bluuebunny/crossref_metadata_2025 huggingface dataset:
The Excision of the Buccal Fat Pad for Cheek Refinement: Volumetric Considerations
Authors: Sezgin Billur , Tatar Sedat , Boge Medine , Ozmen Selahattin , Yavuzer Reha
Published: July 2018

Background

Although the excision of the buccal fat pad has become very popular for achieving a slimmer midface, not all patients are good candidates for this procedure. Unfortunately, studies that provide guidelines by emphasizing volumetric and technical details are limited.

Objectives

The study compared preoperative and postoperative volumetric data to identify the amount of tissue that can safely be removed and important technical concepts involved in lower cheek contouring with buccal fat pad excision.

Methods

Patients complaining of cheek fullness were evaluated to determine if they were good candidates for the procedure. Eligible patients were screened with transbuccal ultrasound to determine tissue volumes and anatomical details. Intraoperative and postoperative, 6th-month volume measurements were undertaken and residual tissues and vascular pedicles reevaluated.

Results

Ultrasound imaging showed that the mean preoperative volume of the fat pads was 11.67 ± 1.44 mL, and the mean postoperative volume was 8.58 ± 1.07 mL. The mean volume of the excised tissues was 2.74 ± 0.69 mL. Postoperative buccal fat pad volume values correlated with the reported average in the literature for the same age group.

Conclusions

Buccal fat pad removal is an effective technique for refining the facial silhouette that should be reserved for patients with increased buccal fat pad volume. Removal of only the excessive portion of the fat pad is important because this structure provides significant volume in the midface that can be difficult to restore once aging affects the surrounding soft and bony tissue.

Level of Evidence: 4
JustOrthologs: a fast, accurate and user-friendly ortholog identification algorithm
Authors: Miller Justin B , Pickett Brandon D , Ridge Perry G
Published: July 2018

Motivation

Orthologous gene identification is fundamental to all aspects of biology. For example, ortholog identification between species can provide functional insights for genes of unknown function and is a necessary step in phylogenetic inference. Currently, most ortholog identification algorithms require all-versus-all BLAST comparisons, which are time-consuming and memory intensive.

Results

In contrast to existing approaches, JustOrthologs exploits the conservation of gene structure by using the lengths of coding sequence regions and dinucleotide percentages to identify orthologs. In comparison to OrthoMCL, OMA and OrthoFinder, JustOrthologs decreases ortholog identification runtime by more than 96% and achieves comparable precision and recall scores. The computational speedup allowed us to conduct pairwise comparisons of 1197 complete genomes (780 eukaryotes and 417 archaea). We confirmed gene annotations for 384 120 genes, grouped 1 675 415 genes in previously unreported ortholog groups, and identified 51 429 potentially mislabeled genes across 622 843 ortholog groups.

Availability and implementation

JustOrthologs is an open source collaborative software package available in the GitHub repository: https://github.com/ridgelab/JustOrthologs/. All test FASTA files used for comparisons are freely available at https://github.com/ridgelab/JustOrthologs/comparisonFastaFiles/. Reference genomes used in this work are available for download from the NCBI repository: ftp://ftp.ncbi.nih.gov/genomes/.

Supplementary information

Supplementary data are available at Bioinformatics online.
The European Registry for Patients with Mechanical Circulatory Support (EUROMACS): first EUROMACS Paediatric (Paedi-EUROMACS) report
Authors: de By Theo M M H , Schweiger Martin , Waheed Hina , Berger Felix , Hübler Michael , Özbaran Mustafa , Maruszewski Bohdan , Napoleone Carlo Pace , Loforte Antonio , Meyns Bart , Miera Oliver ,   Contributing clinicians, Antretter Herwig , Krachak Valeriya , Vanbelleghem Yves , Meyns Bart , Němec Petr , Netuka Ivan , Guihaire Julien , Sandica Eugen , Miera Oliver , Stiller Brigitte , Bodor Gabor , Amodeo Antonio , Iacovoni Attilio , Pace Napoleone Carlo , Loforte Antonio , Pya Yuri , Bogers Ad , Ramjankhan Faiz , Maruszewski Bodhan , Guereta Luis , Schweiger Martin , Carrel Thierry , Sezgin Atilla , Özbaran Mustafa , Pektok Erman
Published: July 2018

OBJECTIVES:

EUROMACS is a registry of the European Association for Cardio-Thoracic Surgery (EACTS) whose purpose is to gather clinical data related to durable mechanical circulatory support for scientific purposes and to publish annual reports. Because the treatment of children with end-stage heart failure has several significantly different characteristics than the treatment of adults, data and outcomes of interventions are analysed in this dedicated paediatric report.

METHODS:

Participating hospitals contributed pre-, peri- and long-term postoperative data on mechanical circulatory support implants to the registry. Data for all implants in paediatric patients (≤19 years of age) performed from 1 January 2000 to 31 December 2017 were analysed. This report includes updates of patient characteristics, implant frequency, outcome (including mortality rates, transplants and recovery rates) as well as adverse events.

RESULTS:

Twenty-five hospitals contributed 237 registered implants in 210 patients (81 ♀, 129 ♂) to the registry. The most frequent diagnosis was any form of cardiomyopathy (71.4%) followed by congenital heart disease (18.6%). Overall mean support time on a device was 11.6 months (±16.5 standard deviation). A total of 173 children (82.4%) survived to transplant, recovery or are ongoing; 37 patients (17.6%) died while on support within the observed follow-up time. At 12 months 38% of patients received transplants, 7% were weaned from their device and 15% died. At 24 months, 51% of patients received transplants, 17% died while on support, 22% were on a device and 9% were explanted due to myocardial recovery. The adverse events rate per 100 patient-months was 11.97 for device malfunction, 2.83 for major bleeding, 2.83 for major infection and 1.52 for neurological events within the first 3 months after implantation.

CONCLUSIONS:

The first paediatric EUROMACS report reveals a low transplant rate in European countries within the first 2 years of implantation compared to US data. The 1-year survival rate seems to be satisfactory. Device malfunction including pump chamber changes due to thrombosis was the most frequent adverse event.
A Longitudinal Study of the Association Between Persistent Pathogens and Incident Depression Among Older U.S. Latinos
Authors: Simanek Amanda M , Zheng Cheng , Yolken Robert , Haan Mary , Aiello Allison E
Published: July 2018

Depression is estimated to affect more than 6.5 million Americans 65 years of age and older and compared with non-Latino whites older U.S. Latinos have a greater incidence and severity of depression, warranting further investigation of novel risk factors for depression onset among this population. We used data on 771/1,789 individuals ≥60 years of age from the Sacramento Area Latino Study on Aging (1998–2008) who were tested for cytomegalovirus (CMV), herpes simplex virus, varicella zoster, Helicobacter pylori, Toxoplasma gondii, and C-reactive protein (CRP) and interleukin-6 (IL-6) level. Among those without elevated depressive symptoms at baseline, we examined the association between each pathogen, inflammatory markers and incident depression over up to nearly 10 years of follow-up using discrete-time logistic regression. We found that only CMV seropositivity was statistically significantly associated with increased odds of incident depression (odds ratio [OR]: 1.38, 95% confidence interval [CI]: 1.00–1.90) in the total sample as well as among women only (OR: 1.70, 95% CI: 1.01–2.86). These associations were not mediated by CRP or IL-6 levels. Our findings suggest that CMV seropositivity may serve as an important risk factor for the onset of depression among older U.S. Latinos, but act outside of inflammatory pathways.
Burden of Human Papillomavirus (HPV)-Related Cancers Attributable to HPVs 6/11/16/18/31/33/45/52 and 58
Authors: de Sanjosé Silvia , Serrano Beatriz , Tous Sara , Alejo Maria , Lloveras Belén , Quirós Beatriz , Clavero Omar , Vidal August , Ferrándiz-Pulido Carla , Pavón Miquel Ángel , Holzinger Dana , Halec Gordana , Tommasino Massimo , Quint Wim , Pawlita Michael , Muñoz Nubia , Bosch Francesc Xavier , Alemany Laia ,   RIS HPV TT, VVAP and Head and Neck study groups, Kulkarni Amit
Published: July 2018

Background

Many countries, mainly high- and upper-middle income, have implemented human papillomavirus (HPV) vaccination programs, with 47 million women receiving the full course of vaccine (three doses) in 2014. To evaluate the potential impact of HPV vaccines in the reduction of HPV-related disease, we aimed to estimate the HPV type distribution and burden of anogenital and head and neck cancers attributable to HPV types (HPVs 16/18/31/33/45/52/58/6/11) included in currently licensed HPV vaccines.

Methods

In all, 18 247 formalin-fixed paraffin-embedded specimens were retrieved from 50 countries. HPV DNA detection and typing were performed with the SPF-10 PCR/DEIA/LiPA25 system. With the exception of cervical cancer, HPV DNA-positive samples were additionally subjected to HPV E6*I mRNA detection and/or p16INK4a immunohistochemistry. For cervical cancer, estimates were based on HPV DNA, whereas for other sites, estimates were based on HPV DNA, E6*I mRNA, and p16INK4a biomarkers.

Results

The addition of HPVs 31/33/45/52/58 to HPVs 16/18/6/11 in the nonavalent HPV vaccine could prevent almost 90% of cervical cancer cases worldwide. For other sites, the nonavalent HPV vaccine could prevent 22.8% of vulvar, 24.5% of penile, 60.7% of vaginal, 79.0% of anal cancers, 21.3% of oropharyngeal, 4.0% of oral cavity, and 2.7% of laryngeal cancer cases.

Conclusions

Our estimations suggest a potential impact of the nonavalent HPV vaccine in reducing around 90% of cervical cancer cases and a global reduction of 50% of all the cases at HPV-related cancer sites.
Gut Microbiota and Clinical Features Distinguish Colonization With Klebsiella pneumoniae Carbapenemase-Producing Klebsiella pneumoniae at the Time of Admission to a Long-term Acute Care Hospital
Authors: Seekatz Anna M , Bassis Christine M , Fogg Louis , Moore Nicholas M , Rhee Yoona , Lolans Karen , Weinstein Robert A , Lin Michael Y , Young Vincent B , Hayden Mary K ,   Centers for Disease Control and Prevention Epicenters Program
Published: July 2018

Background

Identification of gut microbiota features associated with antibiotic-resistant bacterial colonization may reveal new infection prevention targets.

Methods

We conducted a matched, case–control study of long-term acute care hospital (LTACH) patients to identify gut microbiota and clinical features associated with colonization by Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp), an urgent antibiotic resistance threat. Fecal or rectal swab specimens were collected and tested for KPC-Kp; 16S rRNA gene-based sequencing was performed. Comparisons were made between cases and controls in calibration and validation subsamples using microbiota similarity indices, logistic regression, and unit-weighted predictive models.

Results

Case (n = 32) and control (n = 99) patients had distinct fecal microbiota communities, but neither microbiota diversity nor inherent clustering into community types distinguished case and control specimens. Comparison of differentially abundant operational taxonomic units (OTUs) revealed 1 OTU associated with case status in both calibration (n = 51) and validation (n = 80) subsamples that matched the canonical KPC-Kp strain ST258. Permutation analysis using the presence or absence of OTUs and hierarchical logistic regression identified 2 OTUs (belonging to genus Desulfovibrio and family Ruminococcaceae) associated with KPC-Kp colonization. Among clinical variables, the presence of a decubitus ulcer alone was independently and consistently associated with case status. Combining the presence of the OTUs Desulfovibrio and Ruminococcaceae with decubitus ulcer increased the likelihood of KPC-Kp colonization to >38% in a unit-weighted predictive model.

Conclusions

We identified microbiota and clinical features that distinguished KPC-Kp gut colonization in LTACH patients, a population particularly susceptible to KPC-Kp infection. These features may warrant further investigation as markers of risk for KPC-Kp colonization.
LAMOST J221750.59+210437.2: A new member of carbon-enhanced extremely metal-poor stars with excesses of Mg and Si
Authors: Aoki Wako , Matsuno Tadafumi , Honda Satoshi , Ishigaki Miho N , Li Haining , Suda Takuma , Kumar Yerra Bharat
Published: July 2018

We report on the elemental abundances of the carbon-enhanced metal-poor (CEMP) star J2217+2104, discovered through our metal-poor star survey with LAMOST and Subaru. This object is a red giant and has extremely low Fe abundance ([Fe/H] = −4.0) and very large enhancement of C, N, and O with excesses of Na, Mg, Al, and Si. This star is a new example of a small group of such CEMP stars identified by previous studies. We find a very similar abundance pattern for O–Zn in this class of objects that shows enhancement of elements up to Si and normal abundance of Ca and Fe-group elements. Whereas the C/N ratio is different among these stars, the (C + N)/O ratio is similar. This suggests that similar abundance ratios of C were also yielded, relative to O–Zn in progenitors, and was later affected by the CN-cycle. By contrast, the heavy neutron-capture elements Sr and Ba are deficient in J2217+2104, compared to the four objects in this class previously studied. This indicates that the neutron-capture process in the early Galaxy, presumably the r-process, has no direct connection to the phenomenon that has formed such CEMP stars. Comparisons of the abundance pattern that are well determined for such CEMP stars with those of supernova nucleosynthesis models constrain the progenitor mass to be about 25 M⊙, which is not particularly different from the typical mass of progenitors expected for extremely metal-poor stars in general.
Blood Procalcitonin Levels and Duration of Antibiotics in Neonatal Sepsis
Authors: Mathur N B , Behera Bijaylaxmi
Published: July 2018

Objective

To determine the time to normalization of procalcitonin (PCT) levels and duration of antibiotics in neonatal sepsis.

Methods

A prospective observational study design was used. The participants included were neonates with sepsis. The primary outcome measure was time to normalization of PCT levels and duration of antibiotics following clinical resolution.

Results

Time to normalization of PCT levels was 9.6 ± 4.2 days in neonates with septic shock, 6.2 ± 2.5 days in neonates without shock, 9.6 ± 3.1 days in neonates with culture-positive sepsis and 6.4 ± 3.1 days in neonates with culture-negative sepsis. Time to normalization of PCT levels according to the stage of systemic inflammatory response syndrome was 5.8 ± 2.8 days in neonates with sepsis, 6.1 ± 3.1 days in those with sepsis syndrome, 6.3 ± 3.3 days in those with early septic shock and 9.4 ± 3.6 days in those with multiorgan dysfunction syndrome. There was no morbidity and mortality in any neonate in the 4-week follow-up.

Conclusion

The duration of antibiotics can be determined by observing the time to normalization of PCT following clinical resolution of sepsis.
Transient elastography can stratify patients with Child–Pugh A cirrhosis according to risk of early decompensation
Authors: Dillon Audrey , Galvin Zita , Sultan Alyshah A. , Harman David , Guha Indra N. , Stewart Stephen
Published: July 2018

Background

Compensated cirrhosis has a variable prognosis depending on stage. There are currently no straightforward and robust tools in clinical practice to predict decompensation in Child–Pugh A cirrhosis. We set out to determine whether transient elastography (TE) could be used across liver disease aetiologies to determine risk of decompensation.

Patients and methods

Participants were enrolled at two sites (Dublin and Nottingham) and followed up for a minimum of 2 years. The primary outcome of the study was liver decompensation, defined as the development of overt hepatic encephalopathy or ascites or presentation with bleeding varices. All patients received a TE examination to measure liver stiffness measurement (LSM) and had routine blood measurements taken at the baseline visit and on each subsequent visit.

Results

In 259 participants, the overall rate of liver-related outcome was 31 per 1000 person-years (95% confidence interval: 19–47 per 1000 person-years). Of the total population, 6 and 11% developed a liver-related outcome within 2 and 4 years of follow-up, respectively. There were no events in the population with a LSM less than 21 kPa. A LSM of more than 35 kPa was associated with a decompensation risk of 39% at 4 years. For each unit increase in the LSM above 20 kPa, the risk of liver-related outcome increased by 6% (hazard ratio=1.06; 95% confidence interval: 1.04–1.82) after adjusting for age, sex Mayo End Liver Disease Score, cohort source and aetiology.

Conclusion

The risk of liver decompensation increased with increasing LSM in mixed aetiology compensated cirrhosis. LSM may be used to risk stratify patients, potentially reassure patients with low scores, and select patients with higher scores for experimental therapeutic studies with acceptable timelines.
Additional role of liver stiffness measurement in stratifying residual hepatocellular carcinoma risk predicted by serum biomarkers in chronic hepatitis B patients under antiviral therapy
Authors: Song Byeong G. , Sinn Dong H. , Chi Sangah , Kim Kyunga , Kang Wonseok , Gwak Geum-Youn , Paik Yong-Han , Choi Moon S. , Lee Joon H. , Koh Kwang C. , Paik Seung W.
Published: July 2018

Background

The risk of hepatocellular carcinoma (HCC) remains among patients who are treated with antiviral therapy (AVT). The degree of liver fibrosis has been suggested as an important biomarker to stratify the risk of developing HCC. We tested whether liver stiffness (LS) measured using transient elastography is useful over two noninvasive serum biomarkers of fibrosis [the aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 (FIB-4)].

Patients and methods

A retrospective cohort of 1014 CHB patients who were under AVT with nucleos(t)ide analogs for at least a year was analyzed. The risk of HCC development according to serum biomarkers (APRI and FIB-4) and LS was compared.

Results

The HCC risk was higher for those with a higher degree of liver fibrosis, as estimated by the LS, APRI, and FIB-4. When the two serum biomarkers were used to group the patients, the 3-year HCC incidence rates were 7.3, 3.0, and 1.3% for both high APRI (≥0.5) and FIB-4 (≥1.45) scores, either a high APRI or FIB-4 score, and both low APRI and FIB-4 scores, respectively (P<0.001). Among the 758 patients with discordant or both low APRI and FIB-4 scores, the LS value was high (>6) for a significant proportion of the patients (39.9%). The HCC risk was significantly different according to the LS value (3-year HCC incidence rate of 1.1, 2.0, and 6.8% for LS <6, 6–9, and >9, respectively, P<0.001).

Conclusion

Among CHB patients under AVT, LS could stratify risk for HCC, including patients with discordant or both low APRI and FIB-4 score. This finding indicates that LS measurement plays an additional role over the serum biomarkers in stratifying the residual risk of HCC.
Epidemiology of Disease and Mortality From a PICU in Mozambique*
Authors: Punchak Maria , Hall Kaitlin , Seni Amir , Buck W. Chris , DeUgarte Daniel A. , Hartford Emily , Kelly Robert B. , Muando Valéria I.
Published: July 2018

Objectives:

Delivery of pediatric critical care in low-income countries is limited by a lack of infrastructure, resources, and providers. Few studies have analyzed the epidemiology of disease associated with a PICU in a low-income country. The aim of this study was to document the primary diagnoses and the associated mortality rates of patients presenting to a tertiary PICU in Mozambique in order to formulate quality improvement projects through an international academic partnership. We hypothesized that the PICU mortality rate would be high and that sepsis would be a common cause of death.

Design:

Retrospective, observational study.

Setting:

Tertiary academic PICU.

Patients:

All admitted PICU patients.

Interventions:

All available data collection forms containing demographic and clinical data of patients admitted to the PICU at Hospital Central de Maputo, Mozambique from January 2013 to December 2013 were analyzed retrospectively.

Measurements and Main Results:

The patient median age was 2 years (57% male). The most common primary diagnoses were malaria (22%), sepsis (18%), respiratory tract infections (12%), and trauma (6%). The mortality rate was 25%. Mortality rates were highest among patients with sepsis (59%), encephalopathy (56%), noninfectious CNS pathologies (33%), neoplastic diseases (33%), meningitis/encephalitis (29%), burns (26%), and cardiovascular pathologies (26%). The median length of PICU stay was 2 days. HIV exposure/infection had a nonstatistically significant association with mortality. Patients admitted for burns had the highest median length of PICU stay (4 d). Most trauma admissions were male (75%), and approximately half of all trauma admissions had an associated head injury (55%).

Conclusions:

Infectious disease and trauma were highly represented in this Mozambican PICU, and overall mortality was high compared with high-income countries. With this knowledge, targeted collaborative projects in Mozambique can now be created and modified. Further research is needed to monitor the potential benefits of such interventions.
Mesenteric Ischemia
Authors: Canceco Jose , Winokur Elizabeth J.
Published: July 2018

Bedside nurses require excellent observational and assessment skills. Being knowledgeable about common diseases that often affect the population is essential; however, it is often more challenging to be informed about life-threatening conditions that rarely develop. Such is the case with mesenteric ischemia, a rare but complicated condition, which is difficult to diagnose, carries a degree of mortality of about 40%–70%, and is more common in people older than 50 years. Mesenteric ischemia requires that nurses be aware of the different etiologies and presentations of this uncommon disease to alert physicians of changes in a patient's condition and detect clues that may assist with an accurate and prompt diagnosis. Being educated about the diagnostic procedures, possible outcomes, and anticipated care and needs of patients affected by this medical complication is imperative to maintain the health status and well-being of these patients and their families.
NASH Syndrome
Authors: Dominguez Christine
Published: July 2018

Nonalcoholic steatohepatitis (NASH) is a serious and rapidly growing problem affecting a population that was not previously recognized as high risk. Although treatments are limited, shedding light on those with a predisposition may allow for primary prevention, as there is presently no cure other than liver transplant. This study examines the risk factors, genetic predisposition, pathophysiology, and treatment options.
Wild acorn woodpeckers recognize associations between individuals in other groups
Authors: Pardo Michael A. , Sparks Emilee A. , Kuray Tejal S. , Hagemeyer Natasha D. , Walters Eric L. , Koenig Walter D.
Published: July 2018

According to the social intelligence hypothesis, understanding the cognitive demands of the social environment is key to understanding the evolution of intelligence. Many important socio-cognitive abilities, however, have primarily been studied in a narrow subset of the social environment—within-group social interactions—despite the fact that between-group social interactions often have a substantial effect on fitness. In particular, triadic awareness (knowledge about the relationships and associations between others) is critical for navigating many types of complex social interactions, yet no existing study has investigated whether wild animals can track associations between members of other social groups. We investigated inter-group triadic awareness in wild acorn woodpeckers (
Melanerpes formicivorus
), a socially complex group-living bird. We presented woodpeckers with socially incongruous playbacks that simulated two outsiders from different groups calling together, and socially congruous playbacks that simulated two outsiders from the same group calling together. Subjects responded more quickly to the incongruous playbacks, suggesting that they were aware that the callers belonged to two different groups. This study provides the first demonstration that animals can recognize associations between members of other groups under natural circumstances, and highlights the importance of considering how inter-group social selection pressures may influence the evolution of cognition.
Genomic surveillance of Neisseria gonorrhoeae to investigate the distribution and evolution of antimicrobial-resistance determinants and lineages
Authors: Yahara Koji , Nakayama Shu-ichi , Shimuta Ken , Lee Ken-ichi , Morita Masatomo , Kawahata Takuya , Kuroki Toshiro , Watanabe Yuko , Ohya Hitomi , Yasuda Mitsuru , Deguchi Takashi , Didelot Xavier , Ohnishi Makoto
Published: July 2018

The first extensively drug resistant (XDR)Neisseria gonorrhoeaestrain with high resistance to the extended-spectrum cephalosporin ceftriaxone was identified in 2009 in Japan, but no other strain with this antimicrobial-resistance profile has been reported since. However, surveillance to date has been based on phenotypic methods and sequence typing, not genome sequencing. Therefore, little is known about the local population structure at the genomic level, and how resistance determinants and lineages are distributed and evolve. We analysed the whole-genome sequence data and the antimicrobial-susceptibility testing results of 204 strains sampled in a region where the first XDR ceftriaxone-resistantN. gonorrhoeaewas isolated, complemented with 67 additional genomes from other time frames and locations within Japan. Strains resistant to ceftriaxone were not found, but we discovered a sequence type (ST)7363 sub-lineage susceptible to ceftriaxone and cefixime in which the mosaicpenAallele responsible for reduced susceptibility had reverted to a susceptible allele by recombination. Approximately 85 % of isolates showed resistance to fluoroquinolones (ciprofloxacin) explained by linked amino acid substitutions at positions 91 and 95 of GyrA with 99 % sensitivity and 100 % specificity. Approximately 10 % showed resistance to macrolides (azithromycin), for which genetic determinants are less clear. Furthermore, we revealed different evolutionary paths of the two major lineages: single acquisition ofpenAX in the ST7363-associated lineage, followed by multiple independent acquisitions of thepenAX and XXXIV in the ST1901-associated lineage. Our study provides a detailed picture of the distribution of resistance determinants and disentangles the evolution of the two major lineages spreading worldwide.
Assembly of Mb-size genome segments from linked read sequencing of CRISPR DNA targets
Authors: Shin GiWon , Greer Stephanie U. , Xia Li C. , Lee HoJoon , Zhou Jun , Boles T. Christian , Ji Hanlee P.
Published: July 2018

We developed a targeted sequencing method for intact high molecular weight (HMW) DNA targets as large as 0.2 Mb. This process uses HMW DNA isolated from intact cells, custom designed Cas9-guide RNA complexes to generate 0.1 – 0.2 Mb DNA targets, electrophoretic isolation of the DNA targets and sequencing with barcode linked reads. We used alignment methods as well as local assembly of the target regions to identify haplotypes and structural variants (SVs) across multi-Megabase genomic regions. To demonstrate the performance of this approach, we designed three assays that covered a 0.2 Mb region surrounding the BRCA1 gene, a set of 40 overlapping 0.2 Mb targets covering the entire 4-Mb MHC locus, and 18 well-characterized structural variants. Using the highly characterized NA12878 genome, we achieved on-target coverage of more than 50X, while overall whole genome coverage was approximately 4X. We generated haplotypes that completely covered each targeted locus, with a maximum size of 4 Mb (for the MHC region). This method detected structural variants such as deletions and inversions with determination of the exact breakpoints and genotypes. Even breakpoints inside highly homologous segmental duplications are precisely determined with our high-quality assemblies. Overall, this is a new method to sequence large DNA segments.
A chromosome scale assembly of the model desiccation tolerant grass Oropetium thomaeum
Authors: VanBuren Robert , Wai Ching Man , Keilwagen Jens , Pardo Jeremy
Published: July 2018

Oropetium thomaeum is an emerging model for desiccation tolerance and genome size evolution in grasses. A high-quality draft genome of Oropetium was recently sequenced, but the lack of a chromosome scale assembly has hindered comparative analyses and downstream functional genomics. Here, we reassembled Oropetium, and anchored the genome into ten chromosomes using Hi-C based chromatin interactions. A combination of high-resolution RNAseq data and homology-based gene prediction identified thousands of new, conserved gene models that were absent from the V1 assembly. This includes thousands of new genes with high expression across a desiccation timecourse. The sorghum and Oropetium genomes have a surprising degree of chromosome-level collinearity, and several chromosome pairs have near perfect synteny. Other chromosomes are collinear in the gene rich chromosome arms but have experienced pericentric translocations. Together, these resources will be useful for the grass comparative genomic community and further establish Oropetium as a model resurrection plant.
Continuous State HMMs for Modeling Time Series Single Cell RNA-Seq Data
Authors: Lin Chieh , Bar-Joseph Ziv
Published: July 2018

Motivation

Methods for reconstructing developmental trajectories from time series single cell RNA-Seq (scRNA-Seq) data can be largely divided into two categories. The first, often referred to as pseudotime ordering methods, are deterministic and rely on dimensionality reduction followed by an ordering step. The second learns a probabilistic branching model to represent the developmental process. While both types have been successful, each suffers from shortcomings that can impact their accuracy.

Results

We developed a new method based on continuous state HMMs (CSHMMs) for representing and modeling time series scRNA-Seq data. We define the CSHMM model and provide efficient learning and inference algorithms which allow the method to determine both the structure of the branching process and the assignment of cells to these branches. Analyzing several developmental single cell datasets we show that the CSHMM method accurately infers branching topology and correctly and continuously assign cells to paths, improving upon prior methods proposed for this task. Analysis of genes based on the continuous cell assignment identifies known and novel markers for different cell types.

Availability

Software and Supporting website:www.andrew.cmu.edu/user/chiehll/CSHMM/

Contact

zivbj@cs.cmu.edu

Supplementary information

Supplementary data are available atBioinformaticsonline.
Batch Effect Removal via Batch-Free Encoding
Authors: Shaham Uri
Published: July 2018

Biological measurements often contain systematic errors, also known as “batch effects”, which may invalidate downstream analysis when not handled correctly. The problem of removing batch effects is of major importance in the biological community. Despite recent advances in this direction via deep learning techniques, most current methods may not fully preserve the true biological patterns the data contains. In this work we propose a deep learning approach for batch effect removal. The crux of our approach is learning a batch-free encoding of the data, representing its intrinsic biological properties, but not batch effects. In addition, we also encode the systematic factors through a decoding mechanism and require accurate reconstruction of the data. Altogether, this allows us to fully preserve the true biological patterns represented in the data. Experimental results are reported on data obtained from two high throughput technologies, mass cytometry and single-cell RNA-seq. Beyond good performance on training data, we also observe that our system performs well on test data obtained from new patients, which was not available at training time. Our method is easy to handle, a publicly available code can be found at https://github.com/ushaham/BatchEffectRemoval2018.
FASTCAR: Rapid alignment-free prediction of sequence alignment identity scores using self-supervised general linear models
Authors: James Benjamin T. , Luczak Brian B. , Girgis Hani Z.
Published: July 2018

Motivation

Pairwise alignment is a predominant algorithm in the field of bioinformatics. This algorithm is quadratic — slow especially on long sequences. Many applications utilize identity scores without the corresponding alignments. For these applications, we propose FASTCAR. It produces identity scores for pairs of DNA sequences using alignment-free methods and two self-supervised general linear models.

Results

For the first time, the new tool can predict the pair-wise identity score in linear time and space. On two large-scale sequence databases, FASTCAR provided the best compromise between sensitivity and precision while being faster than BLAST by 40% and faster than USEARCH by 6–10 times. Further, FASTCAR is capable of producing the pair-wise identity scores of long DNA sequences — millions-of-nucleotides-long bacterial genomes; this task cannot be accomplished by any alignment-based tool.

Availability

FASTCAR is available at https://github.com/TulsaBioinformaticsToolsmith/FASTCAR and as the Supplementary Dataset 1.

Contact

hani-girgis@utulsa.edu

Supplementary information

Supplementary data are available online.
A positive feedback loop drives centrosome maturation in flies
Authors: Alvarez-Rodrigo Ines , Conduit Paul T. , Baumbach Janina , Novak Zsofia A. , Aydogan Mustafa G. , Wainman Alan , Raff Jordan W.
Published: July 2018

Centrosomes are formed when mother centrioles recruit pericentriolar material (PCM) around themselves. The PCM expands dramatically as cells prepare to enter mitosis (a process termed centrosome maturation), but it is unclear how this expansion is achieved. In flies, Spd-2 and Cnn form an extensive scaffold around the mother centriole that recruits other components of the mitotic PCM, and the Polo-dependent phosphorylation of Cnn at the centrosome is crucial for scaffold assembly. Here we show that, like Cnn, Spd-2 is specifically phosphorylated at centrosomes. This phosphorylation appears to create multiple phosphorylated S-S/T(p) motifs that allow Spd-2 to recruit Polo to the expanding scaffold. If Spd-2 cannot recruit Polo to the expanding scaffold, the scaffold is initially assembled around the mother centriole, but it cannot expand outwards, and centrosome maturation fails. We conclude that Spd-2, Polo and Cnn cooperate to form a positive feedback loop that drives the dramatic expansion of the mitotic centrosome in flies.
Designing robust N-of-1 studies for precision medicine
Authors: Percha Bethany , Baskerville Edward B. , Johnson Matthew , Dudley Joel , Zimmerman Noah
Published: July 2018

Recent advances in molecular biology, sensors, and digital medicine have led to an explosion of products and services for high-resolution monitoring of individual health. The N-of-1 study has emerged as an important methodological tool for harnessing these new data sources, enabling researchers to compare the effectiveness of health interventions at the level of a single individual. We have developed a stochastic time series model that simulates an N-of-1 study, facilitating rapid optimization of N-of-1 study designs and increasing the likelihood of study success while minimizing participant burden. Using simulation, we demonstrate how the number of treatment blocks, ordering of treatments within blocks, duration of each treatment, and sampling frequency affect our ability to detect true differences in treatment efficacy. We provide a set of recommendations for study designs based on treatment, outcome, and instrument parameters, and provide our simulation software as a supplement to the paper.
Structural Basis of ECF-σ-Factor-Dependent Transcription Initiation
Authors: Lin Wei , Mandal Sukhendu , Degen David , Cho Min Sung , Feng Yu , Das Kalyan , Ebright Richard H.
Published: July 2018

Extracytoplasmic (ECF) σ factors, the largest class of alternative σ factors, are related to primary σ factors, but have simpler structures, comprising only two of the six conserved functional modules present in primary σ factors: region 2 (σR2) and region 4 (σR4). Here, we report crystal structures of transcription initiation complexes containing Mycobacterium tuberculosis RNA polymerase (RNAP), M. tuberculosis ECF σ factor σL, and promoter DNA. The structures show that σR2 and σR4 of the ECF σ factor occupy the same sites on RNAP as in primary σ factors, show that the connector between σR2 and σR4 of the ECF σ factor--although unrelated in sequence--follows the same path through RNAP as in primary σ factors, and show that the ECF σ factor uses the same strategy to bind and unwind promoter DNA as primary σ factors. The results define protein-protein and protein-DNA interactions involved in ECF-σ-factor-dependent transcription initiation.
Fitness-Dependent Recombination Can Be Evolutionarily Advantageous in Diploids: a Deterministic Mutation–Selection–Balance Model
Authors: Rybnikov Sviatoslav , Frenkel Zeev , Korol Abraham B.
Published: July 2018

Recombination’s omnipresence in nature is one of the most intriguing problems in evolutionary biology. The question of why recombination exhibits certain general features is no less interesting than that ofwhy it exists at all. One such feature is recombination’s fitness dependence (FD). The so far developed population-genetics models have focused on the evolution of FD recombination mainly in haploids, although the empirical evidence for this phenomenon comes mostly from diploids. Using numerical analysis of modifier models for infinite panmictic populations, we show here that FD recombination can be evolutionarily advantageous in diploids subjected to purifying selection. This advantage is associated with benefits from the differential rate of disruption of lower-vshigher-fitness genotypes, that can be manifested in systems with at least three selected loci. We also show that in systems with linked modifier, an additional contribution to the evolutionary advantage of FD recombination may come from fitness-dependence of the intensity of modifier linkage to the selected system, although the contribution of the last effect vanishes with tighter linkage within the selected system. We also show that in systems with three selected loci, FD recombination may give rise to negative crossover interference, which may be beneficial by itself. Yet, the role of such FD-induced crossover interference in the evolutionary advantage of FD recombination is minor. Remarkably, FD recombination was often favored in situations where any constant non-zero recombination was rejected, implying a relaxation of the rather strict constraints on major parameters (e.g., selection intensity and epistasis) required for the evolutionary advantage of non-zero recombination formulated by classical models.
A novel bioactive molecule 5-β-Hydroxyltridecanyl benzoate identified in Pedalium Murex L. (Gokhru) fruit extracts showed antifungal activity against Sclerotinia sclerotiorum
Authors: Chaudhary Gulshan , Kaushik Nutan , Reddy Pallavolu Maheswara
Published: July 2018

Fruits of Pedalium murex known as, ‘Gokhru’ is predominantly used in Ayurveda for its aphrodisiac properties and use in treatment of urological orders. However till now, bioactivity of this fruit has not been documented for plant protection against phytopathogenes, Hence in this regard, we investigated antimicrobial activity of P. murex fruit extracts (isolated from the different agro climatic zones of India) were tested against twelve microbial phytopathogens. From 29 fruit extracts, only 13 were found to be active against three pathogens viz. Botrytis cinerea, Rhizoctonia solani, and Sclerotinia sclerotiorum. Among the nine TLC fractions only one showed presence of a single peak, thus presence of a single compound in the crude extract. Based on lower IC50 value (328 μg/ml) the crude fruit extract collected from Indore region was further characterized. Evaluation against screened phytopathogens indicates its activity. Further, structural characterization of this compound using FTIR and NMR revealed it to be a novel compound i.e. 5-β-Hydroxyl tridecanyl benzoate. Our study paves a way to investigate effective dose of P. murex fruit extracts to utilize in plant protection programs. In future, a better method is required to scale up the process of bioactive molecule (5-β-Hydroxyl tridecayl benzoate) extraction from P. murex or for its chemical synthesis.
Rudhira/BCAS3 couples microtubules and intermediate filaments to promote cell migration for angiogenic remodeling
Authors: Joshi Divyesh , Inamdar Maneesha S.
Published: July 2018

Blood vessel formation requires endothelial cell (EC) migration that depends on dynamic remodeling of the cytoskeleton. Rudhira/Breast Carcinoma Amplified Sequence 3 (BCAS3) is a cytoskeletal protein essential for EC migration and sprouting angiogenesis during mouse development and implicated in metastatic disease. Here, we report that Rudhira mediates cytoskeleton organization and dynamics during EC migration. Rudhira binds to both microtubules and Vimentin intermediate filaments (IFs) and stabilizes microtubules. Rudhira depletion impairs cytoskeletal crosstalk, microtubule stability and hence focal adhesion disassembly. The BCAS3 domain of Rudhira is necessary and sufficient for microtubule-IF crosslinking and cell migration. Pharmacologically restoring microtubule stability rescues gross cytoskeleton organization and angiogenic sprouting in Rudhira depleted cells. Our study identifies the novel and essential role of Rudhira in cytoskeletal crosstalk and assigns function to the conserved BCAS3 domain. Targeting Rudhira could allow tissue-restricted cytoskeleton modulation to control cell migration and angiogenesis in development and disease.
Quantitative approaches to variant classification increase the yield and precision of genetic testing in Mendelian diseases: The case of hypertrophic cardiomyopathy
Authors: Walsh Roddy , Mazzarotto Francesco , Whiffin Nicola , Buchan Rachel , Midwinter William , Wilk Alicja , Li Nicholas , Felkin Leanne , Ingold Nathan , Govind Risha , Ahmad Mian , Mazaika Erica , Allouba Mona , Zhang Xiaolei , Marvao Antonio de , Day Sharlene M , Ashley Euan , Colan Steven D , Michels Michelle , Pereira Alexandre C , Jacoby Daniel , Ho Carolyn Y , Thomson Kate L , Watkins Hugh , Barton Paul JR , Olivotto Iacopo , Cook Stuart A , Ware James S
Published: July 2018

Background

International guidelines for variant interpretation in Mendelian disease set stringent criteria to report a variant as (likely) pathogenic, prioritising control of false positive rate over test sensitivity and diagnostic yield. Genetic testing is also more likely informative in individuals with well-characterised variants from extensively studied European-ancestry populations. Inherited cardiomyopathies are relatively common Mendelian diseases that allow empirical calibration and assessment of this framework.

Results

We compared rare variants in large hypertrophic cardiomyopathy (HCM) cohorts to reference populations to identify variant classes with high prior likelihoods of pathogenicity, as defined by etiological fraction (EF). Analysis of variant distribution identified regions in which variants are significantly enriched in cases and variant location was a better discriminator of pathogenicity than generic computational functional prediction algorithms. Non-truncating variant classes with an EF≥0.95, and therefore clinically actionable, were identified in 5 established HCM genes. Applying this approach leads to an estimated 14-20% increase in cases with actionable HCM variants.

Conclusions

When found in a patient confirmed to have disease, novel variants in some genes and regions are empirically shown to have a sufficiently high probability of pathogenicity to support a “likely pathogenic” classification, even without additional segregation or functional data. This could increase the yield of high confidence actionable variants, consistent with the framework and recommendations of current guidelines. The techniques outlined offer a consistent, unbiased and equitable approach to variant interpretation for Mendelian disease genetic testing. We propose adaptations to ACMG/AMP guidelines to incorporate such evidence in a quantitative and transparent manner.
Application of an Interpretable Classification Model on Early Folding Residues during Protein Folding
Authors: Bittrich Sebastian , Kaden Marika , Leberecht Christoph , Kaiser Florian , Villmann Thomas , Labudde Dirk
Published: July 2018

Background

Machine learning strategies are prominent tools for data analysis. Especially in life sciences, they have become increasingly important to handle the growing datasets collected by the scientific community. Meanwhile, algorithms improve in performance, but also gain complexity, and tend to neglect interpretability and comprehensiveness of the resulting models.

Results

Generalized Matrix Learning Vector Quantization (GMLVQ) is a supervised, prototype-based machine learning method and provides comprehensive visualization capabilities not present in other classifiers which allow for a fine-grained interpretation of the data. In contrast to commonly used machine learning strategies, GMLVQ is well-suited for imbalanced classification problems which are frequent in life sciences. We present a Weka plug-in implementing GMLVQ. The feasibility of GMLVQ is demonstrated on a dataset of Early Folding Residues (EFR) that have been shown to initiate and guide the protein folding process. Using 27 features, an area under the receiver operating characteristic of 76.6% was achieved which is comparable to other state-of-the-art classifiers.

Conclusions

The application on EFR prediction demonstrates how an easy interpretation of classification models can promote the comprehension of biological mechanisms. The results shed light on the special features of EFR which were reported as most influential for the classification: EFR are embedded in ordered secondary structure elements and they participate in networks of hydrophobic residues. Visualization capabilities of GMLVQ are presented as we demonstrate how to interpret the results.