bluuebunny/crossref_metadata_2025 huggingface dataset:
Excess Cancer Cases and Medical Costs Due to Suboptimal Human Papillomavirus Vaccination Coverage in California
Authors: Baughan Eleonore B. , Keizur Erin M. , Damico Christopher A. , Arnold Elizabeth Mayfield , Ko Jamie S. , Klausner Jeffrey D.
Published: June 2019

Background

Human papillomavirus (HPV) vaccination coverage continues to be at low to moderate levels throughout the United States. HPV infection is linked to multiple types of cancers resulting in high economic and health burden. We aimed to estimate the excess number of cancer cases and associated medical costs due to current HPV vaccination coverage for a 20-year-old birth cohort in California.

Methods

We estimated the lifetime number of cancer cases caused by vaccine-preventable strains of HPV for a cohort of 20 year-olds in California. We then estimated the excess number of cancer cases in that cohort which would occur due to 2017 HPV vaccination coverage compared with an optimal coverage of 99.5%. By multiplying those excess cases by the average cost of treatment, we determined the excess cost due to current HPV vaccination coverage.

Results

With current vaccination coverage in California, the 20-year-old cohort is at risk for an excess 1352 cancer cases that could be prevented with a projected optimal vaccination coverage of 99.5%. The excess cost of treatment for those cancer cases would be US $52.2 million. Male oropharyngeal cancer accounts for the greatest projected cost burden US $21.3 million followed by cervical cancer US $16.1 million.

Conclusions

Increased HPV vaccination coverage in California is needed to reduce economic and health burdens associated with cancers caused by HPV infection.
Comparison of Outcomes between Side-to-End and End-to-End Lymphovenous Anastomoses for Early-Grade Extremity Lymphedema
Authors: AlJindan Fahad K. , Lin Chia-Yu , Cheng Ming-Huei
Published: June 2019

Background:

Lymphovenous anastomosis is technically challenging and can be successfully performed with an advanced operating microscope, supermicrosurgical instruments, and indocyanine green lymphography. This study compared the outcomes between side-to-end and end-to-end lymphovenous anastomosis configurations for unilateral extremity lymphedema.

Methods:

Between April of 2013 and June of 2017, lymphovenous anastomosis was indicated for 58 patients who preoperatively had patent lymphatic ducts by indocyanine green lymphography, including 20 patients with upper limb lymphedema and 38 patients with lower limb lymphedema. Either an end-to-end or a side-to-end lymphovenous anastomosis was used to anastomose the subdermal venule to the lymphatic duct. The circumferential difference and episodes of cellulitis were used as outcome measurements.

Results:

Twenty-three patients underwent an end-to-end lymphovenous anastomosis and 35 patients underwent side-to-end lymphovenous anastomosis. All patients had an immediate patency evaluated by indocyanine green lymphography and patent blue assessments. All patients returned to their daily routine without the use of any compression garments. At an average follow-up of 16.5 months (range, 13.4 to 19.6 months), the improvement of circumferential difference (3.2 percent; range, 1.8 to 4.6 percent) in the side-to-end group was statistically greater than that in the end-to-end group (2.2 percent; range, 1 to 3.4 percent; p = 0.04). The overall episodes of cellulitis were significantly reduced from 1.7 times/year (range, 1.3 to 2.1 times/year) to 0.7 times/year (range, 0.3 to 1.1 times/year; p < 0.001), but no difference was observed between the two groups.

Conclusions:

Both side-to-end and end-to-end lymphovenous anastomosis configurations were effective surgical approaches for improving early-grade extremity lymphedema. Side-to-end lymphovenous anastomosis has the advantages of having greater efficacy for lymph drainage, requiring only one anastomosis and eliminating the need to use compression garments.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Conflict of Interest at Plastic Surgery Conferences: Is It Significant?
Authors: Gray Rachel , Tanna Neil , Kasabian Armen K.
Published: June 2019

Background:

The Physician Payment Sunshine Act requires biomedical companies to disclose financial relationships between themselves and physicians. The authors compared the amount of money received by speakers at the American Society of Plastic Surgeons and the American Society for Aesthetic Plastic Surgery annual conferences with that received by the average plastic surgeon.

Methods:

General payments data were gathered from the Open Payments database for physicians listed as a presenter, moderator, panelist, lecturer, or instructor at the 2017 annual American Society of Plastic Surgeons and American Society for Aesthetic Plastic Surgery conferences. Means and medians of payments to speakers were calculated for each conference. One-tail t tests were used to evaluate differences.

Results:

The mean and median for general payments made to conference speakers at American Society for Aesthetic Plastic Surgery (n = 75) and American Society of Plastic Surgeons (n = 249) meeting were $75,577 and $861 and $27,562 and $1021, respectively. In comparison with the average general payment received by plastic surgeons (mean, $4788; median, $3209), these differences were significant (American Society for Aesthetic Plastic Surgery, p = 0.015; American Society of Plastic Surgeons, p = 0.0004).

Conclusions:

The significant difference in payments to speakers at conferences compared with the average plastic surgeon suggests that biomedical companies may have influence over some of the conference content. Speakers must make clear the full extent of industry relationships that could potentially bias their presentations.
Meta-Analyses in Plastic Surgery: Can We Trust Their Results?
Authors: McGuire Connor , Samargandi Osama A. , Corkum Joseph , Retrouvey Helene , Bezuhly Michael
Published: June 2019

Background:

Meta-analyses are common in the plastic surgery literature, but studies concerning their quality are lacking. The authors assessed the overall quality of meta-analyses in plastic surgery, and attempted to identify variables associated with scientific quality.

Methods:

A systematic review of meta-analyses published in seven plastic surgery journals between 2007 and 2017 was undertaken. Publication descriptors and methodologic details were extracted. Articles were assessed using the following two instruments: A Measurement Tool to Assess Systematic Reviews (AMSTAR) and AMSTAR 2.

Results:

Seventy-four studies were included. The number of meta-analyses per year increased. Most meta-analyses assessed a single intervention (59.5 percent), and pooled a mean of 20.9 studies (range, two to 134), including a mean of 2463 patients (range, 44 to 14,884). Most meta-analyses were published in Plastic and Reconstructive Surgery (44.6 percent) and included midlevel evidence (II to IV) primary studies. Only 16.2 percent of meta-analyses included randomized controlled trials. Meta-analyses generally reported positive (81.1 percent) and significant results (77.0 percent). Median AMSTAR score was 7 of 11 (interquartile range, 5 to 8). Higher AMSTAR scores correlated with more recent meta-analyses that provided a rationale for statistical pooling, and appropriately managed methodologic heterogeneity (r = 0.66; p < 0.01).

Conclusions:

Despite an increase in number and quality, meta-analyses are at high risk of bias because of the low level of evidence of included primary studies and heterogeneity within and between primary studies. Plastic surgeons should be aware of the pitfalls of conducting and interpreting meta-analyses.
Facial Feminization for the Transgender Patient
Authors: Spiegel Jeffrey H.
Published: June 2019

This article provides an overview of the key concepts and techniques of facial feminization surgery. The author reviews 20 years of experience with thousands of patients.
An International Comparison of the Management of Gastrointestinal Surgical Emergencies in Octogenarians—England Versus United States
Authors: Markar Sheraz R. , Vidal-Diez Alberto , Holt Peter J. , Karthikesalingam Alan , Hanna George B.
Published: June 2019

Objective:

To compare the United States and England for the utilization of surgical intervention and in-hospital mortality from 5 gastrointestinal emergencies in octogenarians.

Background:

The proportion of older adults is growing and will represent a substantial challenge to clinicians in the next decade.

Methods:

Between 2006 and 2012, the rate of surgical intervention and in-hospital mortality for 5 index conditions for octogenarians were compared between the United States and England: appendicitis, incarcerated/strangulated abdominal hernia, perforation of esophagus, small or large bowel, and peptic ulcer. Univariate and multivariate analyses were performed to adjust for underlying differences in patient demographics.

Results:

Thirty-two thousand one hundred fifty-one admissions of octogenarians in England for 5 index surgical emergencies were compared with 162,142 admissions in the USA.

Surgical intervention was significantly more common in the USA than in England for all 5 conditions: appendicitis [odds ratio (OR) 4.63, 95% confidence interval (95% CI) 4.21–5.09], abdominal hernia (OR 2.06, 95% CI 1.97–2.15), perforated esophagus (OR 1.71, 95% CI 1.31–2.24), small and large bowel perforation (OR 4.33, 95% CI 4.12–4.56), and peptic ulcer perforation (OR 4.63, 95% CI 4.27–5.02). In-hospital mortality was significantly more common in England than in the USA for all 5 conditions: appendicitis (OR 3.22, 95% CI 2.73–3.78), abdominal hernia (OR 3.49, 95% CI 3.29–3.70), perforated esophagus (OR 4.06, 95% CI 3.03–5.44), small and large bowel perforation (OR 6.97, 95% CI 6.60–7.37), and peptic ulcer perforation (OR 3.67, 95% CI 3.40–3.96).

Conclusion:

Surgery is used less commonly in England for emergency gastrointestinal conditions in octogenarians, which may be associated with a high rate of in-hospital mortality from these conditions compared with the USA.
Predicting Acute Pain After Surgery
Authors: Baca Quentin , Marti Florian , Poblete Beate , Gaudilliere Brice , Aghaeepour Nima , Angst Martin S.
Published: June 2019

Objectives:

To identify perioperative practice patterns that predictably impact postoperative pain.

Background:

Despite significant advances in perioperative medicine, a significant portion of patients still experience severe pain after major surgery. Postoperative pain is associated with serious adverse outcomes that are costly to patients and society.

Methods:

The presented analysis took advantage of a unique observational data set providing unprecedented detailed pharmacological information. The data were collected by PAIN OUT, a multinational registry project established by the European Commission to improve postoperative pain outcomes. A multivariate approach was used to derive and validate a model predictive of pain on postoperative day 1 (POD1) in 1008 patients undergoing back surgery.

Results:

The predictive and validated model was highly significant (P = 8.9E-15) and identified modifiable practice patterns. Importantly, the number of nonopioid analgesic drug classes administered during surgery predicted decreased pain on POD1. At least 2 different nonopioid analgesic drug classes (cyclooxygenase inhibitors, acetaminophen, nefopam, or metamizol) were required to provide meaningful pain relief (>30%). However, only a quarter of patients received at least 2 nonanalgesic drug classes during surgery. In addition, the use of very short-acting opioids predicted increased pain on POD1, suggesting room for improvement in the perioperative management of these patients. Although the model was highly significant, it only accounted for a relatively small fraction of the observed variance.

Conclusion:

The presented analysis offers detailed insight into current practice patterns and reveals modifications that can be implemented in today's clinical practice. Our results also suggest that parameters other than those currently studied are relevant for postoperative pain including biological and psychological variables.
Five-year Longitudinal Cohort Study of Reinterventions After Sleeve Gastrectomy and Roux-en-Y Gastric Bypass
Authors: Li Robert A. , Liu Liyan , Arterburn David , Coleman Karen J. , Courcoulas Anita P. , Fisher David , Haneuse Sebastien , Johnson Eric , Theis Mary Kay , Yoon Tae K. , Fisher Heidi , Fraser James R. , Herrinton Lisa J.
Published: June 2019

Objective:

To compare the long-term risks of reintervention following sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) in a large surgical cohort.

Background:

The use of SG has increased dramatically relative to RYGB for the treatment of obesity. However, long-term risks following SG compared with RYGB have not been adequately defined in a large population-based study.

Methods:

A retrospective longitudinal cohort study of all adult health-plan members undergoing SG or RYGB for obesity in a multistate integrated health care system from January 2005 through September 2015. The risks of nutritional, endoscopic, radiologic, and surgical reintervention as well as the overall risk of any reinterventions at 1, 3, and 5 years were identified using diagnosis and procedure codes from comprehensive electronic medical records.

Results:

The study included 15,319 patients who underwent SG and 19,954 patients who underwent RYGB with a follow-up of 79.2%. The overall risk of any reintervention at 5 years was 21.3% for SG and 28.3% for RYGB (P < 0.0001). After adjustment, SG was associated with fewer reinterventions through 5 years than RYGB (hazard ratio, 0.78; 95% confidence interval, 0.74–0.84). When comparing subcategories, SG also had a lower risk of nutritional, endoscopic, radiologic, and surgical reinterventions when examined versus RYGB. The findings for risks of reinterventions were consistent across clinical subgroups.

Conclusion:

SG has significantly lower risk of reintervention in all categories studied when compared with RYGB at 5-year follow-up. The long-term safety profile of LSG compared with RYGB should be an essential part of the discussion in patient-centered decision making when choosing between bariatric procedure options.
Frailty in Older Patients Undergoing Emergency Laparotomy
Authors: Parmar Kat L. , Law Jennifer , Carter Ben , Hewitt Jonathan , Boyle Jemma M. , Casey Patrick , Maitra Ishaan , Farrell Ian S. , Pearce Lyndsay , Moug Susan J.
Published: June 2019

Objective:

This study aimed to document the prevalence of frailty in older adults undergoing emergency laparotomy and to explore relationships between frailty and postoperative morbidity and mortality.

Summary Background Data:

The majority of adults undergoing emergency laparotomy are older adults (≥65 y) that carry the highest mortality. Improved understanding is urgently needed to allow development of targeted interventions.

Methods:

An observational multicenter (n=49) UK study was performed (March–June 2017). All older adults undergoing emergency laparotomy were included. Preoperative frailty score was calculated using the progressive Clinical Frailty Score (CFS): 1 (very fit) to 7 (severely frail). Primary outcome measures were the prevalence of frailty (CFS 5–7) and its association to mortality at 90 days postoperative. Secondary outcomes included 30-day mortality and morbidity, length of critical care, and overall hospital stay.

Results:

A total of 937 older adults underwent emergency laparotomy: frailty was present in 20%. Ninety-day mortality was 19.5%. After age and sex adjustment, the risk of 90-day mortality was directly associated with frailty: CFS 5 adjusted odds ratio (aOR) 3.18 [95% confidence interval (CI), 1.24–8.14] and CFS 6/7 aOR 6·10 (95% CI, 2.26–16.45) compared with CFS 1. Similar associations were found for 30-day mortality. Increasing frailty was also associated with increased risk of complications, length of Intensive Care Unit, and overall hospital stay.

Conclusions:

A fifth of older adults undergoing emergency laparotomy are frail. The presence of frailty is associated with greater risks of postoperative mortality and morbidity and is independent of age. Frailty scoring should be integrated into acute surgical assessment practice to aid decision-making and development of novel postoperative strategies.
Seasonal contrasts in individual consistency of oriental honey buzzards' migration
Authors: Sugasawa Shoko , Higuchi Hiroyoshi
Published: June 2019

Individual consistency in migration can shine light on the mechanisms of migration. Most studies have reported that birds are more consistent in the timing than in the routes or stopover sites during migration, but some specialist species showed the opposite patterns, being more consistent in spatial than temporal aspects of migration. One possible explanation for this contrast is that specialists rely on particular food or habitat resources, which restrict the migratory routes they can take, leading to high spatial consistency. If this is the case, the effect of specialist foraging should become apparent only when birds forage, instead of fasting and flying continuously. To test this effect, we analysed individual consistency in migration of the oriental honey buzzard (
Pernis ptilorhynchus
), a specialist raptor that feeds on honeybees and wasps, using a long-term tracking dataset. As honey buzzards make extended stopovers during which they forage in spring but not in autumn, the spatial consistency should be higher in spring than in autumn. Honey buzzards were highly consistent in both their migratory routes and stopover sites in Southeast Asia, but only during spring migration. Our results highlight an important link between species' migratory consistency and foraging ecology.
Molecular Profiles of Matched Primary and Metastatic Tumor Samples Support a Linear Evolutionary Model of Breast Cancer
Authors: Chen Runpu , Goodison Steve , Sun Yijun
Published: June 2019

The interpretation of accumulating genomic data with respect to tumor evolution and cancer progression requires integrated models. We developed a computational approach that enables the construction of disease progression models using static sample data. Application to breast cancer data revealed a linear, branching evolutionary model with two distinct trajectories for malignant progression. Here, we used the progression model as a foundation to investigate the relationships between matched primary and metastasis breast tumor samples. Mapping paired data onto the model confirmed that molecular breast cancer subtypes can shift during progression, and supported directional tumor evolution through luminal subtypes to increasingly malignant states. Cancer progression modeling through the analysis of available static samples represents a promising breakthrough. Further refinement of a roadmap of breast cancer progression will facilitate the development of improved cancer diagnostics, prognostics and targeted therapeutics.
Engineering the yeastSaccharomyces cerevisiaefor the production of L-(+)-ergothioneine
Authors: van der Hoek Steven A. , Darbani Behrooz , Zugaj Karolina E. , Prabhala Bala Krishna , Biron Mathias Bernfried , Randelovic Milica , Medina Jacqueline B. , Kell Douglas B. , Borodina Irina
Published: June 2019

L-(+)-Ergothioneine is an unusual, naturally occurring antioxidant nutraceutical that has been shown to help reduce cellular oxidative damage. Humans do not biosynthesise it, so can acquire it only from their diet; it exploits a specific transporter (SLC22A4) for its uptake. ERG is considered to be a nutraceutical and possible vitamin that is involved in the maintenance of health, and seems to be at too low a concentration in several diseasesin vivo. Ergothioneine is thus a potentially useful dietary supplement. Present methods of commercial production rely on extraction from natural sources or on chemical synthesis. Here we describe the engineering of the baker’s yeastSaccharomyces cerevisiaeto produce ergothioneine by fermentation in defined media. After integrating combinations of ERG biosynthetic pathways from different organisms, we screened yeast strains for their production of ERG. The highest-producing strain was also engineered with known ergothioneine transporters. The effect of amino acid supplementation of the medium was investigated and the nitrogen metabolism ofS. cerevisiaewas altered by knock-out ofTOR1 orYIH1. We also optimized the media composition using fractional factorial methods. Our optimal strategy led to a titer of 598 ± 18 mg/L ergothioneine in fed-batch culture in bioreactors. BecauseS. cerevisiaeis a GRAS (‘generally recognised as safe’) organism that is widely used for nutraceutical production, this work provides a promising process for the biosynthetic production of ERG.
The ciliary membrane of polarized epithelial cells stems from a midbody remnant-associated membrane patch with condensed nanodomains
Authors: Bernabé-Rubio Miguel , Bosch-Fortea Minerva , García Esther , de la Serna Jorge Bernardino , Alonso Miguel A.
Published: June 2019

The primary cilium is a specialized plasma membrane protrusion that harbors receptors involved in important signaling pathways. Despite its central role in regulating cellular behavior, the biogenesis of the primary cilium is not fully understood. In fact, the source of the ciliary membrane remains a mystery in cell types that assemble their primary cilium entirely at the cell surface, such as polarized renal epithelial cells. After cytokinesis, the remnant of the midbody of these cells moves to the center of the apical surface, where it licenses the centrosome for ciliogenesis through an unidentified mechanism. Here, to investigate the origin of the ciliary membrane and the role of the midbody remnant, we analyzed membrane compaction and lipid dynamics at the microscale and nanoscale in living renal epithelial MDCK cells. We found that a specialized patch made of condensed membranes with restricted lipid lateral mobility surrounds the midbody remnant. This patch accompanies the remnant on its journey towards the centrosome and, once the two structures have met, the remnant delivers part of membranes of the patch to build the ciliary membrane. In this way, we have determined the origin of the ciliary membrane and the contribution of the midbody remnant to primary cilium formation in cells whose primary cilium is assembled at the plasma membrane.
Clonal evaluation of early onset prostate cancer by expression profiling of ERG, SPINK1,ETV1, andETV4on whole mount radical prostatectomy tissue
Authors: Lu Zhichun , Williamson Sean R. , Carskadon Shannon , Arachchige Pavithra D. , Dhamdhere Gaury , Schultz Daniel S. , Stricker Hans , Peabody James O. , Jeong Wooju , Chitale Dhananjay , Bismar Tarek , Rogers Craig G. , Menon Mani , Gupta Nilesh S. , Palanisamy Nallasivam
Published: June 2019

Expression profiles of ETS related genes and SPINK1 in early onset prostate cancer have not been thoroughly explored. We retrieved 151 radical prostatectomy specimens from young men with prostate cancer (<55yrs) and characterized the expression of ERG, SPINK1,ETV1andETV4by dual immunohistochemistry and dual RNAin-situhybridization. Age, race, family history, preoperative prostate-specific antigen, biochemical recurrence and pathological variables using whole mount radical prostatectomy tissue were collected. 313 tumor nodules from 151 men including 68 (45%) Caucasians and 61 (40%) African Americans. Positive family history of prostate cancer was observed in 65 (43%) patients. Preoperative prostate-specific antigen ranged from 0.3 to 52.7 ng/ml (mean 7.04). Follow-up period ranged from 1 to 123.7 months (Mean 30.3). Biochemical recurrence was encountered in 8/151 (5%). ERG overexpression was observed in 85/151 (56%) cases, followed by SPINK1 in 61/151 (40%),ETV1in 9/149 (6%), andETV4in 4/141 (3%). There were 25/151 (17%) cases showing both ERG and SPINK1 overexpression within different regions of either the same tumor focus or different foci. Higher frequency of ERG overexpression was seen in younger patients (≤ 45 years old) (76% vs. 49%,p= 0.002213), Caucasian men (71% vs. 41%p= 0.000707), organ-confined tumors (64% vs. 33%,p= 0.00079), and tumors of Grade Groups 1 and 2 (62% vs. 26%,p= 0.008794). SPINK1 overexpression was more in African American men (68% vs. 26%,p= 0.00008), in tumors with high tumor volume (> 20%) and with anterior located tumors.ETV1andETV4demonstrated rare overexpression in these tumors, particularly in the higher-grade tumors. This study expands the knowledge of the clonal evolution of multifocal cancer in young patients and support differences in relation to racial background and genetics of prostate cancer.
Dual RNase and β-lactamase activity of a single enzyme encoded in most Archaea
Authors: Diene Seydina M. , Pinault Lucile , Armstrong Nicholas , Azza Said , Keshri Vivek , Khelaifia Saber , Chabrière Eric , Caetano-Anolles Gustavo , Rolain Jean-Marc , Pontarotti Pierre , Raoult Didier
Published: June 2019

β-lactams targeting the bacterial cell wall are not active on archaea. Here, we figure out that annotation of genes as β-lactamase in Archeae on the basis of homologous genes, initially annotated β-lactamases, is a remnant of the identification of the original activities of this group of enzymes, which in fact, have multiple functions including nuclease, ribonuclease, β-lactamase, or glyoxalase; which may specialized over time. We expressed a class B β-lactamase enzyme from Methanosarcina barkeri that digest penicillin G. Moreover, while a weak glyoxalase activity was detected, a significant ribonuclease activity on bacterial and synthetic RNAs was demonstrated. The β-lactamase activity was inhibited by a β-lactamase inhibitor (sulbactam), but its RNAse activity was not. This gene appears to has been transferred to the Flavobacteriaceae group including Elizabethkingia genus in which the expressed gene shows a more specialized activity toward resistance to tienanmicin but no glyoxalase activity. The expressed class C-like β-lactamase gene, also from Methanosarcina sp., shows also hydrolysis activity and was more closely related to DD-peptidase enzymes than known bacterial class C β-lactamases. Our findings highlight the requalification needness of annotated enzymes as β-lactamases and the specification overtime of multipotent enzymes in different ways in Archaea and bacteria.
Decoupling the effects of nutrition, age and behavioral caste on honey bee physiology and immunity
Authors: Corona Miguel , Branchiccela Belen , Madella Shayne , Chen Yanping , Evans Jay
Published: June 2019

Nutritional stress, and especially a dearth of pollen, is considered an important factor associated with honey bee colony losses. We used pollen-restricted colonies as a model to study the nutritional stress conditions experienced in colonies within intensively cultivated agricultural areas. This model was complemented by the establishment of an experimental design, which allowed us to uncouple the effect of nutrition, behavior and age in colonies of similar size and demography. We used this system to determine the effect of pollen restriction on workers’ behavioral development. Then, we analyzed the effect of nutritional stress, behavior and age on the expression of key physiological genes involved in the regulation of division of labor. Finally, we analyzed the effects of these variables on the expression of immune genes and the titers of honey bee viruses. Our results show that pollen restriction led to an increased number of precocious foragers and this behavioral transition was associated with important changes in the expression of nutritionally regulated physiological genes, immunity and viral titers.Vitellogenin (vg)andmajor royal jelly protein1 (mrjp1)were the most predictive markers of nutrition and behavior. The expression of immune genes was primarily affected by behavior, with higher levels in foragers. Deformed wing virus (DWV) titers were significantly affected by behavior and nutritional status, with higher titer in foragers and increased levels associated with pollen ingestion. Correlation analyses support the predominant effect of behavior on immunity and susceptibility to viral infection, revealing that both immune genes and DWV exhibited strong negative correlations with genes associated with nursing, but positive correlations with genes associated with foraging. Our results provide valuable insights into the physiological mechanisms by which nutritional stress induce precocious foraging and increased susceptibility to viral infections.
Night watch during REM sleep for the first-night effect
Authors: Tamaki Masako , Sasaki Yuka
Published: June 2019

We experience disturbed sleep in a new place, and this effect is known as the first-night effect (FNE) in sleep research. We previously demonstrated that the FNE was associated with a protective night-watch system during NREM sleep in one hemisphere, which is shown as interhemispheric asymmetry in sleep depth in the default-mode network (DMN), and interhemispheric asymmetry in increased vigilance to monitor external stimuli. The present study investigated whether rapid eye movement (REM) sleep exhibited a form similar to a night-watch system during NREM sleep. First, we tested whether theta activity, which is an index of the depth of REM sleep, showed interhemispheric asymmetry in association with the FNE, by source-localizing to the DMN. However, interhemispheric asymmetry in theta activity during REM sleep was not found in association with the FNE. Next, we tested whether vigilance, as measured by evoked brain responses to deviant sounds, was increased in one hemisphere and showed interhemispheric asymmetry in association with the FNE during REM sleep. Because vigilance is different between the phasic period where rapid eye movements occur and the tonic period where rapid eye movements do not occur during REM sleep, REM sleep was split into phasic and tonic periods for measurements of evoked brain responses. While the evoked brain responses are generally small during the phasic period without the FNE, we found that the evoked brain response was significantly augmented by the FNE during the phasic period. In contrast, the evoked brain response during the tonic period did not differ by the presence of the FNE. Interhemispheric asymmetry in brain responses was not found during the phasic or tonic periods. These results suggest that a night-watch system for the FNE appears as interhemispheric asymmetry in sleep depth and vigilance during NREM sleep, but it appears as increased vigilance in both hemispheres during the phasic period, when vigilance to external stimuli is generally reduced without the FNE, during REM sleep. Therefore, a night-watch system associated with the FNE may be subserved by different neural mechanisms during NREM and REM sleep.
Variance heterogeneity genome-wide mapping for cadmium in bread wheat reveals novel genomic loci and epistatic interactions
Authors: Hussain Waseem , Campbell Malachy , Jarquin Diego , Walia Harkamal , Morota Gota
Published: June 2019

Genome-wide association mapping identifies quantitative trait loci (QTL) that influence the mean differences between the marker genotypes for a given trait. While most loci influence the mean value of a trait, certain loci, known as variance heterogeneity QTL (vQTL) determine the variability of the trait instead of the mean trait value (mQTL). In the present study, we performed a variance heterogeneity genome-wide association study (vGWAS) for grain cadmium (Cd) concentration in bread wheat. We used double generalized linear model and hierarchical generalized linear model to identify vQTL associated with grain Cd. We identified novel vQTL regions on chromosomes 2A and 2B that contribute to the Cd variation and loci that affect both mean and variance heterogeneity (mvQTL) on chromosome 5A. In addition, our results demonstrated the presence of epistatic interactions between vQTL and mvQTL, which could explain variance heterogeneity. Overall, we provide novel insights into the genetic architecture of grain Cd concentration and report the first application of vGWAS in wheat. Moreover, our findings indicated that epistasis is an important mechanism underlying natural variation for grain Cd concentration.
Temporal quantitative proteomics of protein translation and phosphorylation in synaptic plasticity
Authors: van Gelder Charlotte AGH , Penning Renske , Catsburg Lisa , Hoogenraad Casper C , MacGillavry Harold D , Altelaar Maarten
Published: June 2019

At neuronal synapses, activation of metabotropic glutamate receptors (mGluR1/5) triggers a form of long-term depression (mGluR-LTD) that relies on new protein synthesis and the internalization of AMPA-type glutamate receptors. Dysregulation of these processes has been implicated in the development of mental disorders such as autism spectrum disorders and therefore merit a better understanding on a molecular level. Here, to study mGluR-LTD, we integrated quantitative high-resolution phosphoproteomics with the analyses of newly synthesized proteins via bio-orthogonal amino acids (azidohomoalanine) in a pulsed labeling strategy combined with tandem mass tag label-based quantification in cultured hippocampal neurons stimulated with DHPG. We identified several kinases with important roles in DHPG-mGluR-LTD, which we confirmed using small molecule kinase inhibitors. Furthermore, changes in the AMPA receptor endocytosis pathway in both protein synthesis and protein phosphorylation upon LTD were identified, whereby Intersectin-1 was validated as a vital player in this pathway. This study revealed several novel insights into the molecular mechanisms underlying mGluR-LTD and provides a broad view on its molecular basis, which serves as a rich resource for further analyses.
Neoproterozoic origin and multiple transitions to macroscopic growth in green seaweeds
Authors: Cortona Andrea Del , Jackson Christopher J. , Bucchini François , Van Bel Michiel , D’hondt Sofie , Škaloud Pavel , Delwiche Charles F. , Knoll Andrew H. , Raven John A. , Verbruggen Heroen , Vandepoele Klaas , De Clerck Olivier , Leliaert Frederik
Published: June 2019

The Neoproterozoic Era records the transition from a largely bacterial to a predominantly eukaryotic phototrophic world, creating the foundation for the complex benthic ecosystems that have sustained Metazoa from the Ediacaran Period onward. This study focusses on the evolutionary origins of green seaweeds, which play an important ecological role in the benthos of modern sunlit oceans and likely played a crucial part in the evolution of early animals by structuring benthic habitats and providing novel niches. By applying a phylogenomic approach, we resolve deep relationships of the core Chlorophyta (Ulvophyceae or green seaweeds, and freshwater or terrestrial Chlorophyceae and Trebouxiophyceae) and unveil a rapid radiation of Chlorophyceae and the principal lineages of the Ulvophyceae late in the Neoproterozoic Era. Our time-calibrated tree points to an origin and early diversification of green seaweeds in the late Tonian and Cryogenian periods, an interval marked by two global glaciations, with strong consequent changes in the amount of available marine benthic habitat. We hypothesize that the unicellular and simple multicellular ancestors of green seaweeds survived these extreme climate events in isolated refugia, and diversified following recolonization of benthic environments that became increasingly available as sea ice retreated. An increased supply of nutrients and biotic interactions such as grazing pressure has likely triggered the independent evolution of macroscopic growth via different strategies, including both true multicellularity, and multiple types of giant celled forms.

Significance Statement

Green seaweeds are important primary producers along coastlines worldwide, and likely played a key role in the evolution of animals. To understand their origin and diversification, we resolve key relationships among extant green algae using a phylotranscriptomic approach. We calibrate our tree using available fossil data, to reconstruct important evolutionary events such as transitions to benthic environments, and evolution of macroscopic growth. We estimate green seaweeds to have originated in the late Tonian/Cryogenian Period, followed by a marked Ordovician diversification of macroscopic forms. This ancient proliferation of green seaweeds likely modified shallow marine ecosystems, which set off an evolutionary arms race between ever larger seaweeds and grazers.
Targeting the Cx43 Carboxyl Terminal H2 Domain Preserves Left Ventricular Function Following Ischemia-Reperfusion Injury
Authors: Jiang Jingbo , Palatinus Joseph A. , He Huamei , Iyyathurai Jegan , Jourdan L. Jane , Hoagland Daniel , Bultynck Geert , Wang Zhen , Zhang Zhiwei , Schey Kevin , Poelzing Steven , McGowan Francis X. , Gourdie Robert G.
Published: June 2019

Background

αCT1 is a 25 amino acid therapeutic peptide incorporating the Zonula Occludens-1 (ZO-1)-binding domain of connexin43 (Cx43) that is currently in Phase III clinical testing for healing chronic skin wounds. In preclinical studies in mice, we reported that αCT1 reduces arrhythmias and improves ventricular function following cardiac injury, effects that were accompanied by increases in PKCε phosphorylation of Cx43 at serine 368 (pS368). In this study, we undertake a systematic characterization of the molecular mode-of-action of αCT1 in mitigating the effects of ischemia reperfusion injury on ventricular contractile function.

Methods and Results

To determine the basis of αCT1-mediated increases in pS368 we undertook tandem mass spectrometry of reactants in an in vitro assay of PKCε phosphorylation, identifying an interaction between negatively charged amino acids in the αCT1 Asp-Asp-Leu-Glu-Iso sequence and positively charged lysines (Lys345, Lys346) in a short α-helical sequence (H2) within the Cx43 CT domain. In silico modeling provided further support of the specificity of this interaction, leading us to conclude that αCT1 has potential to directly interact with both Cx43 and ZO-1. Using surface plasmon resonance, thermal shift and phosphorylation assays, we characterized a series of αCT1 variant peptides, identifying sequences competent to interact with either ZO-1 PDZ2 or the Cx43 CT, but with limited or no ability to bind both polypeptides. Based on this analysis, it was found that only those peptides competent to interact with Cx43, but not ZO-1 alone, resulted in increased pS368 phosphorylation in vitro and in vivo. Moreover, in a mouse model of global ischemia reperfusion injury we determined that pre-ischemic infusion only with those peptides competent to bind Cx43 preserved left ventricular (LV) contractile function following injury. Interestingly, a short 9 amino acid (MW=1110) Cx43-binding variant of the original 25 amino acid αCT1 sequence demonstrated potent LV-protecting effects when infused either before or after ischemic injury.

Conclusions

Interaction of αCT1 with the Cx43 CT, but not ZO-1 PDZ2, explains cardioprotection mediated by this therapeutic peptide. Pharmacophores targeting the Cx43 carboxyl terminus could provide a novel translational approach to preservation of ventricular function following ischemic injury.
Dynamic patterns of transcript abundance of transposable element families in maize
Authors: Anderson Sarah N , Stitzer Michelle C , Zhou Peng , Ross-Ibarra Jeffrey , Hirsch Cory D , Springer Nathan M
Published: June 2019

Transposable Elements (TEs) are mobile elements that contribute the majority of DNA sequences in the maize genome. Due to their repetitive nature, genomic studies of TEs are complicated by the difficulty of properly attributing multi-mapped short reads to specific genomic loci. Here, we utilize a method to attribute RNA-seq reads to TE families rather than particular loci in order to characterize transcript abundance for TE families in the maize genome. We applied this method to assess per-family expression of transposable elements in >800 published RNA-seq libraries representing a range of maize development, genotypes, and hybrids. While a relatively small proportion of TE families are transcribed, expression is highly dynamic with most families exhibiting tissue-specific expression. A large number of TE families were specifically detected in pollen and endosperm, consistent with reproductive dynamics that maintain silencing of TEs in the germ line. We find that B73 transcript abundance is a poor predictor of TE expression in other genotypes and that transcript levels can differ even for shared TEs. Finally, by assessing recombinant inbred line and hybrid transcriptomes, complex patterns of TE transcript abundance across genotypes emerged. Taken together, this study reveals a dynamic contribution of TEs to maize transcriptomes.
Cooperation mitigates diversity loss in a spatially expanding microbial population
Authors: Gandhi Saurabh , Korolev Kirill S. , Gore Jeff
Published: June 2019

The evolution and potentially even the survival of a spatially expanding population depends on its genetic diversity, which can decrease rapidly due to a serial founder effect. The strength of the founder effect is predicted to depend strongly on the details of the growth dynamics. Here, we probe this dependence experimentally using a single microbial species, Saccharomyces cerevisiae, expanding in multiple environments that induce varying levels of cooperativity during growth. We observe a drastic reduction in diversity during expansions when yeast grows non-cooperatively on simple sugars, but almost no loss of diversity when cooperation is required to digest complex metabolites. These results are consistent with theoretical expectations. When cells grow independently from each other, the expansion proceeds as a pulled wave driven by the growth at the low-density tip of the expansion front. Such populations lose diversity rapidly because of the strong genetic drift at the expansion edge. In contrast, diversity loss is substantially reduced in pushed waves that arise due to cooperative growth. In such expansions, the low-density tip of the front grows much more slowly and is often reseeded from the genetically diverse population core. Additionally, in both pulled and pushed expansions, we observe a few instances of abrupt changes in allele fractions due to rare fluctuations of the expansion front and show how to distinguish such rapid genetic drift from selective sweeps.

Significance statement

Spatially expanding populations lose genetic diversity rapidly because of the repeated bottlenecks formed at the front as a result of the serial founder effect. However, the rate of diversity loss depends on the specifics of the expanding population, such as its growth and dispersal dynamics. We have previously demonstrated that changing the amount of within-species cooperation leads to a qualitative transition in the nature of expansion from pulled (driven by migration at the low density tip) to pushed (driven by migration from the high density region at the front, but behind the tip). Here we demonstrate experimentally that pushed waves, which emerge in the presence of sufficiently strong cooperation, result in strongly reduced genetic drift during range expansions, thus preserving genetic diversity in the newly colonized region.
The somatic mutation landscape of the human body
Authors: García-Nieto Pablo E. , Morrison Ashby J. , Fraser Hunter B.
Published: June 2019

Somatic mutations in healthy tissues contribute to aging, neurodegeneration, and cancer initiation, yet remain largely uncharacterized. To gain a better understanding of their distribution and functional impacts, we leveraged the genomic information contained in the transcriptome to uniformly call somatic mutations from over 7,500 tissue samples, representing 36 distinct tissues. This catalog, containing over 280,000 mutations, revealed a wide diversity of tissuespecific mutation profiles associated with gene expression levels and chromatin states. We found pervasive negative selection acting on missense and nonsense mutations, except for mutations previously observed in cancer samples, which were under positive selection and were highly enriched in many healthy tissues. These findings reveal fundamental patterns of tissue-specific somatic evolution and shed light on aging and the earliest stages of tumorigenesis.
From plasmodesma geometry to effective symplasmic permeability through biophysical modelling
Authors: Deinum Eva E. , Mulder Bela M. , Benitez-Alfonso Yoselin
Published: June 2019

Regulation of molecular transport via intercellular channels called plasmodesmata (PDs) is important for both coordinating developmental and environmental responses among neighbouring cells, and isolating (groups of) cells to execute distinct programs. Cell-to-cell mobility of fluorescent molecules and PD dimensions (measured from electron micrographs) are both used as methods to predict PD transport capacity (i.e., effective symplasmic permeability), but often yield very different values. Here, we build a theoretical bridge between both experimental approaches by calculating the effective symplasmic permeability from a geometrical description of individual PDs and considering the flow towards them. We find that a dilated central region has the strongest impact in thick cell walls and that clustering of PDs into pit fields strongly reduces predicted permeabilities. Moreover, our open source multi-level model allows to predict PD dimensions matching measured permeabilities and add a functional interpretation to structural differences observed between PDs in different cell walls.
Population Genomics of GII.4 Noroviruses Reveal Complex Diversification and New Antigenic Sites Involved in the Emergence of Pandemic Strains
Authors: Tohma Kentaro , Lepore Cara J. , Gao Yamei , Ford-Siltz Lauren A. , Parra Gabriel I.
Published: June 2019

GII.4 noroviruses are a major cause of acute gastroenteritis. Their dominance has been partially explained by the continuous emergence of antigenically distinct variants. To gain insights on the mechanisms of viral emergence and population dynamics of GII.4 noroviruses, we performed large-scale genomics, structural, and mutational analyses of the viral capsid protein (VP1). GII.4 noroviruses exhibited a periodic replacement of predominant variants with accumulation of amino acid substitutions. Genomic analyses revealed (i) a large number (87%) of conserved residues; (ii) variable residues that map on the previously determined antigenic sites; and (iii) variable residues that map outside of the antigenic sites. Residues from the third pattern formed motifs on the surface of VP1, which suggested extensions of previously predicted and new uncharacterized antigenic sites. The role of two motifs (C and G) in the antigenic make-up of the GII.4 capsid protein was confirmed with monoclonal antibodies and carbohydrate blocking assays. Amino acid profiles from antigenic sites (A, C, D, E, and G) correlated with the circulation patterns of GII.4 variants, with two of them (C and G) containing residues (352, 357, 378) linked with the emergence of new GII.4 variants. Notably, the emergence of each variant was followed by a stochastic diversification with minimal changes at the antigenic sites that did not progress towards the next variant. This study provides a methodological framework for antigenic characterization of viruses, and expands our understanding of the dynamics of GII.4 noroviruses that could facilitate the design of cross-reactive vaccines.

Importance

Noroviruses are an important cause of viral gastroenteritis around the world. An obstacle delaying the development of norovirus vaccines is an inadequate understanding of the role of norovirus diversity in immunity. Using a population genomics approach, we identified new residues on the viral capsid protein (VP1) from GII.4 noroviruses, the predominant genotype, that appear to be involved in the emergence and antigenic topology of GII.4 variants. Careful monitoring of the substitutions in those residues involved in the diversification and emergence of new viruses could help in the early detection of future novel variants with pandemic potential. Therefore, this novel information on the antigenic diversification could facilitate GII.4 norovirus vaccine design.