bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Cognitive-Emotional Intervention on Growth and Posttraumatic Stress in Mothers of Children With Cancer: A Randomized Clinical Trial
Authors: Shakiba Mansour , Latifi Arsalan , Navidian Ali
Published: July 2019

Background:

To diminish the negative impact and improve the positive outcomes on the parents of children with cancer, it is crucial to attend to their problems. This is especially significant in the case of mothers as the main caregivers. The present study aimed at evaluating the efficiency of cognitive-emotional intervention on growth and posttraumatic stress in mothers of children with cancer hospitalized in the chemotherapy ward.

Procedure:

This randomized clinical trial was conducted on 100 mothers of children with cancer who presented to the chemotherapy ward of a hospital located in southeastern Iran in 2018. The eligible mothers were chosen and randomly assigned to intervention and control groups. Mothers in the intervention group as a whole received 5 sessions of cognitive-emotional intervention. The sessions were held twice a week, each lasting 60 to 90 minutes. Sixteen weeks after the intervention, posttest data were collected through the Posttraumatic Stress Disorder Checklist and Posttraumatic Growth Inventory. The data were then analyzed using SPSS 21 utilizing statistical tests including independent and paired t tests, χ2, and covariance analysis.

Results:

The results show that the mean value of posttraumatic stress in mothers of children with cancer after cognitive-emotional training in the intervention group (25.92±5.29) was significantly lower than that in the control group (44.94±11.92; P=0.0001). Moreover, in the posttest, the mean value of posttraumatic growth in the intervention group (92.06±5.50) was significantly more than that in the control group (62.98±15.08; P=0.0001).

Conclusions:

Alleviating posttraumatic stress, the cognitive-emotional intervention proposed in this research had a significant and positive impact on posttraumatic growth in mothers of children diagnosed with cancer. Therefore, implementing this intervention in the chemotherapy department and throughout the course of the children’s treatment is highly recommended for their caregivers, especially mothers of children diagnosed with cancer.
The Experiences of Family Caregivers at the End of Life: Suffering, Compassion Satisfaction and Support of Health Care Professionals
Authors: Ortega-Galán Ángela María , Ruiz-Fernández María Dolores , Carmona-Rega María Inés , Cabrera-Troya José , Ortíz-Amo Rocío , Ibáñez-Masero Olivia
Published: July 2019

A death with dignity is influenced by the quality of care offered to patients. The objective of this study was to identify, through the firsthand experiences and insights of family caregivers, the key elements related to the care offered to patients with a terminal illness at the end of life. This multicenter qualitative study was based on the paradigm of hermeneutic phenomenology. Participants were relatives of patients with terminal illness who had been identified as primary caregivers. Five discussion groups and 41 in-depth interviews were organized with a total of 81 participants. The content of the interviews was analyzed based on the methods developed by Giorgi (J Phenom Psychol 1997;28(2):235-260). The results indicate the existence of 3 dimensions: the caregiver’s suffering, compassion satisfaction with the care provided, and the support of health care professionals. Understanding the experiences of family members providing end-of-life care allows improved care and provides dignity in death. Health and social systems must provide comprehensive assistance covering the different aspects of needed care. Health professionals occupy a privileged position in the care of these patients and their families.
Personalized Wellness Past and Future
Authors: Kanter Mitch , Desrosiers Ashley
Published: July 2019

Personalized wellness encompasses individualized diet treatment plans, exercise regimens, and antistress programs. In time, it will include health and nutrition recommendations and programs based almost solely on one’s genetic profile and predispositions. But how evolved is the science behind these products and services and where do the greatest opportunities lie to improve public health? This article reviews the state of the science and technologies and products currently driving the personalized wellness marketplace. It considers how highly developed genomics science is and whether the field is truly at the point of creating diet and fitness plans for individuals based on their genetic profiles. It is intended to explore how the science and technology may coevolve in the future.
Comparison of Three Gaze-position Calibration Techniques in First Purkinje Image–based Eye Trackers
Authors: Ntodie Michael , Bharadwaj Shrikant R. , Balaji Swaathi , Saunders Kathryn J. , Little Julie-Anne
Published: July 2019

SIGNIFICANCE

This study highlights potential differences that can arise in gaze-position estimates from first Purkinje image–based eye trackers based on how individual Hirschberg ratios (HRs) are calculated.

PURPOSE

The purpose of this study was to evaluate the accuracy and repeatability of eccentric-viewing, prism-based, and theoretical techniques that are routinely used to calibrate HR in first Purkinje image–based eye trackers.

METHODS

Hirschberg ratios of 28 participants (18 to 40 years old) were obtained using the PlusOptix PowerRef 3 photorefractor and eye tracker. In the gold standard eccentric-viewing technique, participants viewed eccentric targets (±12°, 4° steps) at 2 m. In the prism-based technique, 4 to 16Δ-D base-out and base-in prisms were placed in 4Δ-D steps before an eye occluded with an infrared filter; the fellow eye fixated a target at 1 m. Each participant's HR was calculated as the slope of the linear regression of the shift in Purkinje image relative to the pupil center for each target eccentricity or induced prism power. Theoretical HR was calculated from the participant's corneal curvature and anterior chamber depth measures. Data collection was repeated on another visit using all three techniques to assess repeatability. Data were also obtained from an Indian cohort (n = 30, 18 to 40 years old) using similar protocols.

RESULTS

Hirschberg ratio ranged from 10.61 to 14.63°/mm (median, 11.90°/mm) in the eccentric-viewing technique. The prism-based and theoretical techniques demonstrated inaccuracies of 12 and 4% relative to the eccentric-viewing technique. The 95% limits of agreement of intrasubject variability were ±2.00, ±0.40, and ±0.30°/mm for the prism-based, eccentric-viewing, and theoretical techniques, respectively (P > .05). Intraclass correlation coefficients (95% confidence interval) were 0.99 (0.98 to 1.00) for eccentric, 0.99 (0.99 to 1.00) for theoretical, and 0.88 (0.74 to 0.94) for prism-based techniques. Similar results were found for the Indian cohort.

CONCLUSIONS

The prism-based and theoretical techniques both demonstrated relative inaccuracies in measures of HR compared with the eccentric-viewing technique. The prism-based technique exhibited the poorest repeatability.
Prevalence of Refractive Error, Presbyopia, and Spectacle Coverage in Bogotá, Colombia: A Rapid Assessment of Refractive Error
Authors: Casas Luque Luisa , Naidoo Kovin , Chan Ving Fai , Silva Juan Carlos , Naduvilath Thomas John , Peña Fernando , Mayorga Myriam , Ramírez Leonardo
Published: July 2019

SIGNIFICANCE

Uncorrected refractive error is the leading cause of visual impairment; therefore, reducing its prevalence is important worldwide. For two decades, there has not been a comprehensive assessment of refractive error in Latin America.

PURPOSE

The purpose of this study was to determine the current prevalence of refractive error, presbyopia, spectacle coverage, barriers to uptake refractive services, and spectacle correction in people 15 years and older in Bogotá, Colombia.

METHODS

A cross-sectional community-based survey was conducted using 50 randomly selected clusters from 10 districts of Bogotá reflecting the socioeconomic status of the city. Respondents 15 years and older were interviewed and underwent standardized clinical eye examinations. Prevalence of uncorrected refractive error, spectacle coverage, and visual impairment were standardized to 2015 age-sex population distribution of Bogotá and further analyzed.

RESULTS

A total of 2886 subjects (90% of 3206 eligible subjects) participated in the study; 39.1% were male and 60.9% were female in the age range of 15 to 96 years, with a median age of 46 years (interquartile range, 45 to 54 years). Age- and sex-standardized prevalence of visual impairment was 19.3% (95% confidence interval [CI], 17.8 to 20.8%). Prevalence of uncorrected refractive error was 12.5% (95% CI, 11.3 to 13.7%). Prevalence of presbyopia among participants 35 years and older was 55.2% (95% CI, 52.9 to 57.4%). Spectacle coverage was 50.9% for distance vision, and it was 33.9% for presbyopia. Main barrier to spectacle uptake was a limitation in affording spectacles because of economic factors (29.5%).

CONCLUSIONS

This study provides a current estimate of refractive error using the Rapid Assessment of Refractive Error for Colombia and the Latin American region. The prevalence of uncorrected refractive error and presbyopia was high, and the barriers to spectacle uptake were higher in the lowest socioeconomic strata. The results obtained in the present study will help in making evidence-based decisions related to eye care service delivery in Colombia.
Ultrasound-Guided Posterior Tibial Nerve Block for Plantar Foot Foreign Body Removal
Authors: Moake Matthew M. , Presley Bradley C. , Barnes Ryan M.
Published: July 2019

Ultrasound-guided regional anesthesia is a growing modality within the pediatric emergency department. Here we present a case where a posterior tibial nerve block was used for anesthesia during foreign body removal from the plantar foot. We further review the technique and literature regarding this straightforward and highly effective procedure.
Can We Predict Incisional Hernia?
Authors: Basta Marten N. , Kozak Geoffrey M. , Broach Robyn B. , Messa Charles A. , Rhemtulla Irfan , DeMatteo Ron P. , Serletti Joseph M. , Fischer John P.
Published: July 2019

Objective:

The aim of this study was to identify procedure-specific risk factors independently associated with incisional hernia (IH) and demonstrate the feasibility of preoperative risk stratification through the use of an IH risk calculator app and decision–support interface.

Summary Background Data:

IH occurs after 10% to 15% of all abdominal surgeries (AS) and remains among the most challenging, seemingly unavoidable complications. However, there is a paucity of readily available, actionable tools capable of predicting IH occurrence at the point-of-care.

Methods:

Patients (n = 29,739) undergoing AS from 2005 to 2016 were retrospectively identified within inpatient and ambulatory databases at our institution. Surgically treated IH, complications, and costs were assessed. Predictive models were generated using regression analysis and corroborated using a validation group.

Results:

The incidence of operative IH was 3.8% (N = 1127) at an average follow-up of 57.9 months. All variables were weighted according to β-coefficients generating 8 surgery-specific predictive models for IH occurrence, all of which demonstrated excellent risk discrimination (C-statistic = 0.76–0.89). IH occurred most frequently after colorectal (7.7%) and vascular (5.2%) surgery. The most common occurring risk factors that increased the likelihood of developing IH were history of AS (87.5%) and smoking history (75%). An integrated, surgeon-facing, point-of-care risk prediction instrument was created in an app for preoperative estimation of hernia after AS.

Conclusions:

Operative IH occurred in 3.8% of patients after nearly 5 years of follow-up in a predictable manner. Using a bioinformatics approach, risk models were transformed into 8 unique surgery-specific models. A risk calculator app was developed which stakeholders can access to identify high-risk IH patients at the point-of-care.
Adventures with instruments: science and seafaring in the precarious career of Christopher Middleton
Authors: Bennett Jim
Published: July 2019

Christopher Middleton (d. 1770) was a sea captain, first with the Hudson's Bay Company, then in the Royal Navy, who was awarded the Royal Society's Copley Medal in 1742. His early work on magnetic variation in northern latitudes was encouraged by Edmond Halley, as he published a series of tables of variation in the
Philosophical Transactions
. These tables illustrate Middleton's transition from the priorities characteristic of the seaman's interest in variation to the wider, natural philosophical agenda of the Society. They illustrate also his enthusiasm for novel instrumentation, in particular altitude instruments for use at sea, such as Hadley's quadrant. Middleton was persuaded by Arthur Dobbs to resign from the Hudson's Bay Company and accept a commission in the Royal Navy so as to command an expedition to search for a Northwest Passage to the East Indies from Hudson's Bay. It was his report on this voyage that won him the Copley Medal but which also led to a bitter and, for Middleton, ruinous public dispute with Dobbs. Middleton emerges as an outstanding seaman and a worthy, if relatively unknown, medallist.
An antibody-tumor necrosis factor fusion protein that synergizes with oxaliplatin for treatment of colorectal cancer
Authors: Bajic Davor , Chester Kerry A. , Neri Dario
Published: July 2019

We have cloned and characterized a novel fusion protein (Sm3E-TNF), consisting of the monoclonal antibody Sm3E in single-chain Fv fragment format, fused to murine tumor necrosis factor. The protein, which was expressed in mammalian cells and purified as a non-covalent stable homotrimer, bound to the cognate carcinoembryonic antigen (CEA) and retained tumor necrosis factor activity. A quantitative biodistribution experiment, performed in immunocompetent mice with CT26 colon carcinomas transfected with human CEA, revealed that Sm3E-TNF was able to preferentially accumulate in the tumors with excellent selectivity (tumor:blood ratio = 56:1, twenty-four hours after intravenous administration). The fusion protein mediated a rapid hemorrhagic necrosis of a large portion of the tumor mass, but a rim survived and eventually regrew. Surprisingly, the combination of Sm3E-TNF with 5-fluorouracil led to a reduction of therapeutic activity, while a combination with oxaliplatin led to a prolonged stabilization, with complete tumor eradication in 40% of treated mice. These therapy results were confirmed in a second immunocompetent mouse model of colorectal cancer (CEA-transfected C51 tumors) and provide a rationale for the possible clinical use of oxaliplatin in combination with fully-human antibody-TNF fusions.
Structural Basis of Enhanced Facilitated Diffusion of DNA Binding Proteins in Crowded Cellular Milieu
Authors: Dey P. , Bhattacherjee A.
Published: July 2019

DNA binding proteins (DBPs) rapidly recognize and specifically associate with their target DNA sites inside cell nucleus that contains up to 400 g/L macromolecules, most of which are proteins. While the fast association between DBPs and DNA is explained by a facilitated diffusion mechanism, where DBPs adopt a weighted combination of 3D diffusion and 1D sliding and hopping modes of transportation, the role of cellular environment that contains many nonspecifically interacting proteins and other biomolecules is mostly overlooked. By performing large scale computational simulations with an appropriately tuned model of protein and DNA in the presence of nonspecifically interacting bulk and DNA bound crowders (genomic crowders), we demonstrate the structural basis of the enhanced facilitated diffusion of DBPs inside a crowded cellular milieu through novel 1D scanning mechanisms. In the presence of bulk crowders, we identify the protein to float along the DNA under the influence of protein-crowder nonspecific interactions. The search mode is distinctly different compared to usual 1D sliding and hopping dynamics where protein diffusion is regulated by the DNA electrostatics. In contrast, the presence of genomic crowders expedite the target search process by transporting the protein over DNA segments through the formation of a transient protein-crowder bridged complex. By analyzing the ruggedness of the associated potential energy landscape, we underpin the molecular origin of the kinetic advantages of these search modes and show that they successfully explain the experimentally observed acceleration of facilitated diffusion of DBPs by molecular crowding agents and crowder concentration dependent enzymatic activity of transcription factors. Our findings provide crucial insights into gene regulation kinetics inside the crowded cellular milieu.

SIGNIFICANCE

10-40% of the intracellular volume is occupied by proteins, and other biomolecules, collectively known as macromolecular crowders. Their presence has been found to promote faster translocation of DNA binding proteins (DBPs) during the search of their target DNA sites for crucial cellular processes. Using molecular simulations, we probe the underlying structural basis and underscore the existence of novel DNA scanning mechanisms actuated by protein-crowder nonspecific interactions. We show that the observed search modes are kinetically beneficial and can successfully explain the acceleration of facilitated diffusion of DBPs by molecular crowding agents and crowderconcentration dependent enzymatic activity of transcription factors.Our study sheds new light on the long-standing facilitated diffusion problem of DBPs in the crowded cellular environment for regulating gene expression.
DeepPrime2Sec: Deep Learning for Protein Secondary Structure Prediction from the Primary Sequences
Authors: Asgari Ehsaneddin , Poerner Nina , McHardy Alice C. , Mofrad Mohammad R.K.
Published: July 2019

Motivation

Here we investigate deep learning-based prediction of protein secondary structure from the protein primary sequence. We study the function of different features in this task, including one-hot vectors, biophysical features, protein sequence embedding (ProtVec), deep contextualized embedding (known as ELMo), and the Position Specific Scoring Matrix (PSSM). In addition to the role of features, we evaluate various deep learning architectures including the following models/mechanisms and certain combinations: Bidirectional Long Short-Term Memory (BiLSTM), convolutional neural network (CNN), highway connections, attention mechanism, recurrent neural random fields, and gated multi-scale CNN. Our results suggest that PSSM concatenated to one-hot vectors are the most important features for the task of secondary structure prediction.

Results

Utilizing the CNN-BiLSTM network, we achieved an accuracy of 69.9% and 70.4% using ensemble top-k models, for 8-class of protein secondary structure on the CB513 dataset, the most challenging dataset for protein secondary structure prediction. Through error analysis on the best performing model, we showed that the misclassification is significantly more common at positions that undergo secondary structure transitions, which is most likely due to the inaccurate assignments of the secondary structure at the boundary regions. Notably, when ignoring amino acids at secondary structure transitions in the evaluation, the accuracy increases to 90.3%. Furthermore, the best performing model mostly mistook similar structures for one another, indicating that the deep learning model inferred high-level information on the secondary structure.

Availability

The developed software called DeepPrime2Sec and the used datasets are available athttp://llp.berkeley.edu/DeepPrime2Sec.

Contact

mofrad@berkeley.edu
A Multistage Sequencing Strategy Pinpoints Many Novel and Candidate Disease Alleles for Orphan Disease Emery-Dreifuss Muscular Dystrophy and Supports Gene Misregulation as its Pathomechanism
Authors: Meinke Peter , Kerr Alastair R. W. , Czapiewski Rafal , de las Heras Jose I. , Harris Elizabeth , Kölbel Heike , Muntoni Francesco , Schara Ulrike , Straub Volker , Schoser Benedikt , Wehnert Manfred , Schirmer Eric C.
Published: July 2019

Limitations of genome-wide approaches for genetically-heterogenous orphan diseases led us to develop a new approach to identify novel Emery-Dreifuss muscular dystrophy (EDMD) candidate genes. We generated a primer library to genes: (I) linked to EDMD, (II) mutated in related muscular dystrophies, (III) highlighted from limited exome sequencing, (IV) encoding muscle-specific nuclear membrane proteins. Sequencing 56 unlinked EDMD patients yielded confirmed or strong candidate alleles from all categories, accounting for most remaining unlinked patients. Known functions of newly-linked genes argue the EDMD pathomechanism is from altered gene regulation and mechanotransduction through connectivity of candidates from the nuclear envelope to the plasma membrane.
Genetic architecture influences when and how hybridization contributes to colonization
Authors: Reatini Bryan , Vision Todd J.
Published: July 2019

The role of genetic architecture in adaptation to novel environments has received considerable attention when the source of adaptation variation isde novomutation. Relatively less is known when the source of adaptive variation is inter- or intraspecific hybridization. We model hybridization between divergent source populations and subsequent colonization of an unoccupied novel environment using individual-based simulations in order to understand the influence of genetic architecture on the timing of colonization and the mode of adaptation. We find that two distinct categories of genetic architecture facilitate rapid colonization but that they do so in qualitatively different ways. For few and/or tightly linked loci, the mode of adaptation is via the recovery of adaptive parental genotypes. With many unlinked loci, the mode of adaptation is via the generation of novel hybrid genotypes. The first category results in the shortest colonization lag phases across the widest range of parameter space, but further adaptation is mutation limited. The second category takes longer and is more sensitive to genetic variance and dispersal rate, but can facilitate adaptation to environmental conditions which exceed the tolerance of parental populations. These findings have implications for understanding the origins of biological invasions and the success of hybrid populations.
Structural basis of DNA targeting by a transposon-encoded CRISPR-Cas system
Authors: Halpin-Healy Tyler S. , Klompe Sanne E. , Sternberg Samuel H. , Fernández Israel S.
Published: July 2019

Bacteria have evolved adaptive immune systems encoded by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and the CRISPR-associated (Cas) genes to maintain genomic integrity in the face of relentless assault from pathogens and mobile genetic elements [1–3]. Type I CRISPR-Cas systems canonically target foreign DNA for degradation via the joint action of the ribonucleoprotein complex Cascade and the helicase-nuclease Cas3 [4,5] but nuclease-deficient Type I systems lacking Cas3 have been repurposed for RNA-guided transposition by bacterial Tn7-like transposons [6,7]. How CRISPR- and transposon-associated machineries collaborate during DNA targeting and insertion has remained elusive. Here we determined structures of a novel TniQ-Cascade complex encoded by the Vibrio cholerae Tn6677 transposon using single particle electron cryo-microscopy (cryo-EM), revealing the mechanistic basis of this functional coupling. The quality of the cryo-EM maps allowed for de novo modeling and refinement of the transposition protein TniQ, which binds to the Cascade complex as a dimer in a head-to-tail configuration, at the interface formed by Cas6 and Cas7 near the 3’ end of the crRNA. The natural Cas8-Cas5 fusion protein binds the 5’ crRNA handle and contacts the TniQ dimer via a flexible insertion domain. A target DNA-bound structure reveals critical interactions necessary for protospacer adjacent motif (PAM) recognition and R-loop formation. The present work lays the foundation for a structural understanding of how DNA targeting by TniQ-Cascade leads to downstream recruitment of additional transposon-associated proteins, and will guide protein engineering efforts to leverage this system for programmable DNA insertions in genome engineering applications.
Dopaminergic modulation of the exploration/exploitation trade-off in human decision-making
Authors: Chakroun Karima , Mathar David , Wiehler Antonius , Ganzer Florian , Peters Jan
Published: July 2019

A central issue in reinforcement learning and decision-making is whether to exploit knowledge of reward values, or to explore novel options. Although it is widely hypothesized that dopamine neurotransmission plays a key role in regulating this balance, causal evidence for a role of dopamine in human exploration is still lacking. Here, we use a combination of computational modeling, pharmacological intervention and functional magnetic resonance imaging (fMRI) to test for a causal effect of dopamine transmission on the exploration-exploitation trade-off in humans. 31 healthy male subjects performed a restless four-armed bandit task in a within-subjects design under three drug conditions: 150mg of the dopamine precursor L-dopa, 2mg of the D2 receptor antagonist haloperidol, and placebo. In all conditions, choice behavior was best explained by an extension of an established Bayesian learning model accounting for perseveration, uncertainty-based exploration and random exploration. Uncertainty-based exploration was attenuated under L-dopa compared to placebo and haloperidol. There was no evidence for a modulation of prediction error signaling or categorical effects of exploration/exploitation under L-dopa, whereas model-based fMRI revealed that L-dopa attenuated neural representations of overall uncertainty in insula and dorsal anterior cingulate cortex. Our results highlight the computational role of these regions in exploration and suggest that dopamine modulates exploration by modulating how this circuit tracks accumulating uncertainty during decision-making.
Understanding interactions between risk factors, and assessing the utility of the additive and multiplicative models through simulations
Authors: Diaz-Gallo Lina-Marcela , Brynedal Boel , Westerlind Helga , Sandberg Rickard , Ramsköld Daniel
Published: July 2019

Interaction analysis is used to investigate the magnitude of an effect which two risk factors have on disease risk, and on each other. To study interactions, both additive and multiplicative models have been used, although their interpretations are not universally understood. In this study, we set out to investigate the resulting interactions of several risk factors relationships in additive or multiplicative scenarios using simulations, in the context of case-control studies. Our simulation set up showed that independent risk factors approach additive relative risk at low disease prevalence. However, risk factors that contribute to the same chain of events (i.e. have synergy) lead to multiplicative relative risk. Additionally, thresholds on the number of required risk factors for a disease (the multifactorial threshold model) lead to intermediaries between additive and multiplicative risks. We proposed a novel measure of interaction consistent with additive, multiplicative and multifactorial threshold models. Finally, we demonstrate the utility of the simulation strategy and discovered relationships on real data by analyzing and interpreting gene-gene odds ratios from a case-control rheumatoid arthritis study.
Towards the application of Tc toxins as a universal protein translocation system
Authors: Roderer Daniel , Schubert Evelyn , Sitsel Oleg , Raunser Stefan
Published: July 2019

Tc toxins are large bacterial protein complexes that inject cytotoxic enzymes into target cells using a sophisticated syringe-like mechanism. Tc toxins are composed of a membrane translocator and a cocoon that encapsulates a toxic enzyme. The toxic enzyme varies between Tc toxins from different species and is not conserved. Here, we investigated whether the toxic enzyme can be replaced by other small proteins of different origin and properties, namely human Cdc42, herpes simplex virus ICP47, Arabidopsis thaliana iLOV, Escherichia coli DHFR, human Ras-binding domain of CRAF kinase, and tobacco etch virus protease. Using a combination of electron microscopy, X-ray crystallography and in vitro translocation assays, we demonstrate that it is possible to turn Tc toxins into customizable molecular syringes for delivering proteins of interest across membranes. We also infer the guidelines that protein cargos must obey in terms of size, charge, and fold in order to successfully take advantage of this new universal protein translocation system.
Retinal morphology inAstyanax mexicanusduring degeneration
Authors: Emam Amany , Yoffe Marina , Cardona Henry , Soares Daphne
Published: July 2019

The teleostAstyanax mexicanusis extant in two readily available forms. One that lives in Mexican rivers and various convergent forms that live in nearby caves. These fish are born with eyes but in the cavefish they degenerate during development. It is known that the lens of cavefish undergoes apoptosis and that some cells in the neuroretina also die. It has not been described, however, if glia and various components of the neuroretina form before complete eye degeneration. Here we examined the development of the retina of the closest living ancestor that lives in the rivers and members of two lineages of cavefish. We report that although the neuroretina is smaller and more compact, it has all cell types and layers including amacrine cells and Muller glia. While various makers for photoreceptors are present in the cavefish inner segments, the outer segments of the photoreceptors in cavefish are missing from the earliest stages examined. This shows that the machinery for visual transducing discs might still be present but not organized in one part of the cell. It is interesting to note that the deficiencies in Astyanax cavefish resemble retinal diseases, such as retinitis pigmentosa.
Defining chromatin state transitions predicts a network that modulates cell wall remodeling in phosphate-starved rice shoots
Authors: Foroozani Maryam , Zahraeifard Sara , Oh Dong-Ha , Wang Guannan , Dassanayake Maheshi , Smith Aaron
Published: July 2019

Phosphorus (P) is an essential plant macronutrient vital to fundamental metabolic processes. Plant-available P is low in most soils, making it a frequent limiter of growth. Declining P reserves for fertilizer production exasperates this agricultural challenge. Plants modulate complex responses to fluctuating P levels via global transcriptional regulatory networks. Although chromatin structure plays a substantial role in controlling gene expression, the chromatin dynamics involved in regulating P homeostasis have not been determined. Here we define distinct chromatin states across the rice genome by integrating multiple aspects of chromatin structure, including the H2A.Z histone variant, H3K4me3 modification, and nucleosome positioning. In response to P starvation, 40% of all protein-coding genes exhibit a transition from one chromatin state to another at their transcription start site. Several of these transitions are enriched in subsets of genes differentially expressed by P deficiency. The most prominent subset supports the presence of a coordinated signaling network that targets cell wall structure and is regulated in part via a decrease of H3K4me3 at the transcription start site. The P-starvation induced chromatin dynamics and correlated genes identified here will aid in enhancing P-use efficiency in crop plants, benefitting global agriculture.

One sentence summary

Combining data for three components of chromatin structure from control and phosphate-starved rice shoots reveals specific chromatin state transitions that correlate with subsets of functionally distinct differentially-expressed genes.
Functional community assembly and turnover along elevation and latitude
Authors: Jarzyna Marta A. , Quintero Ignacio , Jetz Walter
Published: July 2019

The drivers of community coexistence are known to vary with environment, but their consistency across latitudes and scales, and resulting conservation implications, remain little understood. Here, we combine functional and phylogenetic evidence along elevations to document strong biotic constraints on coexistence in avian communities in both benign (tropical low elevations) and severely harsh (temperate/polar highlands) environments. Assemblages in both are marked by high assemblage functional uniqueness, whereas in tropical highlands and temperate/polar low elevations there is strong functionally redundancy and pronounced environmental constraints. Only in harsh environments is phylogeny an effective surrogate for functional assemblage structure, reflecting nuanced shifts in the position, shape, and composition of measured multivariate trait space along gradients. Independent of scale and latitude, high elevation assemblages emerge as exceptionally susceptible to functional change.
Early diverging fungus Mucor circinelloides lacks centromeric histone CENP-A and displays a mosaic of point and regional centromeres
Authors: Navarro-Mendoza María Isabel , Pérez-Arques Carlos , Panchal Shweta , Nicolás Francisco E. , Mondo Stephen J. , Ganguly Promit , Pangilinan Jasmyn , Grigoriev Igor V. , Heitman Joseph , Sanyal Kaustuv , Garre Victoriano
Published: July 2019

Centromeres are rapidly evolving across eukaryotes, despite performing a conserved function to ensure high fidelity chromosome segregation. CENP-A chromatin is a hallmark of a functional centromere in most organisms. Due to its critical role in kinetochore architecture, the loss of CENP-A is tolerated in only a few organisms, many of which possess holocentric chromosomes. Here, we characterize the consequence of the loss of CENP-A in the fungal kingdom. Mucor circinelloides, an opportunistic human pathogen, lacks CENP-A along with the evolutionarily conserved CENP-C, but assembles a monocentric chromosome with a localized kinetochore complex throughout the cell cycle. Mis12 and Dsn1, two conserved kinetochore proteins were found to bind nine short overlapping regions, each comprising an ∼200-bp AT-rich sequence followed by a centromere-specific conserved motif that echoes the structure of budding yeast point centromeres. Resembling fungal regional centromeres, these core centromere regions are embedded in large genomic expanses devoid of genes yet marked by Grem-LINE1s, a novel retrotransposable element silenced by the Dicer-dependent RNAi pathway. Our results suggest that these hybrid features of point and regional centromeres arose from the absence of CENP-A, thus defining novel mosaic centromeres in this early-diverging fungus.
A selective and rapid cell-permeable inhibitor of human caspase-3
Authors: Solania Angelo , González-Páez Gonzalo E. , Wolan Dennis W.
Published: July 2019

The individual roles and overlapping functionalities the twelve human caspases have during apoptosis and other cellular processes remain poorly resolved primarily due to a lack of chemical tools. Here we present a new selective caspase-3 inhibitor, termed Ac-ATS010-KE, with rapid and irreversible binding kinetics. Relative to previously designed caspase-3-selective molecules that have tremendously abated inhibitory rates and thus limited use in biological settings, the improved kinetics of Ac-ATS010-KE permit its use in a cell-based capacity. We demonstrate that Ac-ATS010-KE prevents apoptosis with comparable efficacy to the general caspase inhibitor Ac-DEVD-KE and surprisingly does so without side-chain methylation. This observation is in contrast to the well-established peptide modification strategy typically employed for improving cellular permeability. Ac-ATS010-KE protects against extrinsic apoptosis, which demonstrates the utility of a thiophene carboxylate leaving group in biological settings, challenges the requisite neutralization of free carboxylic acids to improve cell permeability, and provides a tool-like compound to interrogate the role of caspase-3 in a variety of cellular processes.
Paternal age in rhesus macaques is positively associated with germline mutation accumulation but not with measures of offspring sociability
Authors: Wang Richard J. , Thomas Gregg W.C. , Raveendran Muthuswamy , Harris R. Alan , Doddapaneni Harshavardhan , Muzny Donna M. , Capitanio John P. , Radivojac Predrag , Rogers Jeffrey , Hahn Matthew W.
Published: July 2019

Mutation is the ultimate source of all genetic novelty and the cause of heritable genetic disorders. Mutational burden has been linked to complex disease, including neurodevelopmental disorders such as schizophrenia and autism. The rate of mutation is a fundamental genomic parameter and direct estimates of this parameter have been enabled by accurate comparisons of whole-genome sequences between parents and offspring. Studies in humans have revealed that the paternal age at conception explains most of the variation in mutation rate: each additional year of paternal age in humans leads to approximately 1.5 additional mutations inherited by the child. Here, we present an estimate of the de novo mutation rate in the rhesus macaque (Macaca mulatta) using whole-genome sequence data from 32 individuals in four large pedigrees. We estimated an average mutation rate of 0.58 × 10-8 per base pair per generation (at an average parental age of 7.5 years), much lower than found in direct estimates from great apes (including human, chimpanzee, and gorilla). As in humans, older macaque fathers transmit more mutations to their offspring, approximately 1.5 extra mutations per year in our probands. Mutations at CpG sites accounted for 24% of all observed point mutations. We found that the rate of mutation accumulation after puberty is similar between macaques and humans, but that a smaller number of mutations accumulate before puberty in macaques. We additionally investigated the role of paternal age on offspring sociability, a proxy for normal neurodevelopment. In 203 male macaques studied in large social groups, we found no relationship between paternal age and multiple measures of social function. Our findings are consistent with the hypothesis that the increased risk of neurodevelopmental disorders with paternal age in primates is not primarily due to de novo mutations.
Fighting or Embracing Multiplicity in Neuroimaging? Neighborhood Leverage versus Global Calibration
Authors: Chen Gang , Taylor Paul A. , Cox Robert W. , Pessoa Luiz
Published: July 2019

Neuroimaging faces the daunting challenge of multiple testing – an instance ofmultiplicity– that is associated with two other issues to some extent: low inference efficiency and poor reproducibility. Typically, the same statistical model is applied to each spatial unit independently in the approach of massively univariate modeling. In dealing with multiplicity, the general strategy employed in the field is the same regardless of the specifics: trust the local “unbiased” effect estimates while adjusting the extent of statistical evidence at the global level. However, in this approach, modeling efficiency is compromised because each spatial unit (e.g., voxel, region, matrix element) is treated as an isolated and independent entity during massively univariate modeling. In addition, the required step of multiple testing “correction” by taking into consideration spatial relatedness, orneighborhood leverage, can only partly recoup statistical efficiency, resulting in potentially excessive penalization as well as arbitrariness due to thresholding procedures. Moreover, the assigned statistical evidence at the global level heavily relies on the data space (whole brain or a small volume). The present paper reviews how Stein’s paradox (1956) motivates a Bayesian multilevel (BML) approach that, rather than fighting multiplicity, embraces it to our advantage through aglobal calibrationprocess among spatial units. Global calibration is accomplished via a Gaussian distribution for the cross-region effects whose properties are not a priori specified, but a posteriori determined by the data at hand through the BML model. Our framework therefore incorporates multiplicity as integral to the modeling structure, not a separate correction step. By turning multiplicity into a strength, we aim to achieve five goals: 1) improve model efficiency with higher predictive accuracy, 2) control the errors of incorrect magnitude and incorrect sign, 3) validate each model relative to competing candidates, 4) reduce the reliance and sensitivity on the choice of data space, and 5) encourage full results reporting. Our modeling proposal reverberates with recent proposals to eliminate the dichotomization of statistical evidence (“significant” vs. “non-significant”), to improve the interpretability of study findings, as well as to promote reporting the full gamut of results (not only “significant” ones), thereby enhancing research transparency and reproducibility.
Primitive and modern swimmers solve the challenges of turning similarly to achieve high maneuverability
Authors: Dabiri J. O. , Colin S. P. , Gemmell B. J. , Lucas K. N. , Leftwich Megan C. , Costello John H.
Published: July 2019

Animal swimmers alter trajectories – or turn - for a variety of critical life functions such as feeding, mating and avoiding predation. Yet turning represents a fundamental dilemma based in rotational dynamics: the torque powering a turn is favored by an expanded body configuration, yet minimizing the resistance to a turn (the moment of inertia) is favored by a contracted body configuration. How do animals balance these opposing demands to achieve high maneuverability? By noninvasively measuring fluid and body motions, we found that both jellyfish (Aurelia aurita) and fish (Danio rerio) initially maximized torque using previously undescribed, rapid body movements. Both species then minimized resistance to turning by bending their bodies to reduce their moment of inertia. Use of this sequential solution by such distantly related animals as an invertebrate and a vertebrate suggests strong selection for these turning dynamics that may extend to other swimmers and inform future vehicle designs.
Modeling the control of bacterial infections via antibiotic-induced proviruses
Authors: Clifton Sara M. , Kim Ted , Chandrashekhar Jayadevi H. , O’Toole George A. , Rapti Zoi , Whitaker Rachel J.
Published: July 2019

Most bacteria and archaea are infected by latent viruses that change their physiology and responses to environmental stress. We use a population model of the bacteria-phage relationship to examine the role that latent phage play on the bacterial population over time in response to antibiotic treatment. We demonstrate that the stress induced by antibiotic administration, even if bacteria are resistant to killing by antibiotics, is sufficient to control the infection under certain conditions. This work expands the breadth of understanding of phage-antibiotic synergy to include both temperate and chronic viruses persisting in their latent form in bacterial populations.

Importance

Antibiotic-resistance is a growing concern for management of common bacterial infections. Here we show that antibiotics can be effective at sub-inhibitory levels when bacteria carry latent phage. Our findings suggest that specific treatment strategies based on the identification of latent viruses in individual bacterial strains may be an effective personalized medicine approach to antibiotic stewardship.
Selection may oppose invasion, yet favour fixation: consequences for evolutionary stability
Authors: Molina Chai , Earn David J. D.
Published: July 2019

Models of evolution by natural selection often make the simplifying assumption that populations are infinitely large. In this infinite population limit, rare mutations that are selected against always go extinct, whereas in finite populations they can persist and even reach fixation. Nevertheless, for mutations of small phenotypic effect, it is widely believed that in sufficiently large populations, if selection opposes the invasion of rare mutants, then it also opposes their fixation. Here, we identify circumstances under which infinite-population models do or do not accurately predict evolutionary outcomes in large, finite populations. We show that there is no population size above which considering only invasion generally suffices: for any finite population size, there are situations in which selection opposes the invasion of mutations of arbitrarily small effect, but favours their fixation. This is not an unlikely limiting case; it can occur when fitness is a smooth function of the evolving trait, and when the selection process is biologically sensible. Nevertheless, there are circumstances under which opposition of invasion does imply opposition of fixation: in fact, for the n-player snowdrift game (a common model of cooperation) we identify sufficient conditions under which selection against rare mutants of small effect precludes their fixation—in sufficiently large populations—for any selection process. We also find conditions under which—no matter how large the population—the trait that fixes depends on the selection process, which is important because any particular selection process is only an approximation of reality.
Elasticity and Topography-Controlled Collagen Hydrogels Mimicking Native Cellular Milieus
Authors: Oyama Tomoko Gowa , Oyama Kotaro , Kimura Atsushi , Yoshida Fumiya , Ishida Ryo , Yamazaki Masashi , Miyoshi Hiromi , Taguchi Mitsumasa
Published: July 2019

Accumulating evidence demonstrates that the elasticity and topography of a cell culture substrate influence cell behavior, in addition to its chemical composition. However, cellular responses to in vivo extracellular matrix (ECM), a hydrogel of proteins (mainly collagen) with various elasticity and a nanometer-to micrometer-scale topography, remain to be elucidated owing to a lack of substrate that provides such complex cues. This study introduces novel collagen hydrogels that can combine, for the first time, elastic, topographic, and compositional cues that recapitulate native ECM. A simple and reagent-free method based on radiation crosslinking alters ECM-derived collagen solutions into hydrogels with a well-defined and tunable elastic modulus covering the broad range of soft tissues (1–236 kPa) and microtopographies while ensuring intrinsic biological functionality of collagen. These collagen hydrogels enabled investigating cell responses to soft topographic cues such as those encountered in vivo, revealing that topography overrides the elasticity and structurally constrains cell morphology by controlling actin cytoskeleton organization. The collagen hydrogels not only reduce in vivo and in vitro behavioral disparity of cells by mimicking native ECM but also facilitate the design of artificial ECM to control cell function and fate in tissue engineering and regenerative medicine.