensively studied. Here, we found that mRNA and protein expression of GRINA was upregulated in breast, colon, gastric, and prostate cancers and negatively correlated with patient survival. Also, the upregulation of GRINA expression is associated with hypomethylation of its promoter region. Our GRINA-miRNAs network analysis revealed potential regulatory miRNAs regulating the GRINA expression and its downstream pathways. Next, functional enrichment and pathway analysis of genes commonly co-express with GRINA in breast, colon, gastric, and prostate cancers revealed GRINA regulatory pathways. Concurrently, our upstream regulator analysis revealed possible kinases, transcription factors, and proteins that may potentially regulate GRINA. Overall, this study demonstrates the prognostic significance of GRINA expression and identifies potential regulatory mechanisms, which might have significant implications in targeted therapies for human cancers.
Diverse classes of constraints enable broader applicability of a linear programming-based dynamic metabolic modeling framework
Authors: Lee Justin Y. , Styczynski Mark P.
Published: May 2021

Current metabolic modeling tools suffer from a variety of limitations, from scalability to simplifying assumptions, that preclude their use in many applications. We recently created a modeling framework, LK-DFBA, that addresses a key gap: capturing metabolite dynamics and regulation while retaining a potentially scalable linear programming structure. Key to this framework’s success are the linear kinetics and regulatory constraints imposed on the system. However, while the linearity of these constraints reduces computational complexity, it may not accurately capture the behavior of many biochemical systems. Here, we developed three new classes of LK-DFBA constraints to better model interactions between metabolites and the reactions they regulate. We tested these new approaches on several synthetic and biological systems, and also performed the first-ever comparison of LK-DFBA predictions to experimental data. We found that no single constraint approach was optimal across all systems examined, and systems with the same topological structure but different parameters were often best modeled by different types of constraints. However, we did find that the optimal constraint approach was generally robust to local perturbations of the system, indicating that just a single wild-type dataset could allow identification of the ideal constraint for a given system. These results suggest that the availability of multiple constraint approaches will allow LK-DFBA to model a wider range of metabolic systems.
Leveraging the mass balances of cellular metabolism to infer absolute concentrations from relative abundance metabolomics data
Authors: Lee Justin Y. , Styczynski Mark P.
Published: May 2021

Motivation

As the large-scale study of metabolites and a direct readout of a system’s metabolic state, metabolomics has significant appeal as a source of information for many metabolic modelling platforms and other metabolic analysis tools. However, metabolomics data are typically reported in terms of relative abundances, which precluding use with tools where absolute concentrations are necessary. While chemical standards can be used to determine the absolute concentrations of metabolites, they are often time-consuming to run, expensive, or unavailable for many metabolites. A computational framework that can infer absolute concentrations without the use of chemical standards would be highly beneficial to the metabolomics community.

Results

We have developed and characterized MetaboPAC, a computational strategy that leverages the mass balances of a system to infer absolute concentrations in metabolomics datasets. MetaboPAC uses a kinetic equations approach and an optimization approach to predict the most likely response factors that describe the relationship between absolute concentrations and their relative abundances. We determined that MetaboPAC performed significantly better than the other approaches assessed on noiseless data when at least 60% of kinetic equations are known a priori. Under the most realistic conditions (low sampling frequency, high noise data), MetaboPAC significantly outperformed other methods in the majority of cases when 100% of the kinetic equations were known. For metabolomics datasets extracted from systems that are well-studied and have partially known kinetic structures, MetaboPAC can provide valuable insight about their absolute concentration profiles.
Microinductor-Fused Atomic Force Microscopy Cantilevers for Dynamic Imaging and Multimodal Manipulation
Authors: Mousoulis Charilaos , Xu Xin , Wilson Robert L. , Chado Garrett , Wahlquist Joseph , Stoykovich Mark P. , Ferguson Virginia L. , Ziaie Babak , Neu Corey P.
Published: May 2021

Recent advances in atomic force microscopy (AFM) imaging and force spectroscopy have demonstrated improvements in rapid acquisition of quantitative data for applications in materials science, surface characterization, and biology. However, conventional AFM technology is limited in detection sensitivity and the ability to excite at off-resonance frequencies restricting broad utility of the technology. Here we demonstrate new AFM cantilevers fabricated with a planar microcoil at the tip region, which can be used to generate or sense highly-localized magnetic fields. Torsion/bending actuation of the cantilevers is accomplished with simple experimental configurations, enabling quantitative and simultaneous mapping of both stiffness and friction at the sample surface with more than one order of magnitude improvement in compositional contrast. Our method is compatible with commercial AFM systems, allowing us to clearly resolve small stiffness and friction variations in copolymer and biological samples that were difficult to detect by conventional AFM methods. In combination with fluorescence microscopy, we also generated localized fields to selectively stimulate and monitor structural changes in viable cells with nm-scale detail. Hybrid AFM cantilevers may be useful to characterize a broad range of complex material surfaces, in addition to combined physical and chemical analyses of single cells and biological microenvironments.
Sex Differences in the Incidence and Risk of Ankle-Foot Complex Stress Fractures Among U.S. Military Personnel
Authors: MacGregor Andrew J. , Fogleman Sarah A. , Dougherty Amber L. , Ryans Camille P. , Janney Cory F. , Fraser John J.
Published: May 2021

Background

The objective of this study was to evaluate sex differences in the incidence and risk of ankle-foot complex (AFC) stress fractures among U.S. military personnel, which could assist in developing management strategies as females assume a greater role in U.S. military operations.

Methods

The Defense Medical Epidemiological Database was used to identify all diagnosed AFC stress fractures in military personnel from 2006 to 2015. Cumulative incidence of AFC stress fractures was calculated and compared by year, service branch, and military rank. Sex differences in the risk of AFC stress fractures by occupation were examined, and integrated (i.e., male and female) occupations were compared with non-integrated (i.e., male-only) occupations.

Results

A total of 43,990 AFC stress fractures were identified. The overall incidence rate was 2.76 per 1,000 person-years for males and 5.78 per 1,000 person-years for females. Females consistently had higher incidence of AFC stress fractures across all subgroups, particularly among enlisted personnel. Female enlisted service members had the highest risk of AFC stress fractures in aviation [relative risk (RR) = 5.74; 95% confidence interval [CI] 4.80–6.87] and artillery/gunnery (RR = 5.15; 95% CI 4.62–5.75) occupations. Females in integrated occupations had significantly higher rates of AFC stress fractures than males in both integrated and non-integrated occupations (i.e., special forces, infantry, and mechanized/armor).

Conclusions

Females in the U.S. military have a higher risk of AFC stress fractures than males. As integration of females into previously sex-restricted occupations continues, focused prevention efforts may be needed to reduce injury burden and maximize medical readiness.