bluuebunny/crossref_metadata_2025 huggingface dataset:
Delay in schistosomiasis diagnosis and treatment: a multicenter cohort study in Italy
Authors: Comelli Agnese , Riccardi Niccolò , Canetti Diana , Spinicci Michele , Cenderello Giovanni , Magro Paola , Nicolini Laura Ambra , Marchese Valentina , Zammarchi Lorenzo , Castelli Francesco , Bartoloni Alessandro , Di Biagio Antonio , Caligaris Silvio , Gaiera Giovanni
Published: October 2019

Background

Barriers to access to care, different diagnostic strategies and low awareness remain challenging issues in the fight against schistosomiasis.

Our study aims to examine management of schistosomiasis in migrants attending large tertiary hospitals in Italy, in order to call for a comprehensive approach.

Methods

A retrospective review of schistosomiasis cases was carried out between January 1, 2016, and December 31, 2017, in five large Infectious Disease Centers in Italy. We included all patients diagnosed with schistosomiasis. We differentiated among (i) asymptomatic patients diagnosed by serology either as healthy ‘migrant evaluation’ or as ‘late evaluation’ in patients followed because of a different infection and (ii) patients tested because of a suggestive clinical presentation. Patients characteristics and clinical data were recorded.

Results

One hundred forty-nine patients were included, 137 (91.9%) were male, the median age was 26 years and 70% of them came from Sub-Saharan Africa.

Thirty-eight asymptomatic patients (25.5%) were diagnosed by serology [15, (10.1%) among ‘migrant evaluation’ and 23 (15.4%) among ‘late evaluation’ group], and 111 (74.5%) presented with signs/symptoms.

The median diagnostic delay from arrival in Italy was 31 months: 110 for asymptomatic group and 16 months for symptomatic patients. Among the 111 symptomatic patients, 41 individuals were already followed in our clinics, and they never underwent screening before appearance of evident disease. Among patients with positive serology who were tested by microscopy, 32/86 (37.2%) had confirmed diagnosis. Forty-five (37.8%) patients presented radiologic abnormalities. Praziquantel was the treatment of choice (70.1% for 3 days and 29.9% in a single-day dose), and 77 (51.7%) were lost to follow-up.

Conclusions

In our centers, a high proportion of patients were tested late after arrival, and most of them presented with clinical apparent disease. Well-defined strategies and implementation of recent guidelines are needed to improve early diagnosis and to overcome heterogeneity of practice.
PmiREN: a comprehensive encyclopedia of plant miRNAs
Authors: Guo Zhonglong , Kuang Zheng , Wang Ying , Zhao Yongxin , Tao Yihan , Cheng Chen , Yang Jing , Lu Xiayang , Hao Chen , Wang Tianxin , Cao Xiaoyan , Wei Jianhua , Li Lei , Yang Xiaozeng
Published: October 2019

MicroRNAs (miRNAs) are small non-coding RNA molecules that function as diverse endogenous gene regulators at the post-transcriptional level. In the past two decades, as research effort on miRNA identification, function and evolution has soared, so has the demand for miRNA databases. However, the current plant miRNA databases suffer from several typical drawbacks, including a lack of entries for many important species, uneven annotation standards across different species, abundant questionable entries, and limited annotation. To address these issues, we developed a knowledge-based database called Plant miRNA Encyclopedia (PmiREN, http://www.pmiren.com/), which was based on uniform processing of sequenced small RNA libraries using miRDeep-P2, followed by manual curation using newly updated plant miRNA identification criteria, and comprehensive annotation. PmiREN currently contains 16,422 high confidence novel miRNA loci in 88 plant species and 3,966 retrieved from miRBase. For every miRNA entry, information on precursor sequence, precursor secondary structure, expression pattern, clusters and synteny in the genome, potential targets supported by Parallel Analysis of RNA Ends (PARE) sequencing, and references is attached whenever possible. PmiREN is hierarchically accessible and has eight built-in search engines. We believe PmiREN is useful for plant miRNA cataloguing and data mining, therefore a resource for data-driven miRNA research in plants.
Database resources of the National Center for Biotechnology Information
Authors: Sayers Eric W , Beck Jeff , Brister J Rodney , Bolton Evan E , Canese Kathi , Comeau Donald C , Funk Kathryn , Ketter Anne , Kim Sunghwan , Kimchi Avi , Kitts Paul A , Kuznetsov Anatoliy , Lathrop Stacy , Lu Zhiyong , McGarvey Kelly , Madden Thomas L , Murphy Terence D , O’Leary Nuala , Phan Lon , Schneider Valerie A , Thibaud-Nissen Françoise , Trawick Bart W , Pruitt Kim D , Ostell James
Published: October 2019

The National Center for Biotechnology Information (NCBI) provides a large suite of online resources for biological information and data, including the GenBank® nucleic acid sequence database and the PubMed database of citations and abstracts published in life science journals. The Entrez system provides search and retrieval operations for most of these data from 35 distinct databases. The E-utilities serve as the programming interface for the Entrez system. Custom implementations of the BLAST program provide sequence-based searching of many specialized datasets. New resources released in the past year include a new PubMed interface, a sequence database search and a gene orthologs page. Additional resources that were updated in the past year include PMC, Bookshelf, My Bibliography, Assembly, RefSeq, viral genomes, the prokaryotic genome annotation pipeline, Genome Workbench, dbSNP, BLAST, Primer-BLAST, IgBLAST and PubChem. All of these resources can be accessed through the NCBI home page at www.ncbi.nlm.nih.gov.
Human RAD51 paralogue RAD51C fosters repair of alkylated DNA by interacting with the ALKBH3 demethylase
Authors: Mohan Monisha , Akula Deepa , Dhillon Arun , Goyal Arun , Anindya Roy
Published: October 2019

The integrity of our DNA is challenged daily by a variety of chemicals that cause DNA base alkylation. DNA alkylation repair is an essential cellular defence mechanism to prevent the cytotoxicity or mutagenesis from DNA alkylating chemicals. Human oxidative demethylase ALKBH3 is a central component of alkylation repair, especially from single-stranded DNA. However, the molecular mechanism of ALKBH3-mediated damage recognition and repair is less understood. We report that ALKBH3 has a direct protein-protein interaction with human RAD51 paralogue RAD51C. We also provide evidence that RAD51C–ALKBH3 interaction stimulates ALKBH3-mediated repair of methyl-adduct located within 3′-tailed DNA, which serves as a substrate for the RAD51 recombinase. We further show that the lack of RAD51C–ALKBH3 interaction affects ALKBH3 function in vitro and in vivo. Our data provide a molecular mechanism underlying upstream events of alkyl adduct recognition and repair by ALKBH3.
BBCancer: an expression atlas of blood-based biomarkers in the early diagnosis of cancers
Authors: Zuo Zhixiang , Hu Huanjing , Xu Qingxian , Luo Xiaotong , Peng Di , Zhu Kaiyu , Zhao Qi , Xie Yubin , Ren Jian
Published: October 2019

The early detection of cancer holds the key to combat and control the increasing global burden of cancer morbidity and mortality. Blood-based screenings using circulating DNAs (ctDNAs), circulating RNA (ctRNAs), circulating tumor cells (CTCs) and extracellular vesicles (EVs) have shown promising prospects in the early detection of cancer. Recent high-throughput gene expression profiling of blood samples from cancer patients has provided a valuable resource for developing new biomarkers for the early detection of cancer. However, a well-organized online repository for these blood-based high-throughput gene expression data is still not available. Here, we present BBCancer (http://bbcancer.renlab.org/), a web-accessible and comprehensive open resource for providing the expression landscape of six types of RNAs, including messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), microRNAs (miRNAs), circular RNAs (circRNAs), tRNA-derived fragments (tRFRNAs) and Piwi-interacting RNAs (piRNAs) in blood samples, including plasma, CTCs and EVs, from cancer patients with various cancer types. Currently, BBCancer contains expression data of the six RNA types from 5040 normal and tumor blood samples across 15 cancer types. We believe this database will serve as a powerful platform for developing blood biomarkers.
GenBank
Authors: Sayers Eric W , Cavanaugh Mark , Clark Karen , Ostell James , Pruitt Kim D , Karsch-Mizrachi Ilene
Published: October 2019

GenBank® (www.ncbi.nlm.nih.gov/genbank/) is a comprehensive, public database that contains over 6.25 trillion base pairs from over 1.6 billion nucleotide sequences for 450 000 formally described species. Daily data exchange with the European Nucleotide Archive (ENA) and the DNA Data Bank of Japan (DDBJ) ensures worldwide coverage. Recent updates include a new version of Genome Workbench that supports GenBank submissions, new submission wizards for viral genomes, enhancements to BankIt and improved handling of taxonomy for sequences from pathogens.
Preclinical and clinical relevance of probiotics and synbiotics in colorectal carcinogenesis: a systematic review
Authors: Cruz Bruna C S , Sarandy Mariáurea M , Messias Anny C , Gonçalves Reggiani V , Ferreira Célia L L F , Peluzio Maria C G
Published: October 2019

Context

Recent evidence suggests that modulation of the gut microbiota may help prevent colorectal cancer.

Objective

The aim of this systematic review was to investigate the role of probiotics and synbiotics in the prevention of colorectal cancer and to clarify potential mechanisms involved.

Data Sources

The PubMed, ScienceDirect, and LILACS databases were searched for studies conducted in humans or animal models and published up to August 15, 2018.

Study Selection

Clinical trials and placebo-controlled experimental studies that evaluated the effects of probiotics and synbiotics in colorectal cancer and cancer associated with inflammatory bowel disease were included. Of 247 articles identified, 31 remained after exclusion criteria were applied. A search of reference lists identified 5 additional studies, for a total of 36 included studies.

Data Extraction

Two authors independently assessed risk of bias of included studies and extracted data. Data were pooled by type of study, ie, preclinical or clinical.

Results

The results showed positive effects of probiotics and synbiotics in preventing colorectal cancer. The main mechanisms identified were alterations in the composition and metabolic activity of the intestinal microbiota; reduction of inflammation; induction of apoptosis and inhibition of tumor growth; modulation of immune responses and cell proliferation; enhanced function of the intestinal barrier; production of compounds with anticarcinogenic activity; and modulation of oxidative stress.

Conclusions

Probiotics or synbiotics may help prevent colorectal cancer, but additional studies in humans are required to better inform clinical practice.
A provincial assessment of readiness for paediatric emergencies: What are the existing resource gaps in Alberta?
Authors: Stys Dana , Landry Kerri , Mitra Tatum , Grant Vincent
Published: October 2019

Objectives

A large proportion of all emergency visits for paediatric patients across Canada are to general emergency departments (EDs). These centres may not be adequately equipped to provide optimal care for high acuity paediatric emergencies. The objective of this study was to determine paediatric readiness for general EDs and urgent care centres (UCCs) across Alberta and provide each centre with an overall weighted Paediatric Readiness Score (WPRS).

Methods

A paediatric readiness assessment consisting of 55-questions normalized on a 100-point scale was used to survey 107 general EDs, UCCs, and tertiary paediatric EDs in Alberta, Canada. It addresses six primary categories, including Coordination of Patient Care, Physician/Nurse Staffing and Training, Quality Improvement Activities, Patient Safety Initiatives, Policies and Procedures, and Equipment and Supplies. Descriptive statistics were used to present the WPRS score among different groups. Linear regression models were used to explore factors associated with the score.

Results

The overall response rate was 59.8%. The median overall WPRS (/100) for all general EDs and UCCs was 48.4 ([interquartile range {IQR}] 17.6). Factors that were correlated with overall score included high paediatric patient volume (24.28, 95% confidence interval [CI]: 10.52 to 38.04) and involvement in a simulation education outreach program (9.38, 95% CI: 1.11 to 17.66).

Conclusion

Based on this survey, the WPRS of EDs and UCCs across Alberta suggest a need to improve readiness to respond to high acuity paediatric emergencies in these settings.
Type 2 Diabetes Affects Joint Pain Severity in People with Localized Osteoarthritis: A Retrospective Study
Authors: Alenazi Aqeel M , Obaidat Sakher M , Alshehri Mohammed M , Alothman Shaima , Gray Corey , Rucker Jason , Waitman Lemuel R , Kluding Patricia M
Published: October 2019

Objective

To examine the association between type 2 diabetes (T2D) and pain severity in people with localized osteoarthritis (OA) and to explore the association between glycemic control, measured by hemoglobin A1c (HbA1c) level, and pain severity in people with localized OA and T2D.

Design

Retrospective study.

Setting

A tertiary medical center.

Subjects

Data from 819 patients (mean age = 65.08±9.77 years, 54.3% women) were used.

Methods

Patients were grouped to localized OA only (N = 671) and localized OA+T2D (N = 148) based on diagnosis codes. An index date was set as the first diagnosis date of localized OA and linked to pain severity, measured by numeric rating scale from 0 to 10. HbA1c values were obtained for patients with T2D within six months of the index date. Multiple linear regression was used.

Results

After controlling for age, gender, body mass index (BMI); diagnoses of depression, hypertension, dyslipidemia; OA locations; and medication list (+/- 90 days of the index date), T2D was significantly associated with increased pain severity (B = 1.07, 95% confidence interval [CI] = 0.25 to 1.88, P = 0.014). For patients with T2D and localized OA with available data for HbA1c (N = 87), the results showed that an increased HbA1c value was significantly associated with higher pain severity (B = 0.36, 95% CI = 0.036 to 0.67, P = 0.029) after controlling for age, gender, BMI, medications, and OA locations.

Conclusion

T2D was associated with higher pain severity in people with localized OA, and poor glycemic control was associated with higher pain severity in people with localized OA+T2D. Clinicians should emphasize that better HbA1c control might help with pain management in people with T2D and OA.
Providing Value in Fracture Care: Academic Versus Private Setting
Authors: Lundy Douglas W. , Jahangir A. Alex
Published: October 2019

Although the science of fracture care transcends the setting, the delivery of value may be dramatically different depending on the practice situation. Compared to our colleagues specializing in total joint arthroplasty, trauma surgeons have a greater challenge demonstrating increased quality relative to the cost of care. Although most orthopedic surgeons are in private practice, their individual practice settings vary significantly. Generally speaking, private groups with dynamic and forward-thinking leadership can seize opportunity to increase value in fracture care, and nimble action can improve value for the patient and the practice. Academic medical centers have synergies to enhance integrated medical care, and the tripartite mission of education, research and patient care lend themselves to increasing value. In either setting, leadership in orthopedic surgery can enhance value in fracture care.
Value Denominator: The Fundamentals of Costing for Orthopaedic Surgeons
Authors: Parikh Harsh R. , O'Hara Nathan , Levy Joseph F. , Cunningham Brian P.
Published: October 2019

In any discipline, improving quality and efficiency of services acts as a unifying goal. In health care, the goal of achieving high-value care is the new doctrine for all individual entities: payors, providers, and patients. Value is defined as the ratio of outcomes to costs incurred. Therefore, a strong understanding and interpretation of cost measures is crucial to accurately deriving health care value. Health care costing is not simply limited to the costs of implants or the procedure but the costs required to deliver treatment throughout the episode of care. Consequently, physicians serve a keystone role toward driving change in health care costs and initiate high-value care practices. However, physicians require a better understanding of health care costs and institutional accounting practices. To this effort, it is critical that health care providers begin to close the knowledge gap around health care costing and provide leadership when advocating for high-value patient care. This review is purposed to provide a basic review of fundamental components for health care economics, deciphering health care costing, and preview current strategies that prioritize high-value patient care.
Does Value Matter in Orthopaedic Trauma?: A Survey of Orthopaedic Trauma Association Members
Authors: Gorman Tiffany L. , S. Albersheim Melissa , Parikh Harsh R. , Flagstad Ilexa R. , Okelana A. Bandele , Vang Sandy , Johal Herman , Cunningham Brian P.
Published: October 2019

Objectives:

With value-based payment models on the horizon, this study was designed to examine the perceptions of value-based care among orthopaedic traumatologists and how they influence their practice.

Design:

Systems-based survey study.

Setting:

Orthopaedic Trauma Association (OTA) research surveys.

Participants:

OTA members.

Main Outcome Measure:

Thirty-eight–question surveys focusing on 5 areas related to value-based care: understanding value, assessing interest, barriers, perceptions around implementing value-based strategies, and policy.

Results:

Of 1106 OTA members, 252 members responded for a response rate of 22.7%. Consideration around cost was not different between hospital, academic, and private practice settings (P = 0.47). Previous reported experience in finance increased the amount surgical decision-making was influenced by cost (P < 0.01), along with reported understanding of implant costs (P < 0.01). Over half of the respondents (59.4%) believed value-based payments are coming to orthopaedic trauma. The vast majority (88.5%) believed bundled payments would be unsuccessful or only partially successful. With respect to barriers, a third of respondents (34.7%) indicated accurate cost data prevented the implementation of programs that track and maximize value, another third (31.5%) attributed it to a limited ability to collect patient-reported outcomes, and the rest (33.8%) were split between lack of institutional interest and access to funding.

Conclusion:

Our study indicated the understanding of value in orthopaedic trauma is limited and practice integration is rare. Reported experience in finance was the only factor associated with increased consideration of value-based care in practice. Our results highlight the need for increased exposure and resources to changing health care policy, specifically for orthopaedic traumatologists.

Level of Evidence:

Level V. See Instructions for Authors for a complete description of levels of evidence.
Variation in Implant Selection for Ankle Fractures: Identifying Cost Drivers
Authors: Okelana A. Bandele , McMillan Logan J. , Kibble Kendra , Parikh Harsh R. , Gorman Catlea , Schaefbauer Heather , Cunningham Brian P.
Published: October 2019

Background:

Implant selection is the first opportunity for surgeons to control costs of fracture fixation. The current literature has demonstrated surgeons' poor understanding of implant costs. Our study evaluated implant cost variability for surgically treated ankle fractures and distal tibia fractures. Our hypothesis was that significant cost variation exists among providers. The goal was to identify cost drivers and determine whether specialty training is linked to implant selection.

Methods:

A retrospective 2010–2017 chart review was performed for 1281 patients at a Level I trauma center. Patients were excluded for skeletal immaturity, open fractures, polytrauma, and concurrent surgeries. Variables were assessed included age, sex, body mass index, OTA/AO classification, Weber classification, 1-year reoperation status, surgeon specialty, and use of syndesmotic screws, locking plates, and cannulated screws. Construct cost was determined by using electronic medical record implant model numbers cross-referenced with the chargemaster database. Statistical analysis involved intergroup comparative tests, regression analysis, and goodness-of-fit analyses.

Results:

Implant cost was different among OTA patterns (P < 0.01), highest among 43C ($3771) and lowest with 44A ($819). Construct costs of OTA 43 fractures varied from $2568 to 3771, whereas OTA 44 ranged from $819 to $1474. Costs were comparable across Weber patterns (P = 0.15), with Weber B having the highest ($1494). Costs were highest among reconstructive, podiatry, and spine surgeons, with mean costs of $1804, $1404, and $1396, respectively. Traumatologist constructs had the lowest overall price ($987). A total of 433 (33.8%) procedures used locking plates with 512 (40.0%) using at least one cannulated screw. Locking plates averaged a larger total implant cost ($1947) than nonlocking plates ($1313) but had a comparable reoperation rate (18.5% vs. 17.7%, P = 0.81). Use of a cannulated screw presented a higher total cost ($2008 vs. $1435) with comparable reoperation rates (17.4% vs. 18.8%, P = 0.72). A total of 401 (31.5%) patients received syndesmotic fixation and a significantly higher reoperation rate (17.0% vs. 11.0%, P < 0.01). Overall, 199 patients underwent elective hardware removal, 23 were infected, 7 required revision, and 3 were identified with a nonunion.

Conclusions:

Our study demonstrated significant variability in implant costs for ankle fracture fixation and identified the key cost drivers as locking plates and cannulated screws. Surgical management of ankle fractures could be an ideal setting to pilot economic alignment between physicians and hospitals to drive value.

Level of Evidence:

Level III. Retrospective Cohort.
Treatment Failures of Direct Oral Anticoagulants
Authors: Kajy Marvin , Mathew Anil , Ramappa Preeti
Published: October 2019

Background:

Use of direct oral anticoagulants (DOACs) has increased over the years, because they have become a safe and effective alternative to the Vitamin-K antagonists in various clinical scenarios. With their increased use, reports have emerged describing their failure.

Study Question:

What are the patient characteristics and clinical settings in which DOAC treatment failure manifests?

Data Sources:

We searched published reports in Google Scholar, PubMed, MEDLINE, and Embase from the introduction of DOACs in any therapy until March 2019.

Study Design:

Information on patient characteristics, comorbidities, primary anticoagulation indications, pharmacologic treatment, and outcomes were collected. Primary endpoints were new thrombus formation, failure of resolution of an existing thrombus, or discovery of subtherapeutic drug level. Other endpoints were time to treatment failure, manifestations of treatment failure, and new treatment after DOAC failure.

Results:

Our search yielded 51 manuscripts, describing 79 patients who exhibited DOAC failure. The most common treatment failures were in patients with antiphospholipid syndrome (44.3%), atrial fibrillation (30.4%), and deep venous thrombosis (6.3%). There was a trend toward higher failure rate for rivaroxaban (65.8%) followed by dabigatran (27.8%), apixaban (7.6%), and then edoxaban (1.3%). Each agent had different median failure times. Most common manifestations of treatment failure were stroke/transient ischemic attack (20.3%), pulmonary embolism (19.0%), and deep venous thrombosis (19.0%). More than half of patients were transitioned to a Vitamin-K antagonist after DOAC failure (55.7%).

Conclusions:

Our analysis illustrates that DOACs may fail in the setting of Food and Drug Administration and non–Food and Drug Administration- approved indications. In clinical practice, it may be best to choose between available anticoagulant drugs on a case-by-case basis.
Acoustic crypsis in communication by North Atlantic right whale mother–calf pairs on the calving grounds
Authors: Parks Susan E. , Cusano Dana A. , Van Parijs Sofie M. , Nowacek Douglas P.
Published: October 2019

Mammals with dependent young often rely on cryptic behaviour to avoid detection by potential predators. In the mysticetes, large baleen whales, young calves are known to be vulnerable to direct predation from both shark and orca predators; therefore, it is possible that mother–calf pairs may show cryptic behaviours to avoid the attention of predators. Baleen whales primarily communicate through low-frequency acoustic signals, which can travel over long ranges. In this study, we explore the potential for acoustic crypsis, a form of cryptic behaviour to avoid predator detection, in North Atlantic right whale mother–calf pairs. We predicted that mother–calf pairs would either show reduced calling rates, reduced call amplitude or a combination of these behavioural modifications when compared with other demographic groups in the same habitat. Our results show that right whale mother–calf pairs have a strong shift in repertoire usage, significantly reducing the number of higher amplitude, long-distance communication signals they produced when compared with juvenile and pregnant whales in the same habitat. These observations show that right whale mother–calf pairs rely upon acoustic crypsis, potentially to minimize the risk of acoustic eavesdropping by predators.
Microbes and macro-invertebrates show parallel β-diversity but contrasting α-diversity patterns in a marine natural experiment
Authors: Rapacciuolo Giovanni , Beman J. Michael , Schiebelhut Lauren M. , Dawson Michael N.
Published: October 2019

Documenting ecological patterns across spatially, temporally and taxonomically diverse ecological communities is necessary for a general understanding of the processes shaping biodiversity. A major gap in our understanding remains the comparison of diversity patterns across a broad spectrum of evolutionarily and functionally diverse organisms, particularly in the marine realm. Here, we aim to narrow this gap by comparing the diversity patterns of free-living microbes and macro-invertebrates across a natural experiment provided by the marine lakes of Palau: geographically discrete and environmentally heterogeneous bodies of seawater with comparable geological and climatic history, and a similar regional species pool. We find contrasting patterns of α-diversity but remarkably similar patterns of β-diversity between microbial and macro-invertebrate communities among lakes. Pairwise dissimilarities in community composition among lakes are positively correlated between microbes and macro-invertebrates, and influenced to a similar degree by marked gradients in oxygen concentration and salinity. Our findings indicate that a shared spatio-temporal and environmental context may result in parallel patterns of β-diversity in microbes and macro-invertebrates, in spite of key trait differences between these organisms. This raises the possibility that parallel processes also influence transitions among regional biota across the tree of life, at least in the marine realm.
Experimental evidence that intruder and group member attributes affect outgroup defence and associated within-group interactions in a social fish
Authors: Braga Goncalves Ines , Radford Andrew N.
Published: October 2019

In many social species, individuals communally defend resources from conspecific outsiders. Participation in defence and in associated within-group interactions, both during and after contests with outgroup rivals, is expected to vary between group members because the threat presented by different outsiders is not the same to each individual. However, experimental tests examining both the contributions to, and the consequences of, outgroup conflict for all group members are lacking. Using groups of the cichlid
Neolamprologus pulcher
, we simulated territorial intrusions by different-sized female rivals and altered the potential contribution of subordinate females to defence. Dominant females and subordinate females defended significantly more against size- and rank-matched intruders, while males displayed lower and less variable levels of defence. Large and small, but not intermediate-sized, intruders induced increased levels of within-group aggression during intrusions, which was targeted at the subordinate females. Preventing subordinate females from helping in territorial defence led to significant decreases in post-contest within-group and female-specific submissive and affiliative displays. Together, these results show that the defensive contributions of group members vary greatly depending both on their own traits and on intruder identity, and this variation has significant consequences for within-group social dynamics both during and in the aftermath of outgroup contests.
A continuum of biological adaptations to environmental fluctuation
Authors: Liu Ming , Rubenstein Dustin R. , Liu Wei-Chung , Shen Sheng-Feng
Published: October 2019

Bet-hedging—a strategy that reduces fitness variance at the expense of lower mean fitness among different generations—is thought to evolve as a biological adaptation to environmental unpredictability. Despite widespread use of the bet-hedging concept, most theoretical treatments have largely made unrealistic demographic assumptions, such as non-overlapping generations and fixed or infinite population sizes. Here, we extend the concept to consider overlapping generations by defining bet-hedging as a strategy with lower variance and mean per capita growth rate across different environments. We also define an opposing strategy—the rising-tide—that has higher mean but also higher variance in per capita growth. These alternative strategies lie along a continuum of biological adaptions to environmental fluctuation. Using stochastic Lotka–Volterra models to explore the evolution of the rising-tide versus bet-hedging strategies, we show that both the mean environmental conditions and the temporal scales of their fluctuations, as well as whether population dynamics are discrete or continuous, are crucial in shaping the type of strategy that evolves in fluctuating environments. Our model demonstrates that there are likely to be a wide range of ways that organisms with overlapping generations respond to environmental unpredictability beyond the classic bet-hedging concept.
Role of CRF receptor 1 antagonism in the bed nucleus of the stria terminalis of male rats after intermittent social defeat stress
Authors: Vasconcelos Mailton , Stein Dirson J. , Gallas-Lopes Matheus , Landau Luane , Behrens Luiza , Albrechet-Souza Lucas , Miczek Klaus A. , de Almeida Rosa Maria M.
Published: October 2019

We recently demonstrated that the experience of brief episodes of social defeat caused impairments in social behaviors. Moreover, we provided evidence that the antagonism of corticotropin-releasing factor binding protein (CRFBP) in the bed nucleus of the stria terminalis (BNST) restored social approach in stressed animals. This study aimed to test the relation between corticotropin-releasing factor receptor type 1 (CRFR1) located in the BNST and the establishment of social stress-disrupted behaviors in rats submitted to social defeat in the resident-intruder paradigm. Animals were tested for sweet solution preference, subjected to the elevated-plus maze (EPM), and to the social interaction three-chamber test. Social behavior was tested after BNST drug infusions. The drug used in this study was a CRF receptor 1 antagonist, CP376395 (CP), administered in two doses: 50 ng/0.20 μL/side, and 500 ng/0.20 μL/side. Saline solution was used as vehicle and administered 0.20 μL/side. Socially stressed animals (n = 11) did not differ compared to control animals (n = 11) in the EPM. Stressed animals displayed impaired social behavior, represented by a decrease in time spent in the interaction zone. The lower dose (CP 50 ng/0.20 μL/side) administered intra-BNST restored social behaviors in stressed animals. On the other hand, the higher dose of the CRFR1 antagonist (CP 500 ng/0.20 μL/side) induced social avoidance in rats without a history of agonistic confrontations. These findings implicate BNST CRFR1 signaling in the modulation of social behaviors in rats given the choice to explore an unfamiliar conspecific.
Estrogen Drives Melanocortin Neurons To Increase Spontaneous Activity and Reduce Sedentary Behavior
Authors: Krause William C. , Rodriguez Ruben , Gegenhuber Bruno , Matharu Navneet , Rodriguez Andreas N. , Padilla-Roger Adriana M. , Toma Kenichi , Herber Candice B. , Correa Stephanie M. , Duan Xin , Ahituv Nadav , Tollkuhn Jessica , Ingraham Holly A.
Published: October 2019

Estrogen depletion in rodents and humans leads to inactivity, unhealthy fat accumulation, and diabetes1,2, underscoring the conserved metabolic benefits of estrogen that inevitably decline with aging. In rodents, the preovulatory surge in 17β-estradiol (E2) temporarily allows energy expenditure to outpace energy intake, thus coordinating increased physical activity with peak sexual receptivity. To investigate how estrogen rebalances energy allocation in females, we examine estrogen receptor alpha (ERα) signaling in the ventrolateral ventromedial hypothalamic nucleus (VMHvl)3–7. We uncover a small population of VMHvlERα neurons expressing the melanocortin-4 receptor (MC4R) that integrates estrogen and melanocortin signals and projects to arousal centers in the hippocampus and hindbrain, enabling bursts of physical activity. ERα recruitment to the Mc4r gene promotes upregulation of Mc4r in VMHvl neurons during the preovulatory surge or following E2 treatment. We leveraged three models to stimulate VMHvlMC4R neurons, restore MC4R signaling in the VMHvl of hyperphagic MC4R null females, or increase Mc4r levels in the VMHvl by CRISPR-mediated activation. All models increase spontaneous activity, whereas silencing VMHvlMC4R neurons blunts normal activity. Direct activation of the VMHvlMC4R node overrides the inactivity and hypometabolism following hormone depletion. These data extend the impact of MC4R signaling – the most common cause of monogenic human obesity8 – beyond the regulation of food intake. Our findings also rationalize reported sex differences in melanocortin signaling, including the greater disease severity of MC4R insufficiency in women9. The hormone-dependent node identified here illuminates the power of estrogen in motivating behavior during the female reproductive cycle and for maintaining an active lifestyle.
Freewater EstimatoR using iNtErpolated iniTialization (FERNET): Toward Accurate Estimation of Free Water in Peritumoral Region Using Single-Shell Diffusion MRI Data
Authors: Ould Ismail Abdol Aziz , Parker Drew , Hernandez-Fernandez Moises , Wolf Ronald , Brem Steven , Alexander Simon , Hodges Wes , Pasternak Ofer , Caruyer Emmanuel , Verma Ragini
Published: October 2019

Characterization of healthy versus pathological tissue is a key concern when modeling tissue microstructure in the peritumoral area, confounded by the presence of free water (e.g., edema). Most methods that model tissue microstructure are either based on advanced acquisition schemes not readily available in the clinic, or are not designed to address the challenge of edema. This underscores the need for a robust free water elimination (FWE) method that estimates free water in pathological tissue but can be used with clinically prevalent single-shell diffusion tensor imaging data. FWE in single-shell data requires the fitting of a bi-compartment model, which is an ill-posed problem. Its solution requires optimization, which relies on an initialization step. We propose a novel initialization approach for FWE, FERNET, which improves the estimation of free water in edematous and infiltrated peritumoral regions, using single-shell diffusion MRI data. The method has been extensively investigated on simulated data and healthy and brain tumor datasets, demonstrating its applicability on clinically acquired data. Additionally, it has been applied to data from brain tumor patients to demonstrate the improvement in tractography in the peritumoral region.
An amygdala circuit mediates experience-dependent momentary exploratory arrests
Authors: Botta Paolo , Fushiki Akira , Vicente Ana Mafalda , Hammond Luke A. , Mosberger Alice C. , Gerfen Charles R. , Peterka Darcy , Costa Rui M.
Published: October 2019

Exploration of novel environments ensures survival and evolutionary fitness. This behavior is expressed through exploratory bouts and arrests, which change dynamically based on experience. Neural circuits mediating exploratory behavior should therefore integrate experience and use it to select the proper behavioral output. Using a spatial exploration assay, we uncovered an experience-dependent increase of momentary arrests in visited locations where animals previously arrested. Quantitative analyses of neuronal calcium activity in freely-exploring mice revealed that a large neuronal ensemble in basolateral amygdala is active during self-paced behavioral arrests. This ensemble was recruited in an experience-dependent manner, and closed-loop optogenetic manipulation of these neurons revealed that they are sufficient and necessary to drive experience-dependent arrests. Additionally, we found that neurons in the basolateral amygdala projecting to central amygdala mediate these momentary arrests. These findings uncover an amygdala circuit that mediates momentary exploratory arrests in familiar places, without changing place preference or anxiety/fear-like behaviors.
Structure of E3 ligase E6AP with a novel proteasome-binding site provided by substrate receptor hRpn10
Authors: Buel Gwen R. , Chen Xiang , Chari Raj , O’Neill Maura J. , Ebelle Danielle L. , Jenkins Conor , Sridharan Vinidhra , Tarasov Sergey G. , Tarasova Nadya I. , Andresson Thorkell , Walters Kylie J.
Published: October 2019

Regulated proteolysis by the proteasome involves ∼800 enzymes for substrate modification with ubiquitin, of which ∼600 are E3 ligases. We report here that E6AP/UBE3A is distinguished from other ubiquitin E3 ligases by having a 12 nM binding site at the proteasome contributed by substrate receptor hRpn10/PSMD4/S5a. Intrinsically disordered by itself, and previously uncharacterized, this domain in hRpn10 locks into a novel well-defined helical structure to form an intermolecular 4-helix bundle with the E6AP AZUL domain, which is unique to this E3. We thus name the hRpn10AZUL-binding domain RAZUL. We further find in human cells that loss of RAZUL by CRISPR-based gene editing leads to loss of E6AP at the proteasome, where associated ubiquitin is correspondingly reduced, suggesting that E6AP ubiquitinates substrates at or for the proteasome. Altogether, our findings indicate E6AP to be a privileged E3 for the proteasome, with a dedicated, high affinity binding site contributed by hRpn10.
Examining go-or-grow using fluorescent cell-cycle indicators and cell cycle-inhibiting drugs
Authors: Vittadello Sean T. , McCue Scott W. , Gunasingh Gency , Haass Nikolas K. , Simpson Matthew J.
Published: October 2019

The go-or-grow hypothesis states that adherent cells undergo reversible phenotype switching between migratory and proliferative states, with cells in the migratory state being more motile than cells in the proliferative state. Here we examine go-or-grow in 2-D in vitro assays using melanoma cells with fluorescent cell-cycle indicators and cell cycle-inhibiting drugs. We analyse the experimental data using single-cell tracking to calculate mean diffusivities, and compare motility between cells in different cell-cycle phases and in cell-cycle arrest. Unequivocally, our analysis does not support the go-or-grow hypothesis. We present clear evidence that cell motility is independent of the cell-cycle phase, and non-proliferative arrested cells have the same motility as cycling cells.
Unconstrained multivariate EEG decoding can help detect lexical-semantic processing in individual children
Authors: Petit Selene , Badcock Nicholas A. , Grootswagers Tijl , Woolgar Alexandra
Published: October 2019

In conditions such as minimally-verbal autism, standard assessments of language comprehension are often unreliable. Given the known heterogeneity within the autistic population, it is crucial to design tests of semantic comprehension that are sensitive in individuals. Recent efforts to develop neural signals of language comprehension have focused on the N400, a robust marker of lexical-semantic violation at the group level. However, homogeneity of response in individual neurotypical children has not been established. Here, we presented 20 neurotypical children with congruent and incongruent visual animations and spoken sentences while measuring their neural response using EEG. Despite robust group-level responses, we found high inter-individual variability in response to lexico-semantic anomalies. To overcome this, we analysed our data using temporally and spatially unconstrained MVPA, supplemented by descriptive analyses to examine the timecourse, topography, and strength of the effect. Our results show that neurotypical children exhibit heterogenous responses to lexical-semantic violation, implying that any application to heterogenous disorders such as ASD will require individual-subject analyses that are robust to variation in topology and timecourse of neural responses.
Systems-level physiology of the human red blood cell is computed from metabolic and macromolecular mechanisms
Authors: Yurkovich James T. , Yang Laurence , Palsson Bernhard O.
Published: October 2019

The human red blood cell has served as a starting point for the application and development of systems biology approaches due to its simplicity, intrinsic experimental accessibility, and importance in human health applications. Here, we present a multi-scale computational model of the human red blood cell that accounts for the full metabolic network, key proteins (>95% of proteome mass fraction), and several macromolecular mechanisms. Proteomics data are used to place quantitative constraints on individual protein complexes that catalyze metabolic reactions, as well as a total proteome capacity constraint. We explicitly describe molecular mechanisms—such as hemoglobin binding and the formation and detoxification of reactive oxygen species—and takes standard hematological variables (e.g., hematocrit, hemoglobin concentration) as input, allowing for personalized physiological predictions. This model is built from first principles and allows for direct computation of physiologically meaningful quantities such as the oxygen dissociation curve and an accurate computation of the flux state of the metabolic network. More broadly, this work represents an important step toward including the proteome and its function in whole-cell models of human cells.
Regime shifts in a phage-bacterial ecosystem and strategies for its control
Authors: Maslov Sergei , Sneppen Kim
Published: October 2019

The competition between bacteria often involves both nutrients and phage predators and may give rise to abrupt regime shifts between the alternative stable states characterized by different species compositions. While such transitions have been previously studied in the context of competition for nutrients, the case of phage-induced bistability between competing bacterial species has not been considered yet. Here we demonstrate a possibility of regime shifts in well-mixed phage-bacterial ecosystems. In one of the bistable states the fast-growing bacteria competitively exclude the slow-growing ones by depleting their common nutrient. Conversely, in the second state the slow-growing bacteria with a large burst size generate such a large phage population that the other species cannot survive. This type of bistability can be realized as the competition between a strain of bacteria protected from phage by abortive infection and another strain with partial resistance to phage. It is often desirable to reliably control the state of microbial ecosystems, yet bistability significantly complicates this task. We discuss successes and limitations of one control strategy in which one adds short pulses to populations of individual species. Our study proposes a new type of phage therapy, where introduction of the phage is supplemented by addition of a partially resistant host bacteria.

IMPORTANCE

Phage-microbial communities play an important role in human health as well as natural and industrial environments. Here we show that these communities can assume several alternative species compositions separated by abrupt regime shifts. Our model predicts these regime shifts in the competition between bacterial strains protected by two different phage defense mechanisms: abortive infection/CRISPR and partial resistance. The history dependence caused by regime shifts greatly complicates the task of manipulation and control of a community. We propose and study a successful control strategy via short population pulses aimed at inducing the desired regime shifts. In particular, we predict that a fast-growing pathogen could be eliminated by a combination of its phage and a slower-growing susceptible host.
Hif-1alpha stabilisation is protective against infection in a zebrafish model of comorbidity
Authors: Schild Yves , Mohamed Abdirizak , Wootton Edward J. , Lewis Amy , Elks Philip M.
Published: October 2019

Multi-drug resistant tuberculosis is a worldwide problem and there is an urgent need for host-derived therapeutic targets, circumventing emerging drug resistance. We have previously shown that hypoxia inducible-1α (Hif-1α) stabilisation helps the host to clear mycobacterial infection via neutrophil activation. However, Hif-1α stabilisation has also been implicated in chronic inflammatory diseases caused by prolonged neutrophilic inflammation. Comorbid infection and inflammation can be found together in disease settings, so it is unclear as to whether Hif-1α stabilisation would be beneficial in a holistic disease setting. Here, we set out to understand the effects of Hif-1α on neutrophil behaviour in disease-relevant settings by combining two well-characterisedin vivozebrafish models: TB infection (Mycobacterium marinuminfection) and wounding (tailfin transection). We demonstrate during systemic infection, that wounding leads to increased infection burden, but the protective effect of Hif-1α stabilisation remains. A local Mm infection near to the tailfin wound site caused neutrophil migration between sites that was reduced by Hif-1α stabilisation. Our data indicate that the protective effect of Hif-1α against Mm is maintained in the presence of inflammation, highlighting its potential as a host-derived target against TB infection in a disease relevant setting.