bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of disease-specific care certification on clinical outcome and healthcare performance of myocardial infarction in Taiwan
Authors: Liao Hsun-Hsiang , Wang Pa-Chun , Yeh En-Hui , Lin Chii-Jeng , Chao Ting-Hsing
Published: December 2019

Background:

The relationship between certification for specific disease care and clinical outcome was not well known. Previous studies regarding the effect of certification for acute stroke centers were limited by their cross-sectional design. This study aimed to investigate the effect of disease-specific care (DSC) certification on healthcare performance and clinical outcome of acute myocardial infarction (AMI).

Methods:

This retrospective, longitudinal, controlled study was performed by analyzing the nationwide Taiwan Clinical Performance Indicators dataset from 2011 to 2018. Hospitals undergoing DSC certification for coronary care and reporting AMI indicators 1 year before, during, and 1 year after certification were included in group C, whereas hospitals not seeking DSC certification but reporting AMI indicators during the same period were included in group U. The primary endpoint was in-hospital mortality of AMI.

Results:

In total, 20 hospitals (9 in group C and 11 in group U) and up to 16 173 AMI cases were included for analysis. In-hospital mortality was similar between both groups at baseline. However, the in-hospital mortality was significantly improved during and after certification periods in comparison with that at baseline in group C (6.8% vs 8.4%, p = 0.04; 6.7% vs 8.4%, p = 0.02), whereas there was no significant change in group U, resulting in a statistically significant difference between both groups during and after certification periods (odds ratio = 0.74 [95% CI = 0.60-0.91] and 0.78 [95% CI = 0.64-0.96]). Compared with group U, the improvement in healthcare performance indicators, such as door-to-electrocardiography time <10 minutes, blood testing for low-density lipoprotein cholesterol level, prescribing a beta-blockade or a P2Y12 receptor inhibitor during hospitalization, prescribing a statin on discharge, and consultation for cardiac rehabilitation, was significant in group C.

Conclusion:

The current study demonstrated the beneficial effect of DSC certification on clinical outcome of AMI probably mediated through quality improvement during the healthcare process.
A Quality Improvement Project to Increase Patient Portal Enrollment and Utilization in Women Living With HIV at Risk for Disengagement in Care
Authors: Plimpton Erica
Published: December 2019

Women living with HIV are less likely to be retained and engaged in consistent care than their male counterparts. The purpose of this quality improvement project was to increase the enrollment and utilization rate of a patient portal, an mHealth technology, by women living with HIV at risk of disengagement in care to improve their overall engagement and retention in care. At-risk women were identified, educated on, and enrolled in a patient portal system during routine clinic appointments. Engagement was measured using portal utilization rates and patient-initiated communication and analyzed using descriptive statistics. Paired 2-tailed Student t-tests were used to evaluate changes in adherence rates, viral loads, and CD4+ T-cell counts from 90-day pre-enrollment to 90-day post-enrollment. Overall results indicate improved utilization and engagement through the use of a patient portal system are feasible in this population and promote engagement and retention in care.
Usability and Feasibility of an Innovative mLearning Approach for Nurses Providing Option B+ Services in Manica and Sofala Provinces, Mozambique
Authors: Kim Jane , Floriano Florência , De Castro Georgina , Manuel João Luís , Inguane Celso , Asbjornsdottir Kristjana H. , Chale Falume , Zucule Justina , Sherr Kenneth , Gimbel Sarah
Published: December 2019

The scaling of Option B+ services, whereby all pregnant women who test HIV positive are started on lifelong antiretroviral therapy upon diagnosis regardless of CD4 T-cell count, is ongoing in many high HIV burden, low-resource countries. We developed and evaluated a tablet-based mobile learning (mLearning) training approach to build Option B+ competencies in frontline nurses in central Mozambique. Its acceptability and impact on clinical skills were assessed in maternal child health nurses and managers at 20 intervention and 10 control clinics. Results show that skill and knowledge of nurses at intervention clinics improved threefold compared with control clinics (p = .04), nurse managers at intervention clinics demonstrated a 9- to 10-fold improvement, and nurses reported strong acceptance of this approach. “mLearning” is one viable modality to enhance nurses' clinical competencies in areas with limited health workforce and training budgets. This study's findings may guide future scaling and investments in commercially viable mLearning solutions.
Living With Charcot-Marie-Tooth, Charlie, and Change
Authors: Inman Emma
Published: December 2019

Charcot-Marie-Tooth (CMT) is a hereditary condition that affects the myelin sheath of peripheral nerves causing muscle weakness, atrophy, and peripheral neuropathy. This is a firsthand reflection of living with CMT disease from my personal experience and through my family. I hope this provides informative education to practitioners or individuals who may not be familiar with CMT.
Ureteral stents: the good the bad and the ugly
Authors: Lundeen Colin J. , Forbes Connor M. , Wong Victor K.F. , Lange Dirk , Chew Ben H.
Published: December 2019

Purpose of review

Ureteral stents are necessary in the routine practice of an urologist. Choosing the correct stent and being aware of the options available will allow urologists to provide the best possible care for patients and value to the healthcare system. This review seeks to educate urologists regarding improvements in stent technology currently available or in development.

Recent findings

Research from around the world is underway to discover an ideal stent – one that is comfortable for patients, resists infection and encrustation and is affordable for hospital systems. Stent design alterations and stent coatings are revealing reductions in encrustation and bacterial colonization. Biodegradable stents and magnetic stents are being tested to prevent the discomfort of cystoscopic removal. Intraureteral stents are proving efficacious while eliminating an irritating coil from the bladder and the symptoms associated with it.

The studies highlighted in this review provide encouraging results in the pursuit of the ideal stent while opening discussion around new concepts and further areas of research.
Active surveillance in stage 1 disease: standard of care independent of risk factors?
Authors: Nason Gregory J. , Leao Ricardo , Hamilton Robert J.
Published: December 2019

Purpose of review

Approximately 30% of clinical stage 1 (CS1) nonseminomatous germ cell tumours (NSGCT) and 15–20% of CS1 seminoma relapse without adjuvant treatment. Despite this, the 5-year survival for CS1 is 99%. The purpose of this review is to assess if active surveillance should be standard for all patients with CS1 testis cancer independent of risk factors.

Recent findings

Recent data from Princess Margaret Cancer Centre suggest a nonrisk-adapted surveillance approach avoids treatment in ∼70% of patients. Most relapse early at a median time of 7.4 months. The majority of relapses are confined to the retroperitoneum (66%) and only one modality of treatment is required: chemotherapy only in 61% and RPLND only in 73%.

Surveillance is the preferred option and a safe proven strategy for the management of CS1 disease independent of risk factors. The prognosis for CS1 disease is excellent and the decision to offer surveillance or adjuvant treatment needs to highlight the treatment-related morbidity in an otherwise fit and healthy young man.
Readmission Reduction Strategies for Patients Discharged to Skilled Nursing Facilities
Authors: McHugh John P. , Shield Renee R. , Gadbois Emily A. , Winblad Ulrika , Mor Vincent , Tyler Denise A.
Published: December 2019

Background:

Some hospitals seek integration with skilled nursing facilities (SNFs) to reduce readmissions while others focus more on patients discharged home.

Purpose:

Our objective was to understand different approaches for readmission reduction for patients discharged to SNFs based on contrasting strategies from 2 competing hospital systems.

Methods:

Employing a case study methodology, we compared 1 hospital system that integrated with SNFs to a competing system that did not. We compared interview data from clinical and administrative staff and publicly reported rehospitalization rate changes from the 2 systems.

Results:

Analysis of integrating hospital system interviews noted providing patients detailed discharge information and educating SNF staff regarding care protocols. Integrated hospital system all-cause readmission rates declined by nearly 1 percentage point more than the nonintegrated hospital system (coefficient, −0.008; 95% confidence interval, −0.003 to −0.012) between 2014 and 2017.

Conclusion:

As hospitals explore care transition improvements to SNFs, developing more embedded relationships highlights one approach to improve value.
Total Protein Concentration and Tumor Necrosis Factor α in Tears of Nonproliferative Diabetic Retinopathy
Authors: Amil-Bangsa Nurul Hafizah , Mohd-Ali Bariah , Ishak Bashirah , Abdul-Aziz Che Nurul Nabihah , Ngah Nor Fariza , Hashim Hanizasurana , Ghazali Ahmad Rohi
Published: December 2019

SIGNIFICANCE

Total protein concentration (TPC) and tumor necrosis factor α (TNF-α) concentration in tears are correlated with severity of retinopathy. However, minimal data are available in the literature for investigating tear TPC and TNF-α concentrations in Asian individuals with different severity of nonproliferative diabetic retinopathy (NPDR).

PURPOSE

This study evaluated differences of TPC and TNF-α concentrations in tears at different severity of NPDR among participants with diabetes in comparison with normal participants.

METHODS

A total of 75 participants were categorized based on Early Treatment for Diabetic Retinopathy Study scale, with 15 participants representing each group, namely, normal, diabetes without retinopathy, mild NPDR, moderate NPDR, and severe NPDR. All participants were screened using McMonnies questionnaire. Refraction was conducted subjectively. Visual acuity was measured using a LogMAR chart. Twenty-five microliters of basal tears was collected using glass capillary tubes. Total protein concentration and TNF-α concentrations were determined using Bradford assay and enzyme-linked immunosorbent assay, respectively.

RESULTS

Mean ± SD age of participants (n = 75) was 57.88 ± 4.71 years, and participants scored equally in McMonnies questionnaire (P = .90). Mean visual acuity was significantly different in severe NPDR (P = .003). Mean tear TPC was significantly lower, and mean tear TNF-α concentration was significantly higher in moderate and severe NPDR (P < .001). Mean ± SD tear TPC and TNF-α concentrations for normal were 7.10 ± 1.53 and 1.39 ± 0.24 pg/mL; for diabetes without retinopathy, 6.37 ± 1.65 and 1.53 ± 0.27 pg/mL; for mild NPDR, 6.32 ± 2.05 and 1.60 ± 0.21 pg/mL; for moderate NPDR, 3.88 ± 1.38 and 1.99 ± 0.05 pg/mL; and for severe NPDR, 3.64 ± 1.26 and 2.21 ± 0.04 pg/mL, respectively. Tear TPC and TNF-α concentrations were significantly correlated (r = −0.50, P < .0001). Visual acuity was significantly correlated with tear TPC (r = −0.236, P = .04) and TNF-α concentrations (r = 0.432, P < .0001).

CONCLUSIONS

This cross-sectional study identified differences in tear TPC and TNF-α concentrations with increasing severity of NPDR.
EEG in the Pediatric Intensive Care Unit: An Irish Experience
Authors: MacDarby Laura , Healy Martina , Curley Gerard , McHugh John C.
Published: December 2019

Introduction:

Evidence for continuous EEG monitoring in the pediatric intensive care unit (PICU) is increasing. However, 24/7 access to EEG is not routinely available in most centers, and clinical management is often informed by more limited EEG resources. The experience of EEG was reviewed in a tertiary PICU where 24/7 EEG cover is unavailable.

Methods:

Retrospective EEG and clinical review of 108 PICU patients. Correlations were carried out between EEG and clinical variables including mortality. The role of EEG in clinical decision making was documented.

Results:

One hundred ninety-six EEGs were carried out in 108 PICU patients over 2.5 years (434 hours of recording). After exclusion of 1 outlying patient with epileptic encephalopathy, 136 EEGs (median duration, 65 minutes; range, 20 minutes to 4 hours 40 minutes) were included. Sixty-two patients (57%) were less than 12 months old. Seizures were detected in 18 of 107 patients (17%); 74% of seizures were subclinical; 72% occurred within the first 30 minutes of recording. Adverse EEG findings were associated with high mortality. Antiepileptic drug use was high in the studied population irrespective of EEG seizure detection. Prevalence of epileptiform discharges and EEG seizures diminished with increasing levels of sedation.

Conclusions:

EEG provides important diagnostic information in a large proportion of PICU patients. In the absence of 24/7 EEG availability, empirical antiepileptic drug utilization is high.
Extracellular DNA promotes efficient extracellular electron transfer by pyocyanin in Pseudomonas aeruginosa biofilms
Authors: Saunders Scott H. , Tse Edmund C.M. , Yates Matthew D. , Otero Fernanda Jiménez , Trammell Scott A. , Stemp Eric D.A. , Barton Jacqueline K. , Tender Leonard M. , Newman Dianne K.
Published: December 2019

Extracellular electron transfer (EET), the process whereby cells access electron acceptors or donors that reside many cell lengths away, enables metabolic activity by microorganisms, particularly under oxidant-limited conditions that occur in multicellular bacterial biofilms. Although different mechanisms underpin this process in select organisms, a widespread strategy involves extracellular electron shuttles, redox-active metabolites that are secreted and recycled by diverse bacteria. How these shuttles catalyze electron transfer within biofilms without being lost to the environment has been a long-standing question. Here, we show that phenazine electron shuttles mediate efficient EET through interactions with extracellular DNA (eDNA) inPseudomonas aeruginosabiofilms, which are important in nature and disease. Retention of pyocyanin (PYO) and phenazine carboxamide in the biofilm matrix is facilitated by binding to eDNA. In vitro, different phenazines can exchange electrons in the presence or absence of DNA and phenazines can participate directly in redox reactions through DNA; the biofilm eDNA can also support rapid electron transfer between redox active intercalators. Electrochemical measurements of biofilms indicate that retained PYO supports an efficient redox cycle with rapid EET and slow loss from the biofilm. Together, these results establish that eDNA facilitates phenazine metabolic processes inP. aeruginosabiofilms, suggesting a model for how extracellular electron shuttles achieve retention and efficient EET in biofilms.
Xrn1p Acts at Multiple Steps in the Budding-Yeast RNAi Pathway to Enhance the Efficiency of Silencing
Authors: Getz Matthew A. , Weinberg David E. , Drinnenberg Ines A. , Fink Gerald R. , Bartel David P.
Published: December 2019

RNA interference (RNAi) is a gene-silencing pathway that can play roles in viral defense, transposon silencing, heterochromatin formation, and post-transcriptional gene silencing. Although absent fromSaccharomyces cerevisiae, RNAi is present in other budding-yeast species, includingNaumovozyma castellii, which have an unusual Dicer and a conventional Argonaute that are both required for gene silencing. To identify other factors that act in the budding-yeast pathway, we performed an unbiased genetic selection. This selection identified Xrn1p, the cytoplasmic 5′-to-3′ exoribonuclease, as a cofactor of RNAi in budding yeast. Deletion ofXRN1impaired gene silencing inN. castellii, and this impaired silencing was attributable to multiple functions of Xrn1p, including affecting the composition of siRNA species in the cell, influencing the efficiency of siRNA loading into Argonaute, degradation of cleaved passenger strand, and degradation of sliced target RNA.
Out of the Qinghai-Tibetan Plateau and get flourishing - the evolution of Neodon voles (Rodentia: Cricetidae) revealed by systematic sampling and low coverage whole genome sequencing
Authors: Liu Shaoying , Zhou Chengran , Wan Tao , Meng Guanliang , Murphy W. Robert W. , Fan Zhengxin , Tang Mingkun , Liu Yang , Zeng Tao , Chen Shunde , Zhao Yun , Liu Shanlin
Published: December 2019

Neodon, genus of a short time evolutionary history, was reported to be diverged from its relatives in early stage of Pleistocene. Only 4 species were well documented in Neodon for a long period of time until last years when a systematic work described and added three new species, adjusted three species used to belong to Lasiopodomys, Phaiomys, Microtus to Neodon and removed one species (Neodon juldaschi) to genus Blanfordimys, leading to a total of eight species recorded in Neodon. To gain a better insight into the phylogeny and ecology of Neodon, we have systematically sampled Neodon species along the whole Hengduan and Himalayan Mountains in the last 20 years. In addition to morphological identification, we generated 1x - 15x whole genome sequencing (WGS) data and achieved the mitochondrial genomes and an average of 5,382 nuclear genes for each morpho-species. Both morphology and phylogeny results supported an extra six new species in Neodon (nominated Neodon shergylaensis sp. nov., N. namchabarwaensis sp. nov., N. liaoruii sp. nov., N. chayuensis sp. nov., N. bomiensis sp. nov., and N. bershulaensis sp. nov.). This is the first study that included Neodon samples covering its entire distribution area in China and this systematic sampling also revealed a long-time underestimation of Neodon’s diversity, and suggested its speciation events linked highly to founder event via dispersal (from Plateau to surrounding mountains). The results also revealed that the Qinghai-Tibetan Plateau is the center of origin of Neodon, and the impetus of speciation include climate change, isolation of rivers and mountains.
Computational characteristics of the striatal dopamine system described by reinforcement learning with fast generalization
Authors: Fujita Yoshihisa , Yagishita Sho , Kasai Haruo , Ishii Shin
Published: December 2019

Generalization enables applying past experience to similar but nonidentical situations. Therefore, it may be essential for adaptive behaviors. Recent neurobiological observation indicates that the striatal dopamine system achieves generalization and subsequent discrimination by updating corticostriatal synaptic connections in differential response to reward and punishment. To analyze how the computational characteristics in this system affect behaviors, we proposed a novel reinforcement learning model with multilayer neural networks in which the synaptic weights of only the last layer are updated according to the prediction error. We set fixed connections between the input and hidden layers so as to maintain the similarity of inputs in the hidden-layer representation. This network enabled fast generalization, and thereby facilitated safe and efficient exploration in reinforcement learning tasks, compared to algorithms which do not show generalization. However, disturbance in the network induced aberrant valuation. In conclusion, the unique computation suggested by corticostriatal plasticity has the advantage of providing safe and quick adaptations to unknown environments, but on the other hand has the potential defect which can induce maladaptive behaviors like delusional symptoms of psychiatric disorders.

Author summary

The brain has an ability to generalize knowledge obtained from reward- and punishment-related learning. Animals that have been trained to associate a stimulus with subsequent reward or punishment respond not only to the same stimulus but also to resembling stimuli. How does generalization affect behaviors in situations where individuals are required to adapt to unknown environments? It may enable efficient learning and promote adaptive behaviors, but inappropriate generalization may disrupt behaviors by associating reward or punishment with irrelevant stimuli. The effect of generalization here should depend on computational characteristics of underlying biological basis in the brain, namely, the striatal dopamine system. In this research, we made a novel computational model based on the characteristics of the striatal dopamine system. Our model enabled fast generalization and showed its advantage of providing safe and quick adaptation to unknown environments. By contrast, disturbance of our model induced abnormal behaviors. The results suggested the advantage and the shortcoming of generalization by the striatal dopamine system.
Synesthesia does not help to recover perceptual dominance following flash suppression
Authors: Arias Diana Jimena , Saint-Amour Dave
Published: December 2019

Grapheme-color synesthesia is a perceptual phenomenon that occurs when letters or numbers elicit an abnormal color sensation (e.g., printed black letters are perceived as colored graphemes). Grapheme-color synesthesia is typically reported following explicit presentation of graphemes. Very few studies have investigated color sensations in synesthesia in the absence of visual awareness. To address this issue, we took advantage of the dichoptic flash suppression paradigm to temporarily render a stimulus presented to one eye invisible. Synesthesic alphanumeric and non-synesthetic abstract stimuli were presented to 11 synesthete and 11 matched control participants in achromatic and chromatic experimental conditions. The test stimulus was first displayed to one eye and then masked following the sudden presentation of visual noise in the other eye. The time for an image to be perceived following the onset of the suppressive noise was calculated in each condition. Trials free of flash suppression but mimicking the perceptual suppression of the flash were also tested. Results showed that target detection by synesthetes was significantly better than by controls in the absence of flash suppression. However, no statistically significant difference was found between the groups when the test stimulus was interocularly suppressed, either for synesthetic or non-synesthetic stimuli. This study suggests that synesthesia can be associated with enhanced perception for overt recognition, but does not occur in the absence of visual awareness.
A spatio-temporal mathematical model for the dynamics of paclitaxel in cell monolayers
Authors: Proudfoot Isaac , Vallardi Giulia , Shishikura Yoko , Epemolu Ola , Saurin Adrian T. , Ptashnyk Mariya , Murray Philip J.
Published: December 2019

The authors have withdrawn their manuscript due to the discovery of fundamental issues with the implementation of the ODE/PDE model, whose output was shown in Figure 5 of the original version of this paper, rendering the results and conclusion unreliable. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Boron deficiency-induced root growth inhibition is mediated by brassinosteroid signalling regulation inArabidopsis
Authors: Zhang Cheng , He Mingliang , Wang Sheliang , Chu Liuyang , Wang Chuang , Yang Ningmei , Ding Guangda , Cai Hongmei , Shi Lei , Xu Fangsen
Published: December 2019

Brassinosteroid (BR) is a pivotal phytohormone involved in regulating root development. Boron (B) is an essential micronutrient for plant growth and development, and root growth of plants is rapidly inhibited under B deficiency condition, but the mechanisms are still elusive. Here, we demonstrate that BR plays crucial roles in these processes. We identify BR-related processes underlying B deficiency at the physiological, genetic, molecular/cell biological and transcriptome levels, and provide strong evidences that B deficiency can affect BR signalling, thereby altering root growth. RNA-sequencing analysis reveals a high co-regulation between BR-regulated genes and B deficiency-responsive genes. We found that low B negatively regulates BR signalling to control BR signalling-dependent root elongation,bes1-Dexhibits insensitivity to low B stress, andbri1-301mutants fails to respond to B depletion. Exogenous eBL application can rescue the inhibition of root growth under B deficiency condition, and application of BR biosynthesis inhibitor BRZ aggravates root growth inhibition of wild-type under B deficiency condition. B deficiency reduces the nuclear signal of BES1. We further found that B deficiency reduces the accumulation of brassinolide (BL) by reducingBR6ox1andBR6ox2mRNA level to down-regulate BR signalling and modulate root elongation. Altogether, our results uncover a role of BR signalling in root elongation under B deficiency.

One-sentence summary

B deficiency reduces the accumulation of brassinolide by reducingBR6ox1andBR6ox2mRNA level to down-regulate BR signalling and modulate root elongation.
Cavefish cope with environmental hypoxia by developing more erythrocytes and overexpression of hypoxia inducible genes
Authors: van der Weele Corine M. , Jeffery William R.
Published: December 2019

Dark caves lacking primary productivity can expose subterranean animals to hypoxia. We used the surface-dwelling (surface fish) and cave-dwelling (cavefish) morphs of Astyanax mexicanus as a model for understanding the mechanisms of hypoxia tolerance in the cave environment. Primitive hematopoiesis, which is restricted to the posterior lateral mesoderm in other teleosts, also occurs in the anterior lateral mesoderm in Astyanax, potentially pre-adapting surface fish for hypoxic cave colonization. Cavefish have enlarged both hematopoietic domains and develop more erythrocytes than surface fish, which are required for normal development in both morphs. Laboratory induced hypoxia suppresses growth in surface fish but not in cavefish. Both morphs respond to hypoxia by overexpressing Hypoxia-Inducible Factor (HIF) pathway genes, but some hif genes are constitutively upregulated in normoxic cavefish to similar levels as hypoxic surface fish. We conclude that cavefish cope with hypoxia by increasing erythrocyte development and constitutive HIF gene overexpression.

Astyanax mexicanus cavefish cope with hypoxic environments by expanding embryonic hematopoietic domains, increasing the capacity for erythrocyte development, and constitutive overexpression of hypoxia-inducible genes.
Metabolic switching is impaired by aging and facilitated by ketosis independent of glycogen
Authors: Hernandez Abbi R. , Truckenbrod Leah M. , Federico Quinten P. , Campos Keila T. , Moon Brianna M. , Ferekides Nedi , Hoppe Meagan , D’Agostino Dominic , Burke Sara N.
Published: December 2019

The ability to switch between glycolysis and ketosis promotes survival by enabling metabolism through fat oxidation during periods of fasting. Carbohydrate restriction or stress can also elicit metabolic switching. Keto-adapting from glycolysis is delayed in aged rats, but factors mediating this age-related impairment have not been identified. We measured metabolic switching between glycolysis and ketosis, as well as glycogen dynamics, in young and aged rats undergoing time-restricted feeding (TRF) with a standard diet or a low carbohydrate ketogenic diet (KD). TRF alone reversed markers of insulin-related metabolic deficits and accelerated metabolic switching in aged animals. A KD+TRF, however, provided additive benefits on these variables. Remarkably, the ability to keto-adapt was not related to glycogen levels and KD-fed rats showed an enhanced elevation in glucose following epinephrine administration. This study provides new insights into the mechanisms of keto-adaptation demonstrating the utility of dietary interventions to treat metabolic impairments across the lifespan.
Circuit and synaptic organization of forebrain-to-midbrain pathways that promote and suppress vocalization
Authors: Michael Valerie , Goffinet Jack , Pearson John , Wang Fan , Tschida Katherine , Mooney Richard
Published: December 2019

Animals vocalize only in certain behavioral contexts, but the circuits and synapses through which forebrain neurons trigger or suppress vocalization remain unknown. Here we used transsynaptic tracing to identify two populations of inhibitory neurons that lie upstream of neurons in the periaqueductal gray that gate the production of ultrasonic vocalizations in mice (i.e., PAG-USV neurons). Activating PAG-projecting neurons in the preoptic hypothalamus (POAPAGneurons) elicited USV production in the absence of social cues. In contrast, activating PAG-projecting neurons in the central-medial boundary zone of the amygdala (AmgC/M-PAGneurons) transiently suppressed USV production without disrupting non-vocal social behavior. Optogenetics-assisted circuit mapping in brain slices revealed that POAPAGneurons directly inhibit PAG interneurons, which in turn inhibit PAG-USV neurons, whereas AmgC/M-PAGneurons directly inhibit PAG-USV neurons. These experiments identify two major forebrain inputs to the PAG that trigger and suppress vocalization, respectively, while also establishing the synaptic mechanisms through which these neurons exert opposing behavioral effects.
YSL3-mediated copper distribution is required for fertility, grain yield, and size inBrachypodium
Authors: Sheng Huajin , Jiang Yulin , Ishka Maryam Rahmati , Chia Ju-Chen , Dokuchayeva Tatyana , Kavulych Yana , Zavodna Tetiana-Olena , Mendoza Patrick N. , Huang Rong , Smieshka Louisa M. , Woll Arthur R. , Terek Olga I. , Romanyuk Nataliya D. , Zhou Yonghong , Vatamaniuk Olena K.
Published: December 2019

Addressing the looming global food security crisis requires the development of high yielding crops. In this regard, the deficiency for the micronutrient copper in agricultural soils decreases grain yield and significantly impacts a globally important crop, wheat. In cereals, grain yield is determined by inflorescence architecture, flower fertility, grain size and weight. Whether copper is involved in these processes and how it is delivered to the reproductive organs is not well understood. We show that copper deficiency alters not only the grain set but also flower development in both wheat and it’s recognized model,Brachypodium distachyon, We then show that a brachypodium yellow-stripe-like 3 (YSL3) transporter localizes to the phloem and mediates copper delivery to flag leaves, anthers and pistils. Failure to deliver copper to these structures in theysl3CRISPR/Cas9 mutant results in delayed flowering, altered inflorescence architecture, reduced floret fertility, grain number, size, and weight. These defects are rescued by copper supplementation and are complemented by theYSL3cDNA. This new knowledge will help to devise sustainable approaches for improving grain yield in regions where soil quality is a major obstacle for crop production.
Cell type specific gene expression profiling reveals a role for the complement component C3A in neutrophil migration to tissue damage
Authors: Houseright Ruth A. , Rosowski Emily E. , Lam Pui Ying , Tauzin Sebastien JM , Mulvaney Oscar , Dewey Colin N. , Bennin David , Huttenlocher Anna
Published: December 2019

Following acute injury, leukocytes rapidly infiltrate into tissues. For efficient recruitment, leukocytes must sense and respond to signals from both from the damaged tissue and from one another. However, the cell type specific transcriptional changes that influence leukocyte recruitment and wound healing have not been well characterized. In this study, we performed a large-scale translating ribosome affinity purification (TRAP) and RNA sequencing screen in larval zebrafish to identify genes differentially expressed by neutrophils, macrophages, and epithelial cells in the context of wounding. We identified the complement pathway andc3a.1, homologous to the C3A component of human complement, as significantly increased in neutrophils in response to a wound. We report thatc3a.1−/−zebrafish larvae have impaired neutrophil responses to both tail wounds and localized bacterial infections, as well as increased susceptibility to infection due to a neutrophil-intrinsic function of C3A. We further show that C3A enhances migration of human primary neutrophils to IL-8 and thatc3a.1−/−larvae have impaired neutrophil migrationin vivo, and a decrease in neutrophil directed migration speed early after wounding. Together, our findings suggest a role for C3A in mediating efficient neutrophil migration to damaged tissues and support the power of TRAP to identify cell-specific changes in gene expression associated with wound-associated inflammation.
Heme induces innate immune memory
Authors: Jentho Elisa , Novakovic Boris , Ruiz-Moreno Cristian , Kourtzelis Ioannis , Martins Rui , Chavakis Triantafyllos , Soares Miguel Perreira , Kalafati Lydia , Guerra Joel , Roestel Franziska , Bohm Peter , Godmann Maren , Grinenko Tatyana , Eugster Anne , Beretta Martina , Joosten Leo A.B. , Netea Mihai G. , Stunnenberg Hendrik G. , Bauer Michael , Weis Sebastian
Published: December 2019

Trained immunity defines long-lasting adaptive responses of innate immunity, mediated by transcriptional and epigenetic modifications of myeloid cells. Here, we report that labile heme, an alarmin released extracellularily upon tissue damage and hemolysis, induces trained immunity in human and murine primary cells and in mice. Heme-trainning in monocytes is associated with epigenetic and transcriptional profiles that overlap to some extent with those seen in β-glucan-training, the prototype agonist of trained immunity. In sharp contrast to β-glucan training however, heme-training relied on activation of the Syk/JNK-pathway. Heme training in mice was associated with long-lasting expansion of myeloid-biased progenitor cells as well as with altered chromatin accessibility in hematopoietic stem and progenitor cells. Finally, heme-induced training was protective against bacterial sepsis in mice.

In conclusion, we reveal that heme, abona fidealarmin, induces innate immune memory regulating host response to infection.
Natural hybridization reveals incompatible alleles that cause melanoma in swordtail fish
Authors: Powell Daniel L. , Garcia Mateo , Keegan Mackenzie , Reilly Patrick , Du Kang , Díaz-Loyo Alejandra P. , Banerjee Shreya , Blakkan Danielle , Reich David , Andolfatto Peter , Rosenthal Gil , Schartl Manfred , Schumer Molly
Published: December 2019

The establishment of reproductive barriers between populations is the key process that fuels the evolution of new species. A genetic framework for this process was proposed over 80 years ago, which posits “incompatible” interactions between genes that result in reduced survival or reproduction in hybrids. Despite this foundational work, progress has been slow in identifying individual genes that underlie hybrid incompatibilities, with only a handful known to date. Here, we use a combination of approaches to precisely map the genes that drive the development of a melanoma incompatibility in swordtail fish hybrids. We find that one of the genes involved in this incompatibility also causes melanoma in hybrids between distantly related species. Moreover, we show that this melanoma reduces survival in the wild, likely due to progressive degradation of the fin. Together, this work represents only the second case where the genes underlying a vertebrate hybrid incompatibility have been identified and provides the first glimpse into the action of these genes in natural hybrid populations.

One sentence summary

Using a combination of mapping approaches, we identify interacting genes that lead to melanoma in hybrids and characterize their effects in natural hybrid populations.
Sleep-drive reprograms clock neuronal identity through CREB-binding protein induced PDFR expression
Authors: Klose MK , Shaw PJ
Published: December 2019

Neuronal circuits can be re-modeled by Hebbian plasticity, synaptic scaling and, under some circumstances, activity-dependent respecification of cell-surface receptors. Although the impact of sleep on Hebbian plasticity and synaptic scaling are well studied, sleep’s role in receptor respecification remains unclear. We demonstrate that high sleep-pressure quickly reprograms theDrosophilawake-promoting large-ventrolateral clock-neurons to express the Pigment Dispersing Factor receptor. The addition of this signaling input into the circuit is associated with increased waking and early mating success. The respecification of Pigment Dispersing Factor receptor in both young and adult large ventrolateral neurons requires two dopamine receptors and activation of the transcriptional regulatornejire(CREB-binding protein). These data identify receptor-respecification as an important mechanism to sculpt circuit function to match sleep levels with demand.
Experimentally engineered mutations in a ubiquitin hydrolase, UBP-1, modulatein vivoresistance to artemisinin and chloroquine inPlasmodium berghei
Authors: Simwela Nelson V. , Hughes Katie R. , Roberts A. Brett , Rennie Michael T. , Barrett Michael P. , Waters Andrew P.
Published: December 2019

As resistance to artemisinins (current frontline drugs in malaria treatment) emerges in south East Asia (SEA), there is an urgent need to identify the genetic determinants and understand the molecular mechanisms underpinning such resistance. Such insights could lead to prospective interventions to contain resistance and prevent the eventual spread to other malaria endemic regions. Artemisinin reduced susceptibility in SEA has been primarily linked to mutations inP. falciparumKelch13, which is currently widely recognised as a molecular marker of artemisinin resistance. However, 2 mutations in a ubiquitin hydrolase, UBP-1, have been previously associated with artemisinin resistance in a rodent model of malaria and some cases of UBP-1 mutation variants associating with artemisinin treatment failure have been reported in Africa and SEA. Here, CRISPR-Cas9 genome editing and pre-emptive drug pressures was used to test these artemisinin resistance associated mutations in UBP-1 inP. bergheisensitive linesin vivo. The data demonstrate that the V2721F UBP-1 mutation results in artemisinin resistance and some low-level resistance to chloroquine, while the V2752F mutation results in high-level resistance to chloroquine and moderate resistance to artemisinins. Genetic reversal of the V2752F mutation restored chloroquine sensitivity in these mutant lines while simultaneous introduction of both mutations could not be achieved and appears to be lethal. Interestingly, these mutations carry a detrimental growth defect, which would possibly explain their lack of expansion in natural infection settings. This is the first independent, direct experimental evidence on the role of UBP-1 in artemisinin and chloroquine resistance underin vivoconditions.
3D Bioprinting of Architected Hydrogels from Entangled Microstrands
Authors: Kessel B. , Lee M. , Bonato A. , Tinguely Y. , Tosoratti E. , Zenobi-Wong M.
Published: December 2019

Hydrogels are an excellent biomimetic of the extracellular matrix and have found great use in tissue engineering. Nanoporous monolithic hydrogels have limited mass transport, restricting diffusion of key biomolecules. Structured microbead-hydrogels overcome some of these limitations, but suffer from lack of controlled anisotropy. Here we introduce a novel method for producing architected hydrogels based on entanglement of microstrands. The microstrands are mouldable and form a porous structure which is stable in water. Entangled microstrands are useable as bioinks for 3D bioprinting, where they align during the extrusion process. Cells co-printed with the microstrands show excellent viability and augmented matrix deposition resulting in a modulus increase from 2.7 kPa to 780.2 kPa after 6 weeks of culture. Entangled microstands are a new class of bioinks with unprecedented advantages in terms of scalability, material versatility, mass transport, showing foremost outstanding properties as a bioink for 3D printed tissue grafts.
IMMUNE SYSTEM CHALLENGE IMPROVES COGNITIVE-BEHAVIOURAL RESPONSES AND REVERSES MALARIA-INDUCED COGNITIVE IMPAIRMENT IN MICE
Authors: de Sousa Vieira Luciana Pereira , Ribeiro-Gomes Flávia Lima , de Almeida Roberto Farina , e Souza Tadeu Mello , Werneck Guilherme Loureiro , de Souza Diogo Onofre Gomes , Daniel-Ribeiro Cláudio Tadeu
Published: December 2019

Elements of the immune system are necessary for healthy neurocognitive function, and the pattern of the immune response triggered by different exogenous stimuli may induce regulatory or deregulatory signals that can affect nervous functions. Here we investigate the effect of immune stimulation on behavioural parameters in healthy mice and its impact on cognitive sequelae resulting from non-severe experimental malaria. We show that the immune modulation induced by a specific combination of immune stimuli, classically described as capable of inducing a major type 2 immune response, can improve the long-term memory of healthy adult mice and prevent the negative cognitive-behavioural impairments caused by a single episode of mildPlasmodium bergheiANKA malaria. This finding has implications for the development of immunogens as cognitive adjuvants.
Dual RNA-seq in an aphid parasitoid reveals plastic and evolved adaptation to symbiont-conferred resistance
Authors: Dennis Alice B. , Käch Heidi , Vorburger Christoph
Published: December 2019

Coevolving taxa offer the opportunity to study the genetic basis of rapid reciprocal adaptation. We have used experimental evolution to examine adaptation in the parasitoid waspLysiphlebus fabarumto resistance conferred by the protective endosymbiontHamiltonella defensain its aphid hostAphis fabae. To examine a key stage in parasitoid infection, we have used RNA-seq to study gene expression in 4-5 day old parasitoid larvae contained in still living aphids. With this dual RNA-seq we can simultaneously view expression in individual experimentally evolved parasitoids and the aphids that house them. This gives a view of the sweeping changes in both taxa accompanying successful or unsuccessful infections. Among successful larvae, we find that experimentally evolved populations adapted toH. defensa-protected hosts differ in the expression of genes that include putative toxins and genes to cope with stress. These differences remain even when the larvae are developing in aphids possessing no defensive endosymbionts, suggesting that they are genetically based. In contrast, plastic responses between parasitoids reared in hosts with and withoutH. defensaare relatively small. Although aphids rely largely on their secondary endosymbionts for defense against parasitoids, we identify expression differences in aphids housing different parasitoid phenotypes. Together, these results demonstrate that wild parasitoid populations possess the genetic variation for rapid adaptation to host resistance, resulting in genetically based differences in gene expression that increase their success in parasitizing symbiont-protected host aphids.
Active Notch Signaling is Required for Arm Regeneration in a Brittle Star
Authors: Mashanov Vladimir , Akiona Jennifer , Khoury Maleana , Ferrier Jacob , Reid Robert , Machado Denis Jacob , Zueva Olga , Janies Daniel
Published: December 2019

Cell signaling pathways play vital roles in coordinating cellular events in development. For example, the Notch signaling pathway is highly conserved across all multicellular animals and is known to coordinate a multitude of diverse cellular events, including proliferation, differentiation, fate specification, and cell death. Specific functions of the pathway are, however, highly context-dependent and are not well characterized in post-traumatic regeneration. Here, we use a small-molecule inhibitor of the pathway (DAPT) to demonstrate that Notch signaling is required for proper arm regeneration in the brittle starOphioderma brevispina, a highly regenerative member of the phylum Echinodermata. We also employ a transcriptome-wide gene expression analysis to characterize the downstream genes controlled by the Notch pathway in the brittle star regeneration. We demonstrate that arm regeneration involves an extensive crosstalk between the Notch pathway and other cell signaling pathways. In the regrowing arm, Notch regulates the composition of the extracellular matrix, cell migration, proliferation, and apoptosis, as well as components of the innate immune response. We also show for the first time that Notch signaling regulates the activity of several transposable elements. Our data also suggests that one of the possible mechanisms through which Notch sustains its activity in the regenerating tissues is via suppression of Neuralized1.
Intracellular Energy Variability Modulates Cellular Decision-Making Capacity
Authors: Kerr Ryan , Jabbari Sara , Johnston Iain G.
Published: December 2019

Cells are able to generate phenotypic diversity both during development and in response to stressful and changing environments, aiding survival. The biologically and medically vital process of a cell assuming a functionally important fate from a range of phenotypic possibilities can be thought of as a cell decision. To make these decisions, a cell relies on energy dependent pathways of signalling and expression. However, energy availability is often overlooked as a modulator of cellular decision-making. As cells can vary dramatically in energy availability, this limits our knowledge of how this key biological axis affects cell behaviour. Here, we consider the energy dependence of a highly generalisable decision-making regulatory network, and show that energy variability changes the sets of decisions a cell can make and the ease with which they can be made. Increasing intracellular energy levels can increase the number of stable phenotypes it can generate, corresponding to increased decision-making capacity. For this decision-making architecture, a cell with intracellular energy below a threshold is limited to a singular phenotype, potentially forcing the adoption of a specific cell fate. We suggest that common energetic differences between cells may explain some of the observed variability in cellular decision-making, and demonstrate the importance of considering energy levels in several diverse biological decision-making phenomena.
Novel in-frame FLNB deletion causes Larsen syndrome in a three-generation pedigree
Authors: Hickey Scott E. , Koboldt Daniel C. , Mosher Theresa Mihalic , Brennan Patrick , Schmalz Beth A. , Crist Erin , McBride Kim L. , Adler Brent H. , White Peter , Wilson Richard K.
Published: December 2019

A 4-yr-old female with congenital knee dislocations and joint laxity was noted to have a strong maternal family history comprising multiple individuals with knee problems and clubfeet. As the knee issues were the predominant clinical features, clinical testing included sequencing of LMX1B, TBX2, and TBX4, which identified no significant variants. Research genome sequencing was performed in the proband, parents, and maternal grandfather. A heterozygous in-frame deletion in FLNB c. 5468_5470delAGG, which predicts p.(Glu1823del), segregated with the disease. The variant is rare in the gnomAD database, removes a residue that is evolutionarily conserved, and is predicted to alter protein length. Larsen syndrome may present with pathology that primarily involves one joint and thus may be difficult to differentiate clinically from other skeletal dysplasias or arthrogryposis syndromes. The p.(Glu1823del) variant maps to a filamin repeat domain where other disease-causing variants are clustered, consistent with a probable gain-of-function mechanism. It has reportedly been observed in two individuals in the gnomAD database, suggesting that mild presentations of Larsen syndrome, like the individual reported here, may be underdiagnosed in the general population.