bluuebunny/crossref_metadata_2025 huggingface dataset:
The Rad27 (Fen-1) Nuclease Inhibits Ty1 Mobility in Saccharomyces cerevisiae
Authors: Sundararajan Anuradha , Lee Bum-Soo , Garfinkel David J
Published: April 2021

Although most Ty1 elements in Saccharomyces cerevisiae are competent for retrotransposition, host defense genes can inhibit different steps of the Ty1 life cycle. Here, we demonstrate that Rad27, a structure-specific nuclease that plays an important role in DNA replication and genome stability, inhibits Ty1 at a posttranslational level. We have examined the effects of various rad27 mutations on Ty1 element retrotransposition and cDNA recombination, termed Ty1 mobility. The point mutations rad27-G67S, rad27-G240D, and rad27-E158D that cause defects in certain enzymatic activities in vitro result in variable increases in Ty1 mobility, ranging from 4- to 22-fold. The C-terminal frameshift mutation rad27-324 confers the maximum increase in Ty1 mobility (198-fold), unincorporated cDNA, and insertion at preferred target sites. The null mutation differs from the other rad27 alleles by increasing the frequency of multimeric Ty1 insertions and cDNA recombination with a genomic element. The rad27 mutants do not markedly alter the levels of Ty1 RNA or the TyA1-gag protein. However, there is an increase in the stability of unincorporated Ty1 cDNA in rad27-324 and the null mutant. Our results suggest that Rad27 inhibits Ty1 mobility by destabilizing unincorporated Ty1 cDNA and preventing the formation of Ty1 multimers.
Lateral Elements Inside Synaptonemal Complex-Like Polycomplexes in ndt80 Mutants of Yeast Bind DNA
Authors: Bhuiyan Hasanuzzaman , Dahlfors Gunilla , Schmekel Karin
Published: April 2021

The synaptonemal complex (SC) keeps the synapsed homologous chromosomes together during pachytene in meiotic prophase I. Structures that resemble stacks of SCs, polycomplexes, are sometimes found before or after pachytene. We have investigated ndt80 mutants of yeast, which arrest in pachytene. SCs appear normal in spread chromosome preparations, but are only occasionally found in intact nuclei examined in the electron microscope. Instead, large polycomplexes occur in almost every ndt80 mutant nucleus. Immunoelectron microscopy using DNA antibodies show strong preferential labeling to the lateral element parts of the polycomplexes. In situ hybridization using chromosome-specific probes confirms that the chromosomes in ndt80 mutants are paired and attached to the SCs. Our results suggest that polycomplexes can be involved in binding of chromosomes and possibly also in synapsis.
Female Site-Specific Transposase-Induced Recombination: A High-Efficiency Method for Fine Mapping Mutations on the X Chromosome in Drosophila
Authors: Marcus Jeffrey M
Published: April 2021

P-element transposons in the Drosophila germline mobilize only in the presence of the appropriate transposase enzyme. Sometimes, instead of mobilizing completely, P elements will undergo site-specific recombination with the homologous chromosome. Site-specific recombination is the basis for male recombination mapping, since the male germline does not normally undergo recombination. Site-specific recombination also takes place in females, but this has been difficult to study because of the obscuring effects of meiotic recombination. Using map functions, I demonstrate that it is possible to employ female site-specific transposase-induced recombination (FaSSTIR) to map loci on the X chromosome and predict that FaSSTIR mapping should be more efficient than meiotic mapping over short genetic intervals. Both FaSSTIR mapping and meiotic mapping were used to fine map the crossveinless locus on the X chromosome. Both techniques identified the same 10-kb interval as the probable location of the crossveinless mutation. Over short intervals (< ∼7.6 cM), FaSSTIR produces more informative recombination events than does meiotic recombination. Over longer intervals, FaSSTIR is not always more efficient than meiotic mapping, but it produces the correct gene order. FaSSTIR matches the expectations suggested by the map functions and promises to be a useful technique, particularly for mapping X-linked loci.
Knockout Targeting of the Drosophila Nap1 Gene and Examination of DNA Repair Tracts in the Recombination Products
Authors: Lankenau Susanne , Barnickel Thorsten , Marhold Joachim , Lyko Frank , Mechler Bernard M , Lankenau Dirk-Henner
Published: April 2021

We used ends-in gene targeting to generate knockout mutations of the nucleosome assembly protein 1 (Nap1) gene in Drosophila melanogaster. Three independent targeted null-knockout mutations were produced. No wild-type NAP1 protein could be detected in protein extracts. Homozygous Nap1KO knockout flies were either embryonic lethal or poorly viable adult escapers. Three additional targeted recombination products were viable. To gain insight into the underlying molecular processes we examined conversion tracts in the recombination products. In nearly all cases the I-SceI endonuclease site of the donor vector was replaced by the wild-type Nap1 sequence. This indicated exonuclease processing at the site of the double-strand break (DSB), followed by replicative repair at donor-target junctions. The targeting products are best interpreted either by the classical DSB repair model or by the break-induced recombination (BIR) model. Synthesis-dependent strand annealing (SDSA), which is another important recombinational repair pathway in the germline, does not explain ends-in targeting products. We conclude that this example of gene targeting at the Nap1 locus provides added support for the efficiency of this method and its usefulness in targeting any arbitrary locus in the Drosophila genome.
The Promoter of the Heterochromatic Drosophila Telomeric Retrotransposon, HeT-A, Is Active When Moved Into Euchromatic Locations
Authors: George Janet A , Pardue Mary-Lou
Published: April 2021

The Drosophila telomeric retrotransposon, HeT-A, is found only in heterochromatin; therefore, its promoter must function in this chromatin environment. Studies of position effect variegation suggest that promoters of heterochromatic genes are very different from euchromatic promoters, but this idea has not been tested with isolated promoter sequences. The HeT-A promoter is the first heterochromatin promoter to be isolated and it is of interest to investigate its activity when removed from telomeric heterochromatin. This promoter was initially characterized by testing reporter constructs in transient transfection of cultured cells, an environment that may approximate its endogenous heterochromatin. We now report P-element-mediated transpositions of these constructs, testing the function of different parts of the putative promoter in euchromatin. Expression of endogenous HeT-A RNA shows marked developmental regulation and accumulates preferentially in replicating diploid tissues. HeT-A promoter constructs are active in all euchromatic locations tested and some display aspects of endogenous HeT-A stage- and cell-type expression programs. The activity of each promoter construct in euchromatic locations is also generally consistent with its activity in the transient transfection tests; a possibly significant exception is one sequence segment that appreciably enhanced activity in transient transfection but repressed promoter activity in euchromatin.
Chromatin Immunoprecipitation Reveals That the 180-bp Satellite Repeat Is the Key Functional DNA Element of Arabidopsis thaliana Centromeres
Authors: Nagaki Kiyotaka , Talbert Paul B , Zhong Cathy Xiaoyan , Dawe R Kelly , Henikoff Steven , Jiang Jiming
Published: April 2021

The centromeres of Arabidopsis thaliana chromosomes contain megabases of complex DNA consisting of numerous types of repetitive DNA elements. We developed a chromatin immunoprecipitation (ChIP) technique using an antibody against the centromeric H3 histone, HTR12, in Arabidopsis. ChIP assays showed that the 180-bp centromeric satellite repeat was precipitated with the antibody, suggesting that this repeat is the key component of the centromere/kinetochore complex in Arabidopsis.
The Rise and Fall of Isolation by Distance in the Anadromous Brook Charr (Salvelinus fontinalisMitchill)
Authors: Castric Vincent , Bernatchez Louis
Published: April 2021

Geographic patterns of genetic diversity depend on a species’ demographic properties in a given habitat, which may change over time. The rates at which patterns of diversity respond to changes in demographic properties and approach equilibrium are therefore pivotal in our understanding of spatial patterns of diversity. The brook charr Salvelinus fontinalis is a coastal fish exhibiting limited marine movements, such that a stable one-dimensional isolation-by-distance (IBD) pattern should be observed over the whole range. Its range, however, recently shifted northward such that northern populations may still be in the process of reaching equilibrium. We investigated variation in IBD patterns, genetic divergence, and allelic richness at six microsatellite markers in 2087 anadromous brook charr from 59 rivers along the most likely postglacial colonization route. We observed a decrease in allelic richness, together with an increase in differentiation and a decrease in IBD in the most recently colonized northern populations, as expected following recent colonization. Contrary to expectation, however, similar patterns were also observed at the southernmost part of the range, despite the fact that these populations are not considered to be newly colonized. We propose that the loss of dispersal capabilities associated with anadromy may have caused the southernmost populations to evolve relatively independently of one another. This study thus demonstrated that changes in a species’ geographic range and dispersal capabilities may contribute to shaping geographic patterns of genetic diversity.
Transvection at the End of the Truncated Chromosome in Drosophila melanogaster
Authors: Savitsky Mikhail , Kahn Tatyana , Pomerantseva Ekaterina , Georgiev Pavel
Published: April 2021

The phenomenon of transvection is well known for the Drosophila yellow locus. Thus enhancers of a promoterless yellow locus in one homologous chromosome can activate the yellow promoter in the other chromosome where the enhancers are inactive or deleted. In this report, we examined the requirements for trans-activation of the yellow promoter at the end of the deficient chromosome. A number of truncated chromosomes ending in different areas of the yellow regulatory region were examined in combination with the promoterless y alleles. We found that trans-activation of the yellow promoter at the end of a deficient chromosome required ∼6 kb of an additional upstream sequence. The nature of upstream sequences affected the strength of transvection: addition of gypsy sequences induced stronger trans-activation than addition of HeT-A or yellow sequences. Only the promoter proximal region (within -158 bp of the yellow transcription start) was essential for trans-activation; i.e., transvection did not require extensive homology in the yellow upstream region. Finally, the yellow enhancers located on the two pairing chromosomes could cooperatively activate one yellow promoter.
Microsatellite Allele Sizes: A Simple Test to Assess Their Significance on Genetic Differentiation
Authors: Hardy Olivier J , Charbonnel Nathalie , Fréville Hélène , Heuertz Myriam
Published: April 2021

The mutation process at microsatellite loci typically occurs at high rates and with stepwise changes in allele sizes, features that may introduce bias when using classical measures of population differentiation based on allele identity (e.g., FST, Nei’s Ds genetic distance). Allele size-based measures of differentiation, assuming a stepwise mutation process [e.g., Slatkin’s RST, Goldstein et al.’s (δμ)2], may better reflect differentiation at microsatellite loci, but they suffer high sampling variance. The relative efficiency of allele size- vs. allele identity-based statistics depends on the relative contributions of mutations vs. drift to population differentiation. We present a simple test based on a randomization procedure of allele sizes to determine whether stepwise-like mutations contributed to genetic differentiation. This test can be applied to any microsatellite data set designed to assess population differentiation and can be interpreted as testing whether FST = RST. Computer simulations show that the test efficiently identifies which of FST or RST estimates has the lowest mean square error. A significant test, implying that RST performs better than FST, is obtained when the mutation rate, μ, for a stepwise mutation process is (a) ≥ m in an island model (m being the migration rate among populations) or (b) ≥ 1/t in the case of isolated populations (t being the number of generations since population divergence). The test also informs on the efficiency of other statistics used in phylogenetical reconstruction [e.g., Ds and (δμ)2], a nonsignificant test meaning that allele identity-based statistics perform better than allele size-based ones. This test can also provide insights into the evolutionary history of populations, revealing, for example, phylogeographic patterns, as illustrated by applying it on three published data sets.
Local Superimpositions Facilitate Morphometric Analysis of Complex Articulating Structures
Authors: Rhoda Daniel , Segall Marion , Larouche Olivier , Evans Kory , Angielczyk Kenneth D
Published: April 2021

Synopsis

Articulating structures, such as the vertebrate skeleton or the segmented arthropod exoskeleton, comprise a majority of the morphological diversity across the eukaryotic tree of life. Quantifying the form of articulating structures is therefore imperative for a fuller understanding of the factors influencing biological form. A wealth of freely available 3D data capturing this morphological diversity is stored in online repositories such as Morphosource, but the geometric morphometric analysis of an articulating structure is impeded by arbitrary differences in the resting positions of its individual articulating elements. In complex articulating structures, where the angles between articulating elements cannot be standardized, landmarks on articulating elements must be Procrustes superimposed independently (locally) and then recombined to quantify variation in the entire articulating structure simultaneously. Here, we discuss recent advances in local superimposition techniques, namely the “matched local superimpositions” approach, which incorporates anatomically accurate relative sizes, positions, and orientations of locally-superimposed landmarks, enabling clearer biological interpretation. We also use simulations to evaluate the consequences of choice of superimposition approach. Our results show that local superimpositions will isolate shape variation within locally-superimposed landmark subsets by sacrificing size and positional variation. They may also create morphometric “modules” when there are none by increasing integration within the locally-superimposed subsets; however, this effect is no greater than the spurious between-module integration created when superimposing landmark subsets (i.e., articulating elements) together. Taken together, our results show that local superimposition techniques differ from conventional Procrustes superimpositions in predictable ways. Finally, we use empirical datasets of the skulls of wrasses and colubriform snakes to highlight the promise of local superimpositions and their utility. Complex articulating structures must be studied, and the only current solution to do so is local superimpositions.
Identifying Hospitals in Nepal for Acute Burn Care and Stabilization Capacity Development: Location-Allocation Modeling for Strategic Service Delivery
Authors: Li Kevin , Mehta Kajal , Wright Ada , Lee Joohee , Yadav Manish , Pham Tam N , Rai Shankar M , Nakarmi Kiran , Stewart Barclay
Published: April 2021

In Nepal, preventable death and disability from burn injuries are common due to poor population-level spatial access to organized burn care. Most severe burns are referred to a single facility nationwide, often after suboptimal burn stabilization and/or significant care delay. Therefore, we aimed to identify existing first-level hospitals within Nepal that would optimize population-level access as “burn stabilization points” if their acute burn care capabilities are strengthened. A location-allocation model was created using designated first-level candidate hospitals, a population density grid for Nepal, and road network/travel speed data. Six models (A–F) were developed using cost-distance and network analyses in ArcGIS to identify the three vs five candidate hospitals at ≤2, 6, and 12 travel-hour thresholds that would optimize population-level spatial access. The baseline model demonstrated that currently 20.3% of the national population has access to organized burn care within 2 hours of travel, 37.2% within 6 travel-hours, and 72.6% within 12 travel-hours. If acute burn stabilization capabilities were strengthened, models A to C of three chosen hospitals would increase population-level burn care access to 45.2, 89.4, and 99.8% of the national population at ≤2, 6, and 12 travel-hours, respectively. In models D to F, five chosen hospitals would bring access to 53.4, 95.0, and 99.9% of the national population at ≤2, 6, and 12 travel-hours, respectively. These models demonstrate developing capabilities in three to five hospitals can provide population-level spatial access to acute burn care for most of Nepal’s population. Organized efforts to increase burn stabilization points are feasible and imperative to reduce the rates of preventable burn-related death and disability country-wide.
The Geography of Knowledge and R&D-led Growth
Authors: Aloi Marta , Poyago-Theotoky Joanna , Tournemaine Frédéric
Published: April 2021

We analyse how spatial disparities in innovation activities, coupled with migration costs, affect economic geography, market structure, growth and regional inequality. We provide conditions for existence and uniqueness of a spatial equilibrium, and for the endogenous emergence of industry clusters. Spatial variations in knowledge spillovers lead to spatial concentration of more innovative firms. Migration costs, however, limit the concentration of economic activities in the most productive region. Narrowing the gap in knowledge spillovers across regions raises growth, and reduces regional inequality by making firms more sensitive to wage differentials. The associated change in the industry concentration has positive welfare effects.
Soil burial has a greater effect on litter decomposition rate than nitrogen enrichment in alpine grasslands
Authors: Su Yuan , Le Jiajia , Ma Xiaofei , Zhou Xiaolong , Zhang Yunxin , Gong Yanming , Han Wenxuan , Li Kaihui , Liu Xuejun
Published: April 2021

Aims

Litter is frequently buried in the soil in alpine grasslands due to grassland degradation, serious rodent infestation and frequent strong winds. However, the effects of various litter positions on litter decomposition rates and nutrient dynamics under nitrogen (N) enrichment in such areas remain unknown.

Methods

A field experiment was performed in the alpine grasslands of northwest China to investigate the influence of litter position (surface, buried in the soil and standing) and N enrichment on litter decomposition, using data from two dominant grass species (Festuca ovina and Leymus tianschanicus) in control and N-enriched plots.

Important Findings

Litter decomposition rates were much faster in buried litter and slower in standing litter than in surface litter. N enrichment significantly affected litter quality and then influenced decomposition. But no significant differences in litter mass remaining were observed between control and N-enriched soil burial. These results indicated that N enrichment significantly affected litter decomposition by changes in litter quality. In addition, all litter exhibited net carbon (C) and phosphorus (P) release regardless of treatments. Litter exhibited net N accumulation for litter from the control plots but showed N release for litter from N enrichment plots. These suggested that litter decomposition can be limited by N and N enrichment influenced N cycling of litter. Current study presented direct evidence that soil buried litter exhibited faster mass loss and C release, and that soil burial can be a candidate explanation why litter decomposes faster than expected in dryland.
Pepper NAC-type transcription factor NAC2c balances the trade-off between growth and defense responses
Authors: Cai Weiwei , Yang Sheng , Wu Ruijie , Cao Jianshen , Shen Lei , Guan Deyi , Shuilin He
Published: April 2021

Plant responses to pathogen attacks and high-temperature stress (HTS) are distinct in nature but generally share several signaling components. How plants produce specific responses through these common signaling intermediates remains elusive. With the help of reverse-genetics approaches, we describe here the mechanism underlying trade-offs in pepper (Capsicum annuum) between growth, immunity, and thermotolerance. The NAC-type transcription factor CaNAC2c was induced by HTS and Ralstonia solanacearum infection (RSI). CaNAC2c-inhibited pepper growth, promoted immunity against RSI by activating jasmonate-mediated immunity and H2O2 accumulation, and promoted HTS responses by activating Heat shock factor A5 (CaHSFA5) transcription and blocking H2O2 accumulation. We show that CaNAC2c physically interacts with CaHSP70 and CaNAC029 in a context-specific manner. Upon HTS, CaNAC2c–CaHSP70 interaction in the nucleus protected CaNAC2c from degradation and resulted in the activation of thermotolerance by increasing CaNAC2c binding and transcriptional activation of its target promoters. CaNAC2c did not induce immunity-related genes under HTS, likely due to the degradation of CaNAC029 by the 26S proteasome. Upon RSI, CaNAC2c interacted with CaNAC029 in the nucleus and activated jasmonate-mediated immunity but was prevented from activating thermotolerance-related genes. In non-stressed plants, CaNAC2c was tethered outside the nucleus by interaction with CaHSP70, and thus was unable to activate either immunity or thermotolerance. Our results indicate that pepper growth, immunity, and thermotolerance are coordinately and tightly regulated by CaNAC2c via its inducible expression and differential interaction with CaHSP70 and CaNAC029.
Energy Policy Reversal during the Trump Administration: Examination of Its Legacy and Implications for Federalism
Authors: Yozwiak Madeline , Abell Hannah , Carley Sanya
Published: April 2021

The Trump administration pursued eighty-four energy reversal actions between 2017 and 2020, the majority of which through executive action. In this article, we evaluate the effectiveness of such an administrative presidency in its ability to withstand political and legal challenges. We first set the context of U.S. energy policy predating the Trump administration, and then synthesize the administration’s reversal actions according to the mechanisms, the beneficiaries, and the legal process through which each evolved. We then analyze four reversal case studies that highlight how stakeholders responded to such actions, and the resulting variation in outcomes: the rollback of coal ash standards; the proposed coastal oil and gas auctions; the revocation of California’s vehicle emissions waiver; and the replacement of the Clean Power Plan with the Affordable Clean Energy rule. We find that the administration’s executive approach was regularly checked through litigation by states, interest groups, and industry, or had limited impact due to the high level of regulatory uncertainty that it fostered. We draw implications for ongoing state and federal dynamics and for the lasting durability of the Trump administration’s energy reversal legacy.
Real-life drug persistence in patients with rheumatic diseases treated with CT-P13: a prospective observational cohort study (PERSIST)
Authors: Taylor Peter C , Christensen Robin , Moosavi Shahrzad , Selema Pamela , Guilatco Ruffy , Fowler Heather , Mueller Markus , Liau Katherine F , Haraoui Boulos
Published: April 2021

Objective

The aim was to report results from PERSIST, a real-life, observational, prospective cohort study of CT-P13, an infliximab (IFX) biosimilar, for treatment of patients with RA, AS or PsA who were biologic naïve or switched from an IFX reference product (IFX-RP; Remicade).

Methods

Adult patients were recruited during usual care at 38 sites in Europe and Canada and enrolled by their physicians after meeting eligibility criteria according to the country-approved label for CT-P13. Primary outcomes were to determine drug utilization and treatment persistence and to assess safety. Patients were followed for up to 2 years. Data were analysed and reported descriptively.

Results

Of 351 patients enrolled, 334 were included in the analysis (RA, 40.4%; AS, 34.7%; PsA, 24.9%). The safety analysis set comprised all 328 patients treated with CT-P13. The majority (58.2%) of patients received CT-P13 monotherapy, most (72.6%) by dosing every 6 or 8 weeks. The mean treatment persistence was 449.2 days; 62.3% of patients completed 2 years of treatment. In all, 214 treatment-emergent adverse events (TEAEs) were reported in 38.4% of patients. Most TEAEs were of mild or moderate intensity; 13 were severe. The most commonly reported TEAEs were drug ineffective (9.5%) and infusion-related reactions (5.2%). The most frequently reported infection-related TEAEs were upper respiratory tract infections (3.0%), nasopharyngitis (2.1%) and bronchitis (1.5%). No patients experienced tuberculosis.

Conclusion

Drug utilization and treatment persistence with CT-P13 were consistent with historical reports of IFX-RP in this patient population. Safety findings did not identify new concerns for CT-P13 in the treatment of patients with RA, AS or PsA.

Trial registration

ClinicalTrials.gov: NCT02605642.
Clinical and psychosocioeconomic impact of COVID-19 pandemic on patients of the Indian Progressive Systemic Sclerosis Registry (IPSSR)
Authors: Kavadichanda Chengappa , Shobha Vineeta , Ghosh Parasar , Wakhlu Anupam , Bairwa Devender , Mohanan Manju , Janardana Ramya , Sircar Geetabali , Sahoo Rasmi Ranjan , Joseph Sneha , Negi Vir Singh , Khanna Dinesh , Shenoy Padmanabha
Published: April 2021

Objectives

The aim was to determine the impact of the coronavirus disease 2019 (COVID-19) pandemic on access to health care among patients with scleroderma and to analyse the economic and psychosocial impacts and the infection prevention measures taken by them during the pandemic.

Methods

A 25-item questionnaire designed to assess the components of the objectives was tele-administered between October 2020 and January 2021 to the patients enrolled in the Indian Progressive Systemic Sclerosis Registry.

Results

Of the 428 patients in the registry, 336 took part in the study. A scheduled outpatient visit was missed by 310 (92.3%) patients, and 75 (22.3%) skipped prescription drugs. During the pandemic, 75 (22.3%) had a family member lose a job. Financial difficulties were reported by 155 (46.1%), with 116 (34.5%) patients having to spend an additional INR 4000 (2000–10 000) [USD 54.9 (27.0–137.4)] to continue treatment. Although 35 patients (10.4%) had at least one symptom suggestive of COVID-19, infection was confirmed in only 4. None of them needed hospitalization or had adverse outcomes. Worsening of scleroderma was seen in 133 (39.6%) individuals, with 15 (4.5%) requiring hospitalization. Most (96%) of the patients were aware of infection prevention measures, and 91 (27.1%) had taken unproven prophylactic medications.

Conclusion

Individuals with scleroderma in India have been affected during the pandemic owing to closure of hospital services, lack of transport, loss of jobs and the additional financial burden. Health-care providers should continue to educate patients to stay on their medications and encourage them to be vaccinated for COVID-19.
Frontoparietal, Cerebellum Network Codes for Accurate Intention Prediction in Altered Perceptual Conditions
Authors: Ceravolo L , Schaerlaeken S , Frühholz S , Glowinski D , Grandjean D
Published: April 2021

Integrating and predicting the intentions and actions of others are critical components of social interactions, but the behavioral and neural bases of such mechanisms under altered perceptual conditions are poorly understood. In the present study, we recruited expert violinists and age-matched controls with no musical training and asked them to evaluate simplified dynamic stimuli of violinists playing in a piano or forte communicative intent while undergoing functional magnetic resonance imaging. We show that expertise is needed to successfully understand and evaluate communicative intentions in spatially and temporally altered visual representations of musical performance. Frontoparietal regions—such as the dorsolateral prefrontal cortex and the inferior parietal lobule and sulcus—and various subregions of the cerebellum—such as cerebellar lobules I-IV, V, VI, VIIb, VIIIa, X—a re recruited in the process. Functional connectivity between these brain areas reveals widespread organization, particularly in the dorsolateral prefrontal cortex, inferior frontal gyrus, inferior parietal sulcus, and in the cerebellum. This network may be essential to successfully assess communicative intent in ambiguous or complex visual scenes.
Developing Entrustable Professional Activities for the Training of Translational Scientists: A Modified Delphi Study
Authors: Weggemans Margot M. , ter Haar Nienke M. , Prakken Berent , ten Cate Olle
Published: April 2021

Purpose

Improved training for translational scientists is important to help address the waste of resources and irreproducibility of research outcomes in current translational medicine. However, there are a lack of training programs that cover the full range of knowledge and skills translational scientists need to develop, and many translational research training programs struggle to develop competency frameworks and assessment tools. Entrustable professional activities (EPAs) have been successfully implemented to link competencies with everyday practice in training health care professionals but have not yet been developed for research training. The purpose of the current study was to develop EPAs for translational scientists that could be used for their training and assessment and help increase the transparency and reproducibility of research outcomes and methods by providing best practices for translational research.

Method

In 2019, a modified Delphi technique, preceded by a focus group held in 2018 using a nominal group technique, was used to reach consensus on EPA titles and content among an international panel of 22 translational experts. Mean, standard deviation, and level of agreement were calculated after each round. Consensus was defined as ≥ 80% agreement.

Results

Consensus was reached on 89% of the items after the first round and 100% after the second round. The final list of EPAs consists of 17 EPAs divided over 7 sections.

Conclusions

The concept of EPAs is new to the field of research training. The 17 EPA titles and their descriptions developed in this study may be used as a framework for improved training for translational scientists with the ultimate goal to contribute to closing the gap between bench and bedside, reducing resource waste in science, and increasing the reproducibility of research outcomes.
Quantitative Sensory Testing in Women After Surgery for Breast Cancer
Authors: Dams Lore , Van der Gucht Elien , Meeus Mira , Devoogdt Nele , Smeets Ann , Penen Frauke , De Baerdemaecker Tom , Haenen Vincent , Bernar Koen , De Vrieze Tessa , De Groef An
Published: April 2021

Objectives:

Quantitative sensory testing (QST) is a noninvasive technique to evaluate functioning of the somatosensory system. In many women surgically treated for breast cancer (BC), somatosensory functioning is disturbed with high prevalence of sensory loss and/or pain. The aims of this systematic review were (1) to summarize literature about QST methods; (2) to summarize the results within women surgically treated for BC (patients and survivors); (3) to compare QST results between women surgically treated for BC with and without pain; and (4) to compare the results between women surgically treated for BC and women without history of BC.

Methods:

A systematic literature search was conducted up to February 2020. Included studies had to report on QST methods (mechanical or thermal detection-pain thresholds, pressure pain thresholds [PPT], temporal summation [TS], or conditioned pain modulation [CPM]) in women over 18 years with-without pain, who had undergone unilateral surgery for BC.

Results:

Twenty-eight studies were included. Discrepancies in QST methods were greatest for TS and CPM. A local disturbance in thermal detection and an increased pain facilitation were found in BC survivors with pain in the surgical area. BC survivors with upper limb pain had significantly lower PPT at the surgical area and PPT were also significantly lower compared with women without history of BC, at affected and nonaffected sides for both local and remote body regions.

Discussion:

Standardized QST incorporating assessments of CPM is warranted in order to draw conclusions about neurobiological mechanisms of pain and somatosensory disturbances after surgical treatment for BC and to enhance mechanism-based management of these sequelae.
Pharmacokinetic/Pharmacodynamic Dosage Individualization of Cefepime in Critically Ill Patients: A Case Study
Authors: Goutelle Sylvain , Jay Lucille , Boidin Clément , Cohen Sabine , Bourguignon Laurent , Bleyzac Nathalie , Wallet Florent , Vassal Olivia , Friggeri Arnaud
Published: April 2021

Objective:

The authors report on a case of a 59-year-old man hospitalized in the intensive care unit because of severe SARS-COV-2 infection (COVID-19).

Background:

The patient had several comorbidities, including liver cirrhosis. He developed ventilation-associated bacterial pneumonia for which he was administered cefepime at an initial dose of 2 g/8 hours. Therapeutic drug monitoring was performed, showing overexposure with an initial trough concentration of >60 mg/L.

Methods:

Analysis of pharmacokinetic data and model-based dose adjustment was performed using BestDose software.

Results:

The patient had unexpected pharmacokinetic parameter values. Serum creatinine was only moderately increased, whereas measured creatinine clearance based on urine collection showed impaired renal function. Bacterial minimum inhibitory concentration was also considered in the dosing decisions. After dose reduction to 0.5 g/8 hours, the cefepime trough concentration progressively declined and reached the target values by the end of the therapy. A post-hoc analysis provided a different interpretation of drug overexposure.

Conclusion:

This case report illustrates how physiological, microbiological, and drug concentration data can be used for model-based dosage individualization of cefepime in intensive care unit patients.
Review of the differences in outcomes between males and females after revascularization
Authors: EL-Andari Ryaan , Bozso Sabin J. , Kang Jimmy J.H. , Hedtke Hannah , Nagendran Jeevan
Published: April 2021

Purpose of review

This review aims to compare outcomes of males and females undergoing coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), off-pump CABG (OPCAB), minimally invasive direct CABG (MIDCAB), and robotic total endoscopic CABG (TECAB).

Recent findings

Females demonstrated increased rates of morbidity and mortality post PCI and CABG. In studies that performed risk adjustments, these differences were reduced. Although inferior outcomes were observed for females in some measures, generally outcomes between males and females were comparable post OPCAB, MIDCAB, and TECAB

Previous literature has demonstrated that females undergoing coronary revascularization experience inferior postoperative outcomes when compared to their male counterparts. The discrepancies between males and females narrow, but do not disappear when preoperative risks are accounted for and when considering minimally invasive approaches such as MIDCAB, OPCAB, and TECAB. Minimally invasive cardiac surgery has demonstrated numerous benefits with reduced morbidity, mortality, and shorter recovery times. In patients with increased comorbidities, minimally invasive approaches confer a greater advantage. As females often fall within this category, it is paramount that the diagnosis and referral process be optimized to account for preoperative differences to provide the most beneficial approach if the disparity between the sexes is to be addressed.
New Formula to Predict Heart Rate at Anaerobic Threshold That Considers the Effects of β-Blockers in Patients With Myocardial Infarction
Authors: Nemoto Shinji , Kasahara Yusuke , Izawa Kazuhiro P. , Watanabe Satoshi , Yoshizawa Kazuya , Takeichi Naoya , Kamiya Kentaro , Suzuki Norio , Omiya Kazuto , Kida Keisuke , Matsunaga Atsuhiko , Akashi Yoshihiro J.
Published: April 2021

Purpose:

It is recommended that patients with myocardial infarction (MI) be prescribed exercise by target heart rate (HR) at the anaerobic threshold (AT) via cardiopulmonary exercise testing (CPX). Although percent HR reserve using predicted HRmax (%HRRpred) is used to prescribe exercise if CPX or an exercise test cannot be performed, %HRRpred is especially difficult to use when patients take β-blockers. We devised a new formula to predict HR at AT (HRAT) that considers β-blocker effects in MI patients and validated its accuracy.

Methods:

The new formula was created using the data of 196 MI patients in our hospital (derivation sample), and its accuracy was assessed using the data of 71 MI patients in other hospitals (validation sample). All patients underwent CPX 1 mo after MI onset, and resting HR, resting systolic blood pressure (SBP), and HRAT were measured during CPX.

Results:

The results of multiple regression analysis in the derivation sample gave the following formula (R
2 = 0.605, P < .001): predicted HRAT = 2.035 × (≥65 yr:−1, <65 yr:1) + 3.648 × (body mass index <18.5 kg/m2:−1, body mass index ≥18.5 kg/m2:1) + 4.284 × (β1-blocker(+):−1, β1-blocker(−):1) + 0.734 × (HRrest) + 0.078 × (SBPrest) + 36.812. This formula consists entirely of predictors that can be obtained at rest. HRAT and predicted HRAT with the new formula were not significantly different in the validation sample (mean absolute error: 5.5 ± 4.1 bpm).

Conclusions:

The accuracy of the new formula appeared to be favorable. This new formula may be a practical method for exercise prescription in MI patients, regardless of their β-blocker treatment status, if CPX is unavailable.
Nutrition Metabolism and Infections
Authors: Yang Fang , Yang Yi , Zeng Lingchan , Chen Yiwei , Zeng Gucheng
Published: April 2021

Infection and nutrition are intricately interacted and further influence human health. Infections are a worldwide health problem and malnutrition plays a significant role in the emergence of infection. Growing evidence suggests that the optimization of dietary nutrients intake is crucial in maintaining systemic immunity and may help improve resistance to infections. In this review, we explore a wide range of topics including interactions between nutrients and various infectious diseases. We also discuss the role of diet-induced gut microbiota in the infection-nutrition cycle and review how dietary-microbiome crosstalk may affect disease development and progression, which may provide an attractive option to the design of a diet leading to favorable outcomes in the future. We will also present evidence and propose mechanisms of nutrients that may specifically modulate host immunity and metabolism to infectious pathogens and also cover its influence on nutrition, focusing on immuno-nutrients. We provide representative nutrients in the present review based on their intensive studies and wide acceptance of their immuno-modulating properties. Moreover, the efficacy and translational cost of their plausible utility to be anti-infective nutrients are also reviewed. Finally, we highlight the current progress and challenges to gain a better understanding of the research into microbiota, infectious diseases, and nutrition with an emphasis on future research directions.
A comparison of prognostic performance of perioperative inflammation markers in surgical resection for hepatocellular carcinoma
Authors: Wu Hsiang-Ling , Kuo Hsien-Cheng , Li Chun-Cheng , Wu Yu-Ming , Lin Shih-Pin , Chang Kuang-Yi , Hou Ming-Chih , Tsou Mei-Yung , Cherng Yih-Giun , Chen Jui-Tai , Tai Ying-Hsuan
Published: April 2021

Background:

Systemic inflammation correlates closely with tumor invasion and may predict survival in cancer patients. We aimed to compare the prognostic value of various inflammation-based markers in patients with hepatocellular carcinoma.

Methods:

We consecutively enrolled 1450 patients with primary hepatocellular carcinoma undergoing surgical resection at the medical center between 2005 and 2016 and assessed them through September 2018. Prognostic nutritional index, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio along with their perioperative dynamic changes were analyzed regarding their predictive ability of postoperative disease-free survival and overall survival. We calculated the adjusted hazard ratio (HR) and 95% CI of the association between inflammation-based markers and survival using multiple Cox proportional hazards models. Youden’s index of receiver operating characteristics curves was used to determine optimal cut-off points.

Results:

Prognostic nutritional index was an independent predictor for both disease-free survival (<50.87 vs ≥50.87, HR: 1.274, 95% CI, 1.071–1.517, p = 0.007) and overall survival (<46.65 vs ≥46.65, HR: 1.420, 95% CI, 1.096–1.842, p = 0.008). Besides, the relative change of neutrophil-to-lymphocyte ratio predicted overall survival (<277% vs ≥277%, HR: 1.634, 95% CI, 1.266–2.110, p < 0.001). Combination of both markers offered better prognostic performance for overall survival than either alone. Body mass index, liver cirrhosis, chronic kidney disease, and tumor diameter were significantly associated with both markers.

Conclusion:

Prognostic nutritional index and perioperative relative change of neutrophil-to-lymphocyte ratio independently predict postoperative survival in patients undergoing surgical resection of hepatocellular carcinoma. These results provided important evidence for risk stratification and individualized anti-cancer therapy.
Single-cell RNA sequencing in human lung cancer: Applications, challenges, and pathway towards personalized therapy
Authors: Chong Zhi-Xiong , Ho Wan-Yong , Yeap Swee-Keong , Wang Mong-Lien , Chien Yueh , Verusingam Nalini Devi , Ong Han-Kiat
Published: April 2021

Lung cancer is one of the most prevalent human cancers, and single-cell RNA sequencing (scRNA-seq) has been widely used to study human lung cancer at the cellular, genetic, and molecular level. Even though there are published reviews, which summarized the applications of scRNA-seq in human cancers like breast cancer, there is lack of a comprehensive review, which could effectively highlight the broad use of scRNA-seq in studying lung cancer. This review, therefore, was aimed to summarize the various applications of scRNA-seq in human lung cancer research based on the findings from different published in vitro, in vivo, and clinical studies. The review would first briefly outline the concept and principle of scRNA-seq, followed by the discussion on the applications of scRNA-seq in studying human lung cancer. Finally, the challenges faced when using scRNA-seq to study human lung cancer would be discussed, and the potential applications and challenges of scRNA-seq to facilitate the development of personalized cancer therapy in the future would be explored.
Hepatoma upregulated protein and Ki-67 expression in resectable hepatocellular carcinoma
Authors: Lei Hoa-Jan , Wang Sheng-Yu , Chau Ivy Yenwen , Li Anna Fen-Yau , Chau Yat-Pang , Hsia Cheng-Yuan , Chou Shu-Cheng , Kao Yi-Chu , Chau Gar-Yang
Published: April 2021

Background:

Hepatoma upregulated protein (HURP) and Ki-67 have been identified as cancer-related genes involved in cell growth and proliferation. Previous experimental studies have suggested an essential role for HURP expression in liver carcinogenesis. However, data regarding HURP expression in hepatocellular carcinoma (HCC) and its correlation with patient outcomes are limited. In this study, we examined the clinicopathologic features associated with HURP expression in HCC, and compared them to the results of the Ki-67 study.

Methods:

Eighty-seven resected HCC at tumor, node, metastasis (TNM) stages I (n = 28), II (n = 29), and III (n = 30) were evaluated. HURP and Ki-67 expression were assessed by immunohistochemistry. Multivariate analysis was used to examine the prognostic significance of HURP and Ki-67 expression.

Results:

HURP expression in HCC tissue was observed in 59% of patients and associated with female sex, low white blood cell count, and low platelet count. Ki-67 expression was observed in 67% of patients and associated with younger age, higher serum α-fetoprotein (AFP) levels, and frequent microvascular invasion. Univariate analysis showed that factors related to overall survival were: age >55 years, AFP >20 ng/mL, indocyanine green retention rate at 15 minutes (ICG-15) >15%, tumor size >5 cm, multiple tumors, macrovascular invasion, microvascular invasion, Ki-67 expression, and serum vascular endothelial growth factor >170 pg/mL. HURP expression was not associated with postresection survival. Multivariate analysis indicated that macrovascular invasion, multiple tumors, ICG-15 >15%, and Ki-67 expression were independent factors for overall survival. Multiple tumors and Ki-67 expression were independent factors related to recurrence-free survival.

Conclusion:

In our study, HURP expression in HCC tissue was not associated with post-resection survival. Ki-67 expression was an independent prognostic factor for survival. Our results suggest that the effect of HURP activity on growth, invasion, and postresection outcome of HCC in actual patients is less than previously demonstrated in experimental studies.
Development and Pilot Test of an Online Training to Engage Managers to Support Workplace Wellness
Authors: Hammerback Kristen , Kava Christine M. , Passey Deborah G. , Hahn Justin , Huff Aaron , Kohn Marlana J. , Harris Jeffrey R. , Hannon Peggy A.
Published: April 2021

Objective:

To contribute to a broader understanding of effective implementation strategies to help managers engage employees in workplace wellness.

Methods:

We beta-tested an online training at four Washington state agencies (two test, two control). We administered a post-training evaluation, re-administered an online manager survey and conducted additional interviews with wellness leads.

Results:

Training participation rate was high. The two test agencies experienced a significant increase in the percentage of managers who: agreed that they received training on employee wellness; agreed their agency's culture supports employee wellness; and encouraged their employees to participate in wellness activities. Approximately 80% of managers who received the training agreed they could apply information learned to support employee wellness.

Conclusions:

If proven effective, the training could be administered at a low cost and disseminated to improve employee health.
Surgical Resection of an Arteriovenous Malformation
Authors: Penington Anthony
Published: April 2021

Resection of a large arteriovenous malformation can be one of the most challenging surgical procedures in vascular anomalies. Although the problem of hemostasis draws the most attention, reducing the high recurrence rate after surgery is the true challenge. The technical principles of surgery are the same as for any other resection, but surgery must be guided by an understanding of the unique biology and anatomy of arteriovenous malformation.