bluuebunny/crossref_metadata_2025 huggingface dataset:
Intimate Partner Violence and Women's Health
Authors: Lutgendorf Monica A.
Published: August 2019

Intimate partner violence affects 15–71% of women over their lifetime, resulting in significant stress, negative health effects, and negative economic effects. Features include physical and sexual abuse as well as psychological abuse and controlling behaviors such as reproductive coercion or stalking. Intimate partner violence can occur in both heterosexual and same-sex relationships, though the risk may be higher in lesbian, gay, bisexual, transgender, queer, or questioning couples. Pregnancy remains an especially risky time for escalating abuse and also provides a window of opportunity for screening and intervention. Victims experience many consequences of abuse, including physical injuries, traumatic brain injury, and chronic conditions such as headaches, insomnia, pelvic pain, depression, anxiety, and posttraumatic stress disorder. Homicide is an especially devastating consequence, with 40–45% of female victims killed by an intimate partner, and homicide remains an important cause of pregnancy-related death. Routine screening is recommended by the American College of Obstetricians and Gynecologists and the U.S. Preventive Services Task Force, and obstetrician–gynecologists (ob-gyns) should remain vigilant for signs of abuse in their patients. Often the cycle of abuse makes it difficult for women to break free, and ob-gyns should continue to provide supportive care regardless of a woman’s readiness to leave an abusive relationship.
Disparities Among Cervical Cancer Patients Receiving Brachytherapy
Authors: Bruce Shaina F. , Joshi Tanvi V. , Chervoneva Inna , Yi Misung , Chatterjee-Paer Sudeshna , Burton Elizabeth R. , Edelson Mitchell I. , Sorosky Joel I. , Shahin Mark S.
Published: August 2019

OBJECTIVE:

To evaluate the effects of race and insurance status on the use of brachytherapy for treatment of cervical cancer.

METHODS:

This is a retrospective cohort study of the National Cancer Database. We identified 25,223 patients diagnosed with stage IB2 through IVA cervical cancer who received radiation therapy during their primary treatment from 2004 to 2015. A univariate analysis was used to assess covariate association with brachytherapy. A multivariable regression model was used to evaluate the effect of race and insurance status on rates of brachytherapy treatment. The Cox proportional hazards model and the multiplicative hazard model were used to evaluate overall survival. P<.05 indicated a statistically significant difference for comparisons of primary and secondary outcomes.

RESULTS:

Non-Hispanic black patients received brachytherapy at a significantly lower rate than non-Hispanic white patients (odds ratio [OR] 0.93; 95% CI 0.86–0.99; P=.036); Hispanic (OR 0.93; 95% CI 0.85–1.02; P=.115) and Asian (OR 1.13; 95% CI 0.99–1.29; P=.074) patients received brachytherapy at similar rates. Compared with patients with private insurance, those who were uninsured (OR 0.72; 95% CI 0.65–0.79; P<.001), had Medicaid (OR 0.83; 95% CI 0.77–0.89; P<.001) or Medicare insurance (OR 0.85; 95% CI 0.78–0.92; P<.001) were less likely to receive brachytherapy. Brachytherapy was not found to be a mediator of race and insurance-related disparities in overall survival.

CONCLUSION:

Racial and insurance disparities exist for those who receive brachytherapy, with many patients not receiving the standard of care, but overall survival was not affected.
Endometriosis and Risk of Adverse Pregnancy Outcomes
Authors: Farland Leslie V. , Prescott Jennifer , Sasamoto Naoko , Tobias Deirdre K. , Gaskins Audrey J. , Stuart Jennifer J. , Carusi Daniela A. , Chavarro Jorge E. , Horne Andrew W. , Rich-Edwards Janet W. , Missmer Stacey A.
Published: August 2019

OBJECTIVE:

To investigate the relationship between endometriosis and adverse pregnancy outcomes.

METHODS:

Women between ages 25 and 42 years in 1989 (n=116,429) reported detailed information on pregnancies and reproductive health at baseline and every 2 years thereafter in the Nurses' Health Study II, a cohort study. In 2009, they completed a detailed, pregnancy-focused questionnaire. A total of 196,722 pregnancies were reported. Adverse pregnancy outcomes included spontaneous abortion, ectopic pregnancy, stillbirth, gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (preeclampsia or gestational hypertension), preterm birth, and low birth weight. We estimated the relative risks (RRs) and 95% CIs of adverse pregnancy outcomes comparing pregnancies in women with and without a history of laparoscopically confirmed endometriosis using multivariable log-binomial regression, with generalized estimating equations to account for multiple pregnancies per woman.

RESULTS:

Endometriosis was associated with a greater risk of pregnancy loss (spontaneous abortion: RR 1.40, 95% CI 1.31–1.49; ectopic pregnancy: RR 1.46, 95% CI 1.19–1.80). Endometriosis was also associated with a greater risk of GDM (RR 1.35, 95% CI 1.11–1.63) and hypertensive disorders of pregnancy (RR 1.30, 95% CI 1.16–1.45).

CONCLUSIONS:

We observed an association between laparoscopically confirmed endometriosis and several adverse pregnancy outcomes. Future research should focus on the potential biological pathways underlying these relationships to inform screening or preventive interventions.
Blood Lead Levels in Females of Childbearing Age in Flint, Michigan, and the Water Crisis
Authors: Gómez Hernán F. , Borgialli Dominic A. , Sharman Mahesh , Weber Annika T. , Scolpino Anthony J. , Oleske James M. , Bogden John D.
Published: August 2019

OBJECTIVE:

To compare blood lead levels in females of childbearing age, 12–50 years, living within and adjacent to Flint, Michigan, before, during, and after the Flint River water exposure and compare the levels to those that have been shown to cause fetal loss and preterm birth.

METHODS:

The switch in the community water source to the Flint River occurred on April 25, 2014, and was reverted to the original source on October 15, 2015. Using a retrospective cross-sectional study design using geocoded blood lead levels obtained from all females of childbearing age available from a single hospital database, we compared blood lead levels for the following 18-month time periods: April 25, 2012–October 15, 2013 (PRE), April 25, 2014–October 15, 2015 (DURING), and April 25, 2016–October 15, 2017 (POST).

RESULTS:

Results are reported as geometric mean (95% CI). Within Flint, PRE blood lead levels in females of childbearing age were 0.69 micrograms/dL (95% CI 0.63–0.75), DURING blood lead levels were 0.65 micrograms/dL (95% CI 0.60–0.71), and POST blood lead levels were 0.55 micrograms/dL (95% CI 0.54–0.56). DURING Flint River water exposure blood lead levels were not significantly different than the PRE Flint River water time period. POST Flint River water exposure blood lead levels were significantly lower than both PRE and DURING levels. Overall, lower blood lead levels were found outside the Flint boundary in all cohorts.

CONCLUSION:

Blood lead levels in Flint females of childbearing age did not increase during the Flint River water exposure and subsequent 18-month time period. Mean blood lead levels during the Flint River water exposure are not consistent with the markedly higher blood lead levels reported in the literature to be associated with fetal loss, low birth weight, or preterm birth.
Humerus Nail Retrieval: A Novel New Technique
Authors: Yadav Sandeep K. , Agrawal Alok C.
Published: August 2019

Antegrade humerus nailing in humerus shaft fracture is one of the treatment options that offer the advantage of maintaining the biophysiology of the fracture but while in case of non union with broken implant insitu its removal comes as an greater challenge. Removal of nail with the help of schanz pin in case of extraction system failure is an novel technique with easy availability of pin in operation theatre and having lesser complication like rotaor cuff injury then other removal technique such as using nibbler or pliar. Cost of this technique is very less compared with arthrocopic removal of humerus nail.
PICU Follow-Up: The Impact of Missed School in a Cohort of Children Following PICU Admission
Authors: Kastner Kathleen , Pinto Neethi , Msall Michael E. , Sobotka Sarah
Published: August 2019

Objectives:

For children and their families, PICU admission can be one of the most stressful and traumatic experiences in their lives. Children admitted to the PICU and their parents experience sequelae following admission including psychologic symptoms and lower health-related quality of life. The impact of a PICU admission on school attendance and performance may influence these sequelae. The purpose of our study was to examine how community supports from pediatricians and schools influence school success after critical illness.

Design:

Parents were recruited during their child’s admission to the PICU. Three months after discharge, parents completed follow-up questionnaires via telephone.

Setting:

PICU in an urban academic children's hospital.

Subjects:

Thirty-three parents were enrolled in the study, and 21 (64%) completed phone follow-up.

Measurements and Main Results:

Forty-three percent of children missed 7 or more days of school while admitted to the PICU. Sixty-seven percent of parents reported that their pediatrician did not ask about missed school, and 29% felt their child’s grades worsened since admission. Twenty percent of respondents felt that their child’s school did not provide adequate services to help their child catch up.

Conclusions:

There are missed opportunities for care coordination and educational support after critical illness. The transition back to school is challenging for some children, as reported by parents who described inadequate support from the school after PICU hospitalization and a subsequent decline in their child’s school performance. Additional studies are needed to develop proactive community supports to improve the transition back to school for a child after critical illness.
Mapping the Lipid Layer of the Human Tear Film
Authors: Cohen Yoel , Trokel Stephen , Arieli Yoel , Epshtien Shlomi , Gefen Raanan , Harris Alon
Published: August 2019

Purpose:

To describe a new method to distinguish between normal versus lipid-deficient dry eye using a Tear Film Imager (TFI).

Methods:

Two groups of study subjects, controls versus lipid-deficient dry eye, were tested using the TFI. This instrument provides an accurate measurement of the thickness and spatial distribution of the muco-aqueous and lipid layers of the tear film. The nanometer thickness resolution of the TFI enables the creation of detailed maps of the lipid layer thickness (LLT) across the corneal surface. These maps are captured with a large field of view of 6.5 mm diameter.

Results:

A LLT map taken at 1 second from a blink end in the controls appears uniform, whereas a nonuniform layer was measured in the lipid-deficient dry eye. Lipid map uniformity can quantify the spatial variation of lipid across the cornea. A case study showed the ability to distinguish between controls [lipid map uniformity (LMU) = 14 nm2] and lipid-deficient dry eye (LMU = 125 nm2) through characterization of the LLT distribution.

Conclusions:

High-resolution lateral LLT maps demonstrate the significance of the lipid layer uniformity, which may play an important role in maintaining tear film health. LLT maps and the quantitative LMU could be used to diagnose and treat patients with dry eye.
Assessing the Efficacy of a Silver Carboxylate Antimicrobial Coating on Prosthetic Liners
Authors: Haglin Jack M. , Garcia Dioscaris R. , Roque Daniel L. , Spake Carole S.L. , Jarrell John D. , Born Christopher T.
Published: August 2019

Introduction

One of the leading issues facing persons with amputation is late development of antibiotic-resistant bacterial infections of the residual limb. To reduce this infection risk, this study assessed the antimicrobial properties and profile of a silver carboxylate complex coating applied to samples of common prosthetic liner materials against pathogens frequently encountered in amputation-site infections.

Methods

The antimicrobial efficacy of the coating was measured utilizing a Kirby-Bauer assay with two different types of commercially available prosthetic liners. The assay was run against four pathogens including coagulase-negative Staphylococcus epidermidis, methicillin-sensitive Staphylococcus aureus, Enterococcus faecalis, and multidrug-resistant Acinetobacter baumannii. Observations of bacterial inhibition were made at 24-, 48-, and 72-hr time points for all four pathogens. Dose response curves were created to assess the relative efficacy of the coating against each pathogen independent of prosthetic liners. Graphite furnace atomic absorption spectroscopy (GFAAS) was utilized to measure coating silver elution at 24-, 48-, and 72-hr time points.

Results

All conditions of the coating were variably antimicrobial against all tested pathogens in the Kirby-Bauer analysis. Dose response analysis further demonstrated the coating's antimicrobial profile against all tested pathogens. GFAAS demonstrated consistent silver release of the coating throughout 72 hrs.

Conclusions

The results of this study suggest the tested antimicrobial coating is effective against a broad range of drug-resistant pathogens. Due to its ability to reduce and inhibit bacterial growth along the prosthetic liner surface, the coating shows promise as an effective tool toward mitigating infection and malodor found at the residual limb-liner interface among persons with amputation.
Patient-Centered Goal Setting in Developmental Therapy: Discordance between Documented Goals and Caregiver-Perceived Goals
Authors: Angeli Jennifer M. , Harpster Karen , Huijs Lobke , Seid Michael , Sheehan Amber , Schwab Sarah M.
Published: August 2019

Introduction:

Productive interactions between engaged patients and clinical teams are key to effective clinical practice. Accordingly, the identification of needs and priorities through the process of collaborative goal setting is fundamental to patient-centered care. Executing a goal-setting process that is truly collaborative is challenging; many caregivers do not feel that they are adequately involved in the goal-setting process. This study presents the results of an initiative intended to understand goal concordance between therapists and caregivers.

Methods:

We conducted an observational, cross-sectional design study. Twenty-nine pediatric physical and occupational therapists developed and documented collaborative goals for their patients. Over 6 months, 120 randomly selected caregivers from a weekly list of patients scheduled for a follow-up physical or occupational therapy visit participated. Caregivers completed structured interviews related to their children’s therapy goals. We calculated agreement coefficients between caregiver-perceived goals and therapist-documented goals.

Results:

Overall strength of agreement was poor (M = −0.03, SD = 0.71). There were no significant differences within variables of a goal setter, goal importance, or goal utility. Median agreement coefficients were greatest for goals perceived to be identified solely by the caregiver, perceived as important, and perceived as functionally useful.

Conclusions:

The results of this study underscore the state of discordance in the collaborative goal-setting process in pediatric physical and occupational therapy. Healthcare encounters continue to be framed by provider perspectives and priorities. Developing therapy goals that enhance family involvement, relate to function, and are important to the healthcare consumer may improve the agreement.
Daily Changes in the Expression of Clock Genes in Sepsis and Their Relation with Sepsis Outcome and Urinary Excretion of 6-Sulfatoximelatonin
Authors: Acuña-Fernández Carlos , Marín Jorge Solera , Díaz-Casado María E. , Rusanova Iryna , Darias-Delbey Beneharo , Pérez-Guillama Luis , Florido-Ruiz Javier , Acuña-Castroviejo Darío
Published: August 2019

Background:

Whereas the circadian system controls the daily production of melatonin and the daily activity of the immune system, increasing evidences support the association between circadian misalignment with the alterations in the immune response and melatonin rhythm during sepsis. The aim of this study was to analyze the daily changes in clock genes expression and the urinary excretion of 6-SM (6-sulfatoxymelatonin, the major melatonin metabolite), and their connection with the innate immune activity, oxidative status in blood, and clinical outcome during sepsis.

Methods:

Healthy volunteers, non-septic intensive care unit (ICU) patients, and septic ICU patients, were evaluated. The expression of bmal1, per2, clock, and cry1 genes was determined by polymerase chain reaction in blood; 6-SM was assessed in urine by ELISA; plasma cytokines IL-1β, IL-6, IL-8, TNFα, and IL-10 were determined by a multiplex array method, and lipid peroxidation (LPO) and protein oxidation (AOPP) by spectrophotometry. Hematological and biochemical data, and clinical scores of the patients, were also recorded.

Results:

Clock gene rhythm was maintained in non-septic patients but blunted in septic ones, whereas the innate immune and the oxidative stress responses were significantly higher in the latter. 6-SM excretion was also more elevated in septic than in non-septic patients, and it correlated with the degree of the immune response and oxidative status. 6-SM also correlated with SOFA and procalcitonin in the patients. Proinflammatory cytokines, LPO, and AOPP were normalized in the patients once recovered from sepsis.

Conclusion:

Our data suggest a relationship between clock genes rhythm disruption, the immune response, and the oxidative status, with 6-SM acting as a compensatory response. ICU conditions are not a main clock disrupter because of the significant differences found in the responses of septic versus non-septic patients under the same ICU environment.
Recovery of the gut microbiota after antibiotics depends on host diet and environmental reservoirs
Authors: Ng Katharine M. , Aranda-Diaz Andrés , Tropini Carolina , Frankel Matthew Ryan , Van Treuren William W. , O’Laughlin Colleen , Merrill Bryan D. , Yu Feiqiao Brian , Pruss Kali M. , Oliveira Rita Almeida , Higginbottom Steven K. , Neff Norma F. , Fischbach Michael A. , Xavier Karina B. , Sonnenburg Justin L. , Huang Kerwyn Casey
Published: August 2019

That antibiotics alter microbiota composition and increase infection susceptibility is well known, but their generalizable effects on the gut commensal community and dependence on environmental variables remain open questions. Here, we systematically compared antibiotic responses in gnotobiotic and conventional mice across antibiotics, microbiotas, diets, and housing status. We identify remarkable resilience, whereby a humanized microbiota recovers before drug administration ends, with transient dominance of resistant Bacteroides and taxa-asymmetric reduction in diversity. In other cases, in vitro sensitivities were not predictive of in vivo responses, underscoring the significance of host and community contexts. A fiber-deficient diet exacerbated collapse of the microbiota and delayed recovery, despite the presence of a similar core community across diets at the point of maximal disturbance. Resilience to a second ciprofloxacin treatment was observed via response reprogramming, in which species replacement after ciprofloxacin treatment established resilience to a second treatment, and also through cross housing transmission. Single-housing drastically disrupted recovery, highlighting the importance of environmental microbial reservoirs and suggesting sanitation may exacerbate the duration of antibiotic-mediated disruption. Our findings highlight the ability of the commensal microbiota to deterministically adapt to large perturbations, and the translational potential for modulating diet, sanitation, and microbiota composition during antibiotics.
Genome-wide association analysis of age-at-onset traits using Cox mixed-effects models
Authors: He Liang , Kulminski Alexander M.
Published: August 2019

Age-at-onset is one of the critical phenotypes in cohort studies of age-related diseases. Large-scale genome-wide association studies (GWAS) of age-at-onset can provide more insights into genetic effects on disease progression, and transitions between different stages. Moreover, proportional hazards or Cox regression generally achieves higher statistical power in a cohort study than a binary trait using logistic regression. Although mixed-effects models are widely used in GWAS to correct for population stratification and family structure, application of Cox mixed-effects models (CMEMs) to large-scale GWAS are so far hindered by intractable computational intensity. In this work, we propose COXMEG, an efficient R package for conducting GWAS of age-at-onset using CMEMs. COXMEG introduces fast estimation algorithms for general sparse relatedness matrices including but not limited to block-diagonal pedigree-based matrices. COXMEG also introduces a fast and powerful score test for fully dense relatedness matrices, accounting for both population stratification and family structure. In addition, COXMEG handles positive semidefinite relatedness matrices, which are common in twin and family studies. Our simulation studies suggest that COXMEG, depending on the structure of the relatedness matrix, is 100∼100,000-fold computationally more efficient for GWAS than coxme for a sample consisting of 1000-10,000 individuals. We found that using sparse approximation of relatedness matrices yielded highly comparable performance in controlling false positives and statistical power for an ethnically homogeneous family-based sample. When applying COXMEG to a NIA-LOADFS sample with 3456 Caucasians, we identified theAPOE4variant with strong statistical power (p=1e-101), far more significant than previous studies using a transformed variable and a marginal Cox model. When investigating a multi-ethnic NIA-LOADFS sample including 3456 Caucasians and 287 African Americans, we identified a novel SNP rs36051450 (p=2e-9) nearGRAMD1B, the minor allele of which significantly reduced the hazards of AD in both genders. Our results demonstrated that COXMEG greatly facilitates the application of CMEMs in GWAS of age-at-onset phenotypes.
Top-down control of water intake by the endocannabinoid system
Authors: Zhao Zhe , Soria-Gómez Edgar , Varilh Marjorie , Julio-Kalajzić Francisca , Cannich Astrid , Castiglione Adriana , Vanhoutte Léonie , Duveau Alexia , Zizzari Philippe , Beyeler Anna , Cota Daniela , Bellocchio Luigi , Busquets-Garcia Arnau , Marsicano Giovanni
Published: August 2019

Water intake is regulated by neocortical top-down circuits, but their identity and the cellular mechanisms involved are scantly known. Here, we show that endogenous activation of type-1 cannabinoid receptors (CB1) promotes water intake and that endocannabinoid modulation of excitatory projections from the anterior cingulate cortex to the basolateral amygdala is sufficient to guarantee physiological drinking. These data reveal a new circuit involved in the homeostatic control of water intake.
The gastrointestinal development ‘parts list’: transcript profiling of embryonic gut development in wildtype andRet-deficient mice
Authors: Chatterjee Sumantra , Nandakumar Priyanka , Auer Dallas R. , Gabriel Stacey B. , Chakravarti Aravinda
Published: August 2019

The development of the gut from endodermal tissue to an organ with multiple distinct structures and functions occurs over a prolonged time during embryonic days E10.5-E14.5 in the mouse. During this process, one major event is innervation of the gut by enteric neural crest cells (ENCC) to establish the enteric nervous system (ENS). To understand the molecular processes underpinning gut and ENS development, we generated RNA-seq profiles from wildtype mouse guts at E10.5, E12.5 and E14.5 from both sexes. We also generated these profiles from homozygousRetnull embryos, a model for Hirschsprung disease (HSCR), in whom the ENS is absent. These data reveal four major features: (1) between E10.5 to E14.5 the developmental genetic programs change from expression of major transcription factors (TF) and its modifiers to genes controlling tissue (epithelium, muscle, endothelium) specialization; (2) the major effect ofRetis not only on ENCC differentiation to enteric neurons but also on the enteric mesenchyme and epithelium; (3) a muscle genetic program exerts significant effects on ENS development, and (4) sex differences in gut development profiles are minor. The genetic programs identified, and their changes across development, suggests that both cell autonomous and non-autonomous factors, and interactions between the different developing gut tissues, are important for normal ENS development and its disorders.

Significance statement

The mammalian gut is a complex set of tissues formed during development by orchestrating the timing of expression of many genes. Here we uncover the identity of these genes, their pathways and how they change during gut organogenesis. We used RNA-seq profiling in the wildtype mouse gut in both sexes during development (E10.5 - E14.5), as well as in aRetnull mouse, a model of Hirschsprung disease (HSCR). These studies have allowed us to expand the universe of genes and developmental processes that contribute to enteric neuronal innervation and to its dysregulation in disease.
Human bone marrow mesenchymal stem/stromal cell behaviour is coordinated via mechanically activated osteocyte-derived extracellular vesicles
Authors: Eichholz Kian F. , Woods Ian , Johnson Gillian P. , Shen Nian , Corrigan Michele , Labour Marie-Noelle , Wynne Kieran , Lowry Michelle C. , O’Driscoll Lorraine , Hoey David A.
Published: August 2019

Osteocytes are mechanosensitive cells that are believed to play a fundamental role in coordinating bone mechanoadaptation via the secretion of paracrine factors. However, the exact mechanisms by which osteocytes relay mechanical signals to effector cells is poorly understood. In this study, we demonstrated that osteocytes subjected to a physiologic fluid shear secrete a distinct collection of factors that significantly enhance human MSC recruitment and osteogenesis. Utilising proteomics we generated an extensive map of proteins within the mechanically activated osteocyte secretome, identifying numerous paracrine factors that are modified by mechanical stimulation. Moreover, we identified the presence of extracellular vesicles (EVs) and further demonstrated that these mechanically activated osteocyte derived EVs (MAEVs) coordinate human MSCs recruitment and osteogenesis. This indicates that mechanical conditioning of parent cells can modify EVs and demonstrates the pro-osteogenic potential of MAEVs as a cell-free therapy to enhance bone regeneration and repair in diseases such as osteoporosis.
Expanding a Database-derived Biomedical Knowledge Graph via Multi-relation Extraction from Biomedical Abstracts
Authors: Nicholson David N. , Himmelstein Daniel S. , Greene Casey S.
Published: August 2019

Knowledge graphs support multiple research efforts by providing contextual information for biomedical entities, constructing networks, and supporting the interpretation of high-throughput analyses. These databases are populated via some form of manual curation, which is difficult to scale in the context of an increasing publication rate. Data programming is a paradigm that circumvents this arduous manual process by combining databases with simple rules and heuristics written as label functions, which are programs designed to automatically annotate textual data. Unfortunately, writing a useful label function requires substantial error analysis and is a nontrivial task that takes multiple days per function. This makes populating a knowledge graph with multiple nodes and edge types practically infeasible. We sought to accelerate the label function creation process by evaluating the extent to which label functions could be re-used across multiple edge types. We used a subset of an existing knowledge graph centered on disease, compound, and gene entities to evaluate label function re-use. We determined the best label function combination by comparing a baseline database-only model with the same model but added edge-specific or edge-mismatch label functions. We confirmed that adding additional edge-specific rather than edge-mismatch label functions often improves text annotation and shows that this approach can incorporate novel edges into our source knowledge graph. We expect that continued development of this strategy has the potential to swiftly populate knowledge graphs with new discoveries, ensuring that these resources include cutting-edge results.
Non-oncology drugs are a source of previously unappreciated anti-cancer activity
Authors: Corsello Steven M. , Nagari Rohith T. , Spangler Ryan D. , Rossen Jordan , Kocak Mustafa , Bryan Jordan G. , Humeidi Ranad , Peck David , Wu Xiaoyun , Tang Andrew A. , Wang Vickie M. , Bender Samantha A. , Lemire Evan , Narayan Rajiv , Montgomery Philip , Ben-David Uri , Chen Yejia , Rees Matthew G. , Lyons Nicholas J. , McFarland James M. , Wong Bang T. , Wang Li , Dumont Nancy , O’Hearn Patrick J. , Stefan Eric , Doench John G. , Greulich Heidi , Meyerson Matthew , Vazquez Francisca , Subramanian Aravind , Roth Jennifer A. , Bittker Joshua A. , Boehm Jesse S. , Mader Christopher C. , Tsherniak Aviad , Golub Todd R.
Published: August 2019

Anti-cancer uses of non-oncology drugs have been found on occasion, but such discoveries have been serendipitous and rare. We sought to create a public resource containing the growth inhibitory activity of 4,518 drugs tested across 578 human cancer cell lines. To accomplish this, we used PRISM, which involves drug treatment of molecularly barcoded cell lines in pools. Relative barcode abundance following treatment thus reflects cell line viability. We found that an unexpectedly large number of non-oncology drugs selectively inhibited subsets of cancer cell lines. Moreover, the killing activity of the majority of these drugs was predictable based on the molecular features of the cell lines. Follow-up of several of these compounds revealed novel mechanisms. For example, compounds that kill by inducing PDE3A-SLFN12 complex formation; vanadium-containing compounds whose killing is dependent on the sulfate transporter SLC26A2; the alcohol dependence drug disulfiram, which kills cells with low expression of metallothioneins; and the anti-inflammatory drug tepoxalin, whose killing is dependent on high expression of the multi-drug resistance gene ABCB1. These results illustrate the potential of the PRISM drug repurposing resource as a starting point for new oncology therapeutic development. The resource is available at https://depmap.org.
A size principle for leg motor control inDrosophila
Authors: Azevedo Anthony W , Dickinson Evyn S , Gurung Pralaksha , Venkatasubramanian Lalanti , Mann Richard , Tuthill John C
Published: August 2019

To move the body, the brain must precisely coordinate patterns of activity among diverse populations of motor neurons. In many species, including vertebrates, the motor neurons innervating a given muscle fire in a specific order that is determined by a gradient of cellular size and electrical excitability. This hierarchy allows premotor circuits to recruit motor neurons of increasing force capacity in a task-dependent manner. However, it remains unclear whether such a size principle also applies to species with more compact motor systems, such as the fruit fly,Drosophila melanogaster, which has just 53 motor neurons per leg. Usingin vivocalcium imaging and electrophysiology, we found that genetically-identified motor neurons controlling flexion of the fly tibia exhibit a gradient of anatomical, physiological, and functional properties consistent with the size principle. Large, fast motor neurons control high force, ballistic movements while small, slow motor neurons control low force, postural movements. Intermediate neurons fall between these two extremes. In behaving flies, motor neurons are recruited in order from slow to fast. This hierarchical organization suggests that slow and fast motor neurons control distinct motor regimes. Indeed, we find that optogenetic manipulation of each motor neuron type has distinct effects on the behavior of walking flies.
Dormancy dynamics and dispersal contribute to soil microbiome resilience
Authors: Sorensen Jackson W , Shade Ashley
Published: August 2019

In disturbance ecology, stability is composed of resistance to change and resilience towards recovery after the disturbance subsides. Two key microbial mechanisms that can support microbiome stability include dormancy and dispersal. Specifically, microbial populations that are sensitive to disturbance can be re-seeded by local dormant pools of viable and reactivated cells, or by immigrants dispersed from regional metacommunities. However, it is difficult to quantify the contributions of these mechanisms to stability without, first, distinguishing the active from inactive membership, and, second, distinguishing the populations recovered by local resuscitation from those recovered by dispersed immigrants. Here, we investigate the contributions of dormancy dynamics (activation and inactivation), and dispersal to soil microbial community resistance and resilience. We designed a replicated, 45-week time-series experiment to quantify the responses of the active soil microbial community to a thermal press disturbance, including control mesocosms, disturbed mesocosms without dispersal, and disturbed mesocosms with dispersal after the release of the stressor. Communities were sensitive within one week of warming. Though the disturbed mesocosms did not fully recover within 29 weeks, resuscitation of thermotolerant taxa was key for community transition during the press, and both resuscitation of opportunistic taxa and immigration contributed to community resilience. Also, mesocosms with dispersal were more resilient than mesocosms without. This work advances the mechanistic understanding of how microbiomes respond to disturbances in their environment.
Brain microRNAs among social and solitary bees
Authors: Kapheim Karen M. , Jones Beryl M. , Søvik Eirik , Stolle Eckart , Waterhouse Robert M. , Bloch Guy , Ben-Shahar Yehuda
Published: August 2019

Evolutionary transitions to a social lifestyle in insects are associated with lineage-specific changes in gene expression, but the key nodes that drive these regulatory changes are unknown. We examined the relationship between social organization and lineage-specific microRNAs (miRNAs). Genome scans across 12 bee species showed that miRNA copy-number is mostly conserved and not associated with sociality. However, deep sequencing of small RNAs in six bee species revealed a substantial proportion (20-35%) of detected miRNAs had lineage-specific expression in the brain, 24-72% of which did not have homologs in other species. Lineage-specific miRNAs disproportionately target lineage-specific genes, and have lower expression levels than shared miRNAs. The predicted targets of lineage-specific miRNAs are not enriched for genes with caste-biased expression or genes under positive selection in social species. Together, these results suggest that novel miRNAs may coevolve with novel genes, and thus contribute to lineage-specific patterns of evolution in bees, but do not appear to have significant influence on social evolution. Our analyses also support the hypothesis that many new miRNAs are purged by selection due to deleterious effects on mRNA targets, and suggest genome structure is not as influential in regulating bee miRNA evolution as has been shown for mammalian miRNAs.
Relating Global and Local Connectome Changes to Dementia and Targeted Gene Expression in Alzheimer’s Disease
Authors: Elsheikh Samar S. M. , Chimusa Emile R. ,   Alzheimer’s Disease Neuroimaging Initiative, Mulder Nicola J. , Crimi Alessandro
Published: August 2019

Networks are present in many aspects of our lives, and networks in neuroscience have recently gained much attention leading to novel representations of brain connectivity. The integration of neuroimaging characteristics and genetics data allows a better understanding of the effects of the genetic variations on brain structural and functional connections. The current work uses whole-brain tractography in a longitudinal setting, and by measuring the brain structural connectivity changes studies the neurodegeneration of Alzheimer’s disease. This is accomplished by examining the effect of targeted genetic risk factors on the most common local and global brain connectivity measures. Furthermore, we examined the extent to which Clinical Dementia Rating relates to brain connections longitudinally, as well as to gene expression. Here we show that the expression of PLAU gene increases the change over time in betweenness centrality related to the fusiform gyrus. We also show that the betweenness centrality metric impact dementia-related changes in distinct brain regions. Our findings provide insights into the complex longitudinal interplay between genetics and brain characteristics and highlight the role of Alzheimer’s genetic risk factors in the estimation of regional brain connectivity alterations.
Progressive alignment with Cactus: a multiple-genome aligner for the thousand-genome era
Authors: Armstrong Joel , Hickey Glenn , Diekhans Mark , Deran Alden , Fang Qi , Xie Duo , Feng Shaohong , Stiller Josefin , Genereux Diane , Johnson Jeremy , Marinescu Voichita Dana , Haussler David , Alföldi Jessica , Lindblad-Toh Kerstin , Karlsson Elinor , Jarvis Erich D. , Zhang Guojie , Paten Benedict
Published: August 2019

Cactus, a reference-free multiple genome alignment program, has been shown to be highly accurate, but the existing implementation scales poorly with increasing numbers of genomes, and struggles in regions of highly duplicated sequence. We describe progressive extensions to Cactus that enable reference-free alignment of tens to thousands of large vertebrate genomes while maintaining high alignment quality. We show that Cactus is capable of scaling to hundreds of genomes and beyond by describing results from an alignment of over 600 amniote genomes, which is to our knowledge the largest multiple vertebrate genome alignment yet created. Further, we show improvements in orthology resolution leading to downstream improvements in annotation.
Does microbiome-associated disease affect the inter-subject heterogeneity of human microbiome?
Authors: Ma Zhanshan (Sam) , Li Lianwei
Published: August 2019

Space is a critical and also challenging frontier in human microbiome research. It has been argued that lack of consideration of scales beyond individual and ignoring of microbe dispersal are two crucial roadblocks in preventing deep understanding of the heterogeneity of human microbiome. Assessing and interpreting the spatial distribution (dispersal) of microbes explicitly are particularly challenging, but implicit approaches such as Taylor’s power law (TPL) can still be effective and offer significant insights into the heterogeneity in abundance and distribution of human microbiomes. Here, we investigate the relationship between human microbiome-associated diseases (MADs) and the inter-subject microbiome heterogeneity, or heterogeneity-disease relationship (HDR), by harnessing the power of TPL extensions and by analyzing a big dataset of 25 MAD studies covering all five major microbiome habitats and majority of the high-profile MADs including obesity and diabetes. Our HDR analysis revealed that in approximately 10%-17% of the cases, disease effects were significant—the healthy and diseased cohorts exhibited statistically significant differences. In majority of the MAD cases, the microbiome was sufficiently resilient to endure the disturbances of MADs. Furthermore, comparative analysis with traditional DDR (diversity-disease relationship) results is presented. We postulate that HDR reveals evolutionary characteristics because it utilizes the TPL parameter that implicitly characterizes spatial behavior (dispersion), which is primarily shaped by microbe-host co-evolution and is more robust against disturbances including diseases, while diversity in DDR analysis is primarily an ecological-scale characteristic and is less robust against diseases. Nevertheless, both HDR and DDR cross-verified remarkable resilience of human microbiomes against MADs.

Importance

It has been argued that lack of consideration of scales beyond individual and ignoring of microbe dispersal are two crucial roadblocks in preventing deep understanding of the heterogeneity of human microbiome. Assessing and interpreting the spatial distribution (dispersal) of microbes explicitly are particularly challenging, but implicit approaches such as Taylor’s power law (TPL) can still be effective. Here, we investigate the relationship between human microbiome-associated diseases (MADs) and the inter-subject microbiome heterogeneity, or heterogeneity-disease relationship (HDR), by harnessing the power of TPL extensions and by analyzing a big dataset of 25 MAD studies covering all five major microbiome habitats and majority of the high-profile MADs including obesity and diabetes. We postulate that HDR reveals evolutionary characteristics because it utilizes the TPL parameter that implicitly characterizes spatial behavior (dispersion), which is primarily shaped by microbe-host co-evolution and is more robust against disturbances including diseases than the traditional diversity-disease relationship (DDR).
Can endogenous fluctuations persist in high-diversity ecosystems?
Authors: Roy Felix , Barbier Matthieu , Biroli Giulio , Bunin Guy
Published: August 2019

When can complex ecological interactions drive an entire ecosystem into a persistent non-equilibrium state, where species abundances keep fluctuating without going to extinction? We show that high-diversity spatially-extended systems, in which conditions vary somewhat between spatial locations, can exhibit chaotic dynamics which persist for extremely long times. We develop a theoretical framework, based on dynamical mean-field theory, to quantify the conditions under which these fluctuating states exist, and predict their properties. We uncover parallels with the persistence of externally-perturbed ecosystems, such as the role of perturbation strength, synchrony and correlation time. But uniquely to endogenous fluctuations, these properties arise from the species dynamics themselves, creating feedback loops between perturbation and response. A key result is that the fluctuation amplitude and species diversity are tightly linked, in particular fluctuations enable dramatically more species to coexist than at equilibrium in the very same system. Our findings highlight crucial differences between well-mixed and spatially-extended systems, with implications for experiments and their ability to reproduce natural dynamics. They shed light on the maintenance of biodiversity, and the strength and synchrony of fluctuations observed in natural systems.
Predator prey and the third beneficiary
Authors: Pund Anagha , Holkar Ketki , Watve Milind , Baig Ulfat
Published: August 2019

All bacterial epibiotic predators are rich in secondary metabolites and most genera rich in secondary metabolites have demonstrable predatory abilities. Therefore it is likely that an antibiotic resistant and thereby predation resistant species may benefit not only by escaping predation but also by utilizing nutrients released by lysis of prey cells by predatory bacteria. The resistant organisms may enjoy greater fitness benefits than the predator since they get the benefit without investing in the predation machinery. In our experiment, a marine isolate of Streptomyces atrovirens showed good predatory activity on a range of species including Staphylococcus aureus and Proteus vulgaris. Escherichia coli was resistant to predation by this species. On slide culture with water agar when the predator, S. aureus and E. coli were grown together S. aureus population declined whereas the predation resistant E. coli increased their population as compared to controls. However the growth of E. coli did not affect growth of the predator unfavorably. This strengthens the possibility that evolution of antibiotic resistance not only gave a selective advantage of escaping predation, it also would have increased the fitness of the resistant organism by promoting growth on nutrients released from the prey cells lysed by the predator. When the predator was grown with S. aureus and P. vulgaris as prey, S. aureus declined rapidly whereas P. vulgaris was spared. This suggests that the predator appears to show preference towards prey and in that case even a partial or relative resistance may give substantial advantage to a population.
Engineered cartilage from human chondrocytes with homozygous knockout of cell cycle inhibitor p21
Authors: D’Costa Susan , Rich Matthew J. , Diekman Brian O.
Published: August 2019

Risk factors for the development of osteoarthritis (OA) include genetic background and focal cartilage injury. The search for disease-modifying OA therapies would benefit from a more comprehensive knowledge of the genetic variants that contribute to chondrocyte dysfunction and the barriers to cartilage regeneration. One goal of this study was to establish a system for producing engineered cartilage tissue from genetically-defined primary human chondrocytes through genome editing and single-cell expansion. This process was utilized to investigate the functional effect of bi-allelic knockout of the cell cycle inhibitor p21. The use of ribonucleoprotein (RNP) CRISPR/Cas9 complexes targeting two sites in the coding region of p21 resulted in a high frequency (16%) of colonies with homozygous p21 knockout. Chondrogenic pellet cultures from expanded chondrocytes with complete loss of p21 produced more glycosaminoglycans (GAG) and maintained a higher cell number. Single-cell derived colonies retained the potential for robust matrix production after expansion, allowing for analysis of colony variability from the same population of targeted cells. The effect of enhanced cartilage matrix production in p21 knockout chondrocytes persisted when matrix production from individual colonies was analyzed. Chondrocytes had lower levels of p21 protein with further expansion, and the difference in GAG production with p21 knockout was strongest at early passages. These results support previous findings that implicate p21 as a barrier to cartilage matrix production and regenerative capacity. Further, this work establishes the use of genome-edited human chondrocytes as a promising approach for engineered tissue models containing user-defined gene knockouts and other genetic variants for investigation of OA pathogenesis.
Divergent clonal evolution of a common precursor to mantle cell lymphoma and classic Hodgkin lymphoma
Authors: Tashkandi Hammad , Petrova-Drus Kseniya , Batlevi Connie Lee , Arcila Maria E. , Roshal Mikhail , Sen Filiz , Yao Jinjuan , Baik Jeeyeon , Bilger Ashley , Singh Jessica , de Frank Stephanie , Kumar Anita , Aryeequaye Ruth , Zhang Yanming , Dogan Ahmet , Xiao Wenbin
Published: August 2019

Clonal heterogeneity and evolution of mantle cell lymphoma (MCL) remain unclear despite the progress in our understanding of its biology. Here, we report a 71-yr-old male patient with an aggressive MCL and depict the clonal evolution from initial diagnosis of typical MCL to relapsed blastoid MCL. During the course of the disease, the patient was diagnosed with classic Hodgkin lymphoma (CHL) and received a CHL therapeutic regimen. Molecular analysis by next-generation sequencing of both MCL and CHL demonstrated clonally related CHL with characteristic immunophenotype and PDL1/2 gains. Moreover, our data illustrate the clonal heterogeneity and acquisition of additional genetic aberrations including a rare fusion of SEC22B-NOTCH2 in the process of clonal evolution. Evidence obtained from our comprehensive immunophenotypic and genetic studies indicates that MCL and CHL can originate from a common precursor by divergent clonal evolution, which may pose a therapeutic challenge.