bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic Hypothermia After Cardiac Arrest: Involvement of the Risk Pathway in Mitochondrial PTP-Mediated Neuroprotection
Authors: Jahandiez Vincent , Cour Martin , Abrial Maryline , Loufouat Joseph , Ovize Michel , Argaud Laurent
Published: July 2018

Therapeutic hypothermia is neuroprotective after cardiac arrest (CA) via poorly understood mechanisms. It may prevent mitochondrial permeability transition pore (PTP) opening, an event which plays a pivotal role in ischemia-reperfusion injury. PTP is the main end-effector of the reperfusion injury salvage kinase (RISK) signaling pathway. We hypothesized that therapeutic hypothermia activates the RISK pathway, thereby preventing PTP opening and its deleterious neurological consequences after CA. Four groups of New Zealand White rabbits were subjected to 15 min of CA and 120 min of reperfusion: Control, HT (hypothermia at 32°–34°C), NIM (specific PTP inhibition with N-methyl-4-isoleucine-cyclosporine at the onset of reperfusion), and HT+NIM. A Sham group only underwent surgery. The following measurements were taken: pupillary reflexes and brain damage biomarkers (NSE and S100β), RISK pathway activation in brain cortex (total and phosphorylated forms of both protein kinase B [Akt] and extracellular signal-regulated kinase [ERK]) and PTP opening in isolated brain mitochondria. Therapeutic hypothermia and pharmacological PTP inhibition preserved the pupillary reflexes and prevented the increase in both NSE and S100β (P < 0.05 vs. controls). These two interventions also enhanced (P < 0.05 vs. controls) the phospho-Akt/Akt ratio to a similar extent while preventing a CA-induced increase in phospho-ERK/ERK ratio. This Akt activation in the HT and NIM groups was associated with an attenuation of CA-induced PTP opening. In this model, therapeutic hypothermia promoted the activation of the RISK signaling pathway via Akt and limited CA-induced brain injury by preventing PTP opening.
The Effects of the Duration of Aortic Balloon Occlusion on Outcomes of Traumatic Cardiac Arrest in a Porcine Model
Authors: Xu Jiefeng , Shen Peng , Gao Yuzhi , Xia Senlin , Liu Shaoyun , Li Zilong , Zhou Guangju , Xu Yongan , Zhang Mao
Published: July 2018

Aortic balloon occlusion (ABO) facilitates the success of cardiopulmonary resuscitation (CPR) in non-traumatic cardiac arrest, and is also effective in controlling traumatic hemorrhage; however, a prolonged occlusion results in irreversible organ injury and death. In this study, we investigated the effects of ABO on CPR outcomes and its optimal duration for post-resuscitation organ protection in a porcine model of traumatic cardiac arrest (TCA).

Twenty-seven male domestic pigs weighing 33 ± 4 kg were utilized. Forty percent of estimated blood volume was removed within 20 min. The animals were then subjected to 5 min of untreated ventricular fibrillation and 5 min of CPR. Coincident with the start of CPR, the animals were randomized to receive either 30-min ABO (n = 7), 60-min ABO (n = 8) or control (n = 12). Meanwhile, fluid resuscitation was initiated by the infusion of normal saline with 1.5 times of hemorrhage volume in 1 h, and finished by the reinfusion of 50% of the shed blood in another 1 h. The resuscitated animals were monitored for 6 h and observed for an additional 18 h.

During CPR, coronary perfusion pressure was significantly increased followed by a higher rate of resuscitation success in the 30 and 60-min ABO groups compared with the control group. However, post-resuscitation cardiac, neurologic dysfunction, and injuries were significantly milder accompanied with less renal and intestinal injuries in the 30-min ABO group than in the other two groups.

In conclusion, ABO augmented the efficacy of CPR after TCA, and furthermore a 30-min ABO improved post-resuscitation cardiac and neurologic outcomes without exacerbating the injuries of kidney and intestine.
Medial Thigh Anatomy in Female Cadavers: Clinical Applications to the Transobturator Midurethral Sling
Authors: Shah Nemi M. , Jackson Lindsey A. , Phelan John N. , Corton Marlene M.
Published: July 2018

Background

Mesh resection for refractory pain after transobturator midurethral sling may require exploration of structures different than those involved in insertion. Our objective was to describe the muscular and neurovascular anatomy of the medial thigh compartment.

Methods

Dissections were performed in unembalmed female cadavers. Relationships of medial thigh structures were evaluated relative to the midpubic arch and obturator nerve. An out-to-in transobturator tape was passed in a subset of cadavers, and its relationships to the obturator nerve and adductor muscles were examined. Descriptive statistics were used for analyses.

Results

Sixteen cadavers were examined. The adductor longus muscle was a median of 37 mm (26–50) from the midpubic arch with tendon length of 26 mm (12–53) and width of 16 mm (14–29). The gracilis was 21 mm (17–26) from the midpubic arch with tendon length of 28 mm (15–56) and width of 45 mm (31–68). The obturator nerve was 58 mm (51–63) from the midpubic arch with width of 5 mm (4–7). No differences between measurements in the supine and lithotomy positions were noted. The transobturator tape was 42 mm (30–47) from the midpubic arch, 36 mm (30–44) from the obturator nerve, and 20 mm (5–31) from the closest obturator nerve branch. The transobturator sling passed through the gracilis muscle in all specimens with variable passage through the adductors longus (75%) and brevis (25%).

Conclusions

Familiarity with the medial thigh is essential for surgeons utilizing transobturator midurethral slings. Risks of mesh excision should be weighed against benefits before extensive thigh dissection for pain-related indications.
Spontaneous Transvaginal Sigmoid Colon Evisceration and Sepsis From Complete Procidentia
Authors: Schefter Alexandra M. , Fischer John , Erickson Britt K.
Published: July 2018

Background

Transvaginal bowel evisceration is an exceptionally rare event. Most reported cases are of small bowel evisceration in postmenopausal women who have undergone hysterectomy.

Case

Here, we report an isolated case of complete procidentia and spontaneous sigmoid colon evisceration leading to sepsis in an 89-year-old woman with no surgical history.

Conclusions

We highlight the risk factors, clinical presentation, and treatment options for this unique multidisciplinary emergency.
Roles, Responsibilities, and Implications of Health Care Practitioners Providing Interprofessional Collaborative Practice to the Geriatric Population
Authors: O'Rourke Beth , Widenhoefer Tricia , Reimer Nila , Vazquez Emilio , Wolpert Chantelle
Published: July 2018

Health care providers are facing escalating growth within the number of geriatric patients as well as increased medical complexity and soaring health care costs. There is a movement in place refocusing efforts to provide new models of health care concentrated on treating individual complexities of the aging populations as a team. Research shows interprofessional collaboration improves patient outcomes, patient safety, and staff morale while decreasing hospital admissions, length of hospital stays, and staff turnover. The purpose of this article is to show research supporting the implementation and benefits of interprofessional collaborative practice use in geriatric health care settings.
Interventions to Reduce High-Risk Medication Use in the Geriatric Population
Authors: Stuckey Nathan , Henriksen Brian , Singh Hamdeep , Dawson Amy , Waterson Zachary
Published: July 2018

Background:

The Beers List is a guideline for health care workers to prescribe medications that are safe in the elderly. Using Beers List guidelines in the primary care setting, morbidity and mortality secondary to adverse effects, drug-drug interactions, and falls can be reduced significantly.

Objective:

To improve the quality and decrease the number of high-risk medications prescribed to the geriatric population through an interprofessional appointment approach.

Methods:

A prospective quality improvement project was completed over a 3-month period from August 2016 to November 2016 at a residency training outpatient family medicine clinic. Data on Medicare patients with 1 or more high-risk medication were obtained from the electronic health record (Allscripts NQF 0022). Participants were older than 65 years, with one or more high-risk medication as defined by Medicare. Patients were contacted for medication review appointments via phone and mail. The appointment was scheduled for a total of 60 minutes, with the initial 40 minutes spent with the pharmacy team for a comprehensive, medication reconciliation, and an assessment of their health literacy. Health literacy was assessed with the Short Assessment of Health Literacy. Recommendations for interventions by the interprofessional team were discussed and implemented during the last 20 minutes. Descriptive statistics and 2-sided dependent t tests were used to evaluate the data.

Results:

Thirty-four participants had a mean age of 74 years, 53% were male, 74% Caucasian, 24% African, and 2% Native Americans. Health literacy was good with only 20% below functional. The total high-risk medications dropped from 42 to 28, resulting in a 33% reduction of high-risk medications (P = .0005). There were 6 possible interventions with an average of 2 interventions per participant. The interventions were medication discontinuation for 11.39% (n = 8), changing medications for 7.25% (n = 5), medication reduced for 24.64% (n = 17), patients unwilling to change medications for 5.79% (n = 4), physicians deemed medication necessary for 14.5% (n = 10), and patient education for 36% (n = 25).
Variable Surface Training and Fall Risk in the Older Adult
Authors: Kogler Katherine , Howard Natalie , Schumacher Margaret , Knight Heather
Published: July 2018

Context:

Variable surface balance training is frequently used as a rehabilitative intervention.

Objective:

To determine the effects of variable surface training on fall risk in the older adult and begin to explore evidence-based exercise parameters to drive clinical practice.

Study Selection:

A search on PubMed and CINAHL in March 2016 resulted in 8 randomized control trials to include in this literature review.

Results:

All studies reported statistically significant improvements on at least one outcome measure following variable surface training.

Conclusion:

All health care professionals can refer older adults at risk for falls to physical therapy to help prevent falls before they occur.
A Randomized Controlled Trial of the Prescribed Stepper Walking Program in Preventing Frailty Among the Dwelling Elderly
Authors: Kuo Mei-Chen , Chen Ching-Min , Jeng Chii
Published: July 2018

This is the first article that described the effect of a prescribed stepper walking program based on comprehensive geriatric assessment in preventing the general fitness of older adults. An experimental design was conducted with 36 elderly individuals (experiment = 15, control = 21) who were asked to have a 30-minute stepper walking exercise twice per week in the research center. The effectiveness of the program would be evaluated in 8 weeks. The results indicated that the 6-minute walk test, body mass index, waist-hip ratio, body composition percentage, and 3-m up and go test improved after an 8-week exercise training in the experimental group.
Promoting Vitamin E Awareness and Adequacy Among College Students
Authors: Lacey Janet , Zeswitz Ellen , McGuire Brandon
Published: July 2018

An introductory nutrition course was redesigned to emphasize vitamin E's importance throughout the lifespan by way of a specially developed, PowerPoint presentation and brochure, a food-tasting event, and frequent discussions. Initial and final vitamin E intakes and knowledge were assessed. Forty-six college health students (14 male and 32 female), mean age (standard deviation) 20.5 (1.0) years, initially had low intakes of vitamin E-rich foods. Those with low intakes had a higher percentage of carbohydrates and had a poor knowledge base. Consumption of vitamin E increased substantially for all students by the end of the semester. Given its crucial role in preserving brain health, vitamin E should receive widespread attention to ensure adequacy.
Impact of e-Learning or Blended Learning Versus Face-to-Face Learning in Regard to Physical Examination Skills, Knowledge, and Attitudes Among Health Professions Students
Authors: Tenison Elizabeth , Touger-Decker Riva
Published: July 2018

This review explored research on e-learning (EL), blended learning (BL), and face-to-face learning (F2FL) as teaching strategies for physical examination (PE) in regard to skill, attitude, and knowledge outcomes of students and trainees in the health professions. A search was performed of CINAHL, PubMed, and ProQuest databases; 9 studies were reviewed. Findings revealed EL or BL compared with F2FL may be equally or more effective for PE skill acquisition. However, the results were inconsistent regarding the effectiveness of various teaching platforms on the PE user attitude and knowledge outcomes. Further research is needed to identify the best approaches to teach PE in dietetics education.
Organ Donation Attitudes Among Individuals With Stage 5 Chronic Kidney Disease
Authors: Loughery Caitlin , Andrews Ann M. , Zhang Nanhua , Smith Allyce Haney , Resnicow Ken , Chapman Remonia , Riley Holly Jenkins , Stav Sheri , Yee Jerry
Published: July 2018

Background

The need for transplantable organs drastically outweighs the supply. Misconceptions are a barrier to increasing the rate of donor registration. Individuals with stage 5 chronic kidney disease (CKD) may incorrectly believe they are unable to be donors; however, their attitudes have not been studied. This study aims to explore beliefs of individuals with stage 5 CKD about their ability to donate and test the validity of an organ donation scale.

Methods

We examined the psychometric properties of a new 25-item organ donation scale among 554 patients with stage 5 CKD at 12 dialysis units in southeast Michigan. Patients completed surveys during dialysis treatment with assistance from a program coordinator or social worker.

Results

Two subscales with good psychometric properties were identified: general benefits (α = 0.86) and general barriers (α = 0.80). For both subscales, more positive attitudes were associated with higher intent to sign up on the donor registry, suggesting validity of the scale.

Conclusions

Patients who were older than 60 years, white, or of higher education status reported more positive attitudes. Misconceptions about the ability of patients with stage 5 CKD to donate are common and highlight a need for education about donor eligibility. Individuals with stage 5 CKD may be able to donate organs and tissues.
Pathologies Underlying Longitudinal Cognitive Decline in the Oldest Old
Authors: Nguyen Madeline T. , Mattek Nora , Woltjer Randy , Howieson Diane , Silbert Lisa , Hofer Scott , Kaye Jeffrey , Dodge Hiroko , Erten-Lyons Deniz
Published: July 2018

Background:

Understanding contributions of different brain pathologies to domain-specific cognitive trajectories in the oldest old is crucial to guide future intervention studies.

Methods:

Two-hundred-twenty Oregon Alzheimer’s Disease Center research participants who were cognitively intact at entry were followed on average for 7.3 years with annual neuropsychological testing until death (mean age, 93.7 y) and autopsy. Mixed effects models examined the relationship between trajectories in memory, verbal fluency, and mini-mental state examination (MMSE) and pathology (neurofibrillary tangles, neuritic plaques, gross infarcts, hippocampal sclerosis, Lewy bodies, APOE genotype, age at death, and years of education). The association between the MMSE trajectory and pathologic variables were examined using a Poisson model with MMSE errors as outcomes given the nonlinear distribution of MMSE scores.

Results:

Memory trajectory was associated with the APOε4 allele (P=0.006). Verbal fluency trajectory was associated with gross infarcts (P=0.008). MMSE trajectory was associated with high Braak scores (P=0.03), gross infarcts (P<0.0001), hippocampal sclerosis (P=0.003), moderate neuritic plaques (P=0.04), and the APOε4 allele (P=0.02).

Conclusions:

The association between trajectory of decline in global cognitive scores and multiple brain pathologies highlights the importance of accounting for comorbid pathologies in therapeutic trials aimed at one specific pathology in the oldest old. Only the APOε4 allele showed an association with memory decline, despite accounting for Alzheimer’s disease pathology, suggesting that APOE may be involved in mechanisms beyond amyloid metabolism in its role in memory. Further studies are needed to examine the role of APOE in brain aging.
Composition and consistence of the bacterial microbiome in upper, middle and lower esophagus before and after Lugol’s iodine staining
Authors: Yin Jian , Dong Li , Zhao Jing , Shao Dantong , liu Anqi , Li Juxiao , Yu Aisong , Wei Wenqiang , Chen Wen
Published: July 2018

Esophageal bacteria, as the integral composition of human ecosystem, have been reported to be associated with esophageal lesions. However, few studies focus on microbial compositions in different esophageal segments, especially after Lugol’s iodine staining (LIS) in the endoscopic examination for the screening of esophageal cancer. To investigate the composition of the bacterial microbiome in upper, middle and lower esophagus and if LIS would affect the detection of bacteria, 141 fasting samples including the upper, middle and lower esophagus from 27 participants were collected by brushing the mucosal surface of the esophagus before (Eso) and after (Lug) LIS. Bacterial V3-V4 region of 16S rRNA gene was amplified and sequenced by Illumina’s sequencing platform and analyzed using LEfSe system to identify specific microbiota. The top six abundant bacterial phyla taxa among three locations from both Eso and Lug groups were Proteobacteria, Firmicutes, Bacteroidetes, Actinobacteria, Fusobacteria and TM7. In terms of genera, the bacterium in three locations from two groups was all characterized by a highest relative abundance of Streptococcus. Bacteria diversity and the relative abundance between Eso and Lug were comparable (P > 0.05). Bacteria diversity was consistent in different esophageal locations for an individual, but it was significantly distinguishing in different subjects (P < 0.05). In Conclusion, the bacterial microbiome in healthy esophagus are highly diverse and consistent even among three physiological stenosis at all clades. Lugol’s iodine staining would not change local microenvironment in term of microbial composition. These finding provide an essential baseline for future studies investigating local and systemic bacterial microbiome and esophageal diseases.
Development and Application of a High-Content Virion Display Human GPCR Array
Authors: Syu Guan-Da , Wang Shih-Chin , Ma Guangzhong , Liu Shuang , Pearce Donna , Prakash Atish , Henson Brandon , Weng Lien-Chun , Ghosh Devlina , Ramos Pedro , Eichinger Daniel , Pino Ignacio , Dong Xinzhong , Xiao Jie , Wang Shaopeng , Tao Nongjian , Kim Kwang Sik , Desai Prashant J. , Zhu Heng
Published: July 2018

G protein-coupled receptors (GPCRs) comprise the largest membrane protein family in humans and can respond to a wide variety of ligands and stimuli. Like other multi-pass membrane proteins, the biochemical properties of GPCRs are notoriously difficult to study because they must be embedded in lipid bilayers to maintain their native conformation and function. To enable an unbiased, high-throughput platform to profile biochemical activities of GPCRs in native conformation, we individually displayed 315 human non-odorant GPCRs (>85% coverage) in the envelope of human herpes simplex virus-1 and immobilized on glass to form a high-content Virion Display (VirD) array. Using this array, we found that 50% of the tested commercial anti-GPCR antibodies (mAbs) is ultra-specific, and that the vast majority of those VirD-GPCRs, which failed to be recognized by the commercial mAbs, could bind to their canonical ligands, indicating that they were folded correctly. Next, we used the VirD-GPCR arrays to examine binding specificity of two known peptide ligands and recovered expected interactions, as well as new off-target interactions, three of which were confirmed with real-time kinetics measurements. Finally, we explored the possibility of discovering novel pathogen targets by probing VirD-GPCR arrays with live group B Streptococcus (GBS), a common Gram-positive bacterium causing neonatal meningitis. Using cell invasion assays and a mouse model of hematogenous meningitis, we showed that inhibition of one of the five newly identified GPCRs, CysLTR1, greatly reduced GBS penetration in brain-derived endothelial cells and in mouse brains. Therefore, our work demonstrated that the VirD-GPCR array holds great potential for high-throughput, unbiased screening for small molecule drugs, affinity reagents, and deorphanization.
Genotype-covariate correlation and interaction disentangled by a whole-genome multivariate reaction norm model
Authors: Ni Guiyan , van der Werf Julius , Zhou Xuan , Hyppönen Elina , Wray Naomi R. , Lee Hong
Published: July 2018

The genomics era has brought useful tools to dissect the genetic architecture of complex traits. We propose a reaction norm model (RNM) to tackle genotype-environment correlation and interaction problems in the context of genome-wide association analyses of complex traits. In our approach, an environmental risk factor affecting the trait of interest can be modeled as dependent on a continuous covariate that is itself regulated by genetic as well as environmental factors. Our multivariate RNM approach allows the joint modelling of the relation between the genotype (G) and the covariate (C), so that both their correlation (association) and interaction (effect modification) can be estimated. Hence we jointly estimate genotype-covariate correlation and interaction (GCCI). We demonstrate using simulation that the proposed multivariate RNM performs better than the current state-of-the-art methods that ignore G-C correlation. We apply the method to data from the UK Biobank (N= 66,281) in analysis of body mass index using smoking quantity as a covariate. We find a highly significant G-C correlation, but a negligible G-C interaction. In contrast, when a conventional G-C interaction analysis is applied (i.e., G-C correlation is not included in the model), highly significant G-C interaction estimates are found. It is also notable that we find a significant heterogeneity in the estimated residual variances across different covariate levels probably due to residual-covariate interaction. Using simulation we also show that the residual variances estimated by genomic restricted maximum likelihood (GREML) or linkage disequilibrium score regression (LDSC) can be inflated in the presence of interactions, implying that the currently reported SNP-heritability estimates from these methods should be interpreted with caution. We conclude that it is essential to correctly account for both interaction and correlation in complex trait analyses and that the failure to do so may lead to substantial biases in inferences relating to genetic architecture of complex traits, including estimated SNP-heritability.
AKT, NOTCH and GSK3β interact to trigger early myogenesis in vertebrate embryos
Authors: Lebrun Diane , Rahal Pamela , Morin Valérie , Marcelle Christophe
Published: July 2018

During early embryonic development, migrating neural crest cells expressing the NOTCH ligand Delta1 (DLL1) trigger the activation of NOTCH1 signaling in selected epithelial cells within newly formed somites. A key event in this process is a dramatic inhibition of GSK3β activity, initiated by the activation of NOTCH1 and that takes place independent of its transcriptional function. Here, we investigated the mechanism whereby NOTCH1 exerts its non-canonical function in somites. Using the activation of myogenesis as a read-out of the ability of NOTCH receptors to trigger transcription-independent responses in somites, we found that all NOTCH receptors (1-4) activate MYF5 expression and we showed that the RAM (RBPJ-Associated Molecule) domain of the NOTCH Intracellular Domain (NICD) is necessary and sufficient in this process. We then demonstrated that the NOTCH1 Intracellular Domain (NICD1) physically interacts in the cytosol with GSK3β and with the serine threonine protein kinase AKT. Activating AKT triggers myogenesis, likely via the inhibition of GSK3β. We found that AKT, in a dose-dependent manner, decreases the transcriptional activity of NOTCH, suggesting a role in the balance between the canonical and non-canonical functions of NOTCH. Altogether these data strongly support the hypothesis that transcription-independent function of NICD is a central mechanism driving myogenesis in early somites and suggests that, in this tissue, AKT, NOTCH and GSK3β interact in the cytoplasm to trigger a signaling cascade that leads to the formation of the early myotome in vertebrates.
Human posterior parietal cortex responds to visual stimuli as early as peristriate occipital cortex
Authors: Regev Tamar I. , Winawer Jonathan , Gerber Edden M. , Knight Robert T. , Deouell Leon Y.
Published: July 2018

Much of what is known about the timing of visual processing in the brain is inferred from intracranial studies in monkeys, with human data limited to mainly non-invasive methods with lower spatial resolution. Here, we estimated visual onset latencies from electrocorticographic (ECoG) recordings in a patient who was implanted with 112 sub-dural electrodes, distributed across the posterior cortex of the right hemisphere, for pre-surgical evaluation of intractable epilepsy. Functional MRI prior to surgery was used to determine boundaries of visual areas. The patient was presented with images of objects from several categories. Event Related Potentials (ERPs) were calculated across all categories excluding targets, and statistically reliable onset latencies were determined using a bootstrapping procedure over the single trial baseline activity in individual electrodes. The distribution of onset latencies broadly reflected the known hierarchy of visual areas, with the earliest cortical responses in primary visual cortex, and higher areas showing later responses. A clear exception to this pattern was robust, statistically reliable and spatially localized, very early responses on the bank of the posterior intra-parietal sulcus (IPS). The response in the IPS started nearly simultaneously with responses detected in peristriate visual areas, around 60 milliseconds post-stimulus onset. Our results support the notion of early visual processing in the posterior parietal lobe, not respecting traditional hierarchies, and give direct evidence for the upper limit of onset times of visual responses across the human cortex.
The Project MinE databrowser: bringing large-scale whole-genome sequencing in ALS to researchers and the public
Authors:   Project MinE ALS Sequencing Consortium
Published: July 2018

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive fatal neurodegenerative disease affecting 1 in 350 people. The aim of Project MinE is to elucidate the pathophysiology of ALS through whole-genome sequencing at least 15,000 ALS patients and 7,500 controls at 30X coverage. Here, we present the Project MinE data browser (databrowser.projectmine.com). a unique and intuitive one-stop, open-access server that provides detailed information on genetic variation analyzed in a new and still growing set of 4,366 ALS cases and 1,832 matched controls. Through its visual components and interactive design, the browser specifically aims to be a resource to those without a biostatistics background and allow clinicians and preclinical researchers to integrate Project MinE data into their own research. The browser allows users to query a transcript and immediately access a unique combination of detailed (meta)data, annotations and association statistics that would otherwise require analytic expertise and visits to scattered resources.
An open source platform for analyzing and sharing worm behavior data
Authors: Javer Avelino , Currie Michael , Lee Chee Wai , Hokanson Jim , Li Kezhi , Martineau Céline N , Yemini Eviatar , Grundy Laura J , Li Chris , Ch’ng QueeLim , Schafer William R , Nollen Ellen AA , Kerr Rex , Brown André EX
Published: July 2018

Animal behavior is increasingly being recorded in systematic imaging studies that generate large data sets. To maximize the usefulness of these data there is a need for improved resources for analyzing and sharing behavior data that will encourage re-analysis and method development by computational scientists1. However, unlike genomic or protein structural data, there are no widely used standards for behavior data. It is therefore desirable to make the data available in a relatively raw form so that different investigators can use their own representations and derive their own features. For computational ethology to approach the level of maturity of other areas of bioinformatics, we need to address at least three challenges: storing and accessing video files, defining flexible data formats to facilitate data sharing, and making software to read, write, browse, and analyze the data. We have developed an open resource to begin addressing these challenges using worm tracking as a model.
Moving beyondPvalues: Everyday data analysis with estimation plots
Authors: Ho Joses , Tumkaya Tayfun , Aryal Sameer , Choi Hyungwon , Claridge-Chang Adam
Published: July 2018

Over the past 75 years, a number of statisticians have advised that the data-analysis method known as null-hypothesis significance testing (NHST) should be deprecated (Berkson, 1942; Halsey et al., 2015; Wasserstein et al., 2019). The limitations of NHST have been extensively discussed, with a broad consensus that current statistical practice in the biological sciences needs reform. However, there is less agreement on reform’s specific nature, with vigorous debate surrounding what would constitute a suitable alternative (Altman et al., 2000; Benjamin et al., 2017; Cumming and Calin-Jageman, 2016). An emerging view is that a more complete analytic technique would use statistical graphics to estimate effect sizes and evaluate their uncertainty (Cohen, 1994; Cumming and Calin-Jageman, 2016). As these estimation methods require only minimal statistical retraining, they have great potential to shift the current data-analysis culture away from dichotomous thinking towards quantitative reasoning (Claridge-Chang and Assam, 2016). The evolution of statistics has been inextricably linked to the development of quantitative displays that support complex visual reasoning (Tufte, 2001). We consider that the graphic we describe here asestimation plotis the most intuitive way to display the complete statistical information about experimental data sets. However, a major obstacle to adopting estimation plots is accessibility to suitable software. To lower this hurdle, we have developed free software that makes high-quality estimation plotting available to all. Here, we explain the rationale for estimation plots by contrasting them with conventional charts used to display data with NHST results, and describe how the use of these graphs affords five major analytical advantages.
BASILIScan: a tool for high-throughput analysis of intrinsic disorder patterns in homologous proteins
Authors: Barski Michał S
Published: July 2018

Background

Intrinsic structural disorder is a common property of many proteins, especially in eukaryotic and virus proteomes. The tendency of some proteins or protein regions to exist in a disordered state usually precludes their structural characterisation and renders them especially difficult for experimental handling after recombinant expression.

Results

A new intuitive, publicly-available computational resource, called BASILIScan, is presented here. It provides a BLAST-based search for close homologues of the protein of interest, integrated with a simultaneous prediction of intrinsic disorder together with a robust data viewer and interpreter. This allows for a quick, high-throughput screening, scoring and selection of closely-related yet highly structured homologues of the protein of interest. Comparative parallel analysis of the conservation of extended regions of disorder in multiple sequences is also offered. The use of BASILIScan and its capacity for yielding biologically applicable predictions is demonstrated. Using a high-throughput BASILIScan screen it is also shown that a large proportion of the human proteome displays homologous sequences of superior intrinsic structural order in many related species.

Conclusion

Through the swift identification of intrinsically stable homologues and poorly conserved disordered regions by the BASILIScan software, the chances of successful recombinant expression and compatibility with downstream applications such as crystallisation can be greatly increased.
Inferring interaction partners from protein sequences using mutual information
Authors: Bitbol Anne-Florence
Published: July 2018

Specific protein-protein interactions are crucial in most cellular processes. They enable multiprotein complexes to assemble and to remain stable, and they allow signal transduction in various pathways. Functional interactions between proteins result in coevolution between the interacting partners, and thus in correlations between their sequences. Pairwise maximum-entropy based models have enabled successful inference of pairs of amino-acid residues that are in contact in the three-dimensional structure of multi-protein complexes, starting from the correlations in the sequence data of known interaction partners. Recently, algorithms inspired by these methods have been developed to identify which proteins are specific interaction partners among the paralogous proteins of two families, starting from sequence data alone. Here, we demonstrate that a slightly higher performance for partner identification can be reached by an approximate maximization of the mutual information between the sequence alignments of the two protein families. This stands in contrast with structure prediction of proteins and of multiprotein complexes from sequence data, where pairwise maximum-entropy based global statistical models substantially improve performance compared to mutual information. Our findings entail that the statistical dependences allowing interaction partner prediction from sequence data are not restricted to the residue pairs that are in direct contact at the interface between the partner proteins.

Author summary

Specific protein-protein interactions are at the heart of most intra-cellular processes. Mapping these interactions is thus crucial to a systems-level understanding of cells, and has broad applications to areas such as drug targeting. Systematic experimental identification of protein interaction partners is still challenging. However, a large and rapidly growing amount of sequence data is now available. Recently, algorithms have been proposed to identify which proteins interact from their sequences alone, thanks to the co-variation of the sequences of interacting proteins. These algorithms build upon inference methods that have been used with success to predict the three-dimensional structures of proteins and multi-protein complexes, and their focus is on the amino-acid residues that are in direct contact. Here, we propose a simpler method to identify which proteins interact among the paralogous proteins of two families, starting from their sequences alone. Our method relies on an approximate maximization of mutual information between the sequences of the two families, without specifically emphasizing the contacting residue pairs. We demonstrate that this method slightly outperforms the earlier one. This result highlights that partner prediction does not only rely on the identities and interactions of directly contacting amino-acids.
Effect of feeding and thermal stress on photosynthesis, respiration and the carbon budget of the scleractinian coral Pocillopora damicornis
Authors: Lyndby Niclas Heidelberg , Holm Jacob Boiesen , Wangpraseurt Daniel , Grover Renaud , Rottier Cécile , Kühl Michael , Ferrier-Pagès Christine
Published: July 2018

Studying carbon dynamics in the coral holobiont provides essential knowledge of nutritional strategies and is thus central to understanding coral ecophysiology. In this study, the first aim was to investigate the effect of daily feeding and thermal stress on oxygen (O2) rates measured at polyp-scale with microsensors and at whole fragment scale using incubation methods. The second aim was to assess the carbon budget of the symbiotic association using H13CO3, under the different conditions. Micro- and macro-scale measurements revealed enhanced O2 evolution rates for fed compared to unfed corals. However, gross O2 production in fed corals was increased at high temperature on a macroscale but not on a microscale basis, likely due to a heterogeneous distribution of photosynthesis over the coral surface. Starved corals always exhibited reduced photosynthetic activity at high temperature, which suggests that the nutritional status of the coral host is a key limiting factor for coral productivity under thermal stress. Quantification of photosynthate translocation and carbon budgets showed very low incorporation rates, for both symbionts and host (0.03 - 0.6 μg C cm-2 h-1) equivalent to only 0.008 - 0.6 %, of the photosynthetically fixed carbon for P. damicornis, in all treatments. Carbon loss (via respiration and/or mucus release) was about 41 - 47 % and 52 - 76% of the fixed carbon for starved and fed corals, respectively. Such high loss of translocated carbon suggests that P. damicornis is nitrogen and/or phosphorus limited. Heterotrophy might thus cover a larger portion of the nutritional demand for P. damicornis than previously assumed. Our results suggest that active feeding plays a fundamental role in metabolic dynamics and bleaching susceptibility of corals.
Short-term insurance versus long-term bet-hedging strategies as adaptations to variable environments
Authors: Haaland Thomas Ray , Wright Jonathan , Tufto Jarle , Ratikainen Irja Ida
Published: July 2018

Understanding how organisms adapt to environmental variation is a key challenge of biology. Central to this are bet-hedging strategies that maximize geometric mean fitness across generations, either by being conservative or diversifying phenotypes. Theoretical models of bet-hedging and the multiplicative fitness effects of environmental variation across generations have traditionally assumed that environmental conditions are constant within lifetimes. However, behavioral ecology has revealed adaptive responses to additive fitness effects of environmental variation within lifetimes, either through insurance or risk-sensitive strategies. Here we explore whether the effects of adaptive insurance interact with the evolution of bet-hedging by varying the position and skew of fitness functions within and between lifetimes. When insurance causes the optimal phenotype to shift from the peak to down the less steeply decreasing side of the fitness function, then conservative bet-hedging does not generally evolve on top of this, even if diversifying bet-hedging can. Canalization to reduce phenotypic variation within a lifetime is almost always favored, except when the tails of the fitness function are steeply convex and produce a novel risk-sensitive increase in phenotypic variance akin to diversifying bet-hedging. Importantly, using skewed fitness functions, we provide the first example of how conservative and diversifying bet-hedging strategies might coexist.
Functional cross-talk between allosteric effects of activating and inhibiting ligands underlies PKM2 regulation
Authors: Macpherson Jamie A. , Theisen Alina , Masino Laura , Fets Louise , Driscoll Paul C. , Encheva Vesela , Snijders Ambrosius P. , Martin Stephen R. , Kleinjung Jens , Barran Perdita E. , Fraternali Franca , Anastasiou Dimitrios
Published: July 2018

Allosteric regulation is central to the role of the glycolytic enzyme pyruvate kinase M2 (PKM2) in cellular metabolism. Multiple activating and inhibitory allosteric ligands regulate PKM2 activity by controlling the equilibrium between high activity tetramers and low activity dimers and monomers. However, it remains elusive how allosteric inputs upon simultaneous binding of different ligands are integrated to regulate PKM2 activity. Here, we show that, in the presence of the allosteric inhibitor L-phenylalanine (Phe), the activator fructose 1,6-bisphosphate (FBP) can induce PKM2 tetramerisation, but fails to maximally increase enzymatic activity. Guided by a new computational framework we developed to identify residues that mediate FBP-induced allostery, we generated two PKM2 mutants, A327S and C358A, in which activation by FBP remains intact but cannot be attenuated by Phe. Our findings demonstrate a role for residues involved in FBP-induced allostery in enabling the integration of allosteric input from Phe and reveal a mechanism that underlies the co-ordinate regulation of PKM2 activity by multiple allosteric ligands.
ALSgeneScanner: a pipeline for the analysis and interpretation of DNA NGS data of ALS patients
Authors: Iacoangeli Alfredo , Al Khleifat Ahmad , Sproviero William , Shatunov Aleksey , Jones Ashley R , Opie-Martin Sarah , Naselli Ersilia , Fogh Isabella , Hodges Angela , Dobson Richard J , Newhouse Stephen J , Al-Chalabi Ammar
Published: July 2018

Amyotrophic lateral sclerosis (ALS, MND) is a neurodegenerative disease of upper and lower motor neurons resulting in death from neuromuscular respiratory failure, typically within two years of first symptoms. Genetic factors are an important cause of ALS, with variants in more than 25 genes having strong evidence, and weaker evidence available for variants in more than 120 genes. With the increasing availability of Next-Generation sequencing data, non-specialists, including health care professionals and patients, are obtaining their genomic information without a corresponding ability to analyse and interpret it. Furthermore, the relevance of novel or existing variants in ALS genes is not always apparent. Here we present ALSgeneScanner, a tool that is easy to install and use, able to provide an automatic, detailed, annotated report, on a list of ALS genes from whole genome sequence data in a few hours and whole exome sequence data in about one hour on a readily available mid-range computer. This will be of value to non-specialists and aid in the interpretation of the relevance of novel and existing variants identified in DNA sequencing data.
Tbx1 and Foxi3 genetically interact in the third pharyngeal pouch endoderm required for thymus and parathyroid development
Authors: Hasten Erica , Morrow Bernice E
Published: July 2018

The mechanisms required for segmentation of the pharyngeal apparatus to individual arches are not precisely delineated in mammalian species. Here, using conditional mutagenesis, we found that two transcription factor genes, Tbx1, the gene for 22q11.2 deletion syndrome and Foxi3, genetically interact in the third pharyngeal pouch endoderm for thymus and parathyroid gland development. We found that Tbx1 is autonomously required for the endoderm to form a temporary multilayered epithelium while invaginating. E-cadherin for adherens junctions remains expressed and cells in the apical boundary express ZO-1. Foxi3 is required autonomously to modulate proliferation and promote later restoration of the endoderm to a monolayer once the epithelia meet after invagination. Completion of this process cooccurs with expression of Alcam needed to stabilize adherens junctions and extracellular, Fibronectin. These processes are required in the third pharyngeal pouch to form the thymus and parathyroid glands, disrupted in 22q11.2 deletion syndrome patients.
Salinity shock in Jatropha curcas leaves is more pronounced during recovery than during stress time
Authors: Silva-Santos Leonardo , Corte-Real Natália , Dias-Pereira Jaqueline , Figueiredo Regina C.B.Q. , Endres Lauricio , Pompelli Marcelo F.
Published: July 2018

To verify the possible morphological and ultrastructural differences in the Jatropha curcas leaves, in response to high-intensity salt stress, three genotypes were evaluated (CNPAE183, JCAL171 and CNPAE218). In all the genotypes, 750mM NaCl, added to the nutrient solution, was applied to test its salt tolerance. For the analysis, the leaves were collected at three time points: (i) before stress (time 0 hour); (ii) during stress time (time 50 hours); and (iii) in the recovery period (time 914 hours) when the stressed plants recovered and demonstrated measurements of net photosynthetic with values similar to those demonstrated by the control plants. We showed that regardless of the genotype, saline shock caused an increase in the thickness of the mesophyll, and after the removal of NaCl, the thicker mesophyll remained in the JCAL171 and CNPAE218 genotypes, while the values observed in the CNPAE183 genotype were similar to those before stress. Scanning electron microscopy indicated that the stomata of CNPAE183 are smaller and have a stomatal index higher than the values demonstrated in JCAL171 and CNPAE218. Therefore, among the genotypes analysed, CNPAE183 demonstrates that it could be considered a promising genotype for future studies of genetic improvement that seek elite genotypes tolerant to salinity.

Highlights

This manuscript present the following highlights:

The mesophyll thickness contributes to provide a smaller path for the CO2 to Rubisco J. curcas may reduce mesophyll air spaces as a strategy to mitigate low gas exchange Leaves modulate the expansion of stomata differently than other epidermal cells Smaller stomata with greater pore aperture are more abundant on the abaxial surface CNPAE183 is a candidate for studies in search of elite genotypes tolerant to salinity
Multiple Mechanisms Inactivate the LIN-41 RNA-Binding Protein to Ensure A Robust Oocyte-to-Embryo Transition inCaenorhabditis elegans
Authors: Spike Caroline A. , Huelgas-Morales Gabriela , Tsukamoto Tatsuya , Greenstein David
Published: July 2018

In the nematodeCaenorhabditis elegans,the conserved LIN-41 RNA-binding protein is a translational repressor that coordinately controls oocyte growth and meiotic maturation. LIN-41 exerts these effects, at least in part, by preventing the premature activation of the cyclin-dependent kinase CDK-1. Here we investigate the mechanism by which LIN-41 is rapidly eliminated upon the onset of meiotic maturation. Elimination of LIN-41 requires the activities of CDK-1 and multiple SCF-type ubiquitin ligase subunits, including the conserved substrate adaptor protein SEL-10/Fbw7/Cdc4, suggesting that LIN-41 is a target of ubiquitin-mediated protein degradation. Within the LIN-41 protein, two non-overlapping regions, Deg-A and Deg-B, are individually necessary for LIN-41 degradation; both contain several potential phosphodegron sequences, and at least one of these sites is required for LIN-41 degradation. Finally, Deg-A and Deg-B are sufficient, in combination, to mediate SEL-10-dependent degradation when transplanted into a different oocyte protein. Although LIN-41 is a potent inhibitor of protein translation and M-phase entry, the failure to eliminate LIN-41 from early embryos does not result in the continued translational repression of LIN-41 oocyte mRNA targets. Based on these observations, we propose a molecular model for the elimination of LIN-41 by SCFSEL-10and suggest that LIN-41 is inactivated before it is degraded. Furthermore, we provide evidence that another RNA-binding protein, the GLD-1 tumor suppressor, is regulated similarly. Redundant mechanisms to extinguish translational repression by RNA-binding proteins may both control and provide robustness to irreversible developmental transitions, including meiotic maturation and the oocyte-to-embryo transition.