bluuebunny/crossref_metadata_2025 huggingface dataset:
Fundamentals for a Systematic Approach to Mild and Moderate Inherited Bleeding Disorders: An EHA Consensus Report
Authors: Rodeghiero Francesco , Pabinger Ingrid , Ragni Margaret , Abdul‐Kadir Rezan , Berntorp Erik , Blanchette Victor , Bodó Imre , Casini Alessandro , Gresele Paolo , Lassila Riitta , Leebeek Frank , Lillicrap David , Mezzano Diego , Noris Patrizia , Srivastava Alok , Tosetto Alberto , Windyga Jerzy , Zieger Barbara , Makris Mike , Key Nigel
Published: September 2019

Healthy subjects frequently report minor bleedings that are frequently ‘background noise’ of normality rather than a true disorder. Nevertheless, unexpected or unusual bleeding may be alarming. Thus, the distinction between normal and pathologic bleeding is critical. Understanding the underlying pathologic mechanism in patients with an excessive bleeding is essential for their counseling and treatment. Most of these patients with significant bleeding will result affected by non‐severe inherited bleeding disorders (BD), collectively denominated mild or moderate BD for their relatively benign course. Unfortunately, practical recommendations for the management of these disorders are still lacking due to the current state of fragmented knowledge of pathophysiology and lack of a systematic diagnostic approach. To address this gap, an International Working Group (IWG) was established by the European Hematology Association (EHA) to develop consensus‐based guidelines on these disorders. The IWG agreed that grouping these disorders by their clinical phenotype under the single category of mild‐to‐moderate bleeding disorders (MBD) reflects current clinical practice and will facilitate a systematic diagnostic approach. Based on standardized and harmonized definitions a conceptual unified framework is proposed to distinguish normal subjects from affected patients. The IWG proposes a provisional comprehensive patient‐centered initial diagnostic approach that will result in classification of MBD into distinct clinical‐pathological entities under the overarching principle of clinical utility for the individual patient. While we will present here a general overview of the global management of patients with MBD, this conceptual framework will be adopted and validated in the evidence‐based, disease‐specific guidelines under development by the IWG.
Statin Use is Protective Against Hepatocellular Carcinoma in Patients With Nonalcoholic Fatty Liver Disease
Authors: German Margarita N. , Lutz Megan K. , Pickhardt Perry J. , Bruce Richard J. , Said Adnan
Published: September 2019

Background and Goal:

The incidence of nonalcoholic fatty liver disease (NAFLD)–associated hepatocellular carcinoma (HCC) is rising. We aimed to characterize risk factors for NAFLD-HCC development.

Methods:

We performed a retrospective case-control study of HCC cases from a cohort of NAFLD patients who underwent at least 2 computed tomography scans. NAFLD-HCC cases confirmed on contrast imaging and/or biopsy were included. Controls were NAFLD patients without HCC matched by sex and age. Clinical variables were assessed. Visceral adipose tissue and subcutaneous adipose tissue were measured by computed tomography at 2 timepoints: before HCC diagnosis and at diagnosis.

Results:

We identified 102 subjects [34 HCC cases, 68 controls, 65% (n=66) males, mean age: 69 y] from 2002 to 2016. Cirrhosis was present in 91%. In multivariate analysis, statin use was protective against HCC [odds ratio (OR)=0.20, 95% confidence interval (CI): 0.07-0.60,P=0.004], while hypertension was a risk factor for HCC (OR=5.80, 95% CI: 2.01-16.75,P=0.001). In multivariate analysis, visceral adipose tissue in males was higher before HCC diagnosis and declined by HCC diagnosis in 86%, which was a significant difference compared with controls (OR=2.78, 95% CI: 1.10-7.44,P=0.04).

Conclusions:

In a cohort of NAFLD-HCC patients, statin use was protective against HCC, while hypertension conferred an increased risk. Visceral adiposity at baseline was not a risk factor, but was higher in male patients before HCC development, declining in the majority by HCC diagnosis.
Rapid Titration of Clozapine in Schizophrenia and Bipolar Disorder
Authors: Ifteni Petru , Teodorescu Andreea , Dima Lorena , Burtea Victoria
Published: September 2019

Despite evidence accumulated over 30 years of clozapine efficacy in schizophrenia, its use is suboptimal. Long duration of standard titration and monitoring procedures are strong barriers in clozapine prescribing. The aim of the present paper is to discuss the challenges of rapid clozapine titration. The currently approved/recommended titration methods in US, Europe, and Australia are discussed. The rapid clozapine titration was introduced in our hospital in the early 2000's as “last resort” method for aggressive, belligerent or homicidal patients with schizophrenia and bipolar disorder. In our opinion, rapid clozapine titration might shorten the duration of patient and family suffering associated with uncontrolled psychotic symptoms, reduce the need and risks associated with polypharmacy, and reduce the costs of health care services of prolonged hospitalization. As there are no randomized controlled clinical trials to compare the efficacy and safety of standard versus rapid titration of clozapine in schizophrenia or bipolar disorder, future studies are needed.
The clinical and immune outcomes after food allergen immunotherapy emphasizing the development of tolerance
Authors: Miller Jennifer M. , Davis Carla M. , Anvari Sara
Published: September 2019

Purpose of review

The present review serves to outline the direction of food allergy immunotherapy research with an emphasis on clinical and immunologic outcomes. It helps to delineate sustained unresponsiveness achieved from food immunotherapy as the clinical outcome most similar to immune tolerance.

Recent findings

We will discuss the difference between immune tolerance, desensitization, and sustained unresponsiveness in relation to food immunotherapy by discussing the clinical and immunologic changes which have been recently discovered.

Research has recently shown that oral immunotherapy is most efficacious clinically at achieving desensitization to a food and sustained unresponsiveness.
Mass Casualties and Case Management
Authors: Powell Suzanne K. , Owen Mindy
Published: September 2019

The mass casualty statistics in the United States is numbing. Case managers must be prepared for potential disasters. This Editorial speaks to a case manager's personal experience and calls for others who have been through an experience with mass casualties, so all may better prepare: preparation is the antidote to panic.
Impact of a Preset Daily Cell Phone Alarm on Medication Adherence for Aspirin as Antithrombotic Therapy
Authors: Wittig-Wells Deborah , Higgins Melinda , Carter Jessica , Davis Erica , Holmes Estella , Jacob Ani , Samms-McPherson Jacqueline , Simms Sandra
Published: September 2019

The ability of patients to adhere to medication regimens is considered critical to achieving optimal results. Many patients are discharged with aspirin (ASA) as an anticoagulant for venous thrombosis embolism prophylaxis after joint replacement surgery. In studies where ASA was prescribed as an antithrombotic after selected orthopaedic surgeries, both lack of understanding and missing doses were identified as factors that affected adherence rates (D. Wittig-Wells et al., 2015
,
2017). The purpose of this study was to explore the preliminary impact of a preset telephone alarm on medication adherence in adults prescribed ASA for 35 days after knee or hip arthroplasty. This was a randomized controlled trial (n = 79). Adherence was measured with a four-question self-reporting tool. Average age was 61 years. The majority were female (59.5%) and Caucasian (62.0%) with college or graduate degree-level education (78.5%). When comparing the groups, there were no significant differences between the two groups for the demographics of age, gender, and race. The alarm group had significantly better adherence rates, with fewer people who forgot to take their ASA; only 29.7% of the alarm group ever forgot to take their medication compared with 59.5% of the no-alarm group (p = .008). It seems that simple cell phone alarms can serve as effective reminders to patients to take selected medications as prescribed.
Successful Modified Transoral Endoscopic Parathyroidectomy Vestibular Approach For Secondary Hyperparathyroidism With Ectopic Mediastinal Glands
Authors: Wu Yi-Ju , Cheng Ben-Chung , Chiu Chien-Hua , Huang Shun-Chen , Li Lung-Chih , Chung Sheng-Ying , Den Chen Kuang , Pan Cheng-Chung , Li Jyun-Yi , Lin Hsiao-Wen , Chen Ying-Hsiu , Liang Peii-Ling , Co Jeffrey S. , Chi Shun-Yu , Chou Fong-Fu , Lin Chih-Che
Published: September 2019

Background:

Transoral endoscopic parathyroidectomy vestibular approach for secondary hyperparathyroidism (SHPT) is controversial with regard to the time consumed, safety, and feasibility. We present our initial experience with modified transoral endoscopic parathyroidectomy vestibular approach (m-TOEPVA) procedure for SHPT using total parathyroidectomy with autotransplantation.

Materials and Methods:

We retrospectively reviewed 10 patients with SHPT who underwent the m-TOEPVA procedure from December 2017 to April 2018 at our center.

Results:

There were a total of 6 male individuals and 4 female individuals with a median age of 58.5 years. Among whom, 5 were on hemodialysis and 5 on peritoneal dialysis. The median length of hospital stay and operative time was 5 (4, 5) days, and 321.5 (302.75, 362.25) minutes, respectively. Successful removal of 4 parathyroid glands was achieved in 8 of 10 patients (80%) and, in 8 patients (8/10, 80%), the intact parathyroid hormone successfully dropped to <300 pg/mL at 3 months postoperatively. Two patients with ectopic parathyroid gland in the superior mediastinum were noted preoperatively by MIBI scan and subsequently had successful removal. Except for 1 patient with prolonged hospital stay (11 d) due to hungry bone syndrome, there were no other major complications.

Conclusion:

m-TOEPVA by total parathyroidectomy with autotransplantation for SHPT is feasible, safe, and offers optimal cosmetic results. The most valuable part is that m-TOEPVA provides direct visualization and successful removal of the ectopic parathyroid glands in the superior mediastinum.
More Than 25 Years of Pancreas Graft Survival After Simultaneous Pancreas and Kidney Transplantation: Experience From the World's Largest Series of Long-term Survivors
Authors: Parajuli Sandesh , Bath Natalie M. , Aziz Fahad , Garg Neetika , Muth Brenda , Djamali Arjang , Redfield Robert R. , Kaufman Dixon , Odorico Jon , Mandelbrot Didier , Sollinger Hans
Published: September 2019

Background.

The first simultaneous pancreas and kidney (SPK) transplant was performed in 1966. Early procedures were associated with significant morbidity and mortality and were performed in very low numbers in select patients.

Methods.

This study includes all recipients of an SPK at the University of Wisconsin-Madison between 1986 and 1993, who were actively followed and had a functional pancreas allograft for >25 years as of October 31, 2018.

Results.

A total of 291 SPK were performed during the study period; of these, 39 patients still had a functional graft at last follow up and 9 (18.8%) pancreas grafts were lost due to patient death or graft failure after >25 years. At last follow up, all 39 patients with functional pancreas graft had at least one comorbidity, such as hypertension, hyperlipidemia, or coronary artery disease. Twenty-seven required enteric conversion; 11 patients experienced renal allograft failure (10 underwent a repeat kidney transplant); and 6 required amputation of part of the lower extremity. In the Cox regression analysis, bladder drained pancreas was associated with lower probability of prolonged pancreas graft survival (hazard ratio: 0.52; confidence interval: 0.32-0.85; P = 0.01).

Conclusions.

With careful and detailed follow-up and attention to complications, some recipients of pancreas grafts have outstanding outcomes. As the number of pancreas recipients with prolonged graft survival may be rising, healthcare providers should be aware of the management of complications associated with this unique group of patients.
Bortezomib Against Refractory Antibody-Mediated Rejection After ABO-Incompatible Living-Donor Liver Transplantation: Dramatic Effect in Acute-Phase?
Authors: Tajima Tetsuya , Hata Koichiro , Okajima Hideaki , Nishikori Momoko , Yasuchika Kentaro , Kusakabe Jiro , Yoshizawa Atsushi , Fukumitsu Ken , Anazawa Takayuki , Tanaka Hirokazu , Wada Seidai , Doi Junshi , Takaori-Kondo Akifumi , Uemoto Shinji
Published: September 2019

Antibody-mediated rejection (AMR) is a refractory rejection after donor-specific antibody-positive or ABO blood-type incompatible (ABOi) organ transplantation. Rituximab dramatically improved the outcome of ABOi living-donor liver transplantation (LDLT); however, an effective treatment for posttransplant AMR, once occurred, is yet to be established. A 44-year-old woman with biliary cirrhosis underwent ABOi-LDLT from her sister (AB-to-A). Pretransplant rituximab diminished CD19/20-positive B lymphocytes to 0.6%/0.0%; however, AMR occurred on posttransplant day-6 with marked increase in both CD19/20 cells (17.1%/5.8%) and anti-B IgM/G-titers (1024/512). Despite rituximab readministration, steroid-pulse, intravenous immunoglobulin, and plasmapheresis, AMR was uncontrollable, with further increasing CD19/20 cells (23.0%/0.0%) and antibody-titers (2048/512). Bortezomib (1.0 mg/m2) was thus administered on posttransplant day-9, immediately ameliorating CD19/20 cells (1.3%/0.0%) and antibody-titers (<256/128). Complete remission of refractory AMR was obtained by just 2 doses of bortezomib. Her liver function has been stable thereafter for over 3 years. This case highlighted the efficacy of bortezomib against refractory AMR after ABOi-LDLT. Unlike previous reports, the efficacy was very dramatic, presumably due to the administration timing near the peak of acute-phase AMR.
A structured approach to evaluating life course hypotheses: Moving beyond analyses of exposed versus unexposed in the omics context
Authors: Zhu Yiwen , Simpkin Andrew J. , Suderman Matthew J. , Lussier Alexandre A. , Walton Esther , Dunn Erin C. , Smith Andrew D.A.C.
Published: September 2019

Background

Life course epidemiology provides a framework for studying the effects of time-varying exposures on health outcomes. The structured life course modeling approach (SLCMA) is a theory-driven analytic method that empirically compares multiple prespecified life course hypotheses characterizing time-dependent exposure-outcome relationships to determine which theory best fits the observed data. However, the statistical properties of inference methods used with the SLCMA have not been investigated with high-dimensional omics outcomes.

Methods

We performed simulations and empirical analyses to evaluate the performance of the SLCMA when applied to genome-wide DNA methylation (DNAm). In the simulations, we compared five statistical inference tests used by SLCMA (n=700). For each, we assessed the familywise error rate (FWER), statistical power, and confidence interval coverage to determine whether inference based on these tests was valid in the presence of substantial multiple testing and small effect sizes, two hallmark challenges of inference from omics data. In the empirical analyses, we applied the SLCMA to evaluate the time-dependent relationship of childhood abuse with genome-wide DNAm (n=703).

Results

In the simulations, selective inference and max-|t|-test performed best: both controlled FWER and yielded moderate statistical power. Empirical analyses using SLCMA revealed time-dependent effects of childhood abuse on DNA methylation.

Conclusions

Our findings show that SLCMA, applied and interpreted appropriately, can be used in the omics setting to examine time-dependent effects underlying exposure-outcome elationships over the life course. We provide recommendations for applying the SLCMA in high-throughput settings, which we hope will encourage researchers to move beyond analyses of exposed versus unexposed.

Key messages

The structured life course modeling approach (SLCMA) is an effective approach to directly compare life course theories and can be scaled-up in the omics context to examine nuanced relationships between environmental exposures over the life course and biological processes.

Of the five statistical inference tests assessed in simulations, we recommend the selective inference method and max-|t|-test for post-selection inference in omics applications of the SLCMA.

In an empirical example, we revealed time-dependent effects of childhood abuse on DNA methylation using the SLCMA, with improvement in statistical power when accounting for covariates by applying the Frisch-Waugh-Lovell (FWL) theorem.

Researchers should assess p-values in parallel with effects sizes and confidence intervals, as triangulating multiple forms of statistical evidence can strengthen inferences and point to new directions for replication.
Phasic dopamine enhances the distinct decoding and perceived salience of stimuli
Authors: Oettl Lars-Lennart , Scheller Max , Wieland Sebastian , Haag Franziska , Wolf David , Loeb Cathrin , Ravi Namasivayam , Durstewitz Daniel , Shusterman Roman , Russo Eleonora , Kelsch Wolfgang
Published: September 2019

Subjects learn to assign value to stimuli that predict outcomes. Novelty, rewards or punishment evoke reinforcing phasic dopamine release from midbrain neurons to ventral striatum that mediates expected value and salience of stimuli in humans and animals. It is however not clear whether phasic dopamine release is sufficient to form distinct engrams that encode salient stimuli within these circuits. We addressed this question in awake mice. Evoked phasic dopamine induced plasticity selectively to the population encoding of coincidently presented stimuli and increased their distinctness from other stimuli. Phasic dopamine thereby enhanced the decoding of previously paired stimuli and increased their perceived salience. This dopamine-induced plasticity mimicked population coding dynamics of conditioned stimuli during reinforcement learning. These findings provide a network coding mechanism of how dopaminergic learning signals promote value assignment to stimulus representations.
Coupling Terrestrial Laser Scanning with 3D Fuel Biomass Sampling for Advancing Wildland Fuels Characterization
Authors: Rowell Eric , Loudermilk E. Louise , Hawley Christie , Pokswinski Scott , Seielstad Carl , Queen Lloyd , O’Brien Joseph J. , Hudak Andrew T. , Goodrick Scott , Hiers J. Kevin
Published: September 2019

The spatial pattern of surface fuelbeds in fire-dependent ecosystems are rarely captured using long-standing fuel sampling methods. New techniques, both field sampling and remote sensing, that capture vegetation fuel type, biomass, and volume at super fine-scales (cm to dm) in three-dimensions (3D) are critical to advancing forest fuel and wildland fire science. This is particularly true for computational fluid dynamics fire behavior models that operate in 3D and have implications for wildland fire operations and fire effects research. This study describes the coupling of new 3D field sampling data with terrestrial laser scanning (TLS) data to infer fine-scale fuel mass in 3D. We found that there are strong relationships between fine-scale mass and TLS occupied volume, porosity, and surface area, which were used to develop fine-scale prediction equations using TLS across vegetative fuel types, namely grasses and shrubs. The application of this novel 3D sampling technique to high resolution TLS data in this study represents a major advancement in understanding fire-vegetation feedbacks in highly managed fire-dependent ecosystems.
Angle-tuned Coil: A Focal Spot-size Adjustable Transcranial Magnetic Stimulator
Authors: Meng Qinglei , Bagherzadeh Hedyeh , Loiacono Julian , Du Xiaoming , Hong Elliot , Yang Yihong , Lu Hanbing , Choa Fow-Sen
Published: September 2019

Background

Conventional transcranial magnetic stimulation (TMS) coils are limited by the depth-focality tradeoff rule and the emission field intensity from coils with either small or large apertures will diverge quickly at less than one aperture diameter distance away from the coil. To utilize a better depth-focality tradeoff rule and accomplish deep and focused stimulation, a new approach needs to be employed.

Objectives

We report a new TMS coil design that can deliver deep and spot size adjustable stimulation to deep brain regions.

Methods

In our design, we introduce a magnetic core at the center of a coil to help confine the magnetic field and prevent leakage. We further tilted the wire wrapping angle of the coil to break its ring symmetry and accomplish tunable focusing by adjusting the tilting angle.

Results

By comparing the electric field decay curves of five types of coils, our results concluded the proposed novel method to improve the coils’ depth-focality profile. Both theoretical calculations and experimental data collectively demonstrated that by using a larger tilting angle, we were able to accomplish a more tightly focused stimulation at any distance away from the coil.

Conclusion

Enlarging the tilting angle of the coil wire wrapping and applying magnetic core significantly improved the spatial resolution of the field without inducing considerable effect on field decay speed. Our novel TMS coil design plots a new curve in the depth-focality profile with better performance than the existing conventional coil designs in the tradeoff rule.
I-Impute: a self-consistent method to impute single cell RNA sequencing data
Authors: Feng Xikang , Chen Lingxi , Wang Zishuai , Li Shuai Cheng
Published: September 2019

Single-cell RNA-sequencing (scRNA-seq) is essential for the study of cell-specific transcriptome landscapes. The scRNA-seq techniques capture merely a small fraction of the gene due to “dropout” events. When analyzing with scRNA-seq data, the dropout events receive intensive attentions. Imputation tools are proposed to estimate the values of the dropout events and de-noise the data. To evaluate the imputation tools, researchers have developed different clustering criteria by incorporating the ground-truth cell subgroup labels. There lack measurements without cell subgroup knowledge. A reliable imputation tool should follow the “self-consistency” principle; that is, the tool reports the results only if it finds no further errors or dropouts from the data. Here, we propose “self-consistency” as an explicit evaluation criterion; also, we propose I-Impute, a “self-consistent” method, to impute scRNA-seq data. I-Impute lever-ages continuous similarities and dropout probabilities and refines the data iteratively to make the final output self-consistent. On the in silico data sets, I-Impute exhibited the highest Pearson correlations for different dropout rates consistently compared with the state-of-art methods SAVER and scImpute. On the datasets of 90.87%, 70.98% and 56.65% zero rates, I-Impute exhibited the correlations as 0.78, 0.90, and 0.94, respectively, between ground truth entries and predicted values, while SAVER exhibited the correlations as 0.58, 0.79 and 0.88, respectively and scImpute exhibited correlations as 0.65, 0.86, and 0.93, respectively. Furthermore, we collected three wetlab datasets, mouse bladder cells dataset, embryonic stem cells dataset, and aortic leukocyte cells dataset, to evaluate the tools. I-Impute exhibited feasible cell subpopulation discovery efficacy on all the three datasets. It achieves the highest clustering accuracy compared with SAVER and scImpute; that is, I-Impute displayed the adjusted Rand indices of the three datasets as 0.61, 0.7, 0.52, which improved the indices of SAVER by 0.01 to 0.17, and improved the indices of scImpute by 0.19 to 0.4. Also, I-impute promoted normalized mutual information of the three datasets by 0.01 to 0.09 comparing with SAVER, and by 0.15 to 0.34 comparing with scImpute. I-Impute exhibits robust imputation ability and follows the “self-consistency” principle. It offers perspicacity to uncover the underlying cell subtypes in real scRNA-Seq data. Source code of I-Impute can be accessed at https://github.com/xikanfeng2/I-Impute.
Complex multi-trait responses to multivariate environmental cues in a seasonal butterfly
Authors: Singh Pragya , van Bergen Erik , Brattström Oskar , Osbaldeston Dave , Brakefield Paul M. , Oostra Vicencio
Published: September 2019

Developmental plasticity in a seasonal environment allows an organism to optimally match its life-history traits with the fluctuating conditions. This critically relies on abiotic and biotic factors, such as temperature or food quality, that act as environmental cues and predict seasonal transitions. In most seasonal environments, multiple factors vary together, making it crucial to understand their combined effects on an organism’s phenotype. Here, we study plasticity in a multivariate environment in the butterfly Bicyclus anynana that exhibits two distinct seasonal phenotypes. Temperature is an important cue mediating plasticity in this species, but other environmental cues such as larval host plant quality could also be informative since plant quality deteriorates during the transition from wet to dry season in the field. We examine how temperature and host plant quality interact to affect life-history traits. Using a full-factorial design, we expose cohorts of larvae to either poor (old plants) or high (young plants) quality plants at different temperatures. Our results show that plant quality had a temperature and sex-dependent effect on life-history traits. At lower and intermediate temperatures, it decreased body mass and prolonged development time, indicating that poor plant quality acted as a stressor. However, metabolic rates in adults were not affected, indicating that individuals could, at least in part, compensate for stressful juvenile conditions. In contrast, at higher temperatures poor plant quality induced a partial dry-season phenotype, indicating that it may have acted as an environmental cue. Moreover, poor plant quality, particularly in males, also decreased the correlation between life history traits, signifying disrupted phenotypic integration. Our study reveals complex interactive effects of two environmental variables on seasonal plasticity, reflecting differences in their reliability as seasonal cues. This highlights the importance of studying the combined effects of multiple environmental factors to better understand the regulation of phenotypic plasticity in wild.
PrimPol-dependent single-stranded gap formation mediates homologous recombination at bulky DNA adducts
Authors: Piberger Ann Liza , Bowry Akhil , Kelly Richard D W , Walker Alexandra K , Gonzalez Daniel , Bailey Laura J , Doherty Aidan J , Méndez Juan , Morris Joanna R , Bryant Helen E , Petermann Eva
Published: September 2019

Obstacles on the DNA template can lead to DNA replication fork stalling and genomic rearrangements. RAD51-mediated homologous recombination (HR) can promote restart and repair of stalled forks, but also post-replicative repair once the obstacle has been bypassed. Bulky DNA adducts are important replication-blocking lesions induced by environmental carcinogens, but it is not known whether they activate HR directly at stalled forks, or at gaps left behind ongoing forks. Here we show that in mammalian cells, bulky adducts predominantly induce HR at post-replicative gaps formed by the DNA/RNA primase PrimPol. Using BPDE and other bulky model lesions, we report that RAD51 is not recruited to stalled or collapsed forks, but instead to long gaps formed by PrimPol re-priming activity and resection by MRE11 and EXO1. In contrast, RAD51 loading at DSBs does not require PrimPol. At bulky adducts, PrimPol is required for the induction of sister chromatid exchanges and genetic recombination. Our data support that HR at bulky adducts in mammalian cells involves post-replicative gap repair and define a role for PrimPol in DNA damage tolerance by homologous recombination.
Fertility of Pedicellate Spikelets in Sorghum is Controlled by a Jasmonic Acid Regulatory Module
Authors: Gladman Nicholas , Jiao Yinping , Lee Young Koung , Zhang Lifang , Chopra Ratan , Regulski Michael , Burow Gloria , Hayes Chad , Christensen Shawn A. , Dampanaboina Lavanya , Chen Junping , Burke John , Ware Doreen , Xin Zhanguo
Published: September 2019

As in other cereal crops, the panicles of sorghum (Sorghum bicolor (L.) Moench) comprise two types of floral spikelets (grass flowers). Only sessile spikelets (SSs) are capable of producing viable grains, whereas pedicellate spikelets (PSs) cease development after initiation and eventually abort. Consequently, grain number per panicle (GNP) is lower than the total number of flowers produced per panicle. The mechanism underlying this differential fertility is not well understood. To investigate this issue, we isolated a series of EMS-induced multiseeded (msd) mutants that result in full spikelet fertility, effectively doubling GNP. Previously, we showed that MSD1 is a TCP (Teosinte branched/Cycloidea/PCF) transcription factor that regulates jasmonic acid (JA) biosynthesis, and ultimately floral sex organ development. Here, we show that MSD2 encodes a lipoxygenase (LOX) that catalyzes the first committed step of JA biosynthesis. Further, we demonstrate that MSD1 binds to the promoters of MSD2 and other JA pathway genes. Together, these results show that a JA-induced module regulates sorghum panicle development and spikelet fertility. The findings advance our understanding of inflorescence development and could lead to new strategies for increasing GNP and grain yield in sorghum and other cereal crops.

Significance

Through a single base pair mutation, grain number can be increased by ~200% in the globally important crop Sorghum bicolor. This mutation affects the expression of an enzyme, MSD2, that catalyzes the jasmonic acid pathway in developing floral meristems. The global gene expression profile in this enzymatic mutant is similar to that of a transcription factor mutant, msd1, indicating that disturbing any component of this regulatory module disrupts a positive feedback loop that occurs normally due to regular developmental perception of jasmonic acid. Additionally, the MSD1 transcription factor is able to regulate MSD2 in addition to other jasmonic acid pathway genes, suggesting that it is a primary transcriptional regulator of this hormone signaling pathway in floral meristems.
Invasion implies substitution in ecological communities with class-structured populations
Authors: Priklopil Tadeas , Lehmann Laurent
Published: September 2019

Long-term evolution of quantitative traits is classically and usefully described as the directional change in phenotype due to the recurrent fixation of new mutations. A formal justification for such continual evolution ultimately relies on the “invasion implies substitution”-principle. Here, whenever a mutant allele causing a small phenotypic change can successfully invade a population, the ancestral (or wild-type) allele will be replaced, whereby fostering gradual phenotypic change if the process is repeated. It has been argued that this principle holds in a broad range of situations, including spatially and demographically structured populations experiencing frequency and density dependent selection under demographic and environmental fluctuations. However, prior studies have not been able to account for all aspects of population structure, leaving unsettled the conditions under which the “invasion implies substitution”-principle really holds. In this paper, we start by laying out a program to explore and clarify the generality of the “invasion implies substitution”-principle. Particular focus is given on finding an explicit and functionally constant representation of the selection gradient on a quantitative trait. Using geometric singular perturbation methods, we then show that the “invasion implies substitution”-principle generalizes to well-mixed and scalar-valued polymorphic multispecies ecological communities that are structured into finitely many demographic (or physiological) classes. The selection gradient is shown to be constant over the evolutionary timescale and that it depends only on the resident phenotype, individual growth-rates, population steady states and reproductive values, all of which are calculated from the resident dynamics. Our work contributes to the theoretical foundations of evolutionary ecology.
Parallel clines in native and introduced ragweed populations are likely due to adaptation
Authors: McGoey Brechann V. , Hodgins Kathryn A. , Stinchcombe John R.
Published: September 2019

As introduced species expand their ranges, they often encounter differences in climate which are often correlated with geography. For introduced species, encountering a geographically variable climate sometimes leads to the re-establishment of clines seen in the native range. However, clines can also be caused by neutral processes, and so it is important to gather additional evidence that population differentiation is the result of selection as opposed to non-adaptive processes. Here, we examine phenotypic and genetic differences in ragweed from the native (North America) and introduced (European) ranges. We used a common garden to assess phenotypic differentiation in size and flowering time in ragweed populations. We found significant parallel clines in flowering time in both North America and Europe. Height and branch number had significant clines in North America and, while not statistically significant, the patterns in Europe were the same. We used SNP data to assess population structure in both ranges and to compare phenotypic differentiation to neutral genetic variation. We failed to detect significant patterns of isolation by distance, geographic patterns in population structure, or correlations between the major axes of SNP variation and phenotypes or latitude of origin. We conclude that the clines seen for flowering time and size are most likely the result of adaptation.
Bridging sensory and language theories of dyslexia: towards a multifactorial model
Authors: O’Brien Gabrielle , Yeatman Jason
Published: September 2019

Competing theories of dyslexia posit that reading disability arises from impaired sensory, phonological, or statistical learning mechanisms. Importantly, many theories posit that dyslexia reflects a cascade of impairments emanating from a “core deficit”. Here we collect a battery of psychophysical and language measures in 106 school-aged children to investigate whether dyslexia is best conceptualized under a core-deficit model, or as a disorder with heterogenous origins. Specifically, by capitalizing on the drift diffusion model to separate sensory encoding from task-related influences on performance in a visual motion discrimination experiment, we show that deficits in motion perception, decision making and phonological processing manifest largely independently. Based on statistical models of how variance in reading skill is parceled across measures of sensory encoding, phonological processing and decision-making, our results challenge the notion that a unifying deficit characterizes dyslexia. Instead, these findings indicate a model where reading skill is explained by several distinct, additive predictors, or risk factors, of reading (dis)ability.

Research Highlights

Our research provides direct evidence that a single-mechanism, or core-deficit, model of dyslexia cannot account for the range of linguistic and sensory outcomes in children.

Individual differences in visual motion processing, perceptual decision making, phonological awareness and rapid naming each account for unique variance in reading skill.

Our data support an additive risk-factor model, in which multiple independent dimensions each confer risk for reading difficulties.
Proteasome-mediated protein degradation resets the cell division cycle and triggers ESCRT-III-mediated cytokinesis in an archaeon
Authors: Risa Gabriel Tarrason , Hurtig Fredrik , Bray Sian , Hafner Anne E. , Harker-Kirschneck Lena , Faull Peter , Davis Colin , Papatziamou Dimitra , Mutavchiev Delyan R. , Fan Catherine , Meneguello Leticia , Pulschen Andre Arashiro , Dey Gautam , Culley Siân , Kilkenny Mairi , Pellegrini Luca , de Bruin Robertus A. M. , Henriques Ricardo , Snijders Ambrosius P , Šarić Anđela , Lindås Ann-Christin , Robinson Nick , Baum Buzz
Published: September 2019

The archaeonSulfolobus acidocaldariusis a relative of eukaryotes known to progress orderly through its cell division cycle despite lacking obvious CDK/cyclin homologues. Here, in exploring the mechanisms underpinning archaeal cell division cycle control, we show that the proteasome ofS. acidocaldarius,like its eukaryotic counterpart, regulates the transition from the end of one cell division cycle to the beginning of the next. Further, we identify the archaeal ESCRT-III homologue CdvB as a key target of the proteasome, and show that state-dependent degradation of CdvB triggers archaeal cell division by allowing constriction of a CdvB1:CdvB2 ESCRT-III division ring. These findings suggest an ancient role for proteasome-mediated degradation in resetting the cell division cycle in both archaea and eukaryotes.
Exposure to the RXR agonist SR11237 in early life causes disturbed skeletal morphogenesis in a rat model
Authors: Dupuis Holly , Pest Michael Andrew , Hadzic Ermina , Vo Thin Xuan , Hardy Daniel B. , Beier Frank
Published: September 2019

Longitudinal bone growth occurs through endochondral ossification (EO), controlled by various signaling molecules. Retinoid X Receptor (RXR) is a nuclear receptor with important roles in cell death, development, and metabolism. However, little is known about its role in EO. In this study, the agonist SR11237 was used to evaluate RXR activation on EO.

Rats given SR11237 from post-natal day 5 to 15 were harvested for micro-computed tomography scanning and histology. In parallel, newborn CD1 mouse tibiae were cultured with increasing concentrations of SR11237 for histological and whole mount evaluation.

RXR agonist-treated rats were smaller than controls, and developed dysmorphia of the growth plate. Cells invading the calcified and dysmorphic growth plate appeared pre-hypertrophic in size and shape corresponding with P57 immunostaining. Additionally, SOX9 positive cells were found surrounding the calcified tissue. The epiphysis of SR11237 treated bones showed increased TRAP staining, and additional TUNEL staining at the osteo-chondral junction. MicroCT revealed morphological disorganization in the long bones of treated animals. Isolated mouse long bones treated with SR11237 grew significantly less than their DMSO controls.

This study demonstrates that stimulation of the RXR receptor causes irregular ossification, premature closure of the growth plate, and disrupted long bone growth in rodent models.
Cas9-mediated gene-editing in the malaria mosquito Anopheles stephensi by ReMOT Control
Authors: Macias Vanessa M. , McKeand Sage , Chaverra-Rodriguez Duverney , Hughes Grant L. , Fazekas Aniko , Pujhari Sujit , Jasinskiene Nijole , James Anthony A. , Rasgon Jason L.
Published: September 2019

Innovative tool development is essential for continued advancement in malaria control and depends on a deeper understanding of the molecular mechanisms that govern transmission of malaria parasites by Anopheles mosquitoes. Targeted disruption of genes in mosquito vectors is a powerful method to uncover the underlying biology of vector-pathogen interactions, and genome manipulation technologies can themselves form the basis of mosquito and pathogen control strategies. However, the embryo injection methods used to genetically manipulate mosquitoes, and in particular Anopheles species, are difficult and inefficient, particularly for non-specialist laboratories. We have adapted a strategy called ReMOT Control (Receptor-mediated Ovary Transduction of Cargo) to deliver the Cas9 ribonucleoprotein complex to adult mosquito ovaries and generate targeted and heritable mutations in the malaria vector Anopheles stephensi. We found that gene editing by ReMOT Control in Anopheles mosquitoes was comparable to the technique in Ae. aegypti and as efficient in editing as standard embryo injections. The adaptation of this technology to Anopheles mosquitoes opens up the power of reverse genetics to malaria vector labs that do not have the equipment or technical expertise to perform embryo injections and establishes the flexibility of ReMOT Control for gene-editing in non-Aedes species.
Exploring consumers’ willingness to eat insects in Italy
Authors: Palmieri Nadia , Perito Maria Angela , Macrì Maria Carmela , Lupi Claudio
Published: September 2019

Purpose

The purpose of this paper is to investigate the main factors that may affect Italian consumers’ willingness to eat insects. Italy is a fairly special case among Western countries: in many Italian regions, there is old traditional food with insects.

Design/methodology/approach

Data come from a sample of 456 consumers living in four Italian regions. The empirical investigation involves several steps: modification of class distributions to obtain a balanced sample; model estimation using the least absolute shrinkage and selection operator; model evaluation using out-of-sample classification performance measures; and estimation of the “effect” of each explanatory variable via average predictive comparisons. The uncertainty associated with the whole procedure is evaluated using the bootstrap.

Findings

The interviewed consumers are generally unwilling to eat insect-based food. However, factors such as previous experience, taste expectations and attitude towards both new food experiences and sustainable food play an important role in shaping individual inclination towards eating insects.

Research limitations/implications

The sample analysed in this study is not representative of the whole national population, as it happens in most papers dealing with entomophagy.

Originality/value

The paper revisits the issue using a relatively large sample and sophisticated statistical methods. The likely average effect of each explanatory variable is estimated and discussed in detail. The results provide interesting insights on how to approach a hypothetical Italian consumer in view of the possible development of a new market for edible insects.
Unbundling dynamic capabilities for inter-organizational collaboration
Authors: Petricevic Olga , Verbeke Alain
Published: September 2019

Purpose

The purpose of this paper is to explore two distinct subsets of dynamic capabilities that need to be deployed when pursuing innovation through inter-organizational activities, respectively, in the contexts of broad networks and specific alliances. The authors draw distinctions and explore potential interdependencies between these two dynamic capability reservoirs, by integrating concepts from the theoretical perspectives they are derived from, but which have until now largely ignored each other – the social network perspective and the dynamic capabilities view.

Design/methodology/approach

The authors investigate nanotechnology-driven R&D activities in the 1995–2005 period for 76 publicly traded firms in the electronics and electrical equipment industry and in the chemicals and pharmaceuticals industry, that applied for 580 nanotechnology-related patents and engaged in 2,459 alliances during the observation period. The authors used zero-truncated Poisson regression as the estimation method.

Findings

The findings support conceptualizing dynamic capabilities as four distinct subsets, deployed for sensing or seizing purposes, and across the two different inter-organizational contexts. The findings also suggest potential synergies between these subsets of dynamic capabilities, with two subsets being more macro-oriented (i.e. sensing and seizing opportunities within networks) and the two other ones more micro-oriented (i.e. sensing and seizing opportunities within specific alliances).

Practical implications

The authors show that firms differ in their subsets of dynamic capabilities for pursuing different types of inter-organizational, boundary-spanning relationships (such as alliances vs broader network relationships), which ultimately affects their innovation performance.

Originality/value

The authors contribute to the growing body of work on dynamic capabilities and firm-specific advantages by unbundling the dynamic capability subsets, and investigating their complex interdependencies for managing different types of inter-organizational linkages. The main new insight is that the “linear model” of generating more innovations through higher inter-firm collaboration in an emerging field paints an erroneous picture of how high innovation performance is actually achieved.
The role of felt obligation to mentor in mentor performance
Authors: Maynard-Patrick Stephanie , Baugh S. Gayle
Published: September 2019

Purpose

The authors introduce a new measure of felt obligation to mentor in order to explore generalized reciprocity in mentoring. The purpose of this paper is to explore whether felt obligation to mentor adds prediction to mentor job performance in combination with mentoring functions provided and mentor-assessed benefits and costs of mentoring.

Design/methodology/approach

Hypotheses were tested in a sample of firefighters in the Southwestern USA using moderated regression analysis.

Findings

Protégé reported mentoring functions provided predicted mentor performance, but neither mentoring benefits nor costs predicted mentor performance. Felt obligation to mentor interacted with mentoring functions reported such that mentor performance was highest when both mentoring functions provided and felt obligation to mentor were high.

Research limitations/implications

The results indicate that the new measure may prove to be of value for exploring generalized reciprocity in mentoring. Further, more research using mentoring benefits and costs is merited. Findings are limited by use of a new measure of felt obligation to mentor as well as the fact that the research was conducted in a setting in which employees were expected to serve as mentors.

Practical implications

Organizations may leverage felt obligation to mentor in order to support effective informal or formal mentoring relationships, whereas focusing on the benefits of mentoring may be a less valuable strategy.

Originality/value

The research offers a new measure to help to understand generalized reciprocity as a motivation to mentor as well as suggesting that more empirical attention should be given to the perceived benefits and costs of mentoring.