bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrative Population and Physiological Genomics Reveals Mechanisms of Adaptation in Killifish
Authors: Brennan Reid S , Healy Timothy M , Bryant Heather J , La Van , Schulte Patricia M , Whitehead Andrew
Published: August 2018

Adaptive divergence between marine and freshwater (FW) environments is important in generating phyletic diversity within fishes, but the genetic basis of this process remains poorly understood. Genome selection scans can identify adaptive loci, but incomplete knowledge of genotype–phenotype connections makes interpreting their significance difficult. In contrast, association mapping (genome-wide association mapping [GWAS], random forest [RF] analyses) links genotype to phenotype, but offer limited insight into the evolutionary forces shaping variation. Here, we combined GWAS, RF, and selection scans to identify loci important in adaptation to FW environments. We utilized FW-native and brackish water (BW)-native populations of Atlantic killifish (Fundulus heteroclitus) as well as a naturally admixed population between the two. We measured morphology and multiple physiological traits that differ between populations and may contribute to osmotic adaptation (salinity tolerance, hypoxia tolerance, metabolic rate, body shape) and used a reduced representation approach for genome-wide genotyping. Our results show patterns of population divergence in physiological capabilities that are consistent with local adaptation. Population genomic scans between BW-native and FW-native populations identified genomic regions evolving by natural selection, whereas association mapping revealed loci that contribute to variation for each trait. There was substantial overlap in the genomic regions putatively under selection and loci associated with phenotypic traits, particularly for salinity tolerance, suggesting that these regions and genes are important for adaptive divergence between BW and FW environments. Together, these data provide insight into the mechanisms that enable diversification of fishes across osmotic boundaries.
Low-Dose Gamma Knife Radiosurgery for Acromegaly
Authors: Pai Fu-Yuan , Chen Ching-Jen , Wang Wen-Hsin , Yang Huai-Che , Lin Chung Jung , Wu Hsiu-Mei , Lin Yi-Chun , Chen Harn-Shen , Yen Yu-Shu , Chung Wen-Yuh , Guo Wan-Yuo , Pan David Hung-Chi , Shiau Cheng-Ying , Lee Cheng-Chia
Published: August 2018

Background

Remission rate is associated with higher dose of Gamma Knife Radiosurgery (GKRS; Gamma Knife: Elekta AB, Stockholm, Sweden) for acromegaly, but the dose ≥25 Gy is not always feasible when the functioning adenoma is close to optic apparatus

Objective

To evaluate the efficacy and safety of low-dose (<25 Gy) GKRS in the treatment of patients with acromegaly.

Methods

Single-center retrospective review of acromegaly cases treated with GKRS between June 1994 and December 2016. A total of 76 patients with the diagnosis of acromegaly who were treated with low-dose GKRS were selected for inclusion. Patients were treated with a median margin dose, isodose line, and treatment volume of 15.8 Gy, 57.5%, and 4.8 mL, respectively. Any identifiable portion of the optic apparatus was limited to a radiation dose of 10 Gy. All patients underwent full endocrine, ophthalmological, and imaging evaluation prior to and after GKRS treatments, and results of these were analyzed.

Results

Biochemical remission was achieved in 33 (43.4%) patients. Actuarial remission rates were 20.3%, 49.9%, and 76.3% at 4, 8, and 12 yr, respectively. Absence of cavernous sinus invasion (P = .042) and lower baseline insulin-like growth factor-1 levels (P = .019) were significant predictors of remission. New hormone deficiencies were found in 9 (11.8%) patients. Actuarial hormone deficiency rates were 3%, 14%, and 22.2% at 4, 8, and 10 yr, respectively. Two (2.6%) patients who achieved initial remission experienced recurrence. No optic complications were encountered.

CONCLUSION

Reasonable remission and new hormone deficiency rates can be achieved with low-dose GKRS for acromegaly. These rates may be comparable to those with standard GKRS margin doses.
Occipital Artery to Extradural Vertebral Artery Bypass for Posterior Circulation Ischemia
Authors: Wang Xuan , Tong Xiaoguang , Shi Minggang , Shang Yanguo , Wang Hu
Published: August 2018

BACKGROUND

Posterior circulation ischemic strokes can have devastating consequences, despite medical therapies. Extracranial–intracranial bypass for the augmentation of flow is a treatment option for selected patients with hemodynamic compromise and recurrent ischemia. However, posterior circulation bypass carries a higher risk and lower patency rate than bypass with anterior circulation.

OBJECTIVE

To present the occipital artery to the extradural vertebral artery (OA-eVA) bypass for posterior circulation ischemia.

METHODS

We retrospectively reviewed our experience of the OA-eVA bypass surgery in the treatment of bilateral vertebral steno-occlusive disease.

RESULTS

Seventeen patients were identified. Thirteen patients had bilateral vertebral artery (VA) occlusion (type I), while 4 patients had VA occlusion with contralateral VA severe stenosis (type II). All patients had cerebellar or pons infarction, for which the postoperative bypass patency rate was 100%, with carotid angiogram demonstrating excellent filling of the rostral basilar system or the posterior inferior cerebellar artery territory. The long-term follow-up outcome was favorable (modified Rankin score of 0-2) in 82% of patients (7 patients had complete resolution and 7 had improvement of symptoms) and unfavorable in 18%. One type II case without previous endovascular therapy developed recurrent ischemic onset associated with bypass occlusion.

CONCLUSION

OA-eVA bypass is a minimally invasive and effective alternative to posterior circulation ischemia. It provides sufficient blood flow augmentation to the vertebrobasilar territory. The advantages of this novel therapeutic strategy include avoiding performing craniotomy and deep bypass and achieving shorter operative times compared to conventional bypass surgery.
Political Staff and the Gendered Division of Political Labour in Canada
Authors: Snagovsky Feodor , Kerby Matthew
Published: August 2018

While there is considerable research on elected legislators in a variety of contexts, the academic knowledge about their advisors is very limited. This is surprising, given a considerable portion of work attributed to legislators is performed by political staff. Further, political advising increasingly serves as a training ground for future politicians in many professionalised legislatures. We use a mixed-methods approach to understand how the influence of men and women differs in political advising positions in the case of Canada’s House of Commons, and how this may affect women’s political ambition. We demonstrate while close to an equal number of men and women work for MPs in a political capacity on Parliament Hill, men continue to dominate legislative roles while women continue to dominate administrative roles. Further, legislative work increases political ambition, which means more men benefit from the socialising effects of legislative work than women.
The relationship between buildings and health: a systematic review
Authors: Ige Janet , Pilkington Paul , Orme Judy , Williams Ben , Prestwood Emily , Black D , Carmichael Laurence , Scally Gabriel
Published: August 2018

Background

The built environment exerts one of the strongest directly measurable effects on physical and mental health, yet the evidence base underpinning the design of healthy urban planning is not fully developed.

Method

This study provides a systematic review of quantitative studies assessing the impact of buildings on health. In total, 7127 studies were identified from a structured search of eight databases combined with manual searching for grey literature. Only quantitative studies conducted between January 2000 and November 2016 were eligible for inclusion. Studies were assessed using the quality assessment tool for quantitative studies.

Results

In total, 39 studies were included in this review. Findings showed consistently that housing refurbishment and modifications, provision of adequate heating, improvements to ventilation and water supply were associated with improved respiratory outcomes, quality of life and mental health. Prioritization of housing for vulnerable groups led to improved wellbeing. However, the quality of the underpinning evidence and lack of methodological rigour in most of the studies makes it difficult to draw causal links.

Conclusion

This review identified evidence to demonstrate the strong association between certain features of housing and wellbeing such as adequate heating and ventilation. Our findings highlight the need for strengthening of the evidence base in order for meaningful conclusions to be drawn.
High Humidity and Age-Dependent Fruit Susceptibility Promote Development of Trichothecium Black Spot on Apple
Authors: Dai Pengbo , Liang Xiaofei , Wang Yajing , Gleason Mark L. , Zhang Rong , Sun Guangyu
Published: August 2018

Fruit bagging is a widely used orchard practice in China. Trichothecium black spot (TBS) is a disease highly associated with the fruit bagging. In this study, we characterized in vitro factors affecting the causal agent, Trichothecium roseum, and TBS development and infection histology on field-bagged apple fruit in situ. Under in vitro conditions, conidial germination required exogenous nutrients, and the germination rate was significantly promoted by high humidity, a condition mimicking the bag microenvironment. Germ tubes penetrated fruit via natural openings including stomata, lenticels, and surface cracks. To determine the chronology of infection by T. roseum, ‘Fuji’ fruit were inoculated in the field at different developmental stages. The earliest infection occurred 60 days after full bloom (dafb), and disease incidence increased as fruit maturity advanced. At harvest time (165 dafb), lesions on more recently inoculated fruit (105 dafb, 150 dafb) were larger than lesions from fruit inoculated on earlier dates. Histological observation showed that infection of younger fruit elicited stronger host lignification responses restricting lesion development. Taken together, our results support the hypothesis that high humidity in sealed bags and increased susceptibility associated with advancing fruit maturity are key factors promoting T. roseum infection and TBS symptom development on bagged apple fruit.
Sensitivity of pituitary gonadotropes to hyperglycemia leads to epigenetic aberrations and reduced follicle‐stimulating hormone levels
Authors: Feldman Alona , Saleh Ayah , Pnueli Lilach , Qiao Sen , Shlomi Tomer , Boehm Ulrich , Melamed Philippa
Published: August 2018

The connection between metabolism and reproductive function is well recognized, and we hypothesized that the pituitary gonadotropes, which produce luteinizing hormone and follicle‐stimulating hormone (FSH), mediate some of the effects directly via insulin‐independent glucose transporters, which allow continued glucose metabolism during hyperglycemia. We found that glucose transporter 1 is the predominant glucose transporter in primary gonadotropes and a gonadotrope precursor–derived cell line, and both are responsive to culture in high glucose; moreover, metabolite levels were altered in the cell line. Several of the affected metabolites are cofactors for chromatin‐modifying enzymes, and in the gonadotrope precursor–derived cell line, we recorded global changes in histone acetylation and methylation, decreased DNA methylation, and increased hydroxymethylation, some of which did not revert to basal levels after cells were returned to normal glucose. Despite this weakening of epigenetic‐mediated repression seen in the model cell line, FSH β‐subunit (Fshb) mRNA levels in primary gonadotropes were significantly reduced, apparently due in part to increased autocrine/paracrine effects of inhibin. However, unlike thioredoxin interacting protein and inhibin subunit α, Fshb mRNA levels did not recover after the return of cells to normal glucose. The effect on Fshb expression was also seen in 2 hyperglycemic mouse models, and levels of circulating FSH, required for follicle growth and development, were reduced. Thus, hyperglycemia seems to target the pituitary gonadotropes directly, and the likely extensive epigenetic changes are sensed acutely by Fshb. This scenario would explain clinical findings in which, even after restoration of optimal blood glucose levels, fertility often remains adversely affected. However, the relative accessibility of the pituitary provides a possible target for treatment, particularly crucial in the young in which hyperglycemia is increasingly common and fertility most relevant.—Feldman, A., Saleh, A., Pnueli, L., Qiao, S., Shlomi, T., Boehm, U., Melamed, P. Sensitivity of pituitary gonadotropes to hyperglycemia leads to epigenetic aberrations and reduced follicle‐stimulating hormone levels. FASEB J. 33, 1020–1032 (2019). www.fasebj.org
Trends in Lumbar Fusion Procedure Rates and Associated Hospital Costs for Degenerative Spinal Diseases in the United States, 2004 to 2015
Authors: Martin Brook I. , Mirza Sohail K. , Spina Nicholas , Spiker William R. , Lawrence Brandon , Brodke Darrel S.
Published: August 2018

Study Design.

Analysis of National Inpatient Sample (NIS), 2004 to 2015.

Objective.

Describe recent trends in US rates of lumbar fusion procedures and associated costs, by surgical indication.

Summary of Background Data.

Spinal fusion is appropriate for spinal deformity and instability, but evidence of effectiveness is limited for primary disc herniation and spinal stenosis without instability. It remains controversial for treatment of axial pain secondary to degenerative disc disease. There are potential non-instability, non-deformity indications for fusion surgery, including but not limited to severe foraminal stenosis and third-time disc herniation.

Methods.

Elective lumber fusion trends were reported using Poisson regression, grouped by indication as degenerative scoliosis, degenerative spondylolisthesis, spinal stenosis, disc herniation, and disc degeneration. Generalize linear regression was used to estimate trends in hospital costs, adjusted for age, sex, indication, comorbidity, and inflation.

Results.

Volume of elective lumbar fusion increased 62.3% (or 32.1% per 100,000 US adults), from 122,679 cases (60.4 per 100,000) in 2004 to 199,140 (79.8 per 100,000) in 2015. Increases were greatest among age 65 or older, increasing 138.7% by volume (73.2% by rate), from 98.3 per 100,000 (95% confidence interval [CI] 97.2, 99.3) in 2004 to 170.3 (95% CI 169.2, 171.5) in 2015. Although the largest increases were for spondylolisthesis (+47,390 operations, 111%) and scoliosis (+16,129 operations, 186.6%), disc degeneration, herniation, and stenosis combined to accounted for 42.3% of total elective lumbar fusions in 2015. Aggregate hospital costs increased 177% during these 12 years, exceeding $10 billion in 2015, and averaging more than $50,000 per admission.

Conclusion.

While the prevalence of spinal pathologies is not known, the rate of elective lumbar fusion surgery in the United States increased most for spondylolisthesis and scoliosis, indications with relatively good evidence of effectiveness. The proportion of fusions coded for indications with less evidence of effectiveness has slightly decreased in the most recent years.

Level of Evidence: 3
Transcranial Doppler in the Diagnosis of Cerebral Vasospasm: An Updated Meta-Analysis
Authors: Mastantuono Jean-Mathieu , Combescure Christophe , Elia Nadia , Tramèr Martin R. , Lysakowski Christopher
Published: August 2018

Objectives:

To evaluate the performance of transcranial Doppler and transcranial color-coded duplex Doppler in patients with cerebral vasospasm due to aneurysm rupture. Angiography was considered as the gold standard comparator.

Data Sources:

Search in MEDLINE, Embase, and Central from January 2001 to October 2017, without language restriction. Bibliographies of retrieved articles were screened for additional studies.

Study Selection:

Randomized studies comparing transcranial Doppler or transcranial color-coded duplex Doppler with angiography in adults.

Data Extraction:

Data were extracted independently by several investigators. Sensitivity and specificity were combined across studies using a bivariate model. Preferred Reporting Items for Systematic Reviews and Meta-Analyses was used for reporting and Quality Assessment of Diagnostic Accuracy Studies-2 for quality assessment.

Data Synthesis:

We included 18 studies. Fifteen tested transcranial Doppler. For the middle cerebral artery (10 studies, 1,408 tests), the pooled sensitivity was 66.7% (95% CI, 55.9–75.9) and specificity was 89.5% (80.3–94.7). Three studies (278 tests) tested transcranial color-coded duplex Doppler for the middle cerebral artery. The pooled sensitivity was 81.5% (66.0–90.0), and specificity was 96.6% (93.0–98.0). For an arbitrarily chosen prevalence of vasospasm of 70%, positive and negative predictive values were 93.7% (88.9–96.6) and 53.4% (46.7–60.9) for transcranial Doppler and 98.2% (96.4–99.1) and 69.1% (56.1–80.9) for transcranial color-coded duplex Doppler.

Conclusions:

Assuming a high prevalence of vasospasm of the middle cerebral artery, both transcranial Doppler and transcranial color-coded duplex Doppler are likely to detect it, but neither is useful to exclude it. There is no convincing evidence that the accuracy of transcranial color-coded duplex Doppler is any better than that of transcranial Doppler. For arteries other than middle cerebral artery, there is a lack of evidence of the usefulness of transcranial Doppler.
Timing of Rotavirus Vaccine Doses and Severe Rotavirus Gastroenteritis Among Vaccinated Infants in Low- and Middle-income Countries
Authors: Gruber Joann F. , Becker-Dreps Sylvia , Hudgens Michael G. , Brookhart M. Alan , Thomas James C. , Jonsson Funk Michele
Published: August 2018

Background:

Altering rotavirus vaccine schedules may improve vaccine performance in low- and middle-income countries. We analyzed data from clinical trials of the monovalent (RV1) and pentavalent (RV5) rotavirus vaccines in low- and middle-income countries to understand the association between vaccine dose timing and severe rotavirus gastroenteritis incidence.

Methods:

We assessed the association between variations in rotavirus vaccine administration schedules and severe rotavirus gastroenteritis risk. We used the complement of the Kaplan–Meier survival estimator to estimate risk differences for different schedules. To adjust risk differences (RDs) for confounding, we calibrated estimates in the vaccinated arm using estimates from the placebo arm.

Results:

There were 3,114 and 7,341 children included from the RV1 and RV5 trials, respectively. The 18-month adjusted severe rotavirus gastroenteritis risk was 4.0% (95% confidence interval [CI] = 1.1, 7.1) higher for those receiving their first RV5 dose at <6 versus ≥6 weeks. For RV1, there was a 4.0% (95% CI = 0.0, 8.2) increase in 12-month adjusted risk for a 4- versus 6-week interval between doses. Further analysis revealed those receiving their first RV5 dose at 3–4 and 5–7 weeks had 2.9% (95% CI = 0.8, 5.3) and 1.3% (95% CI = −0.3, 3.0), respectively, higher risk compared with those at 9–12 weeks. Those receiving their first dose at 8 weeks had the lowest risk (RD: −2.6% [95% CI = −5.4, −0.1]) compared with those at 9–12 weeks.

Conclusions:

A modest delay in rotavirus vaccination start and increase in interval between doses may be associated with lower severe rotavirus gastroenteritis risk in low- and middle-income countries.
Age-related Changes in Globe Position
Authors: Shieh Alice C. , Blandford Alexander D. , Hwang Catherine J. , Perry Julian D.
Published: August 2018

Purpose:

To longitudinally evaluate for changes in globe position as part of the natural aging process.

Methods:

A Cleveland Clinic Foundation imaging database of all head imaging scans performed from 1995 to 2017 was used to identify adults with normal orbits undergoing imaging studies at least 20 years apart. A total of 100 patients (200 globes) who had CT or MRI scans were studied. Globe position was determined by measuring the distance from the anterior aspect of the cornea to the zygomaticofrontal processes baseline. Clinically significant changes in globe position were defined as changes of ≥2 mm posteriorly (enophthalmos) or anteriorly (exophthalmos).

Results:

On average, globe projection decreased by 0.25 ± 2.3 and 0.26 ± 2.2 mm in the right and left eyes, respectively. Clinically significant enophthalmos with age was measured in 55 (27.5%) globes in 35 (35%) individuals, while clinically significant exophthalmos with age was measured in 43 (21.5%) globes in 26 (26%) individuals. The proportion of cases that developed enophthalmos, exophthalmos, or experienced no change were not significantly different from each other (p = 0.26). No patients developed clinically significant enophthalmos in one eye and exophthalmos in the other.

Conclusions:

Adults may develop clinically significant enophthalmos, exophthalmos, or no change in globe position over a 20-year period. This lack of uniform change in globe position with age impacts surgical considerations for treatment of the aging periocular region.
Long-Term Continuous-Flow Left Ventricular Assist Device Support After Left Ventricular Outflow Tract Closure
Authors: Kurihara Chitaru , Cohn William E. , Kawabori Masashi , Sugiura Tadahisa , Civitello Andrew B. , Morgan Jeffrey A.
Published: August 2018

Aortic valve insufficiency can be addressed during continuous-flow left ventricular assist device (CF-LVAD) implantation by performing aortic valve repair or replacement, or patch closure of the left ventricular outflow tract (LVOT). However, few studies have examined the safety of long-term CF-LVAD support after LVOT closure. From November 2003 through March 2016, 16 patients with advanced chronic heart failure underwent CF-LVAD implantation and concomitant LVOT closure for severe aortic insufficiency. We compared their long-term outcomes with those of 510 CF-LVAD recipients without concomitant LVOT closure. Total support time was 26.1 patient-years in the LVOT-closure group and 938.6 patient-years in the CF-LVAD–only group. Survival at 30 days, 6 months, 1 year, and 2 years was similar for CF-LVAD–only patients (90.4%, 80.6%, 74.3%, 67.5%) and LVOT-closure patients (81.3%, 81.3%, 75.0%, 68.8%; p = 0.59). There were no deaths related to LVOT closure. The event rate per patient-year for neurologic dysfunction (ND) was 0.23 in the LVOT-closure group (6 ND events) and 0.20 in the CF-LVAD–only group (136 ND events; p = 0.97). We conclude that for select patients with aortic insufficiency who are undergoing CF-LVAD implantation, LVOT closure produces acceptable outcomes and, therefore, is a viable option.
The Importance of Distinguishing Menstrual and Peripheral Blood in Forensic Casework
Authors: Tozzo Pamela , Nespeca Patrizia , Spigarolo Gloria , Caenazzo Luciana
Published: August 2018

This report presents a case of an 18-year-old woman found unconscious by police officers outside a club suspected to be victim of a sexual assault. She was not able to give information about the dynamics of the assault, since she was under the effect of a high amount of alcohol. She affirmed to be virgin.

The forensic genetic analyses were performed on vaginal and rectal swabs as well as bloody-like traces present on the slip. DNA and RNA analysis were performed using a multiplex for 15 autosomal short tandem repeat markers and of 19 primers specific for different tissues, respectively.

No male DNA was identified on vaginal and rectal swabs and on blood spots on the underwear. Blood, vaginal, and skin markers were scored observed in the samples obtained from slip traces and vaginal swab.

The forensic genetic analysis supports the proposition that the victim had a sexual intercourse, in the absence of male biological material, in a case where the victim, altered by high blood alcohol levels, was unable to provide information.
Complications After Scalp Suturing Posttraumatic Avulsion
Authors: Fijałkowska Marta , Antoszewski Bogusław
Published: August 2018

Scalp avulsion is a rare but severe trauma. Most cases of this injury happened as a result of hair entrapment in a high-speed rotating machine. Treatment of scalp avulsion can be challenging. Nowadays, microsurgical scalp replantation has become the treatment of choice. However, there are situations in which replantation or even usage of scalp as composite grafts is not possible. The aim of this paper is to present 2 cases of scalp avulsion, which needed split-thickness skin graft for covering posttraumatic scalp loss. Closing large scalp defects after its avulsion by skin graft is still a viable option, especially when replantation and even usage of scalp as a composite graft is not achievable. Scalp shaving is mandatory before any surgical procedures.
Laparoscopy in Crohn Disease
Authors: Mege Diane , Michelassi Fabrizio
Published: August 2018

Objective:

To identify preoperative characteristics to help in selecting laparoscopy or laparotomy in Crohn disease (CD).

Summary Background:

Laparoscopy in CD is associated with high rates of conversion.

Methods:

All patients undergoing abdominal surgery for CD in 2004 to 2016 by the senior author. Patients operated by laparoscopy, laparotomy, and converted to open were compared.

Results:

Four hundred fifty-eight procedures were performed in 427 patients [F:M 1:1; median age = 41 (12–95) yrs], through laparotomy (n = 157, 34%) or laparoscopy (n = 301, 66%). Laparotomy rates decreased over time. Concomitant surgical procedures requiring laparotomy continued to dictate an open approach throughout the study. Sixty-five cases (21.6%) required conversion to laparotomy which occurred within 15’ from start of case in 77%. Most common reasons for conversion included dense adhesions (34%), pelvic sepsis with fistulizing disease (26%), large inflammatory mass (18%), and thickened mesentery (9%). After multivariate analysis, predictive factors for conversion included recurrent disease after previous small bowel resection, thickened mesentery, large inflammatory mass, and extensive disease.

Conclusion:

Despite the increasing experience with laparoscopy in CD, one-fifth of selected cases still need conversion. Recurrent disease with dense adhesions, pelvic sepsis with fistulizing disease, large inflammatory mass, and thickened mesentery are all conditions predisposing to a conversion. When the severity of these conditions is known preoperatively or a simultaneous procedure requires a laparotomy, an open approach should be considered; if laparoscopy is selected, conversion to laparotomy can be decided early in the performance of the case.
The Strain Ratio as Obtained by Endoscopic Ultrasonography Elastography Correlates With the Stroma Proportion and the Prognosis of Local Pancreatic Cancer
Authors: Shi Si , Liang Chen , Xu Jin , Meng Qingcai , Hua Jie , Yang Xiujiang , Ni Quanxing , Yu Xianjun
Published: August 2018

Objective:

The aim of this study was to investigate the association of the strain ratio (SR) with clinicopathologic features and the prognostic value of the SR in local pancreatic cancer.

Background:

The SR as obtained by endoscopic ultrasonography elastography is useful in the differential diagnosis of pancreatic diseases. However, its role in the prognostic prediction of pancreatic cancer remains unknown.

Methods:

A total of 78 resected pancreatic cancer patients and 93 locally advanced pancreatic cancer (LAPC) patients were enrolled in this study according to the inclusion criteria. Masson trichrome staining was used to evaluate the stromal proportion. Survival rates were calculated according to the Kaplan–Meier method and were compared using the log rank test. Multivariate analysis was performed with a Cox regression model.

Results:

The SR was positively associated with the stromal proportion of resected pancreatic cancer (R = 0.768, P < 0.001). High SR was more likely in males (P = 0.039) and was related to perineural invasion (P = 0.022). High SR predicted unfavorable overall survival (OS) relative to low SR (15.4 vs. 25.8 mo, P = 0.017). SR was confirmed as an independent prognostic factor for resected pancreatic cancer based on multivariate analysis (hazard ratio = 1.939, P = 0.020). For LAPC patients who received nab-paclitaxel and gemcitabine, high SR was associated with improved prognosis (OS: 14.9 vs. 11.6 mo, P = 0.045), but this positive association was not observed in patients treated with other gemcitabine-based regimens (OS: 10.7 vs. 12.4 mo, P = 0.478).

Conclusions:

A high SR as obtained by endoscopic ultrasonography elastography was associated with poor prognosis of resected pancreatic cancer but predicted improved survival for LAPC patients treated with the nab-paclitaxel and gemcitabine regimen.
CryoEM structures of MDA5-dsRNA filaments at different stages of ATP hydrolysis
Authors: Yu Qin , Qu Kun , Modis Yorgo
Published: August 2018

Double-stranded RNA (dsRNA) is a potent proinflammatory signature of viral infection. Long cytosolic dsRNA is recognized by MDA5. The cooperative assembly of MDA5 into helical filaments on dsRNA nucleates the assembly of a multiprotein type-I-interferon signaling platform. Here, we determined cryoEM structures of MDA5-dsRNA filaments with different helical twists and bound nucleotide analogs, at resolutions sufficient to build and refine atomic models. The structures identify the filament forming interfaces, which encode the dsRNA binding cooperativity and length specificity of MDA5. The predominantly hydrophobic interface contacts confer flexibility, reflected in the variable helical twist within filaments. Mutation of filament-forming residues can result in loss or gain of signaling activity. Each MDA5 molecule spans 14 or 15 RNA base pairs, depending on the twist. Variations in twist also correlate with variations in the occupancy and type of nucleotide in the active site, providing insights on how ATP hydrolysis contributes to MDA5-dsRNA recognition.

eTOC

Structures of MDA5 bound to double-stranded RNA reveal a flexible, predominantly hydrophobic filament forming interface. The filaments have variable helical twist. Structures determined with ATP and transition state analogs show how the ATPase cycle is coupled to changes in helical twist, the mode of RNA binding and the length of the RNA footprint of MDA5.

Highlights

CryoEM structures of MDA5-dsRNA filaments determined for three catalytic states

Filament forming interfaces are flexible and predominantly hydrophobic

Mutation of filament-forming residues can cause loss or gain of IFN-β signaling

ATPase cycle is coupled to changes in filament twist and size of the RNA footprint
Physicochemical amino acid properties better describe substitution rates in large populations
Authors: Weber Claudia C. , Whelan Simon
Published: August 2018

Substitutions between chemically distant amino acids are known to occur less frequently than those between more similar amino acids. This knowledge, however, is not reflected in most codon substitution models, which treat all non-synonymous changes as if they were equivalent in terms of impact on the protein. A variety of methods for integrating chemical distances into models have been proposed, with a common approach being to divide substitutions into radical or conservative categories. Nevertheless, it remains unclear whether the resulting models describe sequence evolution better than their simpler counterparts.

We propose a parametric codon model that distinguishes between radical and conservative substitutions, allowing us to assess if radical substitutions are preferentially removed by selection. Applying our new model to a range of phylogenomic data, we find differentiating between radical and conservative substitutions provides significantly better fit for large populations, but see no equivalent improvement for smaller populations. Comparing codon- and amino acid models using these same data shows that alignments from large populations tend to select phylogenetic models containing information about amino acid exchangeabilities, whereas the structure of the genetic code is more important for smaller populations.

Our results suggest selection against radical substitutions is, on average, more pronounced in large populations than smaller ones. The reduced observable effect of selection in smaller populations may be due to stronger genetic drift making it more challenging to detect preferences. Our results imply an important connection between the life history of a phylogenetic group and the model that best describes its evolution.
Unique morphogenetic signatures define mammalian neck muscles and associated connective tissues
Authors: Heude Eglantine , Tesarova Marketa , Sefton Elizabeth M. , Jullian Estelle , Adachi Noritaka , Grimaldi Alexandre , Zikmund Tomas , Kaiser Jozef , Kardon Gabrielle , Kelly Robert G. , Tajbakhsh Shahragim
Published: August 2018

In vertebrates, head and trunk muscles develop from different mesodermal populations and are regulated by distinct genetic networks. Neck muscles at the head-trunk interface remain poorly defined due to their complex morphogenesis and dual mesodermal origins. Here, we use genetically modified mice to establish a 3D model that integrates regulatory genes, cell populations and morphogenetic events that define this transition zone. We show that the evolutionary conserved cucullaris-derived muscles originate from posterior cardiopharyngeal mesoderm, not lateral plate mesoderm, and we define new boundaries for neural crest and mesodermal contributions to neck connective tissue. Furthermore, lineage studies and functional analysis ofTbx1-andPax3-null mice reveal a unique genetic program for somitic neck muscles that is distinct from that of somitic trunk muscles. Our findings unveil the embryological and developmental requirements underlying tetrapod neck myogenesis and provide a blueprint to investigate how muscle subsets are selectively affected in some human myopathies.
Population size history from short genomic scaffolds: how short is too short?
Authors: Gower Graham , Tuke Jono , Rohrlach AB , Soubrier Julien , Llamas Bastien , Bean Nigel , Cooper Alan
Published: August 2018

The Pairwise Sequentially Markov Coalescent (PSMC), and its extension PSMC′, model past population sizes from a single diploid genome. Both models have been widely applied, even to organisms with scaffold-level genome reference assemblies of limited contiguity. However it is unclear how PSMC and PSMC′ perform on short scaffolds. We evaluatedpsmcandmsmc, implementations of the PSMC and PSMC′ models respectively, on simulated genomes with low contiguity, and compared results to those from fully contiguous data. Simulations with scaffolds from 100 Mb to 10 kb revealed thatpsmcmaintains high accuracy down to lengths of 100 kb, whilemsmcis accurate down to 1 Mb. The discrepancy is not due to differing models, but stems from an implementation detail ofmsmc—homozygous tracts at the ends of scaffolds are discarded, makingmsmcunreliable for low contiguity genomes. We recommend excluding data that are aligned to shorter scaffolds when undertaking demographic inference.
Resolving Filament Level Mechanics in Collagen Networks using Activity Microscopy
Authors: Lissek Emanuel N. , Bartsch Tobias F. , Florin Ernst-Ludwig
Published: August 2018

Collagen is the most abundant protein in humans and the primary component of the extracellular matrix, a meshwork of biopolymer networks, which provides structure and integrity to tissues. Its mechanical properties profoundly influence the fate of cells. The cell-matrix interaction, however, is not well understood due to a lack of experimental techniques to study the mechanical interplay between cells and their local environment. Here we introduce Activity Microscopy, a new way to visualize local network mechanics with single filament resolution. Using collagen I networksin vitro, we localize fibril positions in two-dimensional slices through the network with nanometer precision and quantify the fibrils’ transverse thermal fluctuations with megahertz bandwidth. Using a fibril’s thermal fluctuations as an indicator for its tension, we find a heterogeneous stress distribution, where “cold” fibrils with small thermal fluctuations surround regions of highly fluctuating “hot” fibrils. We seed HeLa cells into collagen networks and quantify the anisotropy in the propagation of their forces.
Failure to learn during roving, analysing the unsupervised bias hypothesis
Authors: Higgins David , Herzog Michael
Published: August 2018

We examine the unsupervised bias hypothesis [11] as an explanation for failure to learn two bisection tasks, when task sequencing is randomly alternating (roving). This hypothesis is based on the idea that a covariance based synaptic plasticity rule, which is modulated by a reward signal, can be biased when reward is averaged across multiple tasks of differing difficulties. We find that, in our hands, the hypothesis in its original form can never explain roving. This drives us to develop an extended mathematical analysis, which demonstrates not one but two forms of unsupervised bias. One form interacts with overlapping task representations and the other does not. We find that overlapping task representations are much more susceptible to unsupervised biases than non-overlapping representations. Biases from non-overlapping representations are more likely to stabilise learning. But this in turn is incompatible with the experimental understanding of perceptual learning and task representation, in bisection tasks. Finally, we turn to alternative network encodings and find that they also are unlikely to explain failure to learn during task roving as a result of unsupervised biases. As a solution, we present a single critic hypothesis, which is consistent with recent literature and could explain roving by a, much simpler, certainty normalised reward signalling mechanism.
Reaction times and other skewed distributions: problems with the mean and the median
Authors: Rousselet Guillaume A. , Wilcox Rand R.
Published: August 2018

To summarise skewed (asymmetric) distributions, such as reaction times, typically the mean or the median are used as measures of central tendency. Using the mean might seem surprising, given that it provides a poor measure of central tendency for skewed distributions, whereas the median provides a better indication of the location of the bulk of the observations. However, the sample median is biased: with small sample sizes, it tends to overestimate the population median. This is not the case for the mean. Based on this observation, Miller (1988) concluded that “sample medians must not be used to compare reaction times across experimental conditions when there are unequal numbers of trials in the conditions.” Here we replicate and extend Miller (1988), and demonstrate that his conclusion was ill-advised for several reasons. First, the median’s bias can be corrected using a percentile bootstrap bias correction. Second, a careful examination of the sampling distributions reveals that the sample median is median unbiased, whereas the mean is median biased when dealing with skewed distributions. That is, on average the sample mean estimates the population mean, but typically this is not the case. In addition, simulations of false and true positives in various situations show that no method dominates. Crucially, neither the mean nor the median are sufficient or even necessary to compare skewed distributions. Different questions require different methods and it would be unwise to use the mean or the median in all situations. Better tools are available to get a deeper understanding of how distributions differ: we illustrate a powerful alternative that relies on quantile estimation. All the code and data to reproduce the figures and analyses in the article are available online.
Pooled optical screens in human cells
Authors: Feldman David , Singh Avtar , Schmid-Burgk Jonathan L. , Mezger Anja , Garrity Anthony J. , Carlson Rebecca J. , Zhang Feng , Blainey Paul C.
Published: August 2018

Large-scale genetic screens play a key role in the systematic discovery of genes underlying cellular phenotypes. Pooling of genetic perturbations greatly increases screening throughput, but has so far been limited to screens of enrichments defined by cell fitness and flow cytometry, or to comparatively low-throughput single cell gene expression profiles. Although microscopy is a rich source of spatial and temporal information about mammalian cells, high-content imaging screens have been restricted to much less efficient arrayed formats. Here, we introduce an optical method to link perturbations and their phenotypic outcomes at the singlecell level in a pooled setting. Barcoded perturbations are read out by targetedin situsequencing following image-based phenotyping. We apply this technology to screen a focused set of 952 genes across >3 million cells for involvement in NF-κB activation by imaging the translocation of RelA (p65) to the nucleus, recovering 20 known pathway components and 3 novel candidate positive regulators of IL-1β and TNFα-stimulated immune responses.
FACT activity and histone H3-K56 acetylation promote optimal establishment of chromatin architecture independent of ongoing transcription inSaccharomyces cerevisiae
Authors: McCullough Laura , Pham Trang H. , Parnell Timothy J. , Chandrasekharan Mahesh B. , Stillman David J. , Formosa Tim
Published: August 2018

FACT is a histone chaperone that can destabilize or assemble nucleosomes. Acetylation of histone H3-K56 weakens a histone:DNA contact that is central to FACT activity, suggesting that this modification could affect FACT functions. We tested this by asking how mutations of H3-K56 and FACT affect nucleosome structure, chromatin integrity, and transcription output. Mimics of unacetylated or permanently acetylated H3-K56 had different effects on FACTin vitroandin vivoas expected, but H3-K56 and FACT mutations caused surprisingly similar changes in transcription of individual genes. Notably, neither the changes in transcript levels nor the effects on nucleosome occupancy resulting from mutations conformed to the model that FACT is needed to overcome nucleosomal barriers during transcription initiation or elongation. Instead, the results suggest that both FACT and H3-K56ac are involved in establishing chromatin architecture prior to transcription and restoring it afterwards. They contribute to a process that optimizes transcription frequency, especially at conditionally expressed genes, and restores chromatin integrity after transcription, especially at the +1 nucleosome to block antisense transcription, but FACT appears to be less involved than expected in directly promoting transcription.
Standardized biogeographic grouping system for annotating populations in pharmacogenetic research
Authors: Huddart Rachel , Fohner Alison E. , Whirl-Carrillo Michelle , Wojcik Genevieve L. , Gignoux Christopher R. , Popejoy Alice B. , Bustamante Carlos D. , Altman Russ B. , Klein Teri E.
Published: August 2018

The varying frequencies of pharmacogenetic alleles between populations have important implications for the impact of these alleles in different populations. Current population grouping methods to communicate these patterns are insufficient as they are inconsistent and fail to reflect the global distribution of genetic variability. To facilitate and standardize the reporting of variability in pharmacogenetic allele frequencies, we present seven geographically-defined groups: American, Central/South Asian, East Asian, European, Near Eastern, Oceanian, and Sub-Saharan African, and two admixed groups: African American/Afro-Caribbean and Latino. These nine groups are defined by global autosomal genetic structure and based on data from large-scale sequencing initiatives. We recognize that broadly grouping global populations is an oversimplification of human diversity and does not capture complex social and cultural identity. However, these groups meet a key need in pharmacogenetics research by enabling consistent communication of the scale of variability in global allele frequencies and are now used by PharmGKB.
Individuals with ventromedial frontal damage have more unstable but still fundamentally transitive preferences
Authors: Yu Linda Q. , Dana Jason , Kable Joseph W.
Published: August 2018

The ventromedial frontal lobes (VMF) are important for decision-making, but the precise causal role of the VMF in the decision process has not yet fully been established. Previous studies have suggested that individuals with VMF damage violate transitivity, a hallmark axiom of rational decisions. However, these prior studies cannot properly distinguish whether individuals with VMF damage are truly prone to choosing irrationally from whether their preferences are simply more variable. We had individuals with focal VMF damage, individuals with other frontal damage, and healthy controls make repeated choices across three categories – artwork, chocolate bar brands, and gambles. Using sophisticated tests of transitivity, we find that, without exception, individuals with VMF damage make rational decisions consistent with transitive preferences, even though they exhibit greater variability in their preferences. That is, the VMF is necessary for having strong and reliable preferences, but not for being a rational decision maker. VMF damage affects the noisiness with which value is assessed, but not the consistency with which value is sought.
Evolutionary proteomics reveals distinct patterns of complexity and divergence between Lepidopteran sperm morphs
Authors: Whittington Emma , Karr Tim , Mongue Andrew J. , Dorus Steve , Walters James R.
Published: August 2018

Spermatozoa are one of the most strikingly diverse animal cell types. One poorly understood example of this diversity is sperm heteromorphism, where males produce multiple distinct morphs of sperm in a single ejaculate. Typically, only one morph is capable of fertilization and the function of the non-fertilizing morph, called parasperm, remains to be elucidated. Sperm heteromorphism has multiple independent origins, including Lepidoptera (moths and butterflies), where males produce a fertilizing eupyrene sperm and an apyrene parasperm, which lacks a nucleus and nuclear DNA. Here we report a comparative proteomic analysis of eupyrene and apyrene sperm between two distantly related lepidopteran species, the monarch butterfly (Danausplexippus) and Carolina sphinx month (Manduca sexta). In both species, we identified approximatey 700 sperm proteins, with half present in both morphs and the majority of the remainder specific to eupyrene sperm. Apyrene sperm thus have a distinctly less complex proteome. Gene Ontology (GO) analysis revealed proteins shared between morphs tend to be associated with canonical sperm cell structures (e.g. flagellum) and metabolism (e.g. ATP production). GO terms for morph-specific proteins broadly reflect known structural differences, but also suggest a role for apyrene sperm in modulating female neurobiology. Comparative analysis indicates that proteins shared between morphs are most conserved between species as components of sperm, while morph-specific proteins turn over more quickly, especially in apyrene sperm. The rapid divergence of apyrene sperm content is consistent with a relaxation of selective constraints associated with fertilization and karyogamy. On the other hand, parasperm exhibit greater evolutionary lability, which may reflect adaptive response to shifting regimes of sexual selection. Additionally, we provide the first (to our knowledge) scanning electron micrographs of lepidopteran sperm.