bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient Perceptions of Minimally Invasive Versus Open Spine Surgery
Authors: Narain Ankur S. , Hijji Fady Y. , Duhancioglu Gabriel , Haws Brittany E. , Khechen Benjamin , Manning Blaine T. , Colman Matthew W. , Singh Kern
Published: March 2018

Study Design:

Prospective questionnaire.

Objective:

To describe patient perceptions of minimally invasive spine (MIS) versus open surgery, and to determine which factors are most heavily considered by the patient when choosing between approaches.

Summary of Background Data:

MIS surgery has increased in popularity due to proposed advantages in the perioperative and immediate postoperative periods. However, patient preferences and understanding with regard to the differences between MIS and open surgery have not been elucidated.

Materials and Methods:

An anonymous questionnaire consisting of 30 questions was administered to patients scheduled to see either an MIS surgeon or an open spine surgeon for a clinical evaluation from 2016 to 2017. Six questions asked about patient demographics and medical history. Nine questions asked respondents to rate the importance of several criteria when deciding between MIS and open surgery. In total, 15 multiple choice and free response questions asked respondents about their perceptions of MIS versus open surgery with regard to surgical and physician characteristics.

Results:

In total, 326 patients completed the survey. The 3 most important criteria for patients when choosing between open and MIS surgery were: long-term outcomes, surgeon’s recommendation, and complication risk. When compared with MIS surgery, the majority of patients perceived open surgery to be more painful (83.8%), have increased complication risk (78.5%), have increased recovery time (89.3%), have increased costs (68.1%), and require heavier sedation (62.6%). If required to have spine surgery in the future, the majority of both patient groups would prefer a minimally invasive approach (80.0%).

Conclusions:

Long-term outcomes, surgeon’s recommendation, and complication risk were the most important criteria identified by patients when choosing between open and MIS surgery. Patients also perceived MIS surgery to have advantages over open surgery with regard to postoperative pain, complication risk, recovery time, cost, and anesthesia requirement. Most patients seem to prefer a minimally invasive approach to their treatment.
Influence of Derotation Connectors on 3D Surgical Correction of Adolescent Idiopathic Scoliosis
Authors: Allia Jérémy , Clément Jean-Luc , Rampal Virginie , Leloutre Béatrice , Rosello Olivier , Solla Federico
Published: March 2018

Study Design:

Monocentric study comparing results of simultaneous translation on 2 rods (ST2R) with derotation connectors (prospective series) or without derotation connectors (retrospective series) in Adolescent Idiopathic Scoliosis (AIS) surgery.

Objective:

The objective of this study was to assess if derotation connectors influence axial, coronal, and sagittal results in AIS surgery.

Summary of Background Data:

Conventional reduction techniques remain limited in their ability to reduce axial torsion. Direct vertebral derotation technique accomplishes partial axial derotation but decreases thoracic kyphosis.

Methods:

Monocentric study including AIS surgeries performed using ST2R technique with derotation connectors (group D+, n=44) or without derotation connectors (group D−, n=24). The axial intervertebral rotation was measured between apical and neutral vertebra on pre and postoperative computed tomography scan. T test was used to compare mean values. ANCOVA analyzed the influence of connectors and covariates on the primary outcome, which was the difference between preoperative and postoperative intervertebral rotation.

Results:

The mean axial torsion gain in the D+ group was 23% (+3.84 degrees, 95% confidence interval, +1.95/+5.73). In the D− group, mean axial torsion increase of 4% (−0.42 degrees, 95% confidence interval, −1.19/+2.03). The result was significantly different between the 2 groups (P=0.005). The coronal correction of the main curve angle was 80% in the D+ group and 64% in the D− group (P=0.004). Kyphosis correction was similar between the 2 groups (P=0.3) with significant increase of thoracic kyphosis in the whole series (P=0.02) and no patients with postoperative hypokyphosis <10 degrees. Multivariate analysis confirmed the influence of derotation connectors on both axial and coronal correction (P<0.05).

Conclusions:

The use of derotation connectors in the surgical treatment of AIS significantly improved axial and coronal correction compared to nonuse of connectors without compromising the sagittal plane.
Surgical Strategies to Prevent Adjacent Segment Disease in the Cervical Spine
Authors: Butler Joseph S. , Morrissey Patrick B. , Wagner Scott C. , Kaye I. David , Sebastian Arjun S. , Schroeder Gregory D. , Vaccaro Alexander R. , Hilibrand Alan S.
Published: March 2018

The most popular approach to treating symptomatic cervical disk disease is anterior cervical discectomy and fusion. Although this procedure has significant long-term clinical success, it is associated with progressive adjacent segment degeneration with an annual incidence of ∼3%. Total disk arthroplasty was designed as an alternative to fusion that could preserve segmental motion at the operative level and potentially delay or prevent adjacent-level breakdown. The etiology of adjacent segment pathology (ASP) is multifactorial, and it is likely that most cases of ASP are unavoidable. When attempting to surgically prevent ASP, it is important to consider nonfusion alternatives, be judicious in one’s level selection, and attempt to restore sagittal alignment. When ASP becomes a clinical problem, it is important to have an algorithm for how best to treat it.
Subspine Impingement: Technique for Arthroscopic Decompression
Authors: Putnam Jill A. , Patel Karan A. , Hartigan David E.
Published: March 2018

The anterior inferior iliac spine (AIIS) is a newly recognized etiology of extra-articular hip impingement. The purpose of this article is to describe an arthroscopic technique for AIIS decompression causing extra-articular hip impingement. Arthroscopic decompression of subspine impingement is a novel procedure that can be used to successfully relieve hip pain and improve hip function and range of motion cause by AIIS impingement.
Chapter 7. The Contributions of the ESPGHAN Committees on Nutrition to Paediatric Nutrition
Authors: Hernell Olle , Aggett Peter , Fewtrell Mary , Koletzko Berthold , Rey Jean
Published: March 2018

The first Committee on Nutrition (CoN) was founded in 1974. Two years later nutrition (N) was added to the society's name, which then became ESPGAN. The Committee systematised compositional and quality criteria for breast milk substitutes and food for special medical purposes, the first of many examples on how recommendations and comments published by the Committees on Nutrition (CsoN) were adopted by the European Economic Community, later the European Union and also influenced the World Health Organization/Food and Agriculture Organization of the United Nations Codex standards. A second CoN focusing on preterm infants was established in 1979 and its recommendations on nutrition of these infants were widely implemented. The third and standing CoN, established 1986, started to organise high‐quality symposia at the annual meetings appreciating the need to enhance the expertise in nutritional research. From 1991 the CoN has organised Summer Schools in paediatric nutrition for young colleagues further emphasising its educational interest and more recently an annual, more specialised Nutrition Masterclass. Successively the interest of the CoN has expanded to other areas, such as highlighting dilemmas and uncertainties in the field of nutrition including the design, choice of outcomes and statistical analysis of trials in infant nutrition. The work of the CsoN have had great impact on paediatric nutrition and the committee will continue its important role by writing commentaries and systematic reviews and revising guidelines when required to inform and stimulate discussion among colleagues as well as stimulate training in paediatric nutrition by organising workshops and scientific meetings, training courses, and other approaches, and by interaction with other expert groups.
Sex Differences in Subclinical Coronary Atherosclerotic Plaque Among Individuals With HIV on Antiretroviral Therapy
Authors: Foldyna Borek , Fourman Lindsay T. , Lu Michael T. , Mueller Martin E. , Szilveszter Balint , Neilan Tomas G. , Ho Jennifer E. , Burdo Tricia H. , Lau Emily S. , Stone Lauren A. , Toribio Mabel , Srinivasa Suman , Looby Sara E. , Lo Janet , Fitch Kathleen V. , Zanni Markella V.
Published: March 2018

Background:

In high-resource settings, the HIV-attributable risk of myocardial infarction (MI) is higher among women than among men. The extent to which unique mechanisms contribute to MI risk among women vs. men with HIV remains unclear.

Methods:

Subclinical coronary atherosclerotic plaque characteristics—including high-risk morphology plaque features—were compared among 48 HIV-infected women [48 (41, 54) years] and 97 HIV-infected men [48 (42, 52) years] on stable antiretroviral therapy (ART) without known cardiovascular disease. These individuals had previously completed coronary computed tomography angiography and metabolic/immune phenotyping as part of a prospective study.

Results:

Extending previous analyses, now focusing exclusively on ART-treated participants, we found that HIV-infected women had a lower prevalence of any subclinical coronary atherosclerotic plaque (35% vs. 62%, P = 0.003) and a lower number of segments with plaque (P = 0.01), compared with HIV-infected men. We also report for the first time that ART-treated HIV-infected women had a lower prevalence of high-risk positively remodeled plaque (25% vs. 51%, P = 0.003) and a lower number of positively remodeled plaque segments (P = 0.002). In models adjusting for cardiovascular risk factors, we further showed that male sex remained associated with any coronary plaque [odds ratio 3.8, 95% confidence interval: (1.4 to 11.4)] and with positively remodeled plaque [odds ratio 3.7, 95% confidence interval: (1.4, 10.9)].

Conclusions:

ART-treated HIV-infected women (vs. HIV-infected men) had a lower prevalence and burden of subclinical coronary plaque and high-risk morphology plaque. Thus, unique sex-specific mechanisms beyond subclinical plaque may drive the higher HIV-attributable risk of MI among women vs. men.
The Utility of Failure Modes and Effects Analysis of Consultations in a Tertiary, Academic, Medical Center
Authors: Niv Yaron , Itskoviz David , Cohen Michal , Hendel Hagit , Bar-Giora Yonit , Berkov Evgeny , Weisbord Irit , Leviron Yifat , Isasschar Assaf , Ganor Arian
Published: March 2018

Background:

Failure modes and effects analysis (FMEA) is a tool used to identify potential risks in health care processes. We used the FMEA tool for improving the process of consultation in an academic medical center.

Methods:

A team of 10 staff members—5 physicians, 2 quality experts, 2 organizational consultants, and 1 nurse—was established. The consultation process steps, from ordering to delivering, were computed. Failure modes were assessed for likelihood of occurrence, detection, and severity. A risk priority number (RPN) was calculated. An interventional plan was designed according to the highest RPNs. Thereafter, we compared the percentage of completed computer-based documented consultations before and after the intervention.

Results:

The team identified 3 main categories of failure modes that reached the highest RPNs: initiation of consultation by a junior staff physician without senior approval, failure to document the consultation in the computerized patient registry, and asking for consultation on the telephone. An interventional plan was designed, including meetings to update knowledge of the consultation request process, stressing the importance of approval by a senior physician, training sessions for closing requests in the patient file, and reporting of telephone requests. The number of electronically documented consultation results and recommendations significantly increased (75%) after intervention.

Conclusion:

FMEA is an important and efficient tool for improving the consultation process in an academic medical center.
A Multidisciplinary Discharge Timeout Checklist Improves Patient Education and Captures Discharge Process Errors
Authors: Gao Michael C. , Martin Paul B. , Motal Julius , Gingras Laura F. , Chai Christina , Maikoff Megan E. , Sarkisian Alex M. , Rosenthal Nadine , Eiss Brian M.
Published: March 2018

Objective:

To design and implement a discharge timeout checklist, and to assess its effects on patients' understanding as well as the potential impact on preventable medical errors surrounding hospital discharges to home.

Methods:

Based on the structure successfully used for surgical procedures and using the Model for Improvement framework, we designed a discharge checklist to review and assess patients' understanding of discharge medications, catheters, home care plans, follow-up, symptoms, and who to call with problems after discharge. In parallel, we developed a process of integrating the checklist into the discharge process after routine discharge procedures were completed. We used the checklists to assess patients' level of understanding and need for additional education as well as changes in discharge documentation; we also noted whether good catches of significant errors in the discharge process occurred.

Results:

Over 6 months of study, 190 discharge timeouts out of 429 eligible discharges were completed. Additional education was provided in 53 of 190 discharge timeouts (27.8%), with 62% of this education being related to medications. Twenty-one (11.1%) discharge timeouts resulted in at least one change to the discharge documentation or a good catch.

Conclusions:

A multidisciplinary discharge timeout directly involving the patient can be effective in targeting additional areas for patient education and in potentially reducing preventable adverse events.
Sacroiliitis in Children With Familial Mediterranean Fever
Authors: Aydin Fatma , Özçakar Z. Birsin , Çakar Nilgün , Çelikel Elif , Uncu Nermin , Çelikel Acar Banu , Yalçinkaya Fatoş
Published: March 2018

Background/Objective

Familial Mediterranean fever (FMF) is an autosomal recessive disease, characterized by recurrent, self-limited attacks of fever with serositis. Various diseases were reported to be associated with FMF. The aim of this study was to investigate the frequency and characteristics of sacroiliitis in children with FMF.

Methods

Files of FMF patients who had been seen in 2 reference hospitals in Ankara were retrospectively evaluated. Patients with FMF and concomitant sacroiliitis were included to the study. All patients had magnetic resonance imaging evidence of sacroiliitis.

Results

Among 650 FMF patients, 17 (11 females, 6 males; mean age, 13.32 ± 4.24 years) (2.6%) of them were found to have sacroiliitis. Familial Mediterranean fever diagnosis was done prior to sacroiliitis diagnosis in 11 patients (65%) and concurrently or afterward in 6 patients (35%). Ten patients had isolated sacroiliitis, and 7 had associated diseases (5 enthesitis-related arthritis, 1 psoriatic arthritis, and 1 ulcerative colitis). Arthritis (59%), arthralgia (77%), leg pain (71%), heel pain (41%), and enthesitis (29%) were common complaints. Sacroiliac tenderness was detected in 77%, and M694V mutation in almost 90% of the patients. All patients received colchicine therapy. Additionally, 14 of them were treated with nonsteroidal anti-inflammatory drugs, 10 were on sulfasalazine treatment, and 7 of them were on biological agents.

Conclusions

Sacroiliitis can be seen in patients with FMF during childhood, and M694V mutation seems to be a susceptibility factor for its development. Inflammatory low-back pain and leg and heel pain could suggest sacroiliitis.
Quantitative Assessment of Thyroid, Submandibular, and Parotid Glands Elasticity With Shear-Wave Elastography in Children
Authors: Arioz Habibi Hatice , Memis Durmaz Emine Sebnem , Qarayeva Vusale , Kandemirli Sedat Giray , Kalyoncu Ucar Ayse , Aslan Mine , Apaydin Gozde , Kurugoglu Sebuh , Adaletli Ibrahim
Published: March 2018

Tissue elasticity is becoming a more commonly used parameter in evaluation of parenchyma in inflammatory diseases. Considering the changes in the thyroid and salivary glands with adolescence, determination of mean elasticity ranges with a function of age is necessary to apply ultrasound elastography more widely in the pediatric population.

The thyroid, submandibular, and parotid glands of 127 healthy volunteers (66 males, 61 females; mean age = 10.3 ± 3.9 years; range = 3–17 years) were evaluated with shear-wave elastography.

The mean elasticity values for the thyroid, submandibular, and parotid glands were 14.6 ± 3.3, 11.8 ± 2.2, and 11.8 ± 2.6 kPa, respectively. There was a significant positive correlation between age and elasticity of the thyroid, submandibular, and parotid glands. There was a significant correlation between age and elasticity value of the thyroid gland adjusted for weight and height.

This study provided the baseline quantitative elasticity measures of thyroid, submandibular, and parotid glands, which would be a reference for upcoming studies. In addition, an increase in elasticity value in thyroid gland as a function of age independent of change in weight and height was demonstrated.
Systematic analysis of mouse genome reveals distinct evolutionary and functional properties among circadian and ultradian genes
Authors: Castellana Stefano , Mazza Tommaso , Kappler Martin , Capocefalo Daniele , Genov Nikolai , Biagini Tommaso , Fusilli Caterina , Scholkmann Felix , Relógio Angela , Hogenesch John B. , Mazzoccoli Gianluigi
Published: March 2018

In living organisms, biological clocks regulate 24 h (circadian) molecular, physiological, and behavioral rhythms to maintain homeostasis and synchrony with predictable environmental changes. Harmonics of these circadian rhythms having periods of 8 hours and 12 hours (ultradian) have been documented in several species. In mouse liver, harmonics of the 24-hour period of gene transcription hallmarked genes oscillating with a frequency two or three times faster than the circadian circuitry. Many of these harmonic transcripts enriched pathways regulating responses to environmental stress and coinciding preferentially with subjective dawn and dusk. We hypothesized that these stress anticipatory genes would be more evolutionarily conserved than background circadian and non-circadian genes. To investigate this issue, we performed broad computational analyses of genes/proteins oscillating at different frequency ranges across several species and showed that ultradian genes/proteins, especially those oscillating with a 12-hour periodicity, are more likely to be of ancient origin and essential in mice. In summary, our results show that genes with ultradian transcriptional patterns are more likely to be phylogenetically conserved and associated with the primeval and inevitable dawn/dusk transitions.
Oscillatory dynamics of perceptual to conceptual transformations in the ventral visual pathway
Authors: Clarke Alex , Devereux Barry J. , Tyler Lorraine K.
Published: March 2018

Object recognition requires dynamic transformations of low-level visual inputs to complex semantic representations. While this process depends on the ventral visual pathway (VVP), we lack an incremental account from low-level inputs to semantic representations, and the mechanistic details of these dynamics. Here we combine computational models of vision with semantics, and test the output of the incremental model against patterns of neural oscillations recorded with MEG in humans. Representational Similarity Analysis showed visual information was represented in alpha activity throughout the VVP, and semantic information was represented in theta activity. Furthermore, informational connectivity showed visual information travels through feedforward connections, while visual information is transformed into semantic representations through feedforward and feedback activity, centered on the anterior temporal lobe. Our research highlights that the complex transformations between visual and semantic information is driven by feedforward and recurrent dynamics resulting in object-specific semantics.
Simulations and Electrostatic Analysis Suggest an Active Role for DNA Conformational Changes During Genome Packaging by Bacteriophages
Authors: Sharp Kim A. , Lu Xiang-Jun , Cingolani Gino , Harvey Stephen C.
Published: March 2018

Motors that move DNA, or that move along DNA, play essential roles in DNA replication, transcription, recombination, and chromosome segregation. The mechanisms by which these DNA translocases operate remain largely unknown. Some double-stranded DNA (dsDNA) viruses use an ATP-dependent motor to drive DNA into preformed capsids. These include several human pathogens, as well as dsDNA bacteriophages – viruses that infect bacteria. We previously proposed that DNA is not a passive substrate of bacteriophage packaging motors but is, instead, an active component of the machinery. Computational studies on dsDNA in the channel of viral portal proteins reported here reveal DNA conformational changes consistent with that hypothesis. dsDNA becomes longer (“stretched”) in regions of high negative electrostatic potential, and shorter (“scrunched”) in regions of high positive potential. These results suggest a mechanism that couples the energy released by ATP hydrolysis to DNA translocation: The chemical cycle of ATP binding, hydrolysis and product release drives a cycle of protein conformational changes. This produces changes in the electrostatic potential in the channel through the portal, and these drive cyclic changes in the length of dsDNA. The DNA motions are captured by a coordinated protein-DNA grip-and-release cycle to produce DNA translocation. In short, the ATPase, portal and dsDNA work synergistically to promote genome packaging.
An easy estimate of the PFDD for a plant illuminated with white LEDs: 1000 lx = 15 μmol/s/m2
Authors: Sharakshane Anton
Published: March 2018

Dependencies have been shown and conversion factors have been determined, which allow to estimate PPFD, YPFD and radiometric power density of white LED light according to the known illumination in lux. A technique for estimating photosynthetically active radiation, which has an adequate accuracy for the task of illuminating plants, has been determined.
The Healthy Pregnancy Research Program: Transforming Pregnancy Research Through a ResearchKit App
Authors: Radin Jennifer M. , Steinhubl Steven R. , Su Andrew I. , Bhargava Hansa , Greenberg Benjamin , Bot Brian M. , Doerr Megan , Topol Eric J.
Published: March 2018

Although maternal morbidity and mortality in the U.S. is among the worst of developed countries, pregnant women have been under-represented in research studies, resulting in deficiencies in evidence-based guidance for treatment. There are over two billion smartphone users worldwide, enabling researchers to easily and cheaply conduct extremely large-scale research studies through smartphone apps, especially among pregnant women in whom app use is exceptionally high, predominantly as an information conduit. We developed the first pregnancy research app that is embedded within an existing, popular pregnancy app for self-management and education of expectant mothers. Through the large-scale and simplified collection of survey and sensor generated data via the app, we aim to improve our understanding of factors that promote a healthy pregnancy for both the mother and developing fetus. From the launch of this cohort study on March 16, 2017 through December 17, 2017, we have enrolled 2,058 pregnant women from all 50 states. Our study population is diverse geographically and demographically, and fairly representative of U.S. population averages. We have collected 14,045 individual surveys and 11,669 days of sleep, activity, blood pressure and heart rate measurements during this time. On average, women stayed engaged in the study for 59 days and 45 percent who reached their due date filled out the final outcome survey. During the first nine months, we demonstrated the potential for a smartphone-based research platform to capture an ever-expanding array of longitudinal, objective and subjective participant-generated data from a continuously growing and diverse population of pregnant women.

Funding

Supported in part by the National Institutes of Health (NIH)/National Center for Advancing Translational Sciences grant UL1TR001114 and a grant from the Qualcomm Foundation.
Structure of the chromatin remodelling enzyme Chd1 bound to a ubiquitinylated nucleosome
Authors: Sundaramoorthy Ramasubramanian , Hughes Amanda L. , El-Mkami Hassane , Norman David , Owen-Hughes Tom
Published: March 2018

ATP-dependent chromatin remodelling proteins represent a diverse family of proteins that share ATPase domains that are adapted to regulate protein-DNA interactions. Here we present structures of the yeast Chd1 protein engaged with nucleosomes in the presence of the transition state mimic ADP-beryllium fluoride. The path of DNA strands through the ATPase domains indicates the presence of contacts conserved with single strand translocases and additional contacts with both strands that are unique to Snf2 related proteins. The structure provides connectivity between rearrangement of ATPase lobes to a closed, nucleotide bound state and the sensing of linker DNA. Two turns of linker DNA are prised off the surface of the histone octamer as a result of Chd1 binding, and both the histone H3 tail and ubiquitin conjugated to lysine 120 are re-orientated towards the unravelled DNA. This indicates how changes to nucleosome structure can alter the way in which histone epitopes are presented.
Subnetwork-based prognostic biomarkers exhibit performance and robustness superior to gene-based biomarkers in breast cancer
Authors: Grzadkowski Michal R. , Haider Syed , Sendorek Dorota H. , Boutros Paul C.
Published: March 2018

Background

Effective classification of cancer patients into groups with differential survival remains an important and unsolved challenge. Biomarkers have been developed based on mRNA abundance data, but their replicability and clinical utility is modest. Integrating functional information, such as pathway data, has been suggested to improve biomarker performance. To date, however, the advantages of subnetwork-based biomarkers have not been quantified.

Results

We deeply sampled the population of prognostic gene-based and subnetwork-based biomarkers in a breast cancer meta-dataset of 4,960 patients. Analysing the performance and robustness of 22,000,000 gene biomarkers and 6,250,000 subnetwork biomarkers across twenty different training:testing cohort partitions of the meta-dataset revealed that subnetwork biomarkers exhibit superior overall performance and higher concordance across partitions. We find evidence of an upper bound for optimal biomarker size of ∼200 genes or ∼100 subnetworks. Additionally, with both biomarker feature types, larger biomarkers tend to show less consistency in performance across partitions, suggestive of over-fitting. Finally, an evaluation of varying training cohort sizes quantifies the effects of training cohort size.

Conclusions

Many groups are developing techniques for exploiting network-based representations of biological pathways to characterize cancer and other diseases. By considering the distribution of gene- and subnetwork-based biomarkers, we show that pathway data improves performance and replicability, and that smaller biomarkers are more robust across patient cohorts. These insights may facilitate development of clinically useful biomarkers.
Probing the Acyl Carrier Protein-Enzyme Interactions within Terminal Alkyne Biosynthetic Machinery
Authors: Su Michael , Zhu Xuejun , Zhang Wenjun
Published: March 2018

The alkyne functionality has attracted much interest due to its diverse chemical and biological applications. We recently elucidated an acyl carrier protein (ACP)-dependent alkyne biosynthetic pathway, however, little is known about ACP interactions with the alkyne biosynthetic enzymes, an acyl-ACP ligase (JamA) and a membrane-bound bi-functional desaturase/acetylenase (JamB). Here, we showed that JamB has a more stringent interaction with ACP than JamA. In addition, site directed mutagenesis of a non-cognate ACP significantly improved its compatibility with JamB, suggesting a possible electrostatic interaction at the ACP-JamB interface. Finally, error-prone PCR and screening of a second non-cognate ACP identified hot spots on the ACP that are important for interacting with JamB and yielded mutants which were better recognized by JamB. Our data thus not only provide insights into the ACP interactions in alkyne biosynthesis, but it also potentially aids in future combinatorial biosynthesis of alkyne-tagged metabolites for chemical and biological applications.

Topical Heading

Biomolecular Engineering, Bioengineering, Biochemicals, Biofuels, and Food
Optimizing bioreactor growth of the smallest eukaryote
Authors: Smallwood Chuck R. , Hill Eric A. , Chrisler William , Brookreson Jory , Evans James E.
Published: March 2018

Photosynthetic organisms are adept at circumventing nutrient deprivation. Microalgae in particular present novel adaptations to nutrient and light starvation since they can scavenge external and internal nutrient pools to redistribute energy resources for survival. In this report, a turbidostatic photobioreactor was used to characterize environmental conditions and nutrient requirements for cultures of the smallest free-living eukaryote Ostreococcus tauri. Optimized growth conditions were identified that enable 4-times faster phototrophic growth-rates while increasing total biomass 10-fold. By achieving phototrophic doubling times shorter than 6 hours, these results highlight the potential of this smallest eukaryote for future industrial bioproduct applications.
Automated classification of synaptic vesicles in electron tomograms ofC. elegansusing machine learning
Authors: Kaltdorf Kristin Verena , Theiss Maria , Markert Sebastian Matthias , Zhen Mei , Dandekar Thomas , Stigloher Christian , Kollmannsberger Philip
Published: March 2018

1.

Synaptic vesicles (SVs) are a key component of neuronal signaling and fulfil different roles depending on their composition. In electron micrograms of neurites, two types of vesicles can be distinguished by morphological criteria, the classical “clear core” vesicles (CCV) and the typically larger “dense core” vesicles (DCV), with differences in electron density due to their diverse cargos. Compared to CCVs, the precise function of DCVs is less defined. DCVs are known to store neuropeptides, which function as neuronal messengers and modulators [1]. InC. elegans, they play a role in locomotion, dauer formation, egg-laying, and mechano- and chemosensation [2]. Another type of DCVs, also referred to as granulated vesicles, are known to transport Bassoon, Piccolo and further constituents of the presynaptic density in the center of the active zone (AZ), and therefore are important for synaptogenesis [3].

To better understand the role of different types of SVs, we present here a new automated approach to classify vesicles. We combine machine learning with an extension of our previously developed vesicle segmentation workflow, the ImageJ macro 3D ART VeSElecT. With that we reliably distinguish CCVs and DCVs in electron tomograms ofC. elegansNMJs using image-based features. Analysis of the underlying ground truth data shows an increased fraction of DCVs as well as a higher mean distance between DCVs and AZs in dauer larvae compared to young adult hermaphrodites. Our machine learning based tools are adaptable and can be applied to study properties of different synaptic vesicle pools in electron tomograms of diverse model organisms.

2.

Author summary

Vesicles are important components of the cell, and synaptic vesicles are central for neuronal signaling. Two types of synaptic vesicles can be distinguished by electron microscopy: the classical “clear core” vesicles (CCVs) and the typically larger “dense core” vesicles (DCVs). The distinct appearance of vesicles is caused by their different cargos. To rapidly distinguish between both vesicle types, we present here a new automated approach to classify vesicles in electron tomograms. We combine machine learning with an extension of our previously developed vesicle segmentation workflow, an ImageJ macro, to reliably distinguish CCVs and DCVs using specific image-based features. The approach was trained and validated using data-sets that were hand curated by microscopy experts. Our technique can be transferred to more extensive comparisons in both stages as well as to other neurobiology questions regarding synaptic vesicles.
Lymphocyte activation gene 3 (Lag3) expression is increased in prion infections but does not modify disease progression
Authors: Liu Yingjun , Sorce Silvia , Nuvolone Mario , Domange Julie , Aguzzi Adriano
Published: March 2018

Prion diseases, Alzheimer’s disease and Parkinson’s disease (PD) are fatal degenerative disorders that share common neuropathological and biochemical features, including the aggregation of pathological protein conformers. Lymphocyte activation gene 3 (Lag3, also known as CD223) is a member of the immunoglobulin superfamily of receptors expressed on peripheral immune cells, microglia and neurons, which serves as a receptor for α-synuclein aggregates in PD. Here we examined the possible role of Lag3 in the pathogenesis of prion diseases. Through quantitative real-time PCR and RNA-sequencing, we found that the expression levels of Lag3 were relatively low in the adult mouse brains, yet its expression was increased after prion infection. However, we failed finding significant differences regarding the incubation time, PrPSc load, neurodegeneration, astrocyte and microglia reactions and inflammatory gene expression between the Lag3 knockout mice and wild-type littermate controls after prion infection. We conclude that loss of Lag3 has no significant influence on prion disease pathogenesis. Considering that Lag3 is an immune checkpoint receptor, our results suggest that immune checkpoint inhibition (an increasingly prevalent therapeutic modality against many types of cancer) might not exert positive or negative effects on the progression of prion diseases.
The Mitochondrial DNA Control Region might have useful Diagnostic and Prognostic Biomarkers for Thyroid Tumors
Authors: Bircan Rifat , Gözü Hülya Iliksu , Esra Ulu , Sarikaya Şükran , Gül Aylin Ege , Yaşar Şirin Duygu , Özçelik Serhat , Aral Cenk
Published: March 2018

Background

It is currently present in the literature that mitochondrial DNA (mtDNA) defects are associated with a great number of diseases including cancers. The role of mitochondrial DNA (mtDNA) variations in the development of thyroid cancer is a highly controversial topic. In this study, we investigated the role of mt-DNA control region (CR) variations in thyroid tumor progression and the influence of mtDNA haplogroups on susceptibility to thyroid tumors.

Material & method

For this purpose, totally 108 hot thyroid nodules (HTNs), 95 cold thyroid nodules (CTNs), 48 papillary thyroid carcinoma (PTC) samples with their surrounding tissues and 104 healthy control subject’s blood samples were screened for entire mtDNA CR variations by using Sanger sequencing. The obtained DNA sequences were anaysed with the mistomaster, a web-based bioinformatics tool.

Results

MtDNA haplogroup U was significantly associated with susceptibility to benign and malign thyroid entities on the other hand J haplogroup was associated with a protective role for benign thyroid nodules. Besides, 8 SNPs (T146C, G185A, C194T, C295T, G16129A, T16304C, A16343G and T16362C) in mtDNA CR region were associated with the occurrence of benign and malign thyroid nodules in Turkish population. By contrast with the healthy Turkish population and HTNs, frequency of C7 repeats in D310 polycytosine sequence was found higher in cold thyroid nodules and PTC samples. Beside this, the frequency of somatic mutations in mtMSI regions including T16189C and D514 CA dinucleotide repeats were found higher in PTC samples than the benign thyroid nodules. Conversely, the frequency of somatic mutations in D310 was detected higher in HTNs than CTNs and PTCs.

Conclusion

mtDNA D310 instability do not play a role in tumorogenesis of the PTC but the results indicates that it might be used as a diagnostic clonal expansion biomarker for premalignant thyroid tumor cells. Beside this, D514 CA instability might be used as prognostic biomarker in PTCs. Also, we showed that somatic mutation rate is less frequent in more aggressive tumors when we examined micro- and macro carcinomas as well as BRAFV600E mutation.
Adult influence on juvenile phenotypes by stage-specific pheromone production
Authors: Werner Michael S. , Claaßen Marc H. , Renahan Tess , Dardiry Mohannad , Sommer Ralf. J.
Published: March 2018

Many animal and plant species respond to high or low population densities by phenotypic plasticity. To investigate if specific age classes and/or cross-generational signaling affect(s) phenotypic plasticity, we developed a dye-based method to differentiate co-occurring nematode age classes. We applied this method toPristionchus pacificus, which develops a predatory mouth form to exploit alternative resources and kill competitors in response to high population densities. Remarkably, only adult, but not juvenile, crowding induces the predatory morph in other juveniles. Profiling of secreted metabolites throughout development with HPLC-MS combined with genetic mutants traced this result to the production of adult-specific pheromones. Specifically, theP. pacificus-specific di-ascaroside#1 that induces the predatory morph exhibits a binary induction in adults, even though mouth form is no longer plastic in adults. This cross-generational signaling between adults and juveniles may serve as an indication of rapidly increasing population size. Thus, phenotypic plasticity depends on critical age classes.
Design and evaluation of a large sequence-capture probe set and associated SNPs for diploid and haploid samples of Norway spruce (Picea abies)
Authors: Vidalis Amaryllis , Scofield Douglas G. , Neves Leandro G. , Bernhardsson Carolina , García-Gil María Rosario , Ingvarsson Pär K.
Published: March 2018

Massively parallel sequencing has revolutionized the field of genetics by providing comparatively high-resolution insights into whole genomes for large number of species so far. However, whole-genome resequencing of many conspecific individuals remains cost-prohibitive for most species. This is especially true for species with very large genomes with extensive genomic redundancy, such as the genomes of coniferous trees. The genome assembly for the conifer Norway spruce (Picea abies) was the first published draft genome assembly for any gymnosperm. Our goal was to develop a dense set of genome-wide SNP markers for Norway spruce to be used for assembly improvement and population studies. From 80,000 initial probe candidates, we developed two partially-overlapping sets of sequence capture probes: one developed against 56 haploid megagametophytes, to aid assembly improvement; and the other developed against 6 diploid needle samples, to aid population studies. We focused probe development within genes, as delineated via the annotation of ~67,000 gene models accompanying P. abies assembly version 1.0. The 31,277 probes developed against megagametophytes covered 19,268 gene models (mean 1.62 probes/model). The 40,018 probes developed against diploid tissue covered 26,219 gene modules (mean 1.53 probes/model). Analysis of read coverage and variant quality around probe sites showed that initial alignment of captured reads should be done against the whole genome sequence, rather than a subset of probe-containing scaffolds, to overcome occasional capture of sequences outside of designed regions. All three probe sets, anchored to the P. abies 1.0 genome assembly and annotation, are available for download.
Genomic normalization for sequencing libraries enrichment for rare somatic retroelement insertions
Authors: Komkov Alexander , Nugmanov Gaiaz , Salutina Maria , Minervina Anastasia , Khodosevich Konstantin , Lebedev Yuri , Mamedov Ilgar
Published: March 2018

Background

There is increasing evidence that the transpositional activity of retroelements (REs) is not limited to germ line cells, but often occurs in tumor and normal somatic cells. Somatic transpositions were found in several human tissues and are especially typical for the brain. Several computational and experimental approaches for detection of somatic retroelement insertions was developed in the past few years. These approaches were successfully applied to detect somatic insertions in clonally expanded tumor cells. At the same time, identification of somatic insertions presented in small proportion of cells, such as neurons, remains a considerable challenge.

Results

In this study, we developed a normalization procedure for library enrichment by DNA sequences corresponding to rare somatic RE insertions. Two rounds of normalization increased the number of fragments adjacent to somatic REs in the sequenced sample by more than 26-fold, and the number of identified somatic REs was increased by 7.9-fold.

Conclusions

The developed technique can be used in combination with vast majority of modern RE identification approaches and can dramatically increase their capacity to detect rare somatic RE insertions in different types of cells.
AutonoMouse: High throughput automated operant conditioning shows progressive behavioural impairment with graded olfactory bulb lesions
Authors: Erskine Andrew , Bus Thorsten , Herb Jan T. , Schaefer Andreas T.
Published: March 2018

Operant conditioning is a crucial tool in neuroscience research for probing brain function. While molecular, anatomical and even physiological techniques have seen radical increases in throughput, efficiency, and reproducibility in recent years, behavioural tools have seen much less of an improvement. Here we present a fully automated, high-throughput system for self-initiated conditioning of up to 25 group-housed, radio-frequency identification (RFID) tagged mice over periods of several months and >10^6 trials. We validate this “AutonoMouse” system in a series of olfactory behavioural tasks and show that acquired data is comparable to previous semi-manual approaches. Furthermore, we use AutonoMouse to systematically probe the impact of graded olfactory bulb lesions on olfactory behaviour and resolve the long-standing conundrum about the apparent lack of impact of lesions on olfactory abilities. The modular nature and open-source design of AutonoMouse should allow for similar robust and systematic assessments across neuroscience research areas.
Dorsal Hippocampal Activation Suppresses Neuropathic Pain Behaviors: Chronic pain as extinction-resistant pain-related memory traces
Authors: Xuhong Wei , Ren W. , Centeno M.V. , Procissi D. , Xu Ting , Jabakhanji R. , Martina M. , Radulovic J. , Surmeier D. J. , Liu X.G. , Apkarian A.V.
Published: March 2018

Accumulating evidence suggests the hippocampus being involved in, and modified with, chronic neuropathic pain. However, it is still not clear whether hippocampal activity has direct control over neuropathic behaviors. Here we show that activation of the dorsal, but not ventral, hippocampus, by glutamate microinjection or by chemogenetically increasing excitability (PSAM/PSEM), completely or partially reversed neuropathic behaviors: tactile allodynia and thermal hyperalgesia in the models of spared nerve injury and lumbar spinal nerve ligation. Using a new methodology (chemo-fMRI), where we combine awake resting state brain imaging with viral vector mediated chemogenetic activation (PSAM/PSEM), we could demonstrate that increased excitability of dorsal hippocampus neurons altered resting state functional connectivity within circuitry specifically related to the extent of diminution of neuropathic behavior (tactile allodynia). The identified circuitry most reliably (survived a validation procedure) identified dorsal hippocampal connections to the somatosensory cortex and the thalamus. Moreover, anterograde tracing indicated non-overlapping projections from dorsal and ventral hippocampus. Thus, the present study exhibits a novel causal role for the dorsal hippocampus, and mediating circuitry, controlling neuropathic pain-related behaviors. Altogether, these results imply downregulation of dorsal hippocampus circuitry in chronic neuropathic pain; the activation of which reverses pain behaviors either through disruption of accumulated memories and/or by enhancing extinction circuitry.
Characterisation of palytoxin from an undescribed Palythoa (Anthozoa: Zoantharia: Sphenopidae) with significant in vitro cytotoxic effects on cancer cells at picomolar doses
Authors: Sawelew Ludovic , Gault Frédéric , Nuccio Christopher , Perez Yvan , Lorquin Jean
Published: March 2018

Palytoxin (PlTX), a large polyhydroxylated compound, is among the most potent non-peptide toxin in marine organisms known so far. The literature emphasizes the sodium/potassium pump (NaK) as the privileged target for PlTX when exerting its toxic effects. In this study, we focused on an undescribed species (Palythoa sp. Pc001), a coral species belonging to the genus Palythoa routinely cultivated in aquariums. We demonstrated that this species contains one of the highest yields of pure PlTX production ever found, 2.22 ± 0.41 mg PlTX per gram of wet Palythoa. Using molecular data combined with external morphology, we identified Palythoa sp. Pc001 as the sister species to Palythoa aff. clavata. Further, the clade of a symbiotic Symbiodinium sp. was characterised by DNA barcoding and pigment content. Molecular data showed that Palythoa sp. Pc001 contains ‘generalist’ Symbiodinium belonging to clade C. This paper also describes for the first time the localisation of PlTX and Symbiodinium cells in tissues of a highly toxic Palythoa species. PlTX toxicity was assayed on 72 h-cultured murine and human cancer cells versus the normal human dermal fibroblast (NHDF; PC C12300) cell line. Using MTT colorimetric assay and quantitative videomicroscopy, our results showed much higher in vitro cytotoxic activity on cancer cells (IC50 0.54 ± 0.05 × 10−12 M) than on non-cancerous ones (IC50 > 1 × 10−6 M). Such a strong differential effect has never been reported with respect to the most potent NaK ligands (cardiac glycosides) described so far. Moreover, PlTX displayed similar in vitro growth inhibitory activity in rodent and human cancer cells, although the NaK in rodents displays a double mutation in the α1-subunit that usually decreases the sensitivity to others cardiac glycosides like ouabain, when compared to human cells. This work demonstrates, first, that picomolar concentrations of PlTX have significant higher cytotoxic effects on cancer cells than on non-cancerous ones, and secondly, that this in vitro antitumor effect would not be entirely relied onto its canonical targeting to the NaK α-subunit. Thus, PlTX ranks amongst highly potent anti-cancer drugs as it targets cancers while potentially minimizing the drug’s side effects on healthy cells.