bluuebunny/crossref_metadata_2025 huggingface dataset:
Mycoplasma genitalium Infections With Macrolide and Fluoroquinolone Resistance-Associated Mutations in Heterosexual African American Couples in Alabama
Authors: Xiao Li , Waites Ken B. , Van Der Pol Barbara , Aaron Kristal J. , Hook Edward W. , Geisler William M.
Published: July 2018

Background

Mycoplasma genitalium (MG) is a sexually transmitted pathogen associated with inflammatory syndromes in men and women. Macrolides and fluoroquinolones are recommended MG treatments. The frequency of MG strains with macrolide resistance-associated mutations (MRMs) and quinolone resistance-associated mutations (qRMs) is increasing worldwide, however these data are sparse in populations in the United States.

Methods

We investigated the prevalence of MG infections with MRMs and qRMs and MG infection concordance within African American couples in Birmingham, AL. We used a real-time polymerase chain reaction to detect MG and identify MRMs. quinolone resistance-associated mutations were detected using traditional polymerase chain reactions amplifying regions in gyrA, gyrB, parC, and parE. The MG concordance in couples was evaluated by MG positivity and MG genotypes.

Results

Oral, anal, urine, and/or vaginal specimens were tested from 116 couples. Twenty-eight (12.1%) participants comprising 22 couples tested MG-positive (11.2% in men and 12.9% in women). Macrolide resistance-associated mutations were detected in 17 (60.7%) MG-positive participants, with gender-specific resistance rates of 69.2% for men and 53.3% for women. quinolone resistance-associated mutations were detected in 3 (11.1%) MG-positive participants, all of whom also had MRMs. By MG positivity status, 27.3% of couples were concordant. If MG strain genotypes are also considered, then concordance was 20.0%.

Conclusions

Among heterosexual African Americans with MG infection, about 60% had strains with MRMs and 11% had strains with both MRMs and qRMs, highlighting the potential for MG treatment failure to not only macrolides, but also quinolones. These findings may help to guide clinicians in MG testing and treatment decisions in the United States.
Accuracy of Three Software Applications for Breast Volume Calculations from Three-Dimensional Surface Images
Authors: Wesselius Tycho S. , Verhulst Arico C. , Vreeken Rinaldo D. , Xi Tong , Maal Thomas J. J. , Ulrich Dietmar J. O.
Published: July 2018

Background:

Knowing breast volumes before certain surgeries helps the surgeon to obtain breast symmetry. Calculating breast volumes from three-dimensional surface images is possible with specialized software applications. However, limited data exist concerning the accuracy of such volume calculations. The purpose of this study was to investigate the accuracy of breast volume calculations performed with the 3D BreAST, 3dMD Vultus, and VECTRA software applications.

Methods:

Twenty-six subjects who underwent 44 mastectomies were enrolled. Preoperative three-dimensional surface images were acquired with a VECTRA-XT stereophotogrammetry device. Breast volumes were calculated from these images with the three software applications. The mastectomy specimens were weighed to derive their actual volume and compared with the software calculations.

Results:

For all three methods, a positive correlation between the breast volume and absolute calculation error was found (p < 0.001), but not for the errors as a percentage of the breast volume (p = 0.17, p = 0.80, and p = 0.42). The 3D BreAST, 3dMD Vultus, and VECTRA applications provided mean volume calculation errors of 21, 186, and −32 ml (p = 0.27, p < 0.001, and p = 0.14) or 2 ± 25, 48 ± 26, and −6 ± 27 percent of the breast volume (p = 0.67, p < 0.001, and p = 0.16), respectively.

Conclusions:

Despite that two applications calculated accurate mean breast volumes, all applications showed a high standard deviation in terms of the percentage of the breast volume. Therefore, the usefulness of absolute breast volume calculations from three-dimensional surface images seems limited.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Diagnostic, II.
The Orbital Oval Balance Principle: A Morphometric Clinical Analysis
Authors: Gülbitti Haydar A. , Bouman Theo K. , Marten Timothy J. , van der Lei Berend
Published: July 2018

Background:

The aim of this study was to test the validity of the “orbital oval balance principle,” a system of analysis and guideline that is used among aestheticians, artists, and makeup artists to create and design aesthetically pleasing eyebrows for optimal upper facial appearance. According to this principle, a face is optimally attractive when the eye is centered in an “oval” defined by the lid-cheek junction and the eyebrow.

Methods:

One hundred participants were asked to rank digital morphed images of four female models with four different periorbital proportions: higher or lower lid-cheek junction versus higher or lower eyebrow position. In addition, the participants were asked to quantify seven emotions on these morphed images.

Results:

A higher lid-cheek junction was rated as significantly more attractive with a lower eyebrow position, and a lower lid-cheek junction was regarded far more attractive in combination with a higher eyebrow position. Moreover, a higher lid-cheek junction was rated as more attractive than a lower lid-cheek junction, and elevation of the lid-cheek junction improved the perception of emotions such as tiredness and sadness.

Conclusions:

This study lends support to the orbital oval balance principle that can provide important insight into facial attractiveness to surgeons undertaking procedures intended to improve and rejuvenate facial appearance. Moreover, this study has also shown not only that a high(er) lid-cheek junction is regarded as more youthful and attractive, but that it also may reduce the appearance of tiredness and sadness.
Multimonth Prescription of Antiretroviral Therapy Among Children and Adolescents: Experiences From the Baylor International Pediatric AIDS Initiative in 6 African Countries
Authors: Kim Maria H. , Wanless Richard S. , Caviness Alison Chantal , Golin Rachel , Amzel Anouk , Ahmed Saeed , Mhango Joseph , Damba David , Kayabu Angelina , Chodota Moses , Dlamini Sandile , Chidah Nodumo , Mokhali Mokhitli , Calles Nancy R. , Abrams Elaine J.
Published: July 2018

Background:

To reach 90-90-90 targets, differentiated approaches to care are necessary. We describe the experience of delivering multimonth prescription (MMP) schedules of antiretroviral therapy (ART) to youth at centers of excellence in 6 African countries.

Methods:

We analyzed data from electronic medical records of patients aged 0–19 years started on ART. Patients were eligible to transition from monthly prescribing to MMP when clinically stable [improving CD4+, viral load (VL) suppression, or minimal HIV-associated morbidity] and ART adherent (pill count 95%–105%). Patients were classified as transitioned to MMP after 3 consecutive visits at intervals of >56 days. We used survival analysis to describe death and lost to follow-up. We described adherence and acceptable immunologic response by CD4+ using 6-month and VL suppression (<400 copies per milliliter) using 12-month intervals.

Results:

Twenty-two thousand six hundred fifty-eight patients aged 0–19 years received ART and 14,932 (66%) transitioned to MMP between 2003 and 2015. Of these 2.6% were lost to follow-up and 2.0% died. Median duration of MMP was 3.9 (interquartile range: 2.2–5.9) years. There were significant differences in survival (P < 0.0001) between age groups, worst among those younger than 1 year and 15–19 years. The frequency of favorable clinical endpoints was high throughout the first 5 years of MMP, by year ranging from 87% to 94% acceptable immunologic response, 75% to 80% adherent, and 79% to 85% VL suppression.

Conclusions:

These analyses from 6 African countries demonstrate that youth on ART who transitioned to MMP overall maintained favorable outcomes in terms of death, retention, adherence, immunosuppression, and viral suppression. These results reassure that children and adolescents, who are clinically stable and ART adherent, can do well with reduced visit frequencies and extended ART refills.
Community-Based Interventions to Reach 95-95-95 for Children and Adolescents: An Exploratory Programmatic Review From Lesotho
Authors: Amzel Anouk , Srivastava Meena , Isavwa Anthony , Sanders Jill , Tumbare Esther , Membe Ian , Mirembe Justine , Ntjabane Seema , Raliile Peter , Mohoanyane Matsitso , Ryan Victoria
Published: July 2018

Background:

Viral suppression is the desired outcome for children and adolescents with HIV. In this article, data from districts supporting community interventions (implementation districts) were reviewed and compared with data from districts without community interventions (nonimplementation districts) to explore a potential correlation between community interventions and clinical outcomes.

Setting:

The study was based on data collected from facilities in 6 districts in Lesotho.

Methods:

Twelve-month retention, viral load coverage, and viral suppression data from patients with ART between ages 5 and 24 from facilities in both district types were collected retrospectively.

Results:

Implementation districts showed retention rates of 75%, with 5365 patients (47% of all patients on ART) having documented viral load results and 4641 (87%) being virally suppressed. Retention comparison demonstrated significantly higher rates in implementation districts (73%) as compared to (63%) in nonimplementation districts (P = 0.023). Viral load coverage and suppression comparison found that implementation district hospitals reported 632 (37% of total on ART) patients with a documented viral load, with 539 (85%) virally suppressed, whereas nonimplementation district hospitals reported 220 (31%) patients with viral load results, of whom 181 (82%) were suppressed.

Conclusions:

Overall, retention rates in the implementation districts were reasonable and were significantly better than the rates in the nonimplementation districts.
Congenital Coronary Artery Anomalies and Implications
Authors: Azour Lea , Jacobi Adam H. , Alpert Jeffrey B. , Uppu Santosh , Latson Larry , Mason Derek , Cham Matthew D.
Published: July 2018

This pictorial essay presents cases of congenital coronary artery anomalies, including congenital anomalies of origin, course, and termination. Familiarity with atypical coronary anatomy and clinical presentation may facilitate appropriate diagnosis and management, particularly as cardiac and thoracic computed tomographic utilization increases.
Learning Curve Under Proctorship of Pure Laparoscopic Living Donor Left Lateral Sectionectomy for Pediatric Transplantation
Authors: Broering Dieter C. , Berardi Giammauro , El Sheikh Yasser , Spagnoli Alessandra , Troisi Roberto I.
Published: July 2018

Objective:

To evaluate the learning curve of an expert liver transplantation surgeon approaching fully laparoscopic living donor left lateral sectionectomy (L-LLS) under proctorship.

Background:

Laparoscopic liver resections necessitate a long learning curve trough a stepwise fulfillment of difficulties. L-LLS requires expertise in both living donor liver transplantation and advanced laparoscopic liver surgery. There is currently no data about the learning curve of L-LLS.

Methods:

A total of 72 pure L-LLS were included in this study. A Broken line model was used to identify the periods of the learning curve. A CUSUM analysis of the operative time was performed to evaluate improvements of outcomes with time. To evaluate the relationship between operative time and progressive number of procedures, a linear regression model was applied. A receiver operating characteristic (ROC) curve was carried out to identify the cutoff for completion of the learning curve.

Results:

Operative time decreased with the progressive increase of procedures. Two cutoffs and 3 different periods were identified: cases 1 to 22, cases 23 to 55, and cases 56 to 72. A significant decrease in blood loss and operative time was noted. The CUSUM analysis showed an increase in operative time in the first period, a stable duration in the second period, and a decrease in the last. Blood loss was significantly associated with an increase in operative time (P = 0.003). According to the ROC curve, the learning curve was completed after 25 procedures.

Conclusions:

L-LLS is a safe procedure that can be standardized and successfully taught to surgeons with large experience in donor hepatectomy through a proctored learning curve.
A novel acid catalyst based on super/subcritical CO2-enriched water for the efficient esterification of rosin
Authors: Zhou Dan , Wang Linlin , Chen Xiaopeng , Wei Xiaojie , Liang Jiezhen , Zhang Dong , Ding Guoxin
Published: July 2018

Rosin esters are widely applied as masticatory substances and beverage stabilizers, while classical acid-catalysed processes will lead to metal residue or environmental issues. Super/subcritical CO2–enriched high temperature liquid water (HTLW) as a green acid catalyst in the esterification reaction of rosin with glycerol was investigated. The pH of CO2–H2O binary system, as calculated based on gas–liquid equilibrium, charge balance and chemical equilibrium equations, ranged from 3.49 to 3.70 depending on the reaction conditions, indicating effective acid catalysis. Response surface methodology experiments showed the optimum conditions were 3.5 h, 3.9 MPa CO2pressure, a rosin-to-glycerol molar ratio of 1.32 and 269°C, and an enhanced esterification yield of 94.74% was achieved, which was superior to that obtained using a ZnO catalyst. It was found that the esterification kinetics was a pseudo first-order reaction, and the enthalpy and entropy of activation were calculated using the Arrhenius–Polanyi equation. The presence of super/subcritical CO2-enriched HTLW catalyst can decrease the activation energy and significantly accelerate the reaction rate.
Comprehensive diagnosis of PCDD/F emission from three hazardous waste incinerators
Authors: Cao Xuan , Ji Longjie , Lin Xiaoqing , Stevens William R. , Tang Minghui , Shang Fanjie , Tang Shaofu , Lu Shengyong
Published: July 2018

Comprehensive diagnosis of polychlorinated dibenzo-
p
-dioxin and dibenzofuran (PCDD/F) emissions was systematically conducted on three hazardous waste incinerators (HWIs). Results indicated that PCDD/F mainly existed in the solid phase before the bag filter. This was especially true for higher chlorinated dioxin and furan congeners (hexa-, hepta- and octa-). The aged bag filters tended to increase the gas-phase PCDD/F. Emissions also increased due to PCDD/F desorption from circulated scrubbing solution and plastic packing media used in the wet scrubber. The PCDD/F concentrations were elevated during the start-up process, reaching up to 5.4 times higher than those measured during the normal operating period. The ratios of PCDFs/PCDDs revealed that the surface-catalysed de novo synthesis was the dominant pathway of PCDD/F formation. Installation of more efficient fabric filters, intermittent replacement of circulated scrubbing solution will result in reduced PCDD/F emission. Additionally, 2,3,4,7,8-PeCDF correlated well with the international toxic equivalent quantity (I-TEQ) value, which suggests that 2,3,4,7,8-PeCDF could act as an I-TEQ indicator.
Illuminating gillnets to save seabirds and the potential for multi-taxa bycatch mitigation
Authors: Mangel Jeffrey C. , Wang John , Alfaro-Shigueto Joanna , Pingo Sergio , Jimenez Astrid , Carvalho Felipe , Swimmer Yonat , Godley Brendan J. 
Published: July 2018

Bycatch in net fisheries is recognized as a major source of mortality for many marine species, including seabirds. Few mitigation solutions, however, have been identified. We assessed the effectiveness of illuminating fishing nets with green light emitting diodes (LEDs) to reduce the incidental capture of seabirds. Experiments were conducted in the demersal, set gillnet fishery of Constante, Peru and compared 114 pairs of control and illuminated nets. We observed captures of a total of 45 guanay cormorants (
Phalacrocorax bougainvillii
), with 39 caught in control nets and six caught in illuminated nets. Seabird bycatch in terms of catch-per-unit-effort was significantly (
p
 < 0.05) higher in control nets than in illuminated nets, representing an 85.1% decline in the cormorant bycatch rate. This study, showing that net illumination reduces seabird bycatch and previous studies showing reductions in sea turtle bycatch without reducing target catch, indicates that net illumination can be an effective multi-taxa bycatch mitigation technique. This finding has broad implications for bycatch mitigation in net fisheries given LED technology's relatively low cost, the global ubiquity of net fisheries and the current paucity of bycatch mitigation solutions.
Large numbers of explanatory variables: a probabilistic assessment
Authors: Battey H. S. , Cox D. R.
Published: July 2018

Recently, Cox and Battey (2017
Proc. Natl Acad. Sci. USA
114
, 8592–8595 (
doi:10.1073/pnas.1703764114
)) outlined a procedure for regression analysis when there are a small number of study individuals and a large number of potential explanatory variables, but relatively few of the latter have a real effect. The present paper reports more formal statistical properties. The results are intended primarily to guide the choice of key tuning parameters.
The lingering impact of stress: brief acute glucocorticoid exposure has sustained, dose-dependent effects on reproduction
Authors: Vitousek Maren N. , Taff Conor C. , Ardia Daniel R. , Stedman Jocelyn M. , Zimmer Cedric , Salzman Timothy C. , Winkler David W.
Published: July 2018

Acutely stressful experiences can have profound and persistent effects on phenotype. Across taxa, individuals differ remarkably in their susceptibility to stress. However, the mechanistic causes of enduring stress effects, and of individual differences in stress susceptibility, are poorly understood. Here, we tested whether brief, acute increases in glucocorticoid hormones have persistent effects on phenotype, and whether effects differ according to the magnitude or duration of elevation. We used a novel method to non-invasively manipulate hormone levels on short time scales: the application of corticosterone gel to a model egg secured in the nest. Free-living female tree swallows (
Tachycineta bicolor
) exposed to several brief corticosterone increases during incubation showed dose-dependent differences in behaviour throughout the reproductive period. Birds receiving treatments that simulated higher or longer acute stress responses later provisioned larger broods at lower rates; the resulting offspring were smaller in size. Treatment did not influence female body condition, oxidative stress, reproductive success or inter-annual survival, but exposed females maintained higher baseline corticosterone after treatments ceased. Overall, these results indicate that brief, acute elevations in glucocorticoids in adulthood can have long-term consequences. Furthermore, individuals that mount a greater or longer acute stress response may be more likely to experience lingering effects of stress.
Evidence for human-mediated range expansion and gene flow in an invasive grass
Authors: Arredondo Tina M. , Marchini Gina L. , Cruzan Mitchell B.
Published: July 2018

Cities and adjacent regions represent foci of intense human activity and provide unique opportunities for studying human-mediated dispersal and gene flow. We examined the effect of landscape features on gene flow in the invasive grassBrachypodium sylvaticumacross an urban–rural interface at the edge of its expanding range. We used genome-wide single-nucleotide polymorphism surveys of individuals from 22 locations. Resistance surfaces were created for each landscape feature, using ResistanceGA to optimize resistance parameters. Our Structureanalysis identified three distinct clusters, and diversity analyses support the existence of at least three local introductions. Multiple regression on distance matrices showed no evidence that development, roads, canopy cover or agriculture had a significant influence on genetic distance inB. sylvaticum. Geographical distance was a mediocre predictor of genetic distance and reflected geographical clustering. The model of rivers acting as a conduit explained a large portion of variation in genetic distance, but the lack of evidence of directional gene flow eliminated hydrochory as a dispersal mechanism. These results and observations of the distribution of populations in disturbed sites indicate that the influence of rivers on patterns of dispersal ofB. sylvaticumprobably reflects seed dispersal due to human recreational activity.
The complex genetic architecture of shoot growth natural variation in Arabidopsis thaliana
Authors: Marchadier  , Hanemian  , Tisné  , Bach  , Bazakos  , Gilbault  , Haddadi  , Virlouvet  , Loudet
Published: July 2018

One of the main outcome of quantitative genetics approaches to natural variation is to reveal the genetic architecture underlying the phenotypic space. Complex genetic architectures are described as including numerous loci (or alleles) with small-effect and/or low-frequency in the populations, interactions with the genetic background, environment or age… Linkage or association mapping strategies will be more or less sensitive to this complexity, so that we still have an unclear picture of its extent. By combining high-throughput phenotyping under two environmental conditions with classical QTL mapping approaches in multiple Arabidopsis thaliana segregating populations as well as advanced near isogenic lines construction and survey, we have attempted to push back the limits of our understanding of quantitative phenotypic variation. Integrative traits such as those related to vegetative growth used in this work (highlighting either cumulative growth, growth rate or morphology) all showed complex and dynamic genetic architecture with respect to the segregating population and condition. The more resolutive our mapping approach, the more complexity we uncover, with several instances of QTLs visible in near isogenic lines but not detected with the initial QTL mapping, indicating that our phenotyping resolution was less limiting than the mapping resolution with respect to the underlying genetic architecture. In an ultimate approach to resolve this complexity, we intensified our phenotyping effort to target specifically a 3Mb-region known to segregate for a major quantitative trait gene, using a series of selected lines recombined every 100kb. We discovered that at least 3 other independent QTLs had remained hidden in this region, some with trait- or condition-specific effects, or opposite allelic effects. If we were to extrapolate the figures obtained on this specific region in this particular cross to the genome- and species-scale, we would predict hundreds of causative loci of detectable phenotypic effect controlling these growth-related phenotypes.
Changes in excitability and ion channel expression in neurons of the major pelvic ganglion in female type II diabetic mice
Authors: Gray Michael , Lett Kawasi M. , Garcia Virginia B. , Kyi Cindy W. , Pennington Kathleen A. , Schulz Laura C. , Schulz David J.
Published: July 2018

Bladder cystopathy is a common urological complication of diabetes, and has been associated with changes in parasympathetic ganglionic transmission and some measures of neuronal excitability in male mice. To determine whether type II diabetes also impacts excitability of parasympathetic ganglionic neurons in females, we investigated neuronal excitability and firing properties, as well as underlying ion channel expression, in major pelvic ganglion (MPG) neurons in control, 10-week, and 21-week db/db mice. Type II diabetes in Leprdb/db animals caused a non-linear change in excitability and firing properties of MPG neurons. At 10 weeks, cells exhibited increased excitability as demonstrated by an increased likelihood of firing multiple spikes upon depolarization, decreased rebound spike latency, and overall narrower action potential half-widths as a result of increased depolarization and repolarization slopes. Conversely, at 21 weeks MPG neurons of db/db mice reversed these changes, with spiking patterns and action-potential properties largely returning to control levels. These changes are associated with numerous time-specific changes in calcium, sodium, and potassium channel subunit mRNA levels. However, Principal Components Analysis of channel expression patterns revealed that the rectification of excitability is not simply a return to control levels, but rather a distinct ion channel expression profile in 21-week db/db neurons. These data indicate that type II diabetes can impact the excitability of post-ganglionic, parasympathetic bladder-innervating neurons of female mice, and suggest that the non-linear progression of these properties with diabetes may be the result of compensatory changes in channel expression that act to rectify disrupted firing patterns of db/db MPG neurons.
Molecular basis for the acid initiated uncoating of human enterovirus D68
Authors: Liu Yue , Sheng Ju , Rossmann Michael G.
Published: July 2018

Enterovirus D68 (EV-D68) belongs to a group of enteroviruses that contain a single positive-sense RNA genome surrounded by an icosahedral capsid. Like common cold viruses, EV-D68 mainly causes respiratory infections and is acid labile. The molecular mechanism by which the acid sensitive EV-D68 virions uncoat and deliver their genome into a host cell is unknown. Using cryo-electron microscopy (cryo-EM), we have determined the structures of the full native virion and an uncoating intermediate (the A(altered)-particle) of EV-D68 at 2.2 Å and 2.7 Å resolution. These structures showed that acid treatment of EV-D68 leads to particle expansion, externalization of the viral protein VP1 N-termini from the capsid interior, and formation of pores around the icosahedral two-fold axes through which the viral RNA can exit. Moreover, because of the low stability of EV-D68 at neutral pH, cryo-EM analyses of a mixed population of particles demonstrated the involvement of multiple structural intermediates during virus uncoating. Among these, a previously undescribed state, the expanded (“E1”) particle, shows a majority of internal regions (e.g, the VP1 N-termini) to be ordered as in the full native virion. Thus, the E1 particle acts as an intermediate in the transition from full native virions to A-particles. Molecular determinants, including a histidine-histidine pair near the two-fold axes, were identified that facilitate this transition under acidic conditions. Thus, the present work delineates the pathway of EV-D68 uncoating and provides the molecular basis for the acid lability of EV-D68 and of the related common cold viruses.

Significance Statement

Enterovirus D68 (EV-D68) is an emerging pathogen that primarily causes childhood respiratory infections and is linked to neurological diseases. It was unclear how the virus uncoats and delivers its genome into a host cell to establish viral replication. Using high resolution cryo-electron microscopy, we showed that acid induces structural rearrangements of EV-D68 to initiate genome release from the virus. Structural analyses delineated a viral uncoating pathway that involves multiple distinct conformational states. Particularly, the structure of a previously unknown uncoating intermediate enabled the identification of molecular determinants that facilitate EV-D68 uncoating in an acidic environment. These results advance the knowledge of cell entry of EV-D68 and open up possibilities for developing antiviral therapeutics that impede structural rearrangements of the virus.
The unexpected provenance of components in eukaryotic nucleotide-excision-repair and kinetoplast DNA-dynamics from bacterial mobile elements
Authors: Krishnan Arunkumar , Burroughs A. Maxwell , Iyer Lakshminarayan M. , Aravind L
Published: July 2018

Background

Protein ‘weaponry’ deployed in biological conflicts between selfish elements and their hosts are increasingly recognized as being re-purposed for diverse molecular adaptations in the evolution of several uniquely eukaryotic systems. The anti-restriction protein ArdC, transmitted along with the DNA during invasion, is one such factor deployed by plasmids and conjugative transposons against their bacterial hosts.

Results

Using sensitive computational methods we unify the N-terminal single-stranded DNA-binding domain of ArdC (ArdC-N) with the DNA-binding domains of the nucleotide excision repair (NER) XPC/Rad4 protein andTrypanosomaTc-38 (p38) protein implicated in kinetoplast(k) DNA replication and dynamics. We show that the ArdC-N domain was independently acquired twice by eukaryotes from bacterial mobile elements. One gave rise to the ‘beta-hairpin domains’ of XPC/Rad4 and the other to the Tc-38-like proteins in the stem kinetoplastid. Eukaryotic ArdC-N domains underwent tandem duplications to form an extensive DNA-binding interface. In XPC/Rad4, the ArdC-N domain combined with the inactive transglutaminase domain of a peptide-N-glycanase originally derived from an active archaeal version, often incorporated in systems countering invasive DNA. We also show that parallel acquisitions from conjugative elements and bacteriophages gave rise to the Topoisomerase IA, DNA polymerases IB-Ds, and DNA ligases involved in kDNA dynamics.

Conclusions

We resolve two outstanding questions in eukaryote-biology: 1) origin of the unique DNA lesion-recognition component of NER; 2) origin of the unusual, plasmid-like features of kDNA. These represent a more general trend in the origin of distinctive components of systems involved in DNA dynamics and their links to the ubiquitin system.
Interface residues that drive allosteric transitions also control the assembly of L-lactate Dehydrogenase
Authors: Chen Jie , Thirumalai D.
Published: July 2018

The allosteric enzyme, L-lactate dehydrogenase (LDH), is activated by fructose 1,6-metaphosphate (FBP) to reduce pyruvate to lactate. The molecular details of the FBP-driven transition between the low affinity T-state to the high affinity R-state in LDH, a tetramer composed of identical subunits, are not known. The dynamics of theT→R allosteric transition, investigated using Brownian dynamics (BD) simulations of the Self-Organized Polymer (SOP) model, revealed that coordinated rotations of the subunits drive the T→R transition. We used the structural perturbation method (SPM), which requires only the static structure, to identify the allostery wiring diagram (AWD), a network of residues that transmits signals across the tetramer, as LDH undergoes the T→R transition. Interestingly, the residues that play a major role in the dynamics, which are predominantly localized at the interfaces, coincide with the AWD identified using the SPM. The conformational changes in the T→R transition start from the region near the active site, comprising of helix αC, helix α1/2G, helix α3G and helix α2F, and proceed to other structural units, thus completing the global motion. Brownian dynamics simulations of the tetramer assembly, triggered by a temperature quench from the fully disrupted conformations, show that the bottleneck for assembly is the formation of the correct orientation between the subunits, requiring contacts between the interface residues. Surprisingly, these residues are part of the AWD, which was identified using the SPM. Taken together, our results show that LDH, and perhaps other multi-domain proteins, may have evolved to stabilize distinct states of allosteric enzymes using precisely the same AWD that also controls the functionally relevant allosteric transitions.
MICOM: metagenome-scale modeling to infer metabolic interactions in the gut microbiota
Authors: Diener Christian , Gibbons Sean M. , Resendis-Antonio Osbaldo
Published: July 2018

Compositional changes in the gut microbiota have been associated with a variety of medical conditions such as obesity, Crohn’s disease and diabetes. However, connecting microbial community composition to ecosystem function remains a challenge. Here, we introduce MICOM – a customizable metabolic model of the human gut microbiome. By using a heuristic optimization approach based on L2 regularization we were able to obtain a unique set of realistic growth rates that corresponded well with observed replication rates. We integrated adjustable dietary and taxon abundance constraints to generate personalized metabolic models for individual metagenomic samples. We applied MICOM to a balanced cohort of metagenomes from 186 people, including a metabolically healthy population and individuals with type 1 and type 2 diabetes. Model results showed that individual bacterial genera maintained conserved niche structures across humans, while the community-level production of short chain fatty acids (SCFAs) was heterogeneous and highly individual-specific. Model output revealed complex cross-feeding interactions that would be difficult to measurein vivo. Metabolic interaction networks differed somewhat consistently between healthy and diabetic subjects. In particular MICOM predicted reduced butyrate and propionate production in a diabetic cohort, with restoration of SCFA production profiles found in healthy subjects following metformin treatment. Overall, we found that changes in diet or taxon abundances have highly personalized effects. We believe MICOM can serve as a useful tool for generating mechanistic hypotheses for how diet and microbiome composition influence community function. All methods are implemented in the open source Python package, which is available athttps://github.com/micom-dev/micom.
Progression of chronic kidney disease in African Americans with type 2 diabetes mellitus using topology learning in electronic medical records
Authors: Wang Li , Zheng Xufei , Huang Lynn S. , Xu Jianzhao , Hsu Fang-Chi , Chen Shyh-Huei , Ng Maggie C.Y. , Bowden Donald W. , Freedman Barry I. , Su Jing
Published: July 2018

Background

Chronic kidney disease (CKD) is a common, complex, and heterogeneous disease impacting aging populations. Determining the landscape of disease progression trajectories from midlife to senior age in a “real-world” context allows us to better understand the progression of CKD, the heterogeneity of progression patterns among the risk population, and the interactions with other clinical conditions. Genetics also plays an important role. In previous work, we and others have demonstrated that African Americans with high-risk APOL1 genotypes are more likely to develop CKD, tend to develop CKD earlier, and the disease progresses faster. Diabetes, which is more common in African Americans, also significantly increases risk for CKD.

Data and Method

Electronic medical records (EMRs) were used to outline the first CKD progression trajectory roadmap for an African American population with type 2 diabetes. By linking participants in 5 genome-wide association study (GWAS) to their clinical records at Wake Forest Baptist Medical Center (WFBMC), an EMR-GWAS cohort was established (n = 1,581). Patients’ health status was described by 18 Essential Clinical Indices across 84,009 clinical encounters. A novel graph learning algorithm, Discriminative Dimensionality Reduction Tree (DDRTree) was implemented, to establish the trajectories of declines in health. Moreover, a prediction model for new patients was proposed along the learned graph structure. We annotated these trajectories with clinical and genomic features including kidney function, other major risk indices of CKD, APOL1 genotypes, and age. The prediction power of the learned disease progression trajectories was further examined using the k-nearest neighbor model.

Results

The CKD progression trajectory roadmap revealed diverse kidney failure pathways associated with different clinical conditions. Specifically, we identified one high-risk trajectory and two low-risk trajectories. Switching pathways from low-risk trajectories to the high-risk one was associated with accelerated decline in kidney function. On this roadmap, patients with APOL1 high-risk genotypes were enriched in the high-risk trajectory, suggesting fundamentally different disease progression mechanisms from those without APOL1 risk genotypes. The k-nearest neighbor-based prediction showed effective prediction rate of 87%.

Conclusion

The CKD progression trajectory roadmap revealed novel diverse renal failure pathways in African Americans with type 2 diabetes mellitus and highlights disease progression patterns that associate with APOL1 renal-risk genotypes.
Genome location dictates the transcriptional response to PolC-inhibition inClostridium difficile
Authors: van Eijk Erika , Boekhoud Ilse M. , Kuijper Ed J. , Bos-Sanders Ingrid M.J.G. , Wright George , Smits Wiep Klaas
Published: July 2018

Clostridium difficileis a potentially lethal gut pathogen that causes nosocomial and community acquired infections. Limited treatment options and reports of reduced susceptibility to current treatment emphasize the necessity for novel antimicrobials. The DNA-polymerase of gram-positive organisms is an attractive target for the development of antimicrobials. ACX-362E (N2-(3<,4-Dichlorobenzyl)-7-(2-[1-morpholinyl]ethyl)guanine; MorE-DCBG) is a DNA polymerase inhibitor in pre-clinical development as a novel therapeutic againstC. difficileinfection. This synthetic purine shows preferential activity againstC. difficilePolC over those of other organismsin vitroand is effective in an animal model ofC. difficileinfection. In this study we have determined its efficacy against a large collection of clinical isolates. At concentrations below the minimal inhibitory concentration, the presumed slowing (or stalling) of replication forks due to ACX-362E leads to a growth defect. We have determined the transcriptional response ofC. difficileto replication inhibition and observed an overrepresentation of up-regulated genes near the origin of replication in the presence of PolC-inhibitors, but not when cells were subjected to sub-inhibitory concentrations of other antibiotics. This phenomenon can be explained by a gene dosage shift, as we observed a concomitant increase in the ratio between origin-proximal versus terminus-proximal gene copy number upon exposure to PolC-inhibitors. Moreover, we show that certain genes differentially regulated under PolC-inhibition are controlled by the origin-proximal general stress response regulator sigma factor B. Together, these data suggest that genome location both directly and indirectly determines the transcriptional response to replication inhibition inC. difficile.
Effect of Drought On The Germination of Maize Using PEG (Polyethylene Glycol) As A Substitute For Drought Screening
Authors: Dar I. A. , Dar Kamaluddin. Z. A. , Sofi P.A. , Lone A.A.
Published: July 2018

Drought stress is one of the most important environmental factors in reduction of growth, development and production of plants. Germination of each seed is considered as one of the first and most fundamental life stages of a plant so that, the success in growth and yield production is also depending on this stage. To study the effect of PEG stress on germination and early seedling stages on maize, an experiment were laid out at laboratory conditions of Division of Genetics and Plant Breeding SKUAST-K FoA/RRS Wadura. This investigation was performed as factorial experiment under Complete Randomized Design (CRD) with three replications. Polyethylene glycol stress induced in laboratory caused progressive decline in both the parameters across all genotypes with increase in Polyethylene glycol from 0-20% and both the parameters (length of radical and root biomass) had highest value under control.
Divergent Behavior Amid Convergent Evolution: A Case of Four Desert Rodents Learning to Respond to Known and Novel Vipers
Authors: Bleicher Sonny S. , Kotler Burt P. , Shalev Omri , Austin Dixon , Embar Keren , Brown Joel S.
Published: July 2018

Desert communities word-wide are used as natural laboratories for the study of convergent evolution, yet inferences drawn from such studies are necessarily indirect. Here, we brought desert organisms together (rodents and vipers) from two deserts (Mojave and Negev). Both predators and prey in the Mojave have adaptations that give them competitive advantage compared to their middle-eastern counterparts. Heteromyid rodents, kangaroo rats and pocket mice, have fur-lined cheek pouches that allow the rodents to carry larger loads under predation risk compared to gerbilline rodents. Sidewinder rattlesnakes have heat-sensing pits, allowing them to hunt better on moonless nights when their Negev sidewinding counterpart, the Saharan horned vipers, are visually impaired. In behavioral-assays, we used giving-up density (GUD) to gage how each species of rodent perceived risk posed by known and novel snakes. We repeated this for the same set of rodents at first encounter and again two months later following intensive “natural” exposure to both snake species. Pre-exposure, all rodents identified their evolutionarily familiar snake as a greater risk than the novel one. However, post-exposure all identified the heat-sensing sidewinder rattlesnake as a greater risk. The heteromyids were more likely to avoid encounters with, and discern the behavioral difference among, snakes than their gerbilline counterparts.
Structural analysis of the interaction between the bacterial cell division proteins FtsQ and FtsB
Authors: Kureisaite-Ciziene Danguole , Varadajan Aravindan , McLaughlin Stephen H. , Glas Marjolein , Silva Alejandro Montón , Luirink Rosa , Mueller Carolin , den Blaauwen Tanneke , Grossmann Tom N. , Luirink Joen , Löwe Jan
Published: July 2018

Most bacteria and archaea use similar proteins within their cell division machinery, which uses the tubulin homologue FtsZ as its central organiser. In Gram-negative Escherichia coli bacteria, FtsZ recruits cytosolic, transmembrane, periplasmic and outer membrane proteins, assembling the divisome that facilitates bacterial cell division. One such divisome component, FtsQ, a bitopic membrane protein with a globular domain in the periplasm, has been shown to interact with many other divisome proteins. Despite its otherwise unknown function, it has been shown to be a major divisome interaction hub. Here, we investigated the interactions of FtsQ with FtsB and FtsL, two small bitopic membrane proteins that act immediately downstream of FtsQ. In biochemical assays we show that the periplasmic domains of E. coli FtsB and FtsL interact with FtsQ, but not with each other. Our crystal structure of FtsB bound to the β domain of FtsQ shows that only residues 64-87 of FtsB interact with FtsQ. A synthetic peptide comprising those 24 FtsB residues recapitulates the FtsQ:FtsB interactions. Protein deletions and structure-guided mutant analyses validate the structure. Furthermore, the same structure-guided mutants show cell division defects in vivo that are consistent with our structure of the FtsQ:FtsB complex that shows their interactions as they occur during cell division. Our work provides intricate details of the interactions within the divisome and also provides a tantalising view of a highly conserved protein interaction in the periplasm of bacteria that is an excellent target for cell division inhibitor searches.

Importance

Cells in most bacteria and archaea divide through a cell division process that is characterised through its filamentous organiser, FtsZ protein. FtsZ forms a ring structure at the division site and starts the recruitment of 10-20 downstream proteins that together form an elusive multi-protein complex termed divisome. The divisome is thought to facilitate many of the steps required to make two cells out of one. FtsQ and FtsB are part of the divisome, with FtsQ being a central hub, interacting with most of the other divisome components. Here we show for the first time how FtsQ interacts with its downstream partner FtsB and show that mutations that disturb the interface between the two proteins effectively inhibit cell division.
Probabilistic ancestry maps: a method to assess and visualize population substructures in genetics
Authors: Gaspar Héléna A. , Breen Gerome
Published: July 2018

Principal component analysis (PCA) is a standard method to correct for population stratification in ancestry-specific genome-wide association studies (GWASs) and is used to cluster individuals by ancestry. Using the 1000 genomes project data, we examine how non-linear dimensionality reduction methods such as t-distributed stochastic neighbor embedding (t-SNE) or generative topographic mapping (GTM) can be used to provide improved ancestry maps by accounting for a higher percentage of explained variance in ancestry, and how they can help to estimate the number of principal components necessary to account for population stratification. GTM also generates posterior probabilities of class membership which can be used to assess the probability of an individual to belong to a given population - as opposed to t-SNE, GTM can be used for both clustering and classification. This paper is a first application of GTM for ancestry classification models. Our maps and software are available online.

Author summary

With this paper, we seek to encourage researchers working in genetics to use other methods than PCA to visualize ancestry and identify substructures in populations. We propose to use methods which do not only allow visualization of ancestry, but also the estimation of probabilities of belonging to different ancestry groups.
Population growth affects intrinsic and extrinsic noise in gene expression
Authors: Thomas Philipp
Published: July 2018

Clonal cells of exponentially growing populations vary substantially from cell to cell. The main drivers of this heterogeneity are the population dynamics and stochasticity in the intracellular reactions, which are commonly studied separately. Here we develop an agent-based framework that allows tracking of the biochemical dynamics in every single cell of a growing population that accounts for both of these factors. Apart from the common intrinsic variability of the biochemical reactions, the framework also predicts extrinsic noise arising from fluctuations in the histories of cells without the need to introduce fluctuating rate constants. Instead, these extrinsic fluctuations are explained by cell cycle fluctuations and differences in cell age, which are ubiquitously observed in growing populations. We give explicit formulas to quantify mean molecule numbers, intrinsic and extrinsic noise statistics as measured in two-colour experiments. We find that these statistics may differ significantly depending on the experimental setup used to observe the cells. We illustrate this fact using (i) averages over an isolated cell lineage tracked over many generations as observed in the mother machine, (ii) snapshots of a growing population with known cell ages as recorded in time-lapse microscopy, and (iii) snapshots of unknown cell ages as measured from static images. Our integrated approach applies to arbitrary biochemical networks and generation time distributions. By employing models of stochastic gene expression and feedback regulation, we elucidate that isolated lineages, as compared to snapshot data, can significantly overestimate the mean number of molecules, overestimate extrinsic noise but underestimate intrinsic noise and have qualitatively different sensitivities to cell cycle fluctuations.