bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of “Learn the Signs. Act Early.” Materials on Parental Engagement and Doctor Interaction Regarding Child Development
Authors: Gadomski Anne M. , Riley Moira R. , Scribani Melissa , Tallman Nancy
Published: July 2018

Objective:

To measure the effectiveness of the “Learn the Signs. Act Early.” (LTSAE) educational materials in increasing parent engagement in developmental monitoring during well-child visits.

Methods:

Exit surveys and analysis of audio-taped well-child visits were compared pre- versus post-LTSAE exposure. Before the LTSAE, parents were exposed to usual pediatric clinic developmental surveillance practices. After the LTSAE, parents received LTSAE materials before well-child visits, received age-specific LTSAE checklists at the clinic visit, and were exposed to LTSAE posters in examination rooms. Pediatricians attended a didactic session on developmental screening and LTSAE materials. Children evenly distributed among the ages of 2, 4, 6, 9, 12, and 18 months and 2 and 3 years were consecutively recruited at their well-child visits. After the visit, all parents completed exit surveys that assessed 5 a priori outcomes: milestone awareness, level of concern if the child is late in reaching a milestone, likelihood of bringing up a concern to the doctor, level of confidence in knowing what to do if concerned, or talking about child development during the visit. A 25% visit subsample was audio-taped, transcribed, and coded for parental engagement and nurse/doctor response to parental concern.

Results:

No demographic differences were found between the 181 parents enrolled before the LTSAE and 182 after the LTSAE. LTSAE exposure was significantly higher after the LTSAE (p < 0.0001). After the LTSAE, parent awareness of the number of milestones increased (p = 0.03). Audiotape analysis showed that parents were more engaged in discussions about development post-LTSAE versus pre-LTSAE.

Conclusion:

The LTSAE may improve developmental surveillance by increasing parent's awareness of and discussion about milestones.
Screening for Autism Spectrum Disorder: Profiles of Children Who Are Missed
Authors: Beacham Chloe , Reid Morganne , Bradshaw Jessica , Lambha Meena , Evans Lindsey , Gillespie Scott , Klaiman Cheryl , Richardson Shana S.
Published: July 2018

Objective:

To characterize children presenting with concerns for autism spectrum disorder (ASD) missed by parent-report screeners and to examine benefits of a combined screening approach with the Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) and the Ages and Stages Questionnaire, Third Edition (ASQ-3).

Methods:

Participants included were 154 children aged 16 to 42 months presenting for an evaluation at an autism center. Caregivers completed the M-CHAT-R, ASQ-3, and a demographic questionnaire. Children participated in an autism diagnostic evaluation consisting of the Mullen Scales of Early Learning (Mullen) and Autism Diagnostic Observation Schedule, Second Edition (ADOS-2).

Results:

A total of 124 children (81%) were diagnosed with ASD. The M-CHAT-R identified 85% (n = 105) of these children. Children with ASD missed by the M-CHAT-R had significantly higher scores on the Mullen and significantly lower scores on the ADOS-2. Of the ASQ-3 domains, the majority (n = 102, 82%) of children with ASD failed the communication domain; missed cases showed similar patterns of higher Mullen scores and lower ADOS-2 scores. When adopting a combined screening approach, using a failed screen from either the M-CHAT-R or ASQ-3 communication domain, 93% of children were identified. Parent-reported concerns on an open-ended questionnaire revealed ASD red flags for many missed cases.

Conclusion:

Children with ASD missed by screeners had higher scores on developmental testing and lower scores on the ADOS-2; however, children still performed below average on developmental tests. Our findings suggest that a combined screening approach was most effective for identifying children with ASD from a sample group referred for an ASD evaluation.
Ophthalmic Plastic Surgery in Patients 100 Years and Older
Authors: Wolkow Natalie , Weinberg David A. , Bersani Thomas A. , Yoon Michael K. , Lefebvre Daniel R. , Lee Nahyoung Grace , Sutula Francis C. , Mandeville John T. , Hatton Mark P. , Freitag Suzanne K.
Published: July 2018

Purpose:

The centenarian population is growing and ophthalmic plastic surgeons are providing care to an increasing number of elderly patients. Outcomes of centenarians have not been previously studied in the ophthalmic plastic surgery literature. The goal of the current review was to examine the baseline characteristics, surgical problems, and outcomes of this select group of patients.

Methods:

A retrospective chart review was performed. Patients who underwent ophthalmic plastic surgery at age 100 or older between January 2000 and June 2016 by a member of the New England Oculoplastics Society were included in the study.

Results:

Fifteen patients met inclusion criteria. The majority (66%) were female. More than half (60%) presented with a surgical problem of an urgent nature. Most disorders involved the lacrimal system or eyelids, and many were the result of trauma or infection. There were no cases of orbital tumor or thyroid eye disease. There were no surgical or anesthesia-related complications. Most patients (80%) had no documented history of dementia, and only 1 was diabetic. Notably, 33% of patients presented with no light perception vision in at least 1 eye.

Conclusions:

Ophthalmic plastic surgery can be performed safely in select patients 100 years of age and older. Formal prospective studies are needed to improve surgical care in this group.
Treatment of Articular Cartilage Injuries in the Glenohumeral Joint
Authors: McCarthy Meagan M. , McCarty Eric
Published: July 2018

Articular cartilage injuries in the glenohumeral joint present a unique and difficult problem for the patient and surgeon alike. Various etiologies exist for the development of these cartilage lesions; therefore, treatment options are vast and must be chosen thoughtfully, especially in the young, active patient. Across all treatment modalities, the goal is for the patient to regain lasting function and mobility while decreasing pain.
Traumatic Anterior Instability: Treatment Options for Initial Instability
Authors: Dugas Jeffrey R. , Crozier Matthew W.
Published: July 2018

Because of the lack of bony restraints and minimal articular contact, the glenohumeral joint can attain significant range of motion; however, this results in the propensity for instability. The most generic form of instability, traumatic anterior instability, reliably produces a series of pathoanatomic findings. While reliable, these findings contribute to the complexities of caring for patients after an initial instability event. Numerous studies have examined this issue and determined that careful consideration of patient factors can guide successful treatment, whether it be surgical or nonsurgical, after initial instability. Such forms of treatment have shown to provide a good functional outcome and decreases morbidity. To be able to provide successful treatment requires a thorough understanding of the pathoanatomic of an instability event and the intricacies of the evaluation of a patient after an initial instability event.
Impact of Obesity on Pediatric Acute Recurrent and Chronic Pancreatitis
Authors: Uc Aliye , Zimmerman M. Bridget , Wilschanski Michael , Werlin Steven L. , Troendle David , Shah Uzma , Schwarzenberg Sarah Jane , Rhee Sue , Pohl John F. , Perito Emily R. , Palermo Joseph J. , Ooi Chee Y. , Liu Quin , Lin Tom K. , Morinville Veronique D. , McFerron Brian A. , Husain Sohail Z. , Himes Ryan , Heyman Melvin B. , Gonska Tanja , Giefer Matthew J. , Gariepy Cheryl E. , Freedman Steven D. , Fishman Douglas S. , Bellin Melena D. , Barth Bradley , Abu-El-Haija Maisam , Lowe Mark E.
Published: July 2018

Objective

The aim of this study was to assess the impact of obesity on pediatric acute recurrent pancreatitis or chronic pancreatitis (CP).

Methods

We determined body mass index (BMI) status at enrollment in INSPPIRE (INternational Study group of Pediatric Pancreatitis: In search for a cuRE) cohort using CDC criteria for pediatric-specific BMI percentiles. We used the Cochran-Armitage test to assess trends and the Jonckheere-Terpstra test to determine associations.

Results

Of 446 subjects (acute recurrent pancreatitis, n = 241; CP, n = 205), 22 were underweight, 258 normal weight, 75 overweight, and 91 were obese. The BMI groups were similar in sex, race, and age at presentation. Hypertriglyceridemia was more common in overweight or obese. Obese children were less likely to have CP and more likely to have acute inflammation on imaging. Compared with children with normal weight, obese or overweight children were older at first acute pancreatitis episode and diagnosed with CP at an older age. Obese or overweight children were less likely to undergo medical or endoscopic treatment, develop exocrine pancreatic insufficiency, and require total pancreatectomy with islet autotransplantation. Diabetes was similar among all groups.

Conclusions

Obesity or overweight seems to delay the initial acute pancreatitis episode and diagnosis of CP compared with normal weight or underweight. The impact of obesity on pediatric CP progression and severity deserves further study.
Work–Life BALANCE: How Some Case Managers Do It!
Authors: Powell Suzanne K.
Published: July 2018

Estimates of the health care workforce place the number with burnout symptoms as high as 60%. Case management—whichever discipline you practice in—is a stressful job, fraught with compassion fatigue and physical, mental, and spiritual signs of burnout. If not careful, those feelings can spill into one's entire life. A small convenience sample was used to determine how some case managers find their work–life balance.
Risk Factors for the Development of Postoperative Delirium in Pediatric Intensive Care Patients
Authors: Meyburg Jochen , Dill Mona-Lisa , von Haken Rebecca , Picardi Susanne , Westhoff Jens Hendrik , Silver Gabrielle , Traube Chani
Published: July 2018

Objectives:

To determine and quantify risk factors for postoperative pediatric delirium.

Design:

Single-center prospective cohort study.

Setting:

Twenty-two bed PICU in a tertiary care academic medical center in Germany.

Patients:

All children admitted after major elective surgery (n = 93; 0–17 yr).

Interventions:

After awakening, children were screened for delirium using the Cornell Assessment of Pediatric Delirium bid over a period of 5 days. Demographic and clinical data were collected from the initiation of general anesthesia.

Measurements and Main Results:

A total of 61 patients (66%) were delirious. Younger children developed delirium more frequently, and the symptoms were more pronounced. The number of preceding operations did not influence the risk of delirium. Total IV anesthesia had a lower risk than inhalational anesthesia (p < 0.05). Duration of anesthesia was similar in all groups. Patients with delirium had a longer duration of mechanical ventilation in the PICU (p < 0.001). Significant differences in cumulative doses of various medications (e.g., sedatives, analgesics, and anticholinergics) were noted between groups; these differences were independent of disease severity. Invasive catheters and respiratory devices (p < 0.01) as well as infections (p < 0.001) increased risk of delirium.

Conclusions:

A high prevalence of delirium was noted in the PICU, and several perioperative risk factors were identified. Our data may be a base for development of strategies to prevent and treat postoperative delirium in children.
Effect of Turbinate Intervention on Nasal Functions in Septorhinoplasty Surgery
Authors: Kiliç Erkan , Batioglu-Karaaltin Ayşegül , Ugurlar Müge , Erdur Zülküf Burak , Inci Ender
Published: July 2018

Objective:

This study was performed to evaluate the effect of inferior turbinate reduction on nasal function.

Materials and Methods:

A total of 32 patients who underwent septorhinoplasty (SRP) operation were included in the study and assigned into 2 groups as group I who received inferior turbinate reduction during SRP operation consisted of 17 patients and the group II who consisted of 15 patients without inferior turbinate reduction. For 2 groups before and after surgery, visual analogue score and findings of the acoustic rhinometry were recorded both before and after decongestion of the nasal mucosa.

Results:

Postoperative mean visual analogue scale (VAS) scores revealed a statistically significant reduction compared with preoperative values on right and left side of the nasal cavity, both before and after topical decongestion in group I (P < 0.005). Also in group II, the differences of VAS scores for both sides before and after topical decongestion were statistically significant (P < 0.05). Postoperatively, the increase of the volume measurements at the level of pyriform sinüs (VOL2) value on the right side of the nasal cavity before and after decongestion and volume measurements at the level of the nasal valve (VOL1) values on both sides after topical decongestion were found to be statistically significant in group I. When the VAS scores and acoustic rhinometry measurements of group I and group II patients were compared the difference, for before and after topical decongestion, postoperative mean MCA1 (minimal cross-sectional area at the level of the nasal valve) values for left side and right side of nasal cavity were higher in group I than group II and these differences were statistically significant (P < 0.005).

Conclusions:

As a result, in the SRP operations, turbinoplasty should be implemented by taking into account the function as well as aesthetic concern. Similar results were obtained in other studies that were carried on.
Miniaturized Electromagnetic Device Abutment Improves Stability of the Dental Implants
Authors: Barak Shlomo , Matalon Shlomo , Dolkart Oleg , Zavan Barbara , Mortellaro Carmen , Piattelli Adriano
Published: July 2018

Background:

The overall success and predictability of dental implant treatment hinge on the primary stability, direct bone-to implant contact formation, and quantity and/or quality of residual bone. Pulsed electromagnetic field has been reported to increase bone regeneration in various clinical situations. Therefore, it was hypothesized that devices which could locally generate a Pulsed electromagnetic field would stimulate bone healing and increase bone density surrounding implants.

Objective:

To retrospectively assess the effects of the miniaturized electromagnetic device (MED) on the implants stability for the first time in human subjects, in a prospective case controlled series.

Methods:

Twelve consecutive patients (28 implants) were included in the study.

Twelve MED healing caps and 16 regular control healing caps were inserted. Resonance frequency analysis (RFA) was performed at implant placement and abutment connection and an implant stability quotient value was given for each implant.

Results:

Twenty-eight dental implants were included in the current study. Maxillary implants stability was significantly higher with MED healing cups compared with controls at 15 days postimplantation (66.2 vs 62.1, P = .0008). Resonance frequency analysis test performed at 30 days postimplantation demonstrated significantly increased stability in MED as compared with the control 73.5 ± 3.2 vs 66.7 ± 4.8 in mandibular implants and 74 ± 1.7 vs 65 ± 2.3 in maxillary implants. At the 50 days postimplantation, RFA tests revealed markedly higher stability of the maxillary implants with MED active healing caps compared with nonactive 75.4 ± 5.1 vs 68.5 ± 8.5, respectively.

Conclusions:

We conclude that MED-abutment implants demonstrated a superior stability during the early phase of healing as compared with standard implants.
Machine learning without borders? An adaptable tool to optimize mortality prediction in diverse clinical settings
Authors: Christie S. Ariane , Hubbard Alan E. , Callcut Rachael A. , Hameed Morad , Dissak-Delon Fanny Nadia , Mekolo David , Saidou Arabo , Mefire Alain Chichom , Nsongoo Pierre , Dicker Rochelle A. , Cohen Mitchell Jay , Juillard Catherine
Published: July 2018

BACKGROUND

Mortality prediction aids clinical decision making and is necessary for quality improvement initiatives. Validated metrics rely on prespecified variables and often require advanced diagnostics, which are unfeasible in resource-constrained contexts. We hypothesize that machine learning will generate superior mortality prediction in both high-income and low- and middle-income country cohorts.

METHODS

SuperLearner, an ensemble machine-learning algorithm, was applied to data from three prospective trauma cohorts: a highest-activation cohort in the United States, a high-volume center cohort in South Africa (SA), and a multicenter registry in Cameroon. Cross-validation was used to assess model discrimination of discharge mortality by site using receiver operating characteristic curves. SuperLearner discrimination was compared with standard scoring methods. Clinical variables driving SuperLearner prediction at each site were evaluated.

RESULTS

Data from 28,212 injured patients were used to generate prediction. Discharge mortality was 17%, 1.3%, and 1.7% among US, SA, and Cameroonian cohorts. SuperLearner delivered superior prediction of discharge mortality in the United States (area under the curve [AUC], 94–97%) and vastly superior prediction in Cameroon (AUC, 90–94%) compared with conventional scoring algorithms. It provided similar prediction to standard scores in the SA cohort (AUC, 90–95%). Context-specific variables (partial thromboplastin time in the United States and hospital distance in Cameroon) were prime drivers of predicted mortality in their respective cohorts, whereas severe brain injury predicted mortality across sites.

CONCLUSIONS

Machine learning provides excellent discrimination of injury mortality in diverse settings. Unlike traditional scores, data-adaptive methods are well suited to optimizing precise site-specific prediction regardless of diagnostic capabilities or data set inclusion allowing for individualized decision making and expanded access to quality improvement programming.

LEVEL OF EVIDENCE

Prognostic and therapeutic, level II and III.
Perceptual consciousness and cognitive access from the perspective of capacity-unlimited working memory
Authors: Gross Steven
Published: July 2018

Theories of consciousness divide over whether perceptual consciousness is rich or sparse in specific representational content and whether it requires cognitive access. These two issues are often treated in tandem because of a shared assumption that the representational capacity of cognitive access is fairly limited. Recent research on working memory challenges this shared assumption. This paper argues that abandoning the assumption undermines post-cue–based ‘overflow’ arguments, according to which perceptual consciousness is rich and does not require cognitive access. Abandoning it also dissociates the rich/sparse debate from the access question. The paper then explores attempts to reformulate overflow theses in ways that do not require the assumption of limited capacity. Finally, it discusses the problem of relating seemingly non-probabilistic perceptual consciousness to the probabilistic representations posited by the models that challenge conceptions of cognitive access as capacity-limited.

This article is part of the theme issue ‘Perceptual consciousness and cognitive access'.
Challenges for theories of consciousness: seeing or knowing, the missing ingredient and how to deal with panpsychism
Authors: Lamme Victor A. F.
Published: July 2018

Significant progress has been made in the study of consciousness. Promising theories have been developed and a wealth of experimental data has been generated, both guiding us towards a better understanding of this complex phenomenon. However, new challenges have surfaced. Is visual consciousness about the seeing or the knowing that you see? Controversy about whether the conscious experience is better explained by theories that focus on phenomenal (P-consciousness) or cognitive aspects (A-consciousness) remains, and the debate seems to reach a stalemate. Can we ever resolve this? A further challenge is that many theories of consciousness seem to endorse high degrees of panpsychism—the notion that all beings or even lifeless objects have conscious experience. Should we accept this, or does it imply that these theories require further ingredients that would put a lower bound on beings or devices that have conscious experience? If so, what could these ‘missing ingredients’ be? These challenges are discussed, and potential solutions are offered.

This article is part of the theme issue ‘Perceptual consciousness and cognitive access’.
The methodological puzzle of phenomenal consciousness
Authors: Phillips Ian
Published: July 2018

Is phenomenal consciousness constitutively related to cognitive access? Despite being a fundamental issue for any science of consciousness, its empirical study faces a severe methodological puzzle. Recent years have seen numerous attempts to address this puzzle, either in practice, by offering evidence for a positive or negative answer, or in principle, by proposing a framework for eventual resolution. The present paper critically considers these endeavours, including partial-report, metacognitive and no-report paradigms, as well as the theoretical proposal that we can make progress by studying phenomenal consciousness as a natural kind. It is argued that the methodological puzzle remains obdurately with us and that, for now, we must adopt an attitude of humility towards the phenomenal.

This article is part of the theme issue ‘Perceptual consciousness and cognitive access’.
The offline stream of conscious representations
Authors: Sergent Claire
Published: July 2018

When do we become conscious of a stimulus after its presentation? We would all agree that this necessarily takes time and that it is not instantaneous. Here, I would like to propose not only that conscious access is
delayed
relative to the external stimulation, but also that it can flexibly
desynchronize
from external stimulation; it can process some information ‘offline’, if and when it becomes relevant. Thus, in contrast with initial sensory processing, conscious experience might not strictly follow the sequence of events in the environment. In this article, I will review gathering evidence in favour of this proposition. I will argue that it offers a coherent framework for explaining a great variety of observations in the domain of perception, sensory memory and working memory: the psychological refractory period, the attentional blink, post-dictive phenomena, iconic memory, latent working memory and the newly described retro-perception phenomenon. I will integrate this proposition to the global neuronal workspace model and consider possible underlying brain mechanisms. Finally, I will argue that this capacity to process information ‘offline’ might have made conscious processing evolutionarily advantageous in spite of its sluggishness and capacity limitations.

This article is part of the theme issue ‘Perceptual consciousness and cognitive access’.
Partial report is the wrong paradigm
Authors: Stazicker James
Published: July 2018

Is consciousness independent of the general-purpose information processes known as ‘cognitive access’? The dominant methodology for supporting this independence hypothesis appeals to partial report experiments as evidence for perceptual consciousness in the absence of cognitive access. Using a standard model of evidential support, and reviewing recent elaborations of the partial report paradigm, this article argues that the paradigm has the wrong structure to support the independence hypothesis. Like reports in general, a subject's partial report is evidence that she is conscious of information only where that information is cognitively accessed. So, partial report experiments could dissociate consciousness from cognitive access only if there were uncontroversial evidence for consciousness that did not imply reportability. There is no such evidence. An alternative, broadly Marrian methodology for supporting the independence hypothesis is suggested, and some challenges to it outlined. This methodology does not require experimental evidence for consciousness in the absence of cognitive access. Instead, it focuses on a function of perceptual consciousness when a stimulus is cognitively accessed. If the processes best suited to implement this function exclude cognitive access, the independence hypothesis will be supported. One relevant function of consciousness may be reflected in reason-based psychological explanations of a subject's behaviour.

This article is part of the theme issue ‘Perceptual consciousness and cognitive access’.
Consciousness without report: insights from summary statistics and inattention ‘blindness’
Authors: Usher Marius , Bronfman Zohar Z. , Talmor Shiri , Jacobson Hilla , Eitam Baruch
Published: July 2018

We contrast two theoretical positions on the relation between phenomenal and access consciousness. First, we discuss previous data supporting a mild Overflow position, according to which transient visual awareness can overflow report. These data are open to two interpretations: (i) observers transiently experience specific visual elements outside attentional focus without encoding them into working memory; (ii) no specific visual elements but only statistical summaries are experienced in such conditions. We present new data showing that under data-limited conditions observers cannot discriminate a simple relation (same versus different) without discriminating the elements themselves and, based on additional computational considerations, we argue that this supports the first interpretation: summary statistics (same/different) are grounded on the transient experience of elements. Second, we examine recent data from a variant of ‘inattention blindness’ and argue that contrary to widespread assumptions, it provides further support for Overflow by highlighting another factor, ‘task relevance’, which affects the ability to conceptualize and report (but not experience) visual elements.

This article is part of the theme issue ‘Perceptual consciousness and cognitive access’.
Transcriptome analysis of Azospirillum brasilense vegetative and cyst states reveals large-scale alterations in metabolic and replicative gene expression
Authors: Malinich Elizabeth A. , Bauer Carl E.
Published: July 2018

Several Gram-negative soil bacteria have the ability to differentiate into dormant cysts when faced with harsh environmental conditions. For example, when challenged with nutrient deprivation or desiccation, the plant-growth-promoting bacterium Azospirillum brasilense differentiates from a replicative and motile rod-shaped vegetative cell into a non-motile dormant spherical cyst. Currently, little is known about either the metabolic differences that exist between vegetative and cyst cell types, or about aspects of cyst physiology that allow dormant cells to survive harsh conditions. Here we compared transcriptomic profiles of vegetative and encysted A. brasilense. We observed that approximately one fifth of the A. brasilense transcriptome undergoes changes in expression between replicative vegetative cells and non-replicative cysts. A dramatic alteration in expression of genes involved in cell wall or cell membrane biogenesis was observed, which is congruent with changes in exopolysaccharide and lipid composition that occur between these cell types. Encysted cells also exhibited repressed mRNA abundance of genes involved in amino acid biosynthesis, ribosomal biogenesis and translation. We further observed that cysts create an anaerobic/micro-aerobic environment, as evidenced by repressed expression of oxidative phosphorylation genes coupled with increased expression of nitrate/nitrite reduction and nitrogen fixation genes.
Adaptation of human iPSC-derived cardiomyocytes to tyrosine kinase inhibitors reduces acute cardiotoxicity via metabolic reprogramming
Authors: Wang Huan , Sheehan Robert P. , Palmer Adam C. , Everley Robert A. , Boswell Sarah A. , Ron-Harel Noga , Ringel Alison E. , Holton Kristina M. , Jacobson Connor A. , Erickson Alison R. , Maliszewski Laura , Haigis Marcia C. , Sorger Peter K.
Published: July 2018

Tyrosine kinase inhibitors (TKIs) are widely used to treat solid tumors but can be cardiotoxic. The molecular basis for this toxicity and its relationship to therapeutic mechanisms remain unclear; we therefore undertook a systems-level analysis of human cardiomyocytes exposed to four TKIs. Cardiomyocytes (CMs) differentiated from human induced pluripotent stem cells (hiPSCs) were exposed to sunitinib, sorafenib, lapatinib or erlotinib and responses assessed by functional assays, microscopy, RNA sequencing and mass spectrometry (GEO GSE114686; PRIDE PXD012043). TKIs have diverse effects on hiPSC-CMs distinct from inhibition of tyrosine-kinase mediated signal transduction; cardiac metabolism is particularly sensitive. Following Sorafenib treatment, oxidative phosphorylation is down-regulated, resulting in a profound defect in mitochondrial energetics. Cells adapt by upregulating aerobic glycolysis. Adaptation makes cells less acutely sensitive to Sorafenib, but may have long-term negative consequences. Thus, cardiomyocytes exhibit adaptive responses to anti-cancer drugs conceptually similar to those previously shown in tumors to mediate drug resistance.
Mice developing mammary tumors evolve T cell sequences shared with human breast cancer patients
Authors: Gordin Miri , Philip Hagit , Zilberberg Alona , Gidoni Moriah , Margalit Raanan , Clouser Christopher , Adams Kristofor , Vigneault Francois , Cohen Irun R. , Yaari Gur , Efroni Sol
Published: July 2018

Cancer immunotherapy by checkpoint blockade proves that an effective immune response to a tumor can be induced clinically. However, little is known about the evolution of tumor-associated T-cell receptor (TCR) repertoires without intervention. Here we studied TCR repertoire evolution in mice spontaneously developing mammary tumors; we sequenced peripheral blood alpha and beta TCRs of CD4+CD62L+CD44− T cells monthly for 8 months in 10 FVB/NJ mice transgenic at the Erbb2 locus, all developing tumors; 5 FVB/NJ mice without the transgene were age-matched controls. Sequences were either private (restricted to one mouse) or public (shared among mice); public sequences were either exclusive to the tumor group or inclusive among different groups. We now report that 1), public AA sequences were each encoded by many different nucleotide sequences (NT) recombinations (convergent recombination; CR); 2) mice developing tumors evolved tumor-exclusive public sequences, derived initially from private or from inclusive public sequences; and 3) tumor-exclusive public sequences in mice were also present among published public TCR sequences from human breast cancer patients. These cross-species tumor-exclusive TCR sequences manifested high CR; but the AA sequences shared by mice and humans did not share NT sequences. Thus, tumor-exclusive TCR AA sequences across species are selected from different NT recombination events. The roles of tumor-exclusive TCR repertoires in advancing or inhibiting tumor development and the effects of tumor immunotherapy on these T cells remain to be seen.
Splice junction centric approach to identify translated noncanonical isoforms in the human proteome
Authors: Lau Edward , Han Yu , Lam Maggie P. Y.
Published: July 2018

RNA sequencing has led to the discovery of many transcript isoforms created by alternative splicing, but the translational status and functional significance of most alternative splicing events remain unknown. Here we applied a splice junction-centric approach to survey the landscape of protein alternative isoform expression in the human proteome. We focused on alternative splice events where pairs of splice junctions corresponding to included and excluded exons with appreciable read counts are translated together into selective protein sequence databases. Using this approach, we constructed tissue-specific FASTA databases from ENCODE RNA sequencing data, then reanalyzed splice junction peptides in existing mass spectrometry datasets across 10 human tissues (heart, lung, liver, pancreas, ovary, testis, colon, prostate, adrenal gland, and esophagus). Our analysis reidentified 1,108 non-canonical isoforms annotated in SwissProt. We further found 253 novel splice junction peptides in 212 genes that are not documented in the comprehensive Uniprot TrEMBL or Ensembl RefSeq databases. On a proteome scale, non-canonical isoforms differ from canonical sequences preferentially at sequences with heightened protein disorder, suggesting a functional consequence of alternative splicing on the proteome is the regulation of intrinsically disordered regions. We further observed examples where isoform-specific regions intersect with important cardiac protein phosphorylation sites. Our results reveal previously unidentified protein isoforms and may avail efforts to elucidate the functions of splicing events and expand the pool of observable biomarkers in profiling studies.

Acronyms and Abbreviations

A3SS

alternative 3-prime splice site;

A5SS

alternative 5-prime splice site;

FDR

false discovery rate;

IDR

intrinsically disordered regions;

MXE

mutually exclusive exons;

PSI

percent spliced in;

PTC

premature termination codon;

PTM

post-translational modifications;

SE

skipped exon;

RI

retained intron.
Haplotype-phased common marmoset embryonic stem cells for genome editing using CRISPR/Cas9
Authors: Zhou Bo , Ho Steve S. , Leung Louis C. , Ward Thomas R. , Ho Marcus , Plastini Melanie J. , Vermilyea Scott C. , Emborg Marina E. , Golos Thaddeus G. , Albertelli Megan A. , Mourrain Philippe , Perrin Dimitri , Parker Karen J. , Urban Alexander E.
Published: July 2018

Due to anatomical and physiological similarities to humans, the common marmoset (Callithrix jacchus) is an ideal organism for the study human diseases. Researchers are currently leveraging genome-editing technologies such as CRISPR/Cas9 to genetically engineer marmosets for the in vivo biomedical modeling of human neuropsychiatric and neurodegenerative diseases. The genome characterization of these cell lines greatly reinforces these transgenic efforts. It also provides the genomic contexts required for the accurate interpretation of functional genomics data. We performed haplotype-resolved whole-genome characterization for marmoset ESC line cj367 from the Wisconsin National Primate Research Center. This is the first haplotype-resolved analysis of a marmoset genome and the first whole-genome characterization of any marmoset ESC line. We identified and phased single-nucleotide variants (SNVs) and Indels across the genome. By leveraging this haplotype information, we then compiled a list of cj367 ESC allele-specific CRISPR targeting sites. Furthermore, we demonstrated successful Cas9 Endonuclease Dead (dCas9) expression and targeted localization in cj367 as well as sustained pluripotency after dCas9 transfection by teratoma assay. Lastly, we show that these ESCs can be directly induced into functional neurons in a rapid, single-step process. Our study provides a valuable set of genomic resources for primate transgenics in this post-genome era.
Probing the limits of activity-silent non-conscious working memory
Authors: Trübutschek Darinka , Marti Sébastien , Ueberschär Henrik , Dehaene Stanislas
Published: July 2018

Two types of working memory (WM) have recently been proposed: conscious active WM, depending on sustained neural activity, and activity-silent WM, requiring neither conscious awareness nor accompanying neural activity. However, whether both states support identical forms of information processing is unknown. Theory predicts that activity-silent states are confined to passive storage and cannot operate on stored information. To determine whether an explicit reactivation is required prior to the manipulation of information in WM, we evaluated whether participants could mentally rotate brief visual stimuli of variable subjective visibility. Behaviorally, even for unseen targets, subjects reported the rotated location above chance after several seconds. As predicted, however, such blindsight performance was accompanied by neural signatures of conscious reactivation at the time of mental rotation, including a sustained desynchronization in alpha/beta frequency and a decodable representation of participants’ guess and response. Our findings challenge the concept of genuine non-conscious “working” memory, argue that activity-silent states merely support passive short-term memory, and provide a cautionary note for purely behavioral studies of non-conscious information processing.
Negative memory engrams in the hippocampus enhance the susceptibility to chronic social defeat stress
Authors: Zhang Tian Rui , Larosa Amanda , Di Raddo Marie-Eve , Wong Vanessa , Wong Alice S. , Wong Tak Pan
Published: July 2018

The hippocampus has been highly implicated in depression symptoms. Recent findings suggest that the expression and susceptibility of depression symptoms are related to the enhanced functioning of the hippocampus. We reasoned that hippocampal engrams, which represent ensembles of neurons with increased activity after memory formation, could underlie some contributions of the hippocampus to depression symptoms. Using the chronic social defeat stress (CSDS) model, we examined social defeat-related hippocampal engrams in mice that are either susceptible or resilient to the stressor. TetTag mice were used to label social defeat-related hippocampal ensembles by LacZ. Engram cells correspond to ensembles that were reactivated by the same stressor.

Compared to resilient and non-stressed control mice, we found that in both the dorsal and ventral hippocampal CA1 regions, susceptible mice exhibited a higher reactivation of social defeat-related LacZ-labeled cells (i.e. engram cells). The density of CA1 engram cells correlated with the level of social avoidance. Using DREADD to reactivate social defeat-related but not neutral contextual stimuli-related CA1 engram cells decreased social interaction. Increased engram cells in susceptible mice were region specific and could not be found in the dentate gyrus. Susceptible mice exhibited more negative stimuli-, but not neutral stimuli-, related CA1 engram cells than resilient mice in the dorsal hippocampus. Finally, chronic, but not a short and subthreshold, social defeat protocol was necessary to increase CA1 engram cell density. Together, our findings reveal that the susceptibility to CSDS is regulated by hippocampal CA1 engrams for negative memory. Hippocampal engrams for negative memory may underlie the vulnerability and expression of cognitive symptoms in depression.

Significance statement

We provided evidence that negative memory hippocampal engrams contribute to the susceptibility to developing depression-related behavior after chronic social defeat stress. The activation of positive memory engrams have been shown to alleviate depression-related behaviors, while our findings reveal the pathological roles of negative memory engrams that could lead to those behaviors. Increased negative memory engrams could be a downstream effect of the reported high hippocampal activity in animal models and patients with depression. Unlike affective symptoms, we know much less about the cellular mechanisms of the cognitive symptoms of depression. Given the crucial roles of hippocampal engrams in memory formation, enhanced reactivation of negative memory engrams could be an important cellular mechanism that underlies the cognitive symptoms of depression.
A theoretical approach for discriminating accurately intrinsic pattern of biological systems and recognizing three kind soybean proteomes
Authors: Zou Huabin
Published: July 2018

proteomics is able to reveal plentiful information related to different physiological and pathological states of biology. Further, the determination of accurately proteomic pattern is the essential platform for deeply proteomic research. While this has been somewhat ignored so far. In this article the quantitative standard Pg=61%, a biological similarity constant for discriminating accurately intrinsic proteomic patterns was established depending on biological common heredity and variation information equation in symmetric variation state. On the other hand, a novel theoretical method was proposed for linearly dividing nonlinear data sequence into linear segments. The proteomes of three kind soybeans were precisely distinguished from one another by analyzing their infrared fingerprint spectra relying on this theoretically systemic approach. Additionally, methods employed in this paper enable us to quickly, accurately and quantitatively determine the proteomic patterns without using any prior knowledge and learning samples, and without using electrophoresis, high performance liquid chromatography-mass spectrometry techniques, which are high cost, time-consuming. This approach provide us with an excellent one for quickly accurate determining biological species, physiological states and diagnosing pathological states based on proteomes.
Bangers and cash: Baiting efficiency in a heterogeneous population.
Authors: Indigo Naomi Liza , Smith James , Webb Jonathan K , Phillips Ben
Published: July 2018

The uptake of baits is a key variable in management actions aimed at the vaccination, training, or control of many vertebrate species. Increasingly, however, it is appreciated that individuals of the target species vary in their likelihood of taking baits. To optimise a baiting program, then, we require knowledge, not only on the rate of bait uptake, and how this changes with bait availability, but also knowledge on the proportion of the target population that will take a bait. The invasive cane toad (Rhinella marina) is a major threat to northern quolls (Dasyurus hallucatus), which are poisoned when they attack this novel toxic prey item. Conditioned taste aversion baits (cane toad sausages) can be delivered in the field to train individual northern quolls to avoid toads. Here we report on a large-scale field trial across eleven sites across one large property in Western Australia. Camera trapping and statistical modelling was used to estimate the proportion of baitable animals in the population, and the proportion of these that were baited at varying bait availabilities. Population estimates varied at each site from 3.5 (0.76 SD) to 18 (1.58 SD) individual quolls per site, resulting in a range across sites of 0.6-4 baits available per individual. Bait uptake increased with increasing bait availability. We also estimate that only 62% of individual quolls are baitable, and that a baiting rate of 3 baits per individual (rather than per area) will result in almost all of these baitable individuals being treated. We compared our statistical method with prior data informing the probability of being baitable; and with probability of being baitable set to 1; this resulted in largely differing estimates in relation to an appropriate baiting rate. Data and models such as ours provide wildlife managers with information critical to informed decision making and are fundamental to estimate the cost-efficiency of any baiting campaign.
Characterizing molecular flexibility by combining lRMSD measures
Authors: Cazals F. , Tetley R.
Published: July 2018

The root mean square deviation (RMSD) and the least RMSD are two widely used similarity measures in structural bioinformatics. Yet, they stem from global comparisons, possibly obliterating locally conserved motifs. We correct these limitations with the so-called combined RMSD, which mixes independent lRMSD measures, each computed with its own rigid motion. The combined RMSD can be used to compare (quaternary) structures based on motifs defined from the sequence (domains, SSE), or to compare structures based on structural motifs yielded by local structural alignment methods.

We illustrate the benefits of combined RMSD over the usual RMSD on three problems, namely (i) the analysis of conformational changes based on combined RMSD of rigid structural motifs (case study: a class II fusion protein), (ii) the calculation of structural phylogenies (case study: class II fusion proteins), and (iii) the assignment of quaternary structures for hemoglobin. Using these, we argue that the combined RMSD is a tool a choice to perform positive and negative discrimination of degree of freedom, with applications to the design of move sets and collective coordinates.

Combined RMSD are available within the Structural Bioinformatics Library (http://sbl.inria.fr).
A centrosome calcium signal is essential for mammalian cell mitosis
Authors: Helassa Nordine , Nugues Charlotte , Burgoyne Robert D , Haynes Lee P
Published: July 2018

To generate a complex multicellular organism like a human requires enormous expansion in cell numbers and this is achieved predominantly through mitosis. Defects in mitosis can lead to premature ageing and cancer so understanding how it is regulated has important implications for human disease. Early data from plant and invertebrate model systems indicated that calcium (Ca2+) could influence mitosis. Here we explore this key question in the cell biology of mammalian cells by targeting high affinity genetically encoded Ca2+sensors to mitosis specific subcellular locations. We reveal a prolonged yet spatially restricted Ca2+signal at the centrosomes of mitotic cells using an actin-targeted Ca2+sensor. Local depletion of Ca2+at centrosomes using flash-photolysis of the caged Ca2+chelator diazo-2 arrests mitosis and we provide evidence that this signal emanates from the endoplasmic reticulum. In summary, we characterize a centrosomal Ca2+signal as a functionally essential input into mitosis. This extends our understanding of the complex regulatory network controlling cell division and pinpoints Ca2+as an important controller of this fundamental process.
Hybrid sequence-structure based HMM models leverage the identification of homologous proteins: the example of class II fusion proteins
Authors: Tetley R. , Guardado-Calvo P. , Fedry J. , Rey F. , Cazals F.
Published: July 2018

We present a sequence-structure based method characterizing a set of functionally related proteins exhibiting low sequence identity and loose structural conservation. Given a (small) set of structures, our method consists of three main steps. First, pairwise structural alignments are combined with multi-scale geometric analysis to produce structural motifs i.e. regions structurally more conserved than the whole structures. Second, the sub-sequences of the motifs are used to build profile hidden Markov models (HMM) biased towards the structurally conserved regions. Third, these HMM are used to retrieve from UniProtKB proteins harboring signatures compatible with the function studied, in a bootstrap fashion.

We apply these hybrid HMM to investigate two questions related to class II fusion proteins, an especially challenging class since known structures exhibit low sequence identity (less than 15%) and loose structural similarity (of the order of 15Å in lRMSD). In a first step, we compare the performances of our hybrid HMM against those of sequence based HMM. Using various learning sets, we show that both classes of HMM retrieve unique species. The number of unique species reported by both classes of methods are comparable, stressing the novelty brought by our hybrid models. In a second step, we use our models to identify 17 plausible HAP2-GSC1 candidate sequences in 10 different drosophila melanogaster species. These models are not identified by the PFÅM family HAP2-GCS1 (PF10699), stressing the ability of our structural motifs to capture signals more subtle than whole Pfam domains.

In a more general setting, our method should be of interest for all cases functional families with low sequence identity and loose structural conservation.

Our software tools are available from the FunChaT package of the Structural Bioinformatics Library (http://sbl.inria.fr).