bluuebunny/crossref_metadata_2025 huggingface dataset:
Endoscopic Endonasal Approach to the Upper Cervical Spine for Decompression of the Cervicomedullary Junction Following Occipitocervical Fusion
Authors: Hussain Ibrahim , Schwartz Theodore H. , Greenfield Jeffrey P.
Published: March 2018

Basilar invagination is defined as abnormal upward and/or posterior displacement of the odontoid leading to ventral compression of the cervicomedullary junction. This condition leads to lower cranial neuropathies, sensorimotor deficits, and myelopathy. These symptoms can persist even after posterior decompression, which is an indication for ventral decompression. Transoral approaches to the upper cervical spine carry significant morbidity, limiting their utility. The endonasal approach to the upper cervical spine presents an alternative for patients with amenable anatomy. In this report, we present a case of a patient with type 1 Chiari malformation with persistent symptoms despite adequate posterior decompression through suboccipital craniectomy and C1 laminectomy. A retroflexed odontoid and dorsal clival bone lip contributed to persistent cervicomedullary compression. To address this, we performed a 2-stage procedure: an occiput-to-C4 fusion followed by endoscopic endonasal approach for dorsal clivusectomy, C1 anterior arch resection, and odontoidectomy. In the associated video, Supplemental Digital Content 1 (http://links.lww.com/CLINSPINE/A52), we demonstrate the step-by-step approach for this anterior approach including positioning, dissection through the nasopharyngeal fascia, identification of bony landmarks using an intraoperative CT scanner with 3-dimensional navigation guidance, and drilling/bony decompression of the dorsal clivus, C1, and C2. We also discuss key pearls, pitfalls, and preoperative/postoperative considerations critical to successful outcomes.
The Accurate Free-hand Placement of S2 Alar Iliac (S2AI) Screw
Authors: Fang Taolin , Russo Glenn S. , Schroeder Gregory D. , Kepler Christopher K.
Published: March 2018

Achieving an osseous fusion across the lumbosacral spine is still challenging in spine surgery. For the long multisegmental fusion surgery, it is crucial to build a robust and substantial foundation, which sometimes necessitates the distal spinal fixation to the pelvis. The pelvic fixation technique involves advancing the screw through the alar, thereby providing more purchase across the sacroiliac joint and into the ilium. The S2 alar iliac screws can obtain immediate stability and proper biomechanical strength of constructs. Here we demonstrated our experience of how to place the S2 alar iliac screw accurately as well as some pitfalls and pearls of this technique.
Genetic Variant of SOCS3 Gene is Functionally Associated With Lumbar Adolescent Idiopathic Scoliosis
Authors: Qiao Jun , Xiao Lingyan , Xu Leilei , Qian Bangping , Zhu Zezhang , Qiu Yong
Published: March 2018

Study Design:

This is a genetic association study.

Objective:

To investigate association between suppressor of cytokine signaling-3 (SOCS3) gene polymorphisms and the onset and progression of lumbar adolescent idiopathic scoliosis (AIS) and to further clarify its role in the regulation of SOCS3 expression in AIS patients.

Summary of Background Data:

Some studies showed that muscle development imbalance may be responsible for onset and progression of lumbar AIS. SOCS3 is one of the significant regulators of skeletal muscle development, and in vitro study showed that SOCS3 influences myoblast differentiation.

Materials and Methods:

Rs4969198 was genotyped in 476 lumbar AIS patients and 672 controls. The differences of genotype and allele distributions between patients and controls were calculated using the χ2 test. Paravertebral muscles were collected from 53 AIS, 23 congenital scoliosis, and 18 lumbar disk herniation patients. AIS patients were classified into 3 groups according to the genotypes of each single nucleotide polymorphisms, and 1-way analysis of variance test was used to compare SOCS3 expression among different groups and genotypes.

Results:

Patients were found to have a significantly higher frequency of GG than the controls (40.8% vs. 29.9%, odds ratio=1.36; P=0.000), and the frequency of allele G was found to be remarkably higher in the patients than the controls (65.3% vs. 56.7%, odds ratio=1.15; P=0.000). AIS patients had significantly less muscle expression of the SOCS3 than the congenital scoliosis patients (2.73±2.17 vs. 4.62±2.41; P=0.006) and the lumbar disk herniation patients (2.73±2.17 vs. 4.12±2.93; P=0.009). The SOCS3 expression was significantly correlated with the curve severity (r=0.472; P=0.014).

Conclusions:

The SOCS3 gene is significantly associated with the development of lumbar AIS in Chinese population. Decreased expression of SOCS3 is associated with larger severity of lumbar AIS.

Level of Evidence:

Level III.
Postoperative Infection in Patients Undergoing Posterior Lumbosacral Spinal Surgery
Authors: Chen Shih-Hao , Chen Wen-Jer , Wu Meng-Huang , Liao Jen-Chung , Fu Chen-Ju
Published: March 2018

Surgical site infections after posterior spinal surgery may lead to spondylodiscitis, pseudarthrosis, correction loss, adverse neurological sequelae, sepsis, and poor outcomes if not treated immediately. Infection rates vary depending on the type and extent of operative procedures, use of instrumentation, and patients’ risk factors. Image evaluation is crucial for early diagnosis and should be complementary to clinical routes, laboratory survey, and treatment timing. Magnetic resonance imaging detects early inflammatory infiltration into the vertebrae and soft tissues, including hyperemic changes of edematous marrow, vertebral endplate, and abscess or phlegmon accumulation around the intervertebral disk, epidural, and paravertebral spaces. Aggressive surgical treatment can eradicate infection sources, obtain a stable wound closure, decrease morbidity, and restore spinal integrity. Organ/space infection is defined as any body parts opened to manipulate other than superficial/deep incision. Advanced magnetic resonance imaging evaluating abnormal fluid accumulation, heterogenous contrast enhancement of the endplate erosion due to cage/screw infection is categorized to inform a presumptive diagnosis for early implant salvage. However, patients’ defense response, infection severity, bacteriology, treatment timing, spinal stability, and available medical and surgical options must be fully considered. Revision surgery is indicated for pseudarthrosis, implant loosening with correction loss, recalcitrant spondylodiscitis, and adjacent segment diseases for infection control.
An Overview of Clinically Relevant Biomechanics of the Anterolateral Structures of the Knee
Authors: Kennedy Mitchell I. , LaPrade Christopher M. , Geeslin Andrew G. , LaPrade Robert F.
Published: March 2018

Residual anterolateral rotatory laxity following injury and reconstruction of the anterior cruciate ligament (ACL) has become a popular topic and has generated interest in characterizing the relative contribution from the anterolateral structures of the knee. Studies have reported on the anatomic and biomechanical features of the anterolateral ligament (ALL), revealing a role in restraining internal tibial rotation in both ACL-intact and ACL-deficient knees. The Kaplan fibers of the iliotibial band have also been reported to provide significant restraint to internal tibial rotation. The ACL is the primary restraint to anterior tibial translation, and both the proximal and distal bundles of the iliotibial band, with a divergent orientation, also provide significant static restraint against internal tibial rotation, and each bundle may have a distinct individual role. In the setting of ACL deficiency, subsequent sectioning of the ALL and Kaplan fibers led to further increases in anterior tibial translation. Residual rotatory laxity that may be seen clinically following ACL reconstruction may be attributable to an associated anterolateral structure injury even in the setting of an anatomic ACLR, leading to consideration for a concomitant anterolateral structure reconstruction. Studies evaluating the kinematic influence of anatomic ALL reconstruction or lateral extra-articular tenodesis have focused on internal rotation, axial plane translation, and anterior tibial translation, with variable results having been reported. Further, despite the long history of anterolateral structure reconstruction, most commonly with a lateral extra-articular tenodesis, the clinical use of these combined techniques is still in its relative infancy, and long-term patient outcomes have yet to be published for relative comparisons.
A Meta-analysis of the Association Between Physical Activity and Breast Cancer Mortality
Authors: Lee Junga
Published: March 2018

Background

There are conflicting data on the association between physical activity (PA) intensity and amount and prognosis of breast cancer. It is unknown whether increasing or decreasing PA is associated with all-cause mortality.

Objective

The purpose of this study was to estimate the associations between PA and the risk of mortality.

Methods

MEDLINE and EMBASE were used to find eligible studies published from January 1970 to March 2017 for this meta-analysis. We included 24 studies, with a total of 144 224 patients and follow-up periods ranging from 1.9 to 12.7 years. We categorized the amount of PA as low (<300 min/wk), moderate (300–500 min/wk), and high (>500 min/wk).

Results

We found that high amounts of PA had an inverse relationship with breast-cancer–specific mortality and all-cause morality. Patients who decreased PA after diagnosis showed poorer all-cause mortality, whereas patients who increased PA postdiagnosis had a favorable association with all-cause mortality. Last, patients who met PA guidelines after diagnosis had a lower breast-cancer–specific mortality and all-cause mortality.

Conclusion

Physical activity may play a pivotal role in reducing the risk of death. Getting at least 300 min/wk of moderate-intensity PA will help improve the risk of breast cancer death.

Implications for Practice

Participating in PA is an essential factor in breast cancer care that extends throughout the life span of cancer survivors. Higher levels of PA than current PA guidelines should be recommended to cancer patients.
Roles of Family Caregivers and Perceived Burden When Caring for Hospitalized Adult Cancer Patients
Authors: Muliira Joshua K. , Kizza Irene B. , Nakitende Gloria
Published: March 2018

Background

Family caregivers (FCGs) of adult cancer patients (ACPs) are typically involved in the entire trajectory of cancer disease, from diagnosis to survivorship or end of life. In developing countries, FCGs are more intensely involved in the process of providing care to the hospitalized ACPs because of lack of adequate cancer care resources. Active performance of tasks to meet the needs of ACPs in the hospital setting is likely to elicit significant caregiver burden.

Objective

The aim of this study was to explore the tasks performed and the caregiver burden experienced by FCGs of hospitalized ACPs in a sub-Saharan country.

Methods

A cross-sectional descriptive design was used to collect data from 168 FCGs of ACPs. The Caregiver Burden Scale was used to measure burden.

Results

The most common cancer diagnosis in male and female ACPs was Kaposi's sarcoma (32.1%) and breast cancer (37.9%), respectively. The tasks regularly performed by most FCGs for the ACPs were providing emotional support (79.8%), feeding (68.5%), transporting to other appointments (62.5%), preparing meals (55%), and giving medications (46.4%). Most FCGs (75%) were experiencing severe or very severe general caregiver burden. The dimensions of caregiver burden that were most severely impacted were general strain (70.6%), disappointment (85.8%), and isolation (72%). Predictors of caregiver burden are reported.

Conclusion

Family caregivers of hospitalized ACPs experience severe caregiver burden. The main forms of burden experienced were general strain, disappointment, and isolation.

Implications for Practice

Cancer care services in developing countries should be strengthened with services that address FCGs' emotional needs and human resources to curtail the strain imposed on FCGs.
Longitudinal Clival Fracture in a Child
Authors: Gulen Bedia , Serinken Mustafa , Karcioglu Ozgur , Kucukdagli Okkes Taha
Published: March 2018

Clival fracture is a rare and serious injury, which mostly results in the death of the victim before reaching the hospital. The entity is hardly diagnosed in the early phase because of high mortality rates and deficiencies in completion of radiological imaging. The incidence of diagnoses increased year by year after the usage of computed tomography gained widespread availability. In this article, we aimed to present radiological and clinical characteristics of a 5-year-old patient brought to the emergency department after a motor vehicle accident. The most current recommendations with regard to the management of clival fracture of a pediatric patient are also discussed.
Pathways to Academic Leadership in Plastic Surgery: A Nationwide Survey of Program Directors, Division Chiefs, and Department Chairs of Plastic Surgery
Authors: Fishman Jordan E. , Pang John Henry Y. , Losee Joseph E. , Rubin J. Peter , Nguyen Vu T.
Published: March 2018

Background:

Many aspire to leadership in academic plastic surgery yet there is no well-documented pathway.

Methods:

Information regarding plastic surgery residencies and program directors was obtained from the American Medical Association’s FREIDA database. The division chief or department chair (academic head) of every academic plastic surgery program was identified. One Internet-based survey was distributed to academic heads; another, to program directors.

Results:

Ninety academic heads were identified, 35 of whom also serve as program director. Sixty-seven unique program directors were identified. There was a 51 percent academic head response rate and a 65 percent program director response rate. Academic plastic surgery is overwhelmingly administered by midcareer men. The average program director was appointed at age 45 and has served for 7 years. She or he was trained through the independent track, completed additional training in hand surgery, and is a full professor. She or he publishes two or three peer-reviewed manuscripts per year and spends 9 hours per week in administration. The average academic head was appointed at age 45 and has held the position for 12 years. She or he was trained in the independent model, completed fellowship training, and is a full professor. She or he publishes five peer-reviewed manuscripts per year and spends 12 hours per week involved in administration.

Conclusions:

Program directors and academic heads serve nonoverlapping roles. Few program directors will advance to the role of academic head. Successful applicants to the program director position often serve as an associate program director and are seen as motivated resident educators. In contrast, those faculty members selected for the academic head role are academically accomplished administrators with business acumen.
Comparison of Genotypic and Phenotypic Correlations: Cheverud’s Conjecture in Humans
Authors: Sodini Sebastian M. , Kemper Kathryn E. , Wray Naomi R. , Trzaskowski Maciej
Published: March 2018

Accurate estimation of genetic correlation requires large sample sizes and access to genetically informative data, which are not always available. Accordingly, phenotypic correlations are often assumed to reflect genotypic correlations in evolutionary biology. Cheverud’s conjecture asserts that the use of phenotypic correlations as proxies for genetic correlations is appropriate. Empirical evidence of the conjecture has been found across plant and animal species, with results suggesting that there is indeed a robust relationship between the two. Here, we investigate the conjecture in human populations, an analysis made possible by recent developments in availability of human genomic data and computing resources. A sample of 108,035 British European individuals from the UK Biobank was split equally into discovery and replication datasets. 17 traits were selected based on sample size, distribution and heritability. Genetic correlations were calculated using linkage disequilibrium score regression applied to the genome-wide association summary statistics of pairs of traits, and compared within and across datasets. Strong and significant correlations were found for the between-dataset comparison, suggesting that the genetic correlations from one independent sample were able to predict the phenotypic correlations from another independent sample within the same population. Designating the selected traits as morphological or non-morphological indicated little difference in correlation. The results of this study support the existence of a relationship between genetic and phenotypic correlations in humans. This finding is of specific interest in anthropological studies, which use measured phenotypic correlations to make inferences about the genetics of ancient human populations.
Emergent sub-population behavior uncovered with a community dynamic metabolic model ofEscherichia colidiauxic growth
Authors: Succurro Antonella , Segrè Daniel , Ebenhöh Oliver
Published: March 2018

Microbes have adapted to greatly variable environments in order to survive both short-term perturbations and permanent changes. A classical, yet still actively studied example of adaptation to dynamic environments is the diauxic shift ofEscherichia coli, in which cells grow on glucose until its exhaustion, and then transition to using previously secreted acetate. Here we tested different hypotheses concerning the nature of this transition by using dynamic metabolic modeling. Towards this goal, we developed an open source modeling framework integrating dynamic models (ordinary differential equation systems) with structural models (metabolic networks), which can take into account the behavior of multiple sub-populations, and smooth ux transitions between different time points. We used this framework to model the diauxic shift, first with a singleE. colimodel whose metabolic state represents the overall population average, and then with a community of two sub-populations each growing exclusively on one carbon source (glucose or acetate). After introducing an environment-dependent transition function that determines the balance between different sub-populations, our model generates predictions that are in strong agreement with published data. We thus support recent experimental evidence that, rather than a coordinated metabolic shift, diauxie would be the emergent pattern of individual cells differentiating for optimal growth on different sub-strates. This work offers a new perspective on the use of dynamic metabolic modeling to investigate population heterogeneity dynamics. The proposed approach can easily be applied to other biological systems composed of metabolically distinct, interconverting sub-populations, and could be extended to include single-cell level stochasticity.

Importance

Escherichia colidiauxie is a fundamental example of metabolic adaptation that is not yet completely understood. Further insight into this process can be achieved by integrating experimental and computational modeling methods. We present a dynamic metabolic modeling approach that captures diauxie as an emergent property of sub-population dynamics inE. colimonocultures. Without fine tuning the parameters of theE. colicore metabolic model, we achieve good agreement with published data. Our results suggest that single-organism metabolic models can only approximate the average metabolic state of a population, therefore offering a new perspective on the use of such modeling approaches. The open source modeling framework we provide can be applied to model general sub-population systems in more complex environments, and can be extended to include single-cell level stochasticity.
FIT2 is a lipid phosphate phosphatase crucial for endoplasmic reticulum homeostasis
Authors: Becuwe Michel , Bond Laura M. , Mejhert Niklas , Boland Sebastian , Elliott Shane D. , Cicconet Marcelo , Liu Xinran N. , Graham Morven M. , Walther Tobias C. , Farese Robert V.
Published: March 2018

The endoplasmic reticulum (ER) protein Fat-Induced Transcript 2 (FIT2) has emerged as a key factor in lipid droplet (LD) formation, although its molecular function is unknown. Highlighting its importance, FIT2 orthologs are essential in worms and mice, and FIT2 deficiency causes a deafness/dystonia syndrome in humans. Here we show that FIT2 is a lipid phosphate phosphatase (LPP) enzyme that is required for maintaining the normal structure of the ER. Recombinant FIT2 exhibits LPP activityin vitroand loss of this activity in cells leads to ER membrane morphological changes and ER stress. Defects in LD formation in FIT2 depletion appear to be secondary to membrane lipid abnormalities, possibly due to alterations in phospholipids required for coating forming LDs. Our findings uncover an enzymatic role for FIT2 in ER lipid metabolism that is crucial for ER membrane homeostasis.
Locality Sensitive Imputation for Single-Cell RNA-Seq Data
Authors: Moussa Marmar , Măndoiu Ion I.
Published: March 2018

One of the most notable challenges in single cell RNA-Seq data analysis is the so called drop-out effect, where only a fraction of the transcriptome of each cell is captured. The random nature of drop-outs, however, makes it possible to consider imputation methods as means of correcting for drop-outs. In this paper we study some existing scRNA-Seq imputation methods and propose a novel iterative imputation approach based on efficiently computing highly similar cells. We then present the results of a comprehensive assessment of existing and proposed methods on real scRNA-Seq datasets with varying per cell sequencing depth.
Maturing Mycobacterial Peptidoglycan Requires Non-canonical Crosslinks to Maintain Shape
Authors: Baranowski Catherine , Welsh Michael A. , Sham Lok-To , Eskandarian Haig A. , Lim Hoong C. , Kieser Karen J. , Wagner Jeffrey C. , McKinney John D. , Fantner Georg E. , Ioerger Thomas R. , Walker Suzanne , Bernhardt Thomas G. , Rubin Eric J. , Rego E. Hesper
Published: March 2018

In most well studied rod-shaped bacteria, peptidoglycan is primarily crosslinked by penicillin binding proteins (PBPs). However, in mycobacteria, L,D-transpeptidase (LDT)-mediated crosslinks are highly abundant. To elucidate the role of these unusual crosslinks, we characterized mycobacterial cells lacking all LDTs. We find that LDT-mediated crosslinks are required for rod shape maintenance specifically at sites of aging cell wall, a byproduct of polar elongation. Asymmetric polar growth leads to a non-uniform distribution of these two types of crosslinks in a single cell. Consequently, in the absence of LDT-mediated crosslinks, PBP-catalyzed crosslinks become more important. Because of this,Mycobacterium tuberculosis(Mtb) is more rapidly killed using a combination of drugs capable of PBP- and LDT-inhibition. Thus, knowledge about the single-cell distribution of drug targets can be exploited to more effectively treat this pathogen.
Isw2 and Ino80 chromatin remodeling factors regulate chromatin, replication, and copy number at the yeast ribosomal DNA locus
Authors: Cutler Sam , Lee Laura J , Tsukiyama Toshio
Published: March 2018

In the budding yeastSaccharomyces cerevisiae, ribosomal RNA genes are encoded in a highly repetitive tandem array referred to as the ribosomal DNA (rDNA) locus. The yeast rDNA is the site of a diverse set of DNA-dependent processes, including transcription of ribosomal RNAs by RNA Polymerases I and III, transcription of non-coding RNAs by RNA Polymerase II, DNA replication initiation, replication fork blocking, and recombination-mediated regulation of rDNA repeat copy number. All of this takes place in the context of chromatin, but relatively little is known about the roles played by ATP-dependent chromatin remodeling factors at the yeast rDNA. In this work, we report that the Isw2 and Ino80 chromatin remodeling factors are targeted to this highly repetitive locus. We characterize for the first time their function in modifying local chromatin structure, finding that loss of these factors affects the occupancy of nucleosomes in the 35S ribosomal RNA gene and the positioning of nucleosomes flanking the ribosomal origin of replication. In addition, we report that Isw2 and Ino80 promote efficient firing of the ribosomal origin of replication and facilitate the regulated increase of rDNA repeat copy number. This work significantly expands our understanding of the importance of ATP-dependent chromatin remodeling for rDNA biology.

Author Summary

To satisfy high cellular demand for ribosomes, genomes contain many copies of the genes encoding the RNA components of ribosomes. In the budding yeastSaccharomyces cerevisiae, these ribosomal RNA genes are located in the “ribosomal DNA locus”, a highly repetitive array that contains approximately 150 copies of the same unit, in contrast to the single copies that suffice for most genes. This repetitive quality creates unique regulatory needs. Chromatin structure, the packaging and organization of DNA, is a critical determinant of DNA-dependent processes throughout the genome. ATP-dependent chromatin remodeling factors are important regulators of chromatin structure, and yet relatively little is known about how members of this class of protein affect DNA organization or behavior at the rDNA. In this work, we show that the Isw2 and Ino80 chromatin remodeling factors regulate two features of chromatin structure at the rDNA, the occupancy and the positioning of nucleosomes. In addition, we find that these factors regulate two critical processes that function uniquely at this locus: DNA replication originating from within the rDNA array, and the regulated increase of rDNA repeat copy number.
Using a System’s Equilibrium Behavior to Reduce Its Energy Dissipation in Non-Equilibrium Processes
Authors: Tafoya Sara , Large Steven J. , Liu Shixin , Bustamante Carlos , Sivak David A.
Published: March 2018

Cells must operate far from equilibrium1, utilizing and dissipating energy continuously to maintain their organization and to avoid stasis and death. However, they must also avoid unnecessary waste of energy2. Recent studies have revealed that molecular machines are extremely efficient thermodynamically when compared to their macroscopic counterparts3,4. There are also tantalizing hints of molecular machines conserving energy while operating out of equilibrium5,6. However, the principles governing the efficient out-of-equilibrium operation of molecular machines remain a mystery. A theoretical framework has been recently formulated in which a generalized friction coefficient quantifies the energetic efficiency in non-equilibrium processes7,8. Moreover, it posits that to minimize energy dissipation, external control should drive the system along the reaction coordinate with a speed inversely proportional to the square root of that friction coefficient. Here, we test and validate the predictions of this theory by probing the non-equilibrium energetic efficiency of a single DNA hairpin subjected to unfolding and refolding protocols using a dual-trap optical tweezers.
HDAC11 Suppresses the Thermogenic Program of Adipose Tissue via BRD2
Authors: Bagchi Rushita A. , Ferguson Bradley S. , Stratton Matthew S. , Hu Tianjing , Cavasin Maria A. , Sun Lei , Lin Ying-Hsi , Liu Dianxin , Londono Pilar , Song Kunhua , Pino Maria F. , Sparks Lauren M. , Smith Steven R. , Scherer Philipp E. , Collins Sheila , Seto Edward , McKinsey Timothy A.
Published: March 2018

Little is known about the biological function of histone deacetylase 11 (HDAC11), which is the lone class IV HDAC. Here, we demonstrate that deletion of HDAC11 in mice stimulates brown adipose tissue (BAT) formation and beiging of white adipose tissue (WAT). Consequently, HDAC11-deficient mice exhibit dramatically enhanced thermogenic potential and, in response to high fat feeding, attenuated obesity, insulin resistance, and hepatic steatosis. Ex vivo and cell-based assays revealed that HDAC11 catalytic activity suppresses the BAT transcriptional program, in both the basal state and in response to β-adrenergic receptor signaling, through a mechanism that is dependent on physical association with BRD2, a bromodomain and extraterminal (BET) acetyl-histone binding protein. These findings define a novel epigenetic pathway for the regulation of energy homeostasis, and suggest potential for HDAC11-selective inhibitors for the treatment of obesity and diabetes.
Task activations produce spurious but systematic inflation of task functional connectivity estimates
Authors: Cole Michael W. , Ito Takuya , Schultz Douglas , Mill Ravi , Chen Richard , Cocuzza Carrisa
Published: March 2018

Most neuroscientific studies have focused on task-evoked activations (activity amplitudes at specific brain locations), providing limited insight into the functional relationships between separate brain locations. Task-state functional connectivity (FC) - statistical association between brain activity time series during task performance moves beyond task-evoked activations by quantifying functional interactions during tasks. However, many task-state FC studies do not remove the first-order effect of taskevoked activations prior to estimating task-state FC. It has been argued that this results in the ambiguous inference “likely active or interacting during the task”, rather than the intended inference “likely interacting during the task”. Utilizing a neural mass computational model, we verified that task-evoked activations substantially and inappropriately inflate task-state FC estimates, especially in functional MRI (fMRI) data. Various methods attempting to address this problem have been developed, yet the efficacies of these approaches have not been systematically assessed. We found that most standard approaches for fitting and removing mean task-evoked activations were unable to correct these inflated correlations. In contrast, methods that flexibly fit mean task-evoked response shapes effectively corrected the inflated correlations without reducing effects of interest. Results with empirical fMRI data confirmed the model’s predictions, revealing activation-induced task-state FC inflation for both Pearson correlation and psychophysiological interaction (PPI) approaches. These results demonstrate that removal of mean task-evoked activations using an approach that flexibly models task-evoked response shape is an important preprocessing step for valid estimation of task-state FC.

Highlights

Computational model shows task inflation of functional connectivity estimates

Hemodynamic responses cause task activations to further inflate estimates

Standard approaches to remove task activations leave many false positives

Methods that flexibly fit hemodynamic response shape effectively correct inflation

Correction of functional connectivity inflation verified with empirical fMRI data
Oxford Nanopore MinION sequencing enables rapid whole-genome assembly ofRickettsia typhiin a resource-limited setting
Authors: Elliott Ivo , Batty Elizabeth M. , Ming Damien , Robinson Matthew T. , Nawtaisong Pruksa , de Cesare Mariateresa , Newton Paul N. , Bowden Rory
Published: March 2018

The infrastructure challenges and costs of next-generation sequencing have been largely overcome, for many sequencing applications, by Oxford Nanopore Technologies’ portable MinION sequencer. However the question remains open whether MinION-based bacterial whole-genome sequencing (WGS) is by itself sufficient for the accurate assessment of phylogenetic and epidemiological relationships between isolates and whether such tasks can be undertaken in resource-limited settings. To investigate this question, we sequenced the genome of an isolate ofRickettsia typhi, an important and neglected cause of fever across much of the tropics and subtropics, for which only three genomic sequences previously existed. We prepared and sequenced libraries on a MinION in Vientiane, Lao PDR using v9.5 chemistry and in parallel we sequenced the same isolate on the Illumina platform in a genomics laboratory in the UK. The MinION sequence reads yielded a single contiguous assembly, in which the addition of Illumina data revealed 226 base-substitution and 5,856 in/del errors. The combined assembly represents the first complete genome sequence of a humanR. typhiisolate collected in the last 50 years and differed from the genomes of existing strains collected over a 90-year time period at very few sites, and with no re-arrangements. Filtering based on the known error profile of MinION data improved the accuracy of the Nanopore-only assembly. However, the frequency of false-positive errors remained greater than true sequence divergence from recorded sequences. While Nanopore-only sequencing cannot yet recover phylogenetic signal inR. typhi, such an approach may be applicable for more diverse organisms.
System level analyses of motor-related neural activities in larval Drosophila
Authors: Yoon Youngteak , Park Jeonghyuk , Taniguchi Atsushi , Kohsaka Hiroshi , Nakae Ken , Nonaka Shigenori , Ishii Shin , Nose Akinao
Published: March 2018

The way in which the central nervous system (CNS) governs animal movement is complex and difficult to solve solely by the analyses of muscle movement patterns. We tackle this problem by observing the activity of a large population of neurons in the CNS of larval Drosophila. We focused on two major behaviors of the larvae, forward and backward locomotion, and analyzed the neuronal activity related to these behaviors during fictive locomotion that spontaneously occurs in the isolated CNS. We expressed genetically-encoded calcium indicator, GCaMP, and a nuclear marker in all neurons and used digital scanned light-sheet microscopy to record neural activities in the entire ventral nerve cord at a fast frame rate. We developed image processing tools that automatically detect the cell position based on the nuclear staining and allocate the activity signals to each detected cell. We also applied a machine learning-based method that we developed recently to assign motor status in each time frame. Based on these methods, we find cells whose activity is biased to forward versus backward locomotion and vice versa. In particular, we identified a group of neurons near the boundary of subesophageal zone (SEZ) and thoracic neuromeres, which are strongly active during an early phase of backward but not forward fictive locomotion. Our experimental procedure and computational pipeline enable systematic identification of neurons to show characteristic motor activities in larval Drosophila.
Can AI reproduce observed chemical diversity?
Authors: Benhenda Mostapha
Published: March 2018

Generating diverse molecules with desired chemical properties is important for drug discovery. The use of generative neural networks is promising for this task. To facilitate evaluation of generative models, this paper introduces a metric of internal chemical diversity, and raises the following challenge: can a nontrivial AI model reproduce observed internal diversity for desired molecules? To illustrate this metric, a mini-benchmark is performed with two generative models: a Reinforcement Learning model and the recently introduced ORGAN. The aim of this paper is to encourage research about internal diversity metrics.
Accurate Filtering of Privacy-Sensitive Information in Raw Genomic Data
Authors: Decouchant Jérémie , Fernandes Maria , Völp Marcus , Couto Francisco M , Esteves-Veríssimo Paulo
Published: March 2018

Sequencing thousands of human genomes has enabled breakthroughs in many areas, among them precision medicine, the study of rare diseases, and forensics. However, mass collection of such sensitive data entails enormous risks if not protected to the highest standards. In this article, we follow the position and argue that post-alignment privacy is not enough and that data should be automatically protected as early as possible in the genomics workflow, ideally immediately after the data is produced. We show that a previous approach for filtering short reads cannot extend to long reads and present a novel filtering approach that classifies raw genomic data (i.e., whose location and content is not yet determined) into privacy-sensitive (i.e., more affected by a successful privacy attack) and non-privacy-sensitive information. Such a classification allows the fine-grained and automated adjustment of protective measures to mitigate the possible consequences of exposure, in particular when relying on public clouds. We present the first filter that can be indistinctly applied to reads of any length, i.e., making it usable with any recent or future sequencing technologies. The filter is accurate, in the sense that it detects all known sensitive nucleotides except those located in highly variable regions (less than 10 nucleotides remain undetected per genome instead of 100,000 in previous works). It has far less false positives than previously known methods (10% instead of 60%) and can detect sensitive nucleotides despite sequencing errors (86% detected instead of 56% with 2% of mutations). Finally, practical experiments demonstrate high performance, both in terms of throughput and memory consumption.
A human pathogenic bacteriumShigellaproliferates in the plant through the adoption of type III effectors for Shigellosis
Authors: Jo Sung Hee , Lee Jiyoung , Park Eunsook , Kim Dong Wook , Lee Dae Hee , Ryu Choong Min , Choi Doil , Park Jeong Mee
Published: March 2018

Human enteropathogenic bacteria has been reported to be transmitted by fresh vegitables.Shigella, which infects primates, is reportedly transmitted by fresh vegetables; however, its molecular interactions with plants have not been elucidated. Here, we show that fourShigellastrains,S. boydii(S. b),S. sonnei,S. flexneri2a (S. f2a), andS. flexneri5a (S. f5a), proliferated at different levels inArabidopsis thaliana. Microscopic studies revealed that these bacteria were present inside leaves and damaged plant cells. Green fluorescent protein (GFP)-taggedS. bandS. f5a colonized in leaves only, andS. f2a colonized both leaves and roots. Using mutants lacking type III secretion systems (T3SS), we found that T3SS ofShigellathat regulate the pathogenesis of Shigellosis in humans also play a central role in proliferation inArabidopsis.Strikingly, the immunosuppressive activity of two T3S effectors, OspF and OspG, were needed for the proliferation ofShigellainArabidopsis. Of note, delivery of OspF or OspG effectors inside of plant cells uponShigellainoculation was confirmed by using a split GFP system, respectively. These findings demonstrate that the human pathogenShigellacan proliferate in plants by adoption of immunosuppressive machinery for its original host human.
Internal model recalibration does not deteriorate with age while motor adaptation does
Authors: Vandevoorde Koenraad , de Xivry Jean-Jacques Orban
Published: March 2018

A wide range of motor function declines with aging. Motor adaptation, which occurs when participants learn to reach accurately to a target despite a perturbation, does not deviate from this rule. There are currently three major hypotheses that have been put forward to explain this age-related decline in adaptation: deterioration of internal model recalibration due to age-related cerebellar degeneration, impairment of the cognitive component of motor adaptation, and deficit in the retention of the learned movement. In the present study, we systematically investigated these three hypotheses in a large sample of older women and men. We demonstrate that age-related deficits in motor adaptation are not due to impaired internal model recalibration or impaired retention of motor memory. Rather, we found that the cognitive component was reduced in older people. Therefore, our study suggests the interesting possibility that cerebellar-based mechanisms do not deteriorate with age despite cerebellar degeneration. In contrast, internal model recalibration appears to compensate for deficits in the cognitive component of this type of learning.
Holographic optical trapping Raman micro-spectroscopy of interacting live cells
Authors: Sinjab F. , Elsheikha H. M. , Awuah D. , Gibson G. , Padgett M. , Ghaemmaghami A. M. , Notingher I.
Published: March 2018

We present a combined holographic optical tweezers and confocal Raman spectroscopy instrument which allows fast, flexible, and interactive manipulation with molecular measurement of interacting live cell systems. Multiple laser foci created using a spatial light modulator are simultaneously used for optical trapping and spontaneous Raman spectroscopy. To enable confocal Raman measurements with high spectral resolution, a digital micro-mirror device was used to generate reflective pinholes which are matched to each laser trap. We demonstrate this unique capability by initiating complex interactions between multiple live cells whilst non-invasively acquiring Raman spectra of the processes with high spatial, spectral, and temporal resolution.
Mass spectra alignment using virtual lock-masses
Authors: Brochu Francis , Plante Pier-Luc , Drouin Alexandre , Gagnon Dominic , Richard Dave , Durocher Francine , Diorio Caroline , Marchand Mario , Corbeil Jacques , Laviolette François
Published: March 2018

Mass spectrometry is a valued method to evaluate the metabolomics content of a biological sample. The recent advent of rapid ionization technologies such as Laser Diode Thermal Desorption (LDTD) and Direct Analysis in Real Time (DART) has rendered high-throughput mass spectrometry possible. It is used for large-scale comparative analysis of populations of samples. In practice, many factors resulting from the environment, the protocol, and even the instrument itself, can lead to minor discrepancies between spectra, rendering automated comparative analysis difficult. In this work, a sequence/pipeline of algorithms to correct variations between spectra is proposed. The algorithms correct multiple spectra by identifying peaks that are common to all and, from those, computes a spectrum-specific correction. We show that these algorithms increase comparability within large datasets of spectra, facilitating comparative analysis, such as machine learning.
Widespread noncoded amino acids in human proteome
Authors: Yang Jing-Hua , Chen Xinjun , Gong Jing , Lv Xin , Zhao Han , Li Cuiling , Bi Baibing , Wang Fengqin , Sun Shengnan , Wang Xingyuan , Zhang Haobo , Huang Tao , Azadzoi Kazem , Shi Feng , Kong Xianglong , Shu Minglei , Wang Yinglong , Huang Wan , Chin Y. Eugene , Chen Zhinan , Chen Zi-Jiang
Published: March 2018

Proteins are usually deciphered by translation of the coding genome; however, their amino acid residues are seldom determined directly across the proteome. Herein, we describe a systematic workflow for identifying all possible protein residues that differ from the coding genome, termed noncoded amino acids (ncAAs). By measuring the mass differences between the coding amino acids and the actual protein residues in human spermatozoa, over a million nonzero delta masses were detected, fallen into 424 high-quality Gaussian clusters and 571 high-confidence ncAAs spanning 29,053 protein sites. Most ncAAs are novel with unresolved side-chains and discriminative between healthy individuals and patients with oligoasthenospermia. For validation, 40 out of 98 ncAAs that matched with amino acid substitutions were confirmed by exon sequencing. This workflow revealed the widespread existence of previously unreported ncAAs in the sperm proteome, which represents a new dimension on the understanding of amino acid polymorphisms at the proteomic level.

Highlights

571 ncAAs spanning 108,000 protein sites were identified in human sperm proteome.

Most ncAAs are novel with unresolved sidechains and found at unreported protein sites.

Exon sequencing confirmed 40 of 98 ncAAs that matched with amino acid substitutions.

Many ncAAs are linked with disease and have potential for diagnosis and targeting.

eTOC Blurb

We describe a systematic identification of all possible protein residues that were not encoded by their genomic sequences. A total of 571 high-confidence most novel noncoded amino acids were identified in human sperm proteome, corresponding to over 108,000 ncAA-containing protein sites. For validation, 40 out of 98 ncAAs that matched to amino acid substitutions were confirmed by exon sequencing. These ncAAs are discriminative between individuals and expand our understanding of amino acid polymorphisms in human proteomes and diseases.
Effective bulk modulus of the pore fluid at patchy saturation
Authors: Wollner Uri , Dvorkin Jack
Published: March 2018

We explore a package of parallel porous layers, each filled with a different fluid. Assume that this package is sampled by an elastic wave with the wavelength much larger than the thickness of an individual layer. Also assume that the layers are hydraulically isolated from each other, meaning that the diffusion length is smaller than that of the individual layer. This assumption is relevant to a patchy saturation scenario. Suppose that we wish to conduct the fluid substitution operation on this package treated as a single porous elastic body. What is the effective bulk modulus of the pore fluid to be used in this operation that will result in the same elastic modulus as computed by Backus averaging the individual moduli of the layers? We address this question analytically by assuming that the porosity, dry frame, and the mineral matrix properties of the individual layers are the same for all layers. The only difference between the layers is the pore fluid. We find that the resulting effective bulk modulus of the fluid thus derived falls between the arithmetic and harmonic averages of the fluid bulk moduli in the layers. It can be approximated by a linear combination of these two bounds where the weights are 0.50 and 0.50 or 0.75 for the arithmetic average and 0.25 for the harmonic average, depending on the elastic moduli of the dry frame, the mineral, and the pore fluids. This solution also provides a relation between the effective bulk modulus of the pore fluid in the system under examination and water saturation to be used in the fluid substitution operation at a coarse spatial scale.