bluuebunny/crossref_metadata_2025 huggingface dataset:
Science Communication in the Age of Misinformation
Authors: Goldstein Carly M , Murray Eleanor J , Beard Jennifer , Schnoes Alexandra M , Wang Monica L
Published: January 2021

Behavioral medicine scientists, practitioners, and educators can engage in evidence-based science communication strategies to amplify the science and combat misinformation. Such efforts are critical to protect public health during crises such as the COVID-19 pandemic and to promote overall well-being.
Management of Distress in Patients with Cancer—Are We Doing the Right Thing?
Authors: Dekker Joost , Graves Kristi D , Badger Terry A , Diefenbach Michael A
Published: January 2021

Background

Screening for distress and referral for the provision of psychosocial care is currently the preferred approach to the management of distress in patients with cancer. To date, this approach has shown a limited effect on the reduction of distress. Recent commentaries have argued that the implementation of distress screening should be improved. On the other hand, the underlying assumption that a referral for psychosocial care is required for distressed patients can be questioned. This has led to the development of an alternative approach, called emotional support and case finding.

Purpose

In the context of finding innovative solutions to tomorrow’s health challenges, we explore ways to optimize distress management in patients with cancer.

Methods and Results

We discuss three different approaches: (i) optimization of screening and referral, (ii) provision of emotional support and case finding, and (iii) a hybrid approach with multiple assessments, using mobile technology.

Conclusions

We suggest continued research on the screening and referral approach, to broaden the evidence-base on improving emotional support and case finding, and to evaluate the utility of multiple assessments of distress with new interactive mobile tools. Lessons learned from these efforts can be applied to other disease areas, such as cardiovascular disease or diabetes.
Angry in America: Psychophysiological Responses to Unfair Treatment
Authors: Thayer Julian F , Carnevali Luca , Sgoifo Andrea , Williams DeWayne P
Published: January 2021

Background

African Americans have the highest rates of hypertension-related disease of any ethnic group in the USA. Importantly, racism and discrimination have been linked to these higher rates of morbidity and mortality. Discrimination is deleterious not only to those that are the recipients of this unfair treatment but also to the partners and family members of those affected as well to those that perpetrate this bias.

Purpose

In this paper, we identify a unique pattern of physiological response to unfair treatment, we have called the “cardiovascular conundrum.” This pattern is characterized by greater heart rate variability and greater total peripheral resistance in African Americans compared to their European American counterparts.

Methods and Results

We review the evidence supporting the existence of this pattern and propose several physiological and psychological factors that might underpin it. We also propose a number of factors that might help to mitigate the deleterious effects associated with it.

Conclusions

Whereas the context of the current review is on Black/White disparities the framework we propose may be relevant to others exposed to unfair treatment. Ultimately, the systemic factors that perpetuate these inequalities will require that we first acknowledge and then face the challenges they present if we are to address the wealth and health disparities in our country.
The Association Between Psychological Distress and Cancer Mortality in the United States: Results from the 1997–2014 NHIS-NDI Record Linkage Study
Authors: Lee Hyunjung , Singh Gopal K
Published: January 2021

Background/Purpose

Psychological distress can influence cancer mortality through socioeconomic disadvantage, health-risk behaviors, or reduced access to care. These disadvantages can result in higher risks of cancer occurrence, a delayed cancer diagnosis, hamper adherence to treatment, and provoke inflammatory responses leading to cancer. Previous studies have linked psychological distress to cancer mortality. However, studies are lacking for the U.S. population.

Methods

This study examines the Kessler six-item psychological distress scale as a risk factor for U.S. cancer mortality using the pooled 1997–2014 data from the National Health Interview Survey (NHIS) linked to National Death Index (NDI) (N = 513,012). Cox proportional hazards regression was used to model survival time as a function of psychological distress and sociodemographic and behavioral covariates.

Results

In Cox models with 18 years of mortality follow-up, the cancer mortality risk was 80% higher (hazard ratio [HR] = 1.80; 95% CI = 1.64, 1.97) controlling for age; 61% higher (HR = 1.61; 95% CI = 1.46, 1.76) in the SES-adjusted model, and 33% higher (HR = 1.33; 95% CI = 1.21, 1.46) in the fully-adjusted model among adults with serious psychological distress (SPD), compared with adults without psychological distress. Males, non-Hispanic Whites, and adults with incomes at or above 400% of the federal poverty level had greater cancer mortality risk associated with SPD. Using an 8 years of mortality follow-up, those with SPD had 108% increased adjusted risks of mortality from breast cancer.

Conclusion

Our study findings underscore the significance of addressing psychological well-being in the population as a strategy for reducing cancer mortality.
HSP70gene expression responses to the temperature stress in pufferfish (Takifugu rubripes)
Authors: Fan Kun-peng , Hua Xin-tong , Liu Ya-fang , Zhang Zhi-qiang , Li Xiao-hao , Liu Ying , Liu Peng-fei
Published: January 2021

In this study, we isolated and characterized HSP70 cDNA from pufferfish (Takifugu rubripes). The 3053 bp full-length TrHSP70 sequence consisted of a 167 bp 5′-UTR (untranslated region), a 2535 bp open reading frame, and a 351 bp 3′-UTR. BLAST analysis revealed that the TrHSP70 shared high similarity with HSP70 sequences in other species. In our study, we set 3 experimental groups as H1 group (20 °C), H2 group (24 °C), and H3 group (28 °C) for checking the expression level of TrHSP70 in T. rubripes. Tissue-specific gene expression results showed that TrHSP70 had higher expression in the intestines than other tissues of the T. rubripes by RT-qPCR. In the experimental group, we found that the expression of TrHSP70 was upregulated in different tissues in the H3 group. The results show that TrHSP70 is a constitutively expressed gene, which plays an important role in maintaining normal physiological function and coping with stress.
Testing the niche differentiation hypothesis in wild capuchin monkeys with polymorphic color vision
Authors: DePasquale Allegra N , Webb Shasta E , Williamson Rachel E , Fedigan Linda M , Melin Amanda D
Published: January 2021

The polymorphic color vision system present in most North, Central, and South American monkeys is a textbook case of balancing selection, yet the mechanism behind it remains poorly understood. Previous work has established task-specific foraging advantages to different color vision phenotypes: dichromats (red-green colorblind) are more efficient foraging for invertebrates, while trichromats (color “normal” relative to humans) are more efficient foraging for “reddish” ripe fruit, suggesting that niche differentiation may underlie the maintenance of color vision variation. We explore a prediction of the niche differentiation hypothesis by asking whether dichromatic and trichromatic capuchin monkeys (Cebus imitator) diverge in their foraging activity budget, specifically testing whether dichromats forage more frequently for invertebrates and trichromats forage more frequently for “reddish” ripe fruit. To assess this, we analyze a large data set of behavioral scan samples (n = 21 984) from 48 wild adult female capuchins of known color vision genotype, dominance rank, and reproductive status, together with models of food conspicuity. We find no significant differences between dichromats and trichromats in the frequency of scans spent foraging for different food types but do find that nursing females forage less overall than cycling females. Our results suggest that the potential for color-vision-based niche differentiation in foraging time may be curtailed by the energetic requirements of reproduction, behavioral synchrony caused by group living, and/or individual preferences. While niche differentiation in activity budgets by color vision type is not apparent, fine-scale niche differentiation may be occurring. This research enhances our understanding of the evolutionary processes maintaining sensory polymorphisms.
PhenoTagger: a hybrid method for phenotype concept recognition using human phenotype ontology
Authors: Luo Ling , Yan Shankai , Lai Po-Ting , Veltri Daniel , Oler Andrew , Xirasagar Sandhya , Ghosh Rajarshi , Similuk Morgan , Robinson Peter N , Lu Zhiyong
Published: January 2021

Motivation

Automatic phenotype concept recognition from unstructured text remains a challenging task in biomedical text mining research. Previous works that address the task typically use dictionary-based matching methods, which can achieve high precision but suffer from lower recall. Recently, machine learning-based methods have been proposed to identify biomedical concepts, which can recognize more unseen concept synonyms by automatic feature learning. However, most methods require large corpora of manually annotated data for model training, which is difficult to obtain due to the high cost of human annotation.

Results

In this article, we propose PhenoTagger, a hybrid method that combines both dictionary and machine learning-based methods to recognize Human Phenotype Ontology (HPO) concepts in unstructured biomedical text. We first use all concepts and synonyms in HPO to construct a dictionary, which is then used to automatically build a distantly supervised training dataset for machine learning. Next, a cutting-edge deep learning model is trained to classify each candidate phrase (n-gram from input sentence) into a corresponding concept label. Finally, the dictionary and machine learning-based prediction results are combined for improved performance. Our method is validated with two HPO corpora, and the results show that PhenoTagger compares favorably to previous methods. In addition, to demonstrate the generalizability of our method, we retrained PhenoTagger using the disease ontology MEDIC for disease concept recognition to investigate the effect of training on different ontologies. Experimental results on the NCBI disease corpus show that PhenoTagger without requiring manually annotated training data achieves competitive performance as compared with state-of-the-art supervised methods.

Availabilityand implementation

The source code, API information and data for PhenoTagger are freely available at https://github.com/ncbi-nlp/PhenoTagger.

Supplementary information

Supplementary data are available at Bioinformatics online.
Nothing in Evolution Makes Sense Except in the Light of Biology
Authors: Reiskind Martha O Burford , Moody Michael L , Bolnick Daniel I , Hanifin Charles T , Farrior Caroline E
Published: January 2021

A key question in biology is the predictability of the evolutionary process. If we can correctly predict the outcome of evolution, we may be better equipped to anticipate and manage species’ adaptation to climate change, habitat loss, invasive species, or emerging infectious diseases, as well as improve our basic understanding of the history of life on Earth. In the present article, we ask the questions when, why, and if the outcome of future evolution is predictable. We first define predictable and then discuss two conflicting views: that evolution is inherently unpredictable and that evolution is predictable given the ability to collect the right data. We identify factors that generate unpredictability, the data that might be required to make predictions at some level of precision or at a specific timescale, and the intellectual and translational value of understanding when prediction is or is not possible.
Growth Hormone Releasing Hormone Reduces Circulating Markers of Immune Activation in Parallel with Effects on Hepatic Immune Pathways in Individuals with HIV-infection and Nonalcoholic Fatty Liver Disease
Authors: Stanley Takara L , Fourman Lindsay T , Wong Lai Ping , Sadreyev Ruslan , Billingsley James M , Feldpausch Meghan N , Zheng Isabel , Pan Chelsea S , Boutin Autumn , Lee Hang , Corey Kathleen E , Torriani Martin , Kleiner David E , Chung Raymond T , Hadigan Colleen M , Grinspoon Steven K
Published: January 2021

Background

The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis modulates critical metabolic pathways; however, little is known regarding effects of augmenting pulsatile GH secretion on immune function in humans. This study used proteomics and gene set enrichment analysis to assess effects of a GH releasing hormone (GHRH) analog, tesamorelin, on circulating immune markers and liver tissue in people with human immunodeficiency virus (HIV) (PWH) and nonalcoholic fatty liver disease (NAFLD).

Methods

92 biomarkers associated with immunity, chemotaxis, and metabolism were measured in plasma samples from 61 PWH with NAFLD who participated in a double-blind, randomized trial of tesamorelin versus placebo for 12 months. Gene set enrichment analysis was performed on serial liver biopsies targeted to immune pathways.

Results

Tesamorelin, compared to placebo, decreased interconnected proteins related to cytotoxic T-cell and monocyte activation. Circulating concentrations of 13 proteins were significantly decreased, and no proteins increased, by tesamorelin. These included 4 chemokines (CCL3, CCL4, CCL13 [MCP4], IL8 [CXCL8]), 2 cytokines (IL-10 and CSF-1), and 4 T-cell associated molecules (CD8A, CRTAM, GZMA, ADGRG1), as well as ARG1, Gal-9, and HGF. Network analysis indicated close interaction among the gene pathways responsible for these proteins, with imputational analyses suggesting down-regulation of a closely related cluster of immune pathways. Targeted transcriptomics using liver tissue confirmed a significant end-organ signal of down-regulated immune activation pathways.

Conclusions

Long-term treatment with a GHRH analog reduced markers of T-cell and monocyte/macrophage activity, suggesting that augmentation of the GH axis may ameliorate immune activation in an HIV population with metabolic dysregulation, systemic and end organ inflammation.

Clinical Trials Registration. NCT02196831.
Secondary hyperparathyroidism and adverse health outcomes in adults with chronic kidney disease
Authors: Xu Yang , Evans Marie , Soro Marco , Barany Peter , Carrero Juan Jesus
Published: January 2021

Background

Secondary hyperparathyroidism (sHPT) develops frequently in patients with chronic kidney disease (CKD). However, the burden and long-term impact of sHPT on the risk of adverse health outcomes are not well studied.

Methods

We evaluated all adults receiving nephrologist care in Stockholm during 2006–11 who were not undergoing kidney replacement therapy and had not developed sHPT. Incident sHPT was identified by using clinical diagnoses, initiated medications or two consecutive parathyroid hormone (PTH) measurements ≥130 pg/mL. We characterized sHPT incidence by estimated glomerular filtration rate (eGFR) strata, evaluated clinical predictors and quantified the association between incident sHPT (time-varying exposure) and the risk of fractures, CKD progression, major adverse cardiovascular events (MACEs) and death.

Results

We identified 2556 adults with CKD Stages 1–5 (mean age 66 years, 38% women), of whom 784 developed sHPT during follow-up. The incidence of sHPT increased with advancing CKD: from 57 cases/1000 person-years in CKD Stage G3 to 230 cases/1000 person-years in Stage G5. In multivariable analyses, low eGFR was the strongest sHPT predictor, followed by young age, male sex and diabetes. Incident sHPT was associated with a 1.3-fold (95% confidence interval 1.1–1.8) increased risk of death, a 2.2-fold (1.42–3.28) higher risk of MACEs, a 5.0-fold (3.5–7.2) higher risk of CKD progression and a 1.3-fold (1.5–2.2) higher risk of fractures. Results were consistent in stratified analyses and after excluding early events.

Conclusions

Our findings illustrate the burden of sHPT in advanced CKD and highlight the susceptibility for adverse outcomes of patients developing sHPT. This may inform clinical decisions regarding pre-sHPT risk stratification, PTH monitoring and risk-prevention strategies post-sHPT development.
Development and Validation of Measurement Traceability for In Situ Immunoassays
Authors: Torlakovic Emina E , Sompuram Seshi R , Vani Kodela , Wang Lili , Schaedle Anika K , DeRose Paul C , Bogen Steven A
Published: January 2021

Background

Immunoassays for protein analytes measured in situ support a $2 billion laboratory testing industry that suffers from significant interlaboratory disparities, affecting patient treatment. The root cause is that immunohistochemical testing lacks the generally accepted tools for analytic standardization, including reference standards and traceable units of measure. Until now, the creation of these tools has represented an insoluble technical hurdle.

Methods

We address the need with a new concept in metrology—that is, linked traceability. Rather than calculating analyte concentration directly, which has proven too variable, we calculate concentration by measuring an attached fluorescein, traceable to NIST Standard Reference Material 1934, a fluorescein standard.

Results

For validation, newly developed estrogen receptor (ER) calibrators were deployed in tandem with an array of 80 breast cancer tissue sections in a national external quality assessment program. Laboratory performance was assessed using both the ER standards and the tissue array. Similar to previous studies, the tissue array revealed substantial discrepancies in ER test results among the participating laboratories. The new ER calibrators revealed a broad range of analytic sensitivity, with the lower limits of detection ranging from 7310 to 74 790 molecules of ER. The data demonstrate, for the first time, that the variable test results correlate with analytic sensitivity, which can now be measured quantitatively.

Conclusions

The reference standard enables precise interlaboratory alignment of immunohistochemistry test sensitivity for measuring cellular proteins in situ. The introduction of a reference standard and traceable units of measure for protein expression marks an important milestone.
Physiological responses of gopher tortoises (Gopherus polyphemus) to trapping
Authors: Goessling Jeffrey M , Mendonça Mary T
Published: January 2021

With a growing number of species of conservation concern, understanding the physiological effects of routine sampling of vertebrate species remains a priority to maintain the welfare status of wildlife and ensure such activities are not counter to conservation goals. The gopher tortoise (Gopherus polyphemus) is a species of conservation concern throughout its range and is among the most frequently trapped turtles globally (for both research and conservation activities). Several studies have found equivocal results on the effects of trapping and handling on the glucocorticoid stress response. In this study, we tested how multiple physiological biomarkers (i.e. plasma lactate, corticosterone (cort), heterophil:lymphocyte ratio (HLR) and bactericidal ability (BA)) respond to four different combinations of trapping conditions in comparison to baseline reference sampling. We found that trapping and handling of gopher tortoises yielded a rapid rise in plasma lactate concentration followed by elevations of cort and stress-associated immune changes. In visibly distressed animals that were in traps for fewer than 2 hours, lactate, cort, HLR and BA were all elevated, and generally more so than animals that remained calm in traps for a similar amount of time. Animals that had been trapped and then held for a 3-hour restraint showed similar degrees of physiological alteration as those that showed outward signs of distress. This study demonstrates that trapping may yield physiological disturbances in gopher tortoises, although the intensity of this response is highly variable between individuals and the duration of such alterations remains unknown. This research emphasizes the need for continued work to refine trapping and handling processes in an effort to minimize impacts on individuals and populations.
Relationship between lipoproteins, thrombosis, and atrial fibrillation
Authors: Ding Wern Yew , Protty Majd B , Davies Ian G , Lip Gregory Y H
Published: January 2021

The prothrombotic state in atrial fibrillation (AF) occurs as a result of multifaceted interactions, known as Virchow’s triad of hypercoagulability, structural abnormalities, and blood stasis. More recently, there is emerging evidence that lipoproteins are implicated in this process, beyond their traditional role in atherosclerosis. In this review, we provide an overview of the various lipoproteins and explore the association between lipoproteins and AF, the effects of lipoproteins on haemostasis, and the potential contribution of lipoproteins to thrombogenesis in AF. There are several types of lipoproteins based on size, lipid composition, and apolipoprotein category, namely: chylomicrons, very low-density lipoprotein, low-density lipoprotein (LDL), intermediate-density lipoprotein, and high-density lipoprotein. Each of these lipoproteins may contain numerous lipid species and proteins with a variety of different functions. Furthermore, the lipoprotein particles may be oxidized causing an alteration in their structure and content. Of note, there is a paradoxical inverse relationship between total cholesterol and LDL cholesterol (LDL-C) levels, and incident AF. The mechanism by which this occurs may be related to the stabilizing effect of cholesterol on myocardial membranes, along with its role in inflammation. Overall, specific lipoproteins may interact with haemostatic pathways to promote excess platelet activation and thrombin generation, as well as inhibiting fibrinolysis. In this regard, LDL-C has been shown to be an independent risk factor for thromboembolic events in AF. The complex relationship between lipoproteins, thrombosis and AF warrants further research with an aim to improve our knowledge base and contribute to our overall understanding of lipoprotein-mediated thrombosis.
Long-Term Efficacy and Safety of Ozanimod in Moderately to Severely Active Ulcerative Colitis: Results From the Open-Label Extension of the Randomized, Phase 2 TOUCHSTONE Study
Authors: Sandborn William J , Feagan Brian G , Hanauer Stephen , Vermeire Severine , Ghosh Subrata , Liu Wenzhong J , Petersen AnnKatrin , Charles Lorna , Huang Vivian , Usiskin Keith , Wolf Douglas C , D’Haens Geert
Published: January 2021

Background and Aims

This analysis examined the long-term safety and efficacy of ozanimod in patients with moderately to severely active ulcerative colitis [UC] with ≥ 4 years of follow-up in the phase 2 TOUCHSTONE open-label extension [OLE].

Methods

Patients receiving placebo or ozanimod HCl 0.5 mg or 1 mg during the double-blind period could enter the OLE [ozanimod HCl 1 mg daily]. Partial Mayo score [pMS] clinical response and remission were assessed through OLE week 200 and summarized descriptively using observed cases [OC] and non-responder imputation [NRI]. Endoscopy was required at OLE week 56 and the end of treatment. Parameters associated with endoscopy were summarized at weeks 56 and 104 [OC], and week 56 [NRI]. C-reactive protein and faecal calprotectin were assessed. Adverse events were monitored throughout the study.

Results

Of 197 patients receiving double-blind treatment, 170 entered the OLE. Discontinuation rates were 28% at year 1 and 15–18% annually through year 4. Partial Mayo measures indicated clinical response and remission rates at OLE week 200 of 93.3% and 82.7%, respectively, using OC and 41% and 37% with the more conservative NRI analysis. At weeks 56 and 104, respectively, histological remission rates were 46.3% and 38.5%, and endoscopic improvement rates were 46.4% and 46.5% [OC]. No new safety signals were identified during ≥ 4 years of follow-up.

Conclusions

There was a high rate of continued study participation and long-term benefit with ozanimod HCl 1 mg daily based on clinical, histological and biomarker measures in patients with moderately to severely active UC in the TOUCHSTONE OLE. [NCT02531126]
Prognostic value of inflammatory biomarkers and GRACE score for cardiac death and acute kidney injury after acute coronary syndromes
Authors: Rossi Valentina A , Denegri Andrea , Candreva Alessandro , Klingenberg Roland , Obeid Slayman , Räber Lorenz , Gencer Baris , Mach François , Nanchen David , Rodondi Nicolas , Heg Dik , Windecker Stephan , Buhmann Joachim , Ruschitzka Frank , Lüscher Thomas F , Matter Christian M
Published: January 2021

Aims 

The aim of this study was to analyse the role of inflammation and established clinical scores in predicting acute kidney injury (AKI) after acute coronary syndromes (ACS).

Methods and results 

In a prospective multicentre cohort including 2034 patients with ACS undergoing percutaneous coronary intervention, high-sensitivity C-reactive protein (hsCRP), neutrophil count, neutrophil-to-lymphocyte ratio (NL-ratio), and creatinine were measured at the index procedure. AKI (n = 39, defined according to RIFLE criteria) and major cardiovascular and cerebrovascular events were adjudicated after 1 year. Associations between inflammation, AKI, and cardiac death (CD) were assessed by C-statistics and Cox proportional hazard models with log-rank test to compare survival. Patients with ACS with elevated neutrophil count >7.8 × 109/L, NL-ratio >5, combined neutrophil-count/creatinine, or NL-ratio/creatinine at baseline showed a higher incidence of AKI (all P < 0.05) and CD (all P < 0.001). The risk of AKI, CD, and their combination was increased in patients with higher neutrophil count/creatinine (heart rate (HR) = 3.7, 95% cardiac index (CI) 1.9–7.1; HR = 2.7, 95% CI 1.6–4.6; HR = 3.2, 95% CI 2.1–4.9); NL-ratio/creatinine (HR = 2.1, 95% CI 1.6–4.1; HR = 2.2, 95% CI 1.3–3.8; HR = 2.3, 95% CI 1.5–3.5); and hsCRP (HR = 1.8, 95% CI 0.9–3.5; HR = 2.2, 95% CI 1.3–3.6; HR = 1.9, 95% CI 1.2–2.8) after adjustment for age, diabetes, hypertension, previous heart failure, kidney function, haemodynamic instability at admission, statin, and renin–angiotensin–aldosterone antagonists use. Subjects with higher GRACE score 1.0/NL-ratio had higher rate of AKI, CD, and both (HR = 1.4, 95% CI 0.5–4.2; HR = 2.7, 95% CI 1.3–5.9; HR = 2.1, 95% CI 1–4.3).

Conclusions 

Inflammation markers may predict AKI after correction for renal function at the index procedure. hsCRP performed better than the NL-ratio. However, the integration of inflammation markers to traditional risk factors or scores does not add prognostic information.

Trial registration 

ClinicalTrials.gov, NCT01000701.
Firm-specific responses to energy policies in Dutch horticulture
Authors: Los Evert , Gardebroek Cornelis , Huirne Ruud
Published: January 2021

Reducing the usage of fossil fuels is a central issue in ongoing policy debates. This in particular holds for Dutch horticulture, given its energy-intensive production. We analyse differences in energy usage and price responsiveness of horticultural firms by estimating energy demand functions using a Bayesian random coefficient model. Beyond, the effects of a proposed energy tax are assessed. Allowing for firm-specific energy price coefficients gives a better model fit compared to conventional models with fixed slope parameters. This confirms that firms respond differently to energy prices, which is taken into account in simulating the effects of more restrictive energy policies. The results show that larger-sized firms use less gas per square meter yet also point at a considerable spread in additional energy expenses between firms.
Precision Medicine and cardiac channelopathies: when dreams meet reality
Authors: Gnecchi Massimiliano , Sala Luca , Schwartz Peter J
Published: January 2021

Precision Medicine (PM) is an innovative approach that, by relying on large populations’ datasets, patients’ genetics and characteristics, and advanced technologies, aims at improving risk stratification and at identifying patient-specific management through targeted diagnostic and therapeutic strategies. Cardiac channelopathies are being progressively involved in the evolution brought by PM and some of them are benefiting from these novel approaches, especially the long QT syndrome. Here, we have explored the main layers that should be considered when developing a PM approach for cardiac channelopathies, with a focus on modern in vitro strategies based on patient-specific human-induced pluripotent stem cells and on in silico models. PM is where scientists and clinicians must meet and integrate their expertise to improve medical care in an innovative way but without losing common sense. We have indeed tried to provide the cardiologist’s point of view by comparing state-of-the-art techniques and approaches, including revolutionary discoveries, to current practice. This point matters because the new approaches may, or may not, exceed the efficacy and safety of established therapies. Thus, our own eagerness to implement the most recent translational strategies for cardiac channelopathies must be tempered by an objective assessment to verify whether the PM approaches are indeed making a difference for the patients. We believe that PM may shape the diagnosis and treatment of cardiac channelopathies for years to come. Nonetheless, its potential superiority over standard therapies should be constantly monitored and assessed before translating intellectually rewarding new discoveries into clinical practice.
Democratization of fungal highway columns as a tool to investigate bacteria associated with soil fungi
Authors: Junier Pilar , Cailleau Guillaume , Palmieri Ilona , Vallotton Celine , Trautschold Olivia C , Junier Thomas , Paul Christophe , Bregnard Danae , Palmieri Fabio , Estoppey Aislinn , Buffi Matteo , Lohberger Andrea , Robinson Aaron , Kelliher Julia M , Davenport Karen , House Geoffrey L , Morales Demosthenes , Gallegos-Graves La Verne , Dichosa Armand E K , Lupini Simone , Nguyen Hang N , Young Jamey D , Rodrigues Debora F , Parra-Vasquez A Nicholas G , Bindschedler Saskia , Chain Patrick S G
Published: January 2021

Bacteria–fungi interactions (BFIs) are essential in ecosystem functioning. These interactions are modulated not only by local nutritional conditions but also by the physicochemical constraints and 3D structure of the environmental niche. In soils, the unsaturated and complex nature of the substrate restricts the dispersal and activity of bacteria. Under unsaturated conditions, some bacteria engage with filamentous fungi in an interaction (fungal highways) in which they use fungal hyphae to disperse. Based on a previous experimental device to enrich pairs of organisms engaging in this interaction in soils, we present here the design and validation of a modified version of this sampling system constructed using additive printing. The 3D printed devices were tested using a novel application in which a target fungus, the common coprophilous fungus Coprinopsis cinerea, was used as bait to recruit and identify bacterial partners using its mycelium for dispersal. Bacteria of the genera Pseudomonas, Sphingobacterium and Stenotrophomonas were highly enriched in association with C. cinerea. Developing and producing these new easy-to-use tools to investigate how bacteria overcome dispersal limitations in cooperation with fungi is important to unravel the mechanisms by which BFIs affect processes at an ecosystem scale in soils and other unsaturated environments.
Comparative study of sodium bicarbonate- and magnesium hydroxide-based gastric antacids for the effectiveness of Salmonella delivered Brucella antigens against wild type challenge in BALB/c mice
Authors: Hewawaduge Chamith , Senevirathne Amal , Yang Myeon-Sik , Jeong Tae-Won , Kim Bumseok , Lee John Hwa
Published: January 2021

We compared the effects of two antacid formulations based on sodium bicarbonate and magnesium hydroxide on a Salmonella-delivered oral Brucella live attenuated vaccine. We conducted a series of in vitro and in vivo experiments to investigate the pH buffering capacity, buffering longevity and the effects of these formulations on the survival of Salmonella under neutralized pH conditions and its impact on immune responses. Magnesium hydroxide had a greater, stable and prolonged buffering capacity than sodium bicarbonate and was safer when administered orally. Oral administration of sodium bicarbonate resulted in discomfort as reflected by mouse behavior and mild muscle tremors, whereas mice treated with magnesium hydroxide and PBS were completely normal. Gastric survival studies using BALB/c mice revealed that a higher number of Salmonella reached the intestine when the magnesium hydroxide-based antacid buffer was administrated. Co-administration with attenuated Salmonella secreting Brucella antigens, SodC and Omp19 along with individual antacid formulations, significantly enhanced the antigen-specific protective immune responses against virulent Brucella challenge. Together, our results indicated that the pre vaccinated oral administration of bicarbonate-citric acid or magnesium hydroxide-based neutralizing buffers significantly counteract stomach acidity by maintaining the viability of an oral enteric vaccine formulation.
Ethanol Disrupts Hormone-Induced Calcium Signaling in Liver
Authors: Gaspers Lawrence D , Thomas Andrew P , Hoek Jan B , Bartlett Paula J
Published: January 2021

Receptor-coupled phospholipase C (PLC) is an important target for the actions of ethanol. In the ex vivo perfused rat liver, concentrations of ethanol >100 mM were required to induce a rise in cytosolic calcium (Ca2+) suggesting that these responses may only occur after binge ethanol consumption. Conversely, pharmacologically achievable concentrations of ethanol (≤30 mM) decreased the frequency and magnitude of hormone-stimulated cytosolic and nuclear Ca2+ oscillations and the parallel translocation of protein kinase C-β to the membrane. Ethanol also inhibited gap junction communication resulting in the loss of coordinated and spatially organized intercellular Ca2+ waves in hepatic lobules. Increasing the hormone concentration overcame the effects of ethanol on the frequency of Ca2+ oscillations and amplitude of the individual Ca2+ transients; however, the Ca2+ responses in the intact liver remained disorganized at the intercellular level, suggesting that gap junctions were still inhibited. Pretreating hepatocytes with an alcohol dehydrogenase inhibitor suppressed the effects of ethanol on hormone-induced Ca2+ increases, whereas inhibiting aldehyde dehydrogenase potentiated the inhibitory actions of ethanol, suggesting that acetaldehyde is the underlying mediator. Acute ethanol intoxication inhibited the rate of rise and the magnitude of hormone-stimulated production of inositol 1,4,5-trisphosphate (IP3), but had no effect on the size of Ca2+ spikes induced by photolysis of caged IP3. These findings suggest that ethanol inhibits PLC activity, but does not affect IP3 receptor function. We propose that by suppressing hormone-stimulated PLC activity, ethanol interferes with the dynamic modulation of [IP3] that is required to generate large, amplitude Ca2+ oscillations.
MutSα mismatch repair protein stability is governed by subunit interaction, acetylation, and ubiquitination
Authors: Arlow Tim , Kim Junwon , Haye-Bertolozzi Joanna E. , Martínez Cristina Balbás , Fay Caitlin , Zorensky Emma , Rose Mark D. , Gammie Alison E.
Published: January 2021

In eukaryotes, DNA mismatch recognition is accomplished by the highly conserved MutSα (Msh2/Msh6) and MutSβ (Msh2/Msh3) complexes. Previously, in the yeast Saccharomyces cerevisiae, we determined that deleting MSH6 caused wild-type Msh2 levels to drop by ∼50%. In this work, we determined that Msh6 steady-state levels are coupled to increasing or decreasing levels of Msh2. Although Msh6 and Msh2 are reciprocally regulated, Msh3 and Msh2 are not. Msh2 missense variants that are able to interact with Msh6 were destabilized when Msh6 was deleted; in contrast, variants that fail to dimerize were not further destabilized in cells lacking Msh6. In the absence of Msh6, Msh2 is turned over at a faster rate and degradation is mediated by the ubiquitin-proteasome pathway. Mutagenesis of certain conserved lysines near the dimer interface restored the levels of Msh2 in the absence of Msh6, further supporting a dimer stabilization mechanism. We identified two alternative forms of regulation both with the potential to act via lysine residues, including acetylation by Gcn5 and ubiquitination by the Not4 ligase. In the absence of Gcn5, Msh2 levels were significantly decreased; in contrast, deleting Not4 stabilized Msh2 and Msh2 missense variants with partial function. The stabilizing effect on Msh2 by either the presence of Msh6 or the absence of Not4 are dependent on Gcn5. Taken together, the results suggest that the wild-type MutSα mismatch repair protein stability is governed by subunit interaction, acetylation, and ubiquitination.
A possible case of negative segregation distortion in the SD system of Drosophila melanogaster.
Authors: Hiraizumi Y
Published: January 2021

Models proposed to explain segregation distortion in Drosophila melanogaster are based partly upon the observation that, in the Sd heterozygous Rspi/Rsps male, the chromosome carrying the sensitive Rsps allele is distorted, but the chromosome carrying the insensitive Rspi allele is not. The results of the present study suggest that this may not always be the case. Under a certain genotypic condition, the chromosome carrying the Rsps allele can be transmitted to the progeny in frequencies of more than 0.5 (about 0.6), or correspondingly, the chromosome carrying the Rspi allele may be distorted with respect to the one with the Rsps allele. Thus, the relative sensitivity and insensitivity of the two Rsp alleles in a male are not absolute, but relative; and they may be reversed depending upon the residual genotype. If this is true, a major modification of the current models or a proposal of an entirely new model may become necessary to explain the mechanism of segregation distortion satisfactorily.
A generalized approach for estimating effective population size from temporal changes in allele frequency.
Authors: Waples R S
Published: January 2021

The temporal method for estimating effective population size (Ne) from the standardized variance in allele frequency change (F) is presented in a generalized form. Whereas previous treatments of this method have adopted rather limiting assumptions, the present analysis shows that the temporal method is generally applicable to a wide variety of organisms. Use of a revised model of gene sampling permits a more generalized interpretation of Ne than that used by some other authors studying this method. It is shown that two sampling plans (individuals for genetic analysis taken before or after reproduction) whose differences have been stressed by previous authors can be treated in a uniform way. Computer simulations using a wide variety of initial conditions show that different formulas for computing F have much less effect on Ne than do sample size (S), number of generations between samples (t), or the number of loci studied (L). Simulation results also indicate that (1) bias of F is small unless alleles with very low frequency are used; (2) precision is typically increased by about the same amount with a doubling of S, t, or L; (3) confidence intervals for Ne computed using a chi 2 approximation are accurate and unbiased under most conditions; (4) the temporal method is best suited for use with organisms having high juvenile mortality and, perhaps, a limited effective population size.
DNA repair and the evolution of transformation in Bacillus subtilis. II. Role of inducible repair.
Authors: Wojciechowski M F , Hoelzer M A , Michod R E
Published: January 2021

In Bacillus subtilis, DNA repair and recombination are intimately associated with competence, the physiological state in which the bacterium can bind, take up and recombine exogenous DNA. Previously, we have shown that the homologous DNA transformation rate (ratio of transformants to total cells) increases with increasing UV dosage if cells are transformed after exposure to UV radiation (UV-DNA), whereas the transformation rate decreases if cells are transformed before exposure to UV (DNA-UV). In this report, by using different DNA repair-deficient mutants, we show that the greater increase in transformation rate in UV-DNA experiments than in DNA-UV experiments does not depend upon excision repair or inducible SOS-like repair, although certain quantitative aspects of the response do depend upon these repair systems. We also show that there is no increase in the transformation rate in a UV-DNA experiment when repair and recombination proficient cells are transformed with nonhomologous plasmid DNA, although the results in a DNA-UV experiment are essentially unchanged by using plasmid DNA. We have used din operon fusions as a sensitive means of assaying for the expression of genes under the control of the SOS-like regulon in both competent and noncompetent cell subpopulations as a consequence of competence development and our subsequent experimental treatments. Results indicate that the SOS-like system is induced in both competent and noncompetent subpopulations in our treatments and so should not be a major factor in the differential response in transformation rate observed in UV-DNA and DNA-UV treatments. These results provide further support to the hypothesis that the evolutionary function of competence is to bring DNA into the cell for use as template in the repair of DNA damage.
Pheromones and pheromone receptors are the primary determinants of mating specificity in the yeast Saccharomyces cerevisiae.
Authors: Bender A , Sprague G F
Published: January 2021

Saccharomyces cerevisiae has two haploid cell types, a and alpha, each of which produces a unique set of proteins that participate in the mating process. We sought to determine the minimum set of proteins that must be expressed to allow mating and to confer specificity. We show that the capacity to synthesize alpha-factor pheromone and a-factor receptor is sufficient to allow mating by mat alpha 1 mutants, mutants that normally do not express any alpha- or a-specific products. Likewise, the capacity to synthesize a-factor receptor and alpha-factor pheromone is sufficient to allow a ste2 ste6 mutants, which do not produce the normal a cell pheromone and receptor, to mate with wild-type a cells. Thus, the a-factor receptor and alpha-factor pheromone constitute the minimum set of alpha-specific proteins that must be produced to allow mating as an alpha cell. Further evidence that the pheromones and pheromone receptors are important determinants of mating specificity comes from studies with mat alpha 2 mutants, cells that simultaneously express both pheromones and both receptors. We created a series of strains that express different combinations of pheromones and receptors in a mat alpha 2 background. These constructions reveal that mat alpha 2 mutants can be made to mate as either a cells or as alpha cells by causing them to express only the pheromone and receptor set appropriate for a particular cell type. Moreover, these studies show that the inability of mat alpha 2 mutants to respond to either pheromone is a consequence of two phenomena: adaptation to an autocrine response to the pheromones they secrete and interference with response to alpha factor by the a-factor receptor.
The genetics of postzygotic isolation in the Drosophila virilis group.
Authors: Orr H A , Coyne J A
Published: January 2021

In a genetic study of postzygotic reproductive isolation among species of the Drosophila virilis group, we find that the X chromosome has the largest effect on male and female hybrid sterility and inviability. The X alone has a discernible effect on postzygotic isolation between closely related species. Hybridizations involving more distantly related species also show large X-effects, although the autosomes may also play a role. In the only hybridization yet subjected to such analysis, we show that hybrid male and female sterility result from the action of different X-linked loci. Our results accord with genetic studies of other taxa, and support the view that both Haldane's rule (heterogametic F1 sterility or inviability) and the large effect of the X chromosome on reproductive isolation result from the accumulation by natural selection of partially recessive or underdominant mutations. We also describe a method that allows genetic analysis of reproductive isolation between species that produce completely sterile or inviable hybrids. Such species pairs, which represent the final stage of speciation, cannot be analyzed by traditional methods. The X chromosome also plays an important role in postzygotic isolation between these species.
Isolation and characterization of dominant female sterile mutations of Drosophila melanogaster. I. Mutations on the third chromosome.
Authors: Erdélyi M , Szabad J
Published: January 2021

Fifty-one dominant female sterile (Fs) mutations linked to the third chromosome of Drosophila melanogaster are described. EMS induced Fs mutations arise with the frequency of one Fs per about 2500 recessive lethals. Complementation analysis of the revertants showed that these Fs mutations represent 27-34 loci, about 60% of the third chromosome units mutable to dominant female sterility by EMS. The Fs mutations were mapped on the basis of mitotic recombination induced in the female (in 16 cases also in the male) germ-line. Behavior of the revertants and the Fs+ germ-line clones demonstrate the gain-of-function nature of the Fs alleles. With two exceptions, the Fs(3) mutations are germ-line dependent. Novel phenotypes appeared in most of the Fs mutations. With eight exceptions, the Fs(3) mutations are fully penetrant, in some cases with variable expressivity. One of the Fs(3) mutations is a non-ovary-dependent egg retention mutation, two others alter egg shape, and 27 bring about arrest in development at about the time of fertilization. In 21 of the Fs(3) mutations embryos develop to the larval stage of differentiation; this group includes 5 new alleles of Toll and 4 of easter.
The impact of maternal uterine genotype on postnatal growth and adult body size in mice.
Authors: Cowley D E , Pomp D , Atchley W R , Eisen E J , Hawkins-Brown D
Published: January 2021

Embryo transfers were used to demonstrate that the genotype of the mother providing the uterine developmental environment significantly influences postnatal growth and adult body size of her progeny. Irrespective of their own genotype, mouse embryos transferred into the uterus of an inbred strain with large body size (C3H) had greater body weights, longer tails and higher growth rates than those transferred into the uterus of a strain with small body size (SWR). Uterine heterosis on body size was smaller than progeny heterosis, and both progeny and uterine heterosis persisted in adult mice. Uterine litter size was significantly negatively associated with body weight, tail length, growth rate and the timing of developmental events. The inbred SWR strain was more sensitive to the embryo transfer procedure than the C3H strain, but effects due to embryo transfer were moderate. Prenatal uterine effects have ramifications for biotechnologies utilizing embryo transfer as well as predictions about evolutionary change by selection.