bluuebunny/crossref_metadata_2025 huggingface dataset:
Hemoglobin at High Altitude as Related to Age
Authors: Dill D B , Terman J W , Hall F G
Published: January 2020

During the summer of 1962 the early phase of acclimatization to high altitude was studied in 6 of those who participated in the international high-altitude expedition to Chile in 1935. Ages of the 6 ranged from 58 to 71. Two also had taken part in a high-altitude study in 1929. In their earlier years these subjects had had an increase in hemoglobin concentration beginning with their arrival at high altitude. This response has been well established, especially by the Pike's Peak party led by Haldane and the work of Hurtado and associates in Peru. On the other hand, 5 of the 6 in the 1962 party exhibited a decrease in hemoglobin concentration during the first few days. The greatest decrease was observed in the oldest subject. His hemoglobin was 88% of his sea level value after 9 days at altitude and remained below his sea level value for another week. No observations were made on blood volume; hence, we can only speculate regarding possible related changes.
High-Temperature Operation of Oxygen Electrode Giving Fast Response for Respiratory Gas Sampling
Authors: Severinghaus John W
Published: January 2020

The 98% response time of the membrane-covered Clark-type polarographic oxygen electrode may be reduced to 0.4 sec. by heating the electrode and the gas sample flowing past it to 80° when the electrode is covered with 0.25-mil (6 µ) Teflon membrane. The design of the microcathode electrode has been modified slightly to prevent drying out of the electrolyte and pressure changes within the electrolyte cavity. The relationship of output current to temperature approaches a plateau at this temperature which suggests that for reasonably accurate operation, temperature regulation may not be as crucial as it is at body temperature.
Genetic lineage tracing reveals poor angiogenic potential of cardiac endothelial cells
Authors: Kocijan Tea , Rehman Michael , Colliva Andrea , Groppa Elena , Leban Matteo , Vodret Simone , Volf Nina , Zucca Gabriele , Cappelletto Ambra , Piperno Giulia Maria , Zentilin Lorena , Giacca Mauro , Benvenuti Federica , Zhou Bin , Adams Ralf H , Zacchigna Serena
Published: January 2020

Aims

Cardiac ischaemia does not elicit an efficient angiogenic response. Indeed, lack of surgical revascularization upon myocardial infarction results in cardiomyocyte death, scarring, and loss of contractile function. Clinical trials aimed at inducing therapeutic revascularization through the delivery of pro-angiogenic molecules after cardiac ischaemia have invariably failed, suggesting that endothelial cells in the heart cannot mount an efficient angiogenic response. To understand why the heart is a poorly angiogenic environment, here we compare the angiogenic response of the cardiac and skeletal muscle using a lineage tracing approach to genetically label sprouting endothelial cells.

Methods and results

We observed that overexpression of the vascular endothelial growth factor in the skeletal muscle potently stimulated angiogenesis, resulting in the formation of a massive number of new capillaries and arterioles. In contrast, response to the same dose of the same factor in the heart was blunted and consisted in a modest increase in the number of new arterioles. By using Apelin-CreER mice to genetically label sprouting endothelial cells we observed that different pro-angiogenic stimuli activated Apelin expression in both muscle types to a similar extent, however, only in the skeletal muscle, these cells were able to sprout, form elongated vascular tubes activating Notch signalling, and became incorporated into arteries. In the heart, Apelin-positive cells transiently persisted and failed to give rise to new vessels. When we implanted cancer cells in different organs, the abortive angiogenic response in the heart resulted in a reduced expansion of the tumour mass.

Conclusion

Our genetic lineage tracing indicates that cardiac endothelial cells activate Apelin expression in response to pro-angiogenic stimuli but, different from those of the skeletal muscle, fail to proliferate and form mature and structured vessels. The poor angiogenic potential of the heart is associated with reduced tumour angiogenesis and growth of cancer cells.
MMP inhibitors attenuate doxorubicin cardiotoxicity by preventing intracellular and extracellular matrix remodelling
Authors: Chan Brandon Y H , Roczkowsky Andrej , Cho Woo Jung , Poirier Mathieu , Sergi Consolato , Keschrumrus Vic , Churko Jared M , Granzier Henk , Schulz Richard
Published: January 2020

Aims

Heart failure is a major complication in cancer treatment due to the cardiotoxic effects of anticancer drugs, especially from the anthracyclines such as doxorubicin (DXR). DXR enhances oxidative stress and stimulates matrix metalloproteinase-2 (MMP-2) in cardiomyocytes. We investigated whether MMP inhibitors protect against DXR cardiotoxicity given the role of MMP-2 in proteolyzing sarcomeric proteins in the heart and remodelling the extracellular matrix.

Methods and results

Eight-week-old male C57BL/6J mice were treated with DXR weekly with or without MMP inhibitors doxycycline or ONO-4817 by daily oral gavage for 4 weeks. Echocardiography was used to determine cardiac function and left ventricular remodelling before and after treatment. MMP inhibitors ameliorated DXR-induced systolic and diastolic dysfunction by reducing the loss in left ventricular ejection fraction, fractional shortening, and E′/A′. MMP inhibitors attenuated adverse left ventricular remodelling, reduced cardiomyocyte dropout, and prevented myocardial fibrosis. DXR increased myocardial MMP-2 activity in part also by upregulating N-terminal truncated MMP-2. Immunogold transmission electron microscopy showed that DXR elevated MMP-2 levels within the sarcomere and mitochondria which were associated with myofilament lysis, mitochondrial degeneration, and T-tubule distention. DXR-induced myofilament lysis was associated with increased titin proteolysis in the heart which was prevented by ONO-4817. DXR also increased the level and activity of MMP-2 in human embryonic stem cell-derived cardiomyocytes, which was reduced by ONO-4817.

Conclusions

MMP-2 activation is an early event in DXR cardiotoxicity and contributes to myofilament lysis by proteolyzing cardiac titin. Two orally available MMP inhibitors ameliorated DXR cardiotoxicity by attenuating intracellular and extracellular matrix remodelling, suggesting their use may be a potential prophylactic strategy to prevent heart injury during chemotherapy.
Incorporation of a unified protein abundance dataset into the Saccharomyces genome database
Authors: Nash Robert S , Weng Shuai , Karra Kalpana , Wong Edith D , Engel Stacia R , Cherry J Michael ,   SGD Project
Published: January 2020

The identification and accurate quantitation of protein abundance has been a major objective of proteomics research. Abundance studies have the potential to provide users with data that can be used to gain a deeper understanding of protein function and regulation and can also help identify cellular pathways and modules that operate under various environmental stress conditions. One of the central missions of the Saccharomyces Genome Database (SGD; https://www.yeastgenome.org) is to work with researchers to identify and incorporate datasets of interest to the wider scientific community, thereby enabling hypothesis-driven research. A large number of studies have detailed efforts to generate proteome-wide abundance data, but deeper analyses of these data have been hampered by the inability to compare results between studies. Recently, a unified protein abundance dataset was generated through the evaluation of more than 20 abundance datasets, which were normalized and converted to common measurement units, in this case molecules per cell. We have incorporated these normalized protein abundance data and associated metadata into the SGD database, as well as the SGD YeastMine data warehouse, resulting in the addition of 56 487 values for untreated cells grown in either rich or defined media and 28 335 values for cells treated with environmental stressors. Abundance data for protein-coding genes are displayed in a sortable, filterable table on Protein pages, available through Locus Summary pages. A median abundance value was incorporated, and a median absolute deviation was calculated for each protein-coding gene and incorporated into SGD. These values are displayed in the Protein section of the Locus Summary page. The inclusion of these data has enhanced the quality and quantity of protein experimental information presented at SGD and provides opportunities for researchers to access and utilize the data to further their research.
Labour Market Shocks and the Demand for Trade Protection: Evidence from Online Surveys
Authors: Di Tella Rafael , Rodrik Dani
Published: January 2020

We study preferences for government action in response to layoffs resulting from different types of labour-market shocks. We consider: technological change, a demand shift, bad management and three kinds of international outsourcing. Support for government intervention rises sharply in response to shocks and is heavily biased towards trade protection. Trade shocks generate more demand for protectionism and, among trade shocks, outsourcing to a developing country elicits greater demand for protectionism. The ‘bad management’ shock is the only scenario that induces a desired increase in compensatory transfers. Trump supporters are more protectionist than Clinton supporters, but preferences seem easy to manipulate: Clinton supporters primed with trade shocks are as protectionist as baseline Trump voters. Highlighting labour abuses in the exporting country increases the demand for trade protection by Clinton supporters but not Trump supporters.
Long-term outcomes of upfront surgery in patients with resectable pathological N2 non-small-cell lung cancer
Authors: Yun Jae Kwang , Bok Jin San , Lee Geun Dong , Kim Hyeong Ryul , Kim Yong-Hee , Kim Dong Kwan , Park Seung-Il , Choi Sehoon
Published: January 2020

OBJECTIVES

Although the standard treatment for pathological N2 (pN2) non-small-cell lung cancer (NSCLC) patients is definitive chemoradiation, surgery can be beneficial for resectable pN2 disease. Herein, we report the long-term clinical outcomes of upfront surgery followed by adjuvant treatment for selected patients with resectable pN2 disease.

METHODS

We performed a retrospective analysis of clinical outcomes for patients with pN2 disease who underwent surgery as the first-line therapy. Multivariable Cox regression analysis was used to identify the significant factors for overall survival (OS) and recurrence-free survival.

RESULTS

From 2004 to 2015, a total of 706 patients with pN2 NSCLC underwent complete anatomical resection at our institution. The patients’ clinical N stages were cN0, 308 (43.6%); cN1, 123 (17.4%) and cN2, 275 (39.0%). Adjuvant chemotherapy, radiotherapy and chemoradiotherapy were administered to 169 (23.9%), 115 (17.4%) and 299 patients (42.4%), respectively. With a median follow-up of 40 months, the respective median time and 5-year rate of OS were 52 months and 44.7%. According to subdivided pN2 descriptors, the median OS time was 80, 53 and 37 months for patients with pN2a1, pN2a2 and pN2b, respectively. Adjuvant chemotherapy was a significant prognostic factor for both OS [hazard ratio (HR) 0.39, 95% confidence interval (CI) 0.28–0.52; P < 0.001] and recurrence-free survival (HR 0.42, 95% CI 0.30–0.58; P < 0.001).

CONCLUSIONS

Upfront surgery followed by adjuvant therapy for resectable N2 disease showed favourable outcomes compared to those reported in previous studies. Adjuvant chemotherapy is essential to improve the prognosis for patients undergoing upfront surgery for N2 disease.
Which Countries Send More Delegates to Climate Change Conferences? Analysis of UNFCCC COPs, 1995–2015
Authors: Kaya Ayse , Schofield Lynne Steuerle
Published: January 2020

The size of national delegations at the most critical intergovernmental climate change conferences—the annual gatherings of the Conference of the Parties (COPs) of the United Nations Framework Convention on Climate Change—vary greatly. The literature has emphasized the importance of national delegation size (NDS) for states’ formal and informal participation in climate change negotiations. To our knowledge, however, this is the first paper to comprehensively examine the determinants of NDS from 1995–2015. The findings highlight a country's resources and its interest in the mitigation of fossil fuel emissions as important determinants of its NDS. In contrast, the evidence for a connection between vulnerability to climate change and NDS is limited. Interest group politics appear more important than civil society or bureaucratic influence in determining NDS. In terms of policy implications, the distance between the country and the COP location is a robust deterrent of larger delegations, and there is a nonlinear relationship between NDS and financial capacity. Further, there are differences across Annex I and non-Annex I countries.
BetaScan2: Standardized Statistics to Detect Balancing Selection Utilizing Substitution Data
Authors: Siewert Katherine M , Voight Benjamin F
Published: January 2020

Long-term balancing selection results in a build-up of alleles at similar frequencies and a deficit of substitutions when compared with an outgroup at a locus. The previously published β(1) statistics detect balancing selection using only polymorphism data. We now propose the β(2) statistic which detects balancing selection using both polymorphism and substitution data. In addition, we derive the variance of all β statistics, allowing for their standardization and thereby reducing the influence of parameters which can confound other selection tests. The standardized β statistics outperform existing summary statistics in simulations, indicating β is a well-powered and widely applicable approach for detecting balancing selection. We apply the β(2) statistic to 1000 Genomes data and report two missense mutations with high β scores in the ACSBG2 gene. An implementation of all β statistics and their standardization are available in the BetaScan2 software package at https://github.com/ksiewert/BetaScan.
Complete Genome Sequencing of FourArcobacterSpecies Reveals a Diverse Suite of Mobile Elements
Authors: Miller William G , Yee Emma , Bono James L
Published: January 2020

Arcobacter species are recovered from a wide variety of sources, including animals, food, and both fresh and marine waters. Several Arcobacter species have also been recovered from human clinical samples and are thus associated tentatively with food- and water-borne human illnesses. Genome sequencing of the poultry isolate Arcobacter cibarius H743 and the Arcobacter acticola, Arcobacter pacificus, and Arcobacter porcinus type strains identified a large number and variety of insertion sequences. This study presents an analysis of these A. acticola, A. cibarius, A. pacificus, and A. porcinus IS elements. The four genomes sequenced here contain 276 complete and degenerate IS elements, representing 13 of the current 29 prokaryotic IS element families. Expansion of the analysis to include 15 other previously sequenced Arcobacter spp. added 73 complete and degenerate IS elements. Several of these IS elements were identified in two or more Arcobacter species, suggesting movement by horizontal gene transfer between the arcobacters. These IS elements are putatively associated with intragenomic deletions and inversions, and tentative movement of antimicrobial resistance genes. The A. cibarius strain H743 megaplasmid contains multiple IS elements common to the chromosome and, unusually, a complete ribosomal RNA locus, indicating that larger scale genomic rearrangements, potentially resulting from IS element-mediated megaplasmid cointegration and resolution may be occurring within A. cibarius and possibly other arcobacters. The presence of such a large and varied suite of mobile elements could have profound effects on Arcobacter biology and evolution.
Patients’ and Caregivers’ Attitudes Toward Deprescribing in Singapore
Authors: Kua Chong-Han , Reeve Emily , Tan Doreen S Y , Koh Tsingyi , Soong Jie Lin , Sim Marvin J L , Zhang Tracy Y , Chen Yi Rong , Ratnasingam Vanassa , Mak Vivienne S L , Lee Shaun Wen Huey ,   Pharmaceutical Society of Singapore Deprescribing Workgroup
Published: January 2020

Background

Knowledge of decision-making preference of patients and caregivers is needed to facilitate deprescribing. This study aimed to assess the perspectives of caregivers and older adults towards deprescribing in an Asian population. Secondary objectives were to identify and compare characteristics associated with these attitudes and beliefs.

Method

A cross-sectional survey of two groups of participants was conducted using the Revised Patients’ Attitudes Towards Deprescribing questionnaire. Descriptive results were reported for participants’ characteristics and questionnaire responses from four factors (belief in medication inappropriateness, medication burden, concerns about stopping, and involvement) and two global questions. Correlation between participant characteristics and their responses was analyzed.

Results

A total of 1,057 (615 older adults; 442 caregivers) participants were recruited from 10 institutions in Singapore. In which 511 (83.0%) older adults and 385 (87.1%) caregivers reported that they would be willing to stop one or more of their medications if their doctor said it was possible, especially among older adults recruited from acute-care hospitals (85.3%) compared with older adults in community pharmacies (73.6%). Individuals who take more than five medications and those with higher education were correlated with greater agreement in inappropriateness and involvement, respectively.

Conclusions

Clinicians should consider discussing deprescribing with older adults and caregivers in their regular clinical practice, especially when polypharmacy is present. Further research is needed into how to engage older adults and caregivers in shared decision making based on their attitudes toward deprescribing.
A mouse model for kinesin family member 11 (Kif11)-associated familial exudative vitreoretinopathy
Authors: Wang Yanshu , Smallwood Philip M , Williams John , Nathans Jeremy
Published: January 2020

During mitosis, Kif11, a kinesin motor protein, promotes bipolar spindle formation and chromosome movement, and during interphase, Kif11 mediates diverse trafficking processes in the cytoplasm. In humans, inactivating mutations in KIF11 are associated with (1) retinal hypovascularization with or without microcephaly and (2) multi-organ syndromes characterized by variable combinations of lymphedema, chorioretinal dysplasia, microcephaly and/or mental retardation. To explore the pathogenic basis of KIF11-associated retinal vascular disease, we generated a Kif11 conditional knockout (CKO) mouse and investigated the consequences of early postnatal inactivation of Kif11 in vascular endothelial cells (ECs). The principal finding is that postnatal EC-specific loss of Kif11 leads to severely stunted growth of the retinal vasculature, mildly stunted growth of the cerebellar vasculature and little or no effect on the vasculature elsewhere in the central nervous system (CNS). Thus, in mice, Kif11 function in early postnatal CNS ECs is most significant in the two CNS regions—the retina and cerebellum—that exhibit the most rapid rate of postnatal growth, which may sensitize ECs to impaired mitotic spindle function. Several lines of evidence indicate that these phenotypes are not caused by reduced beta-catenin signaling in ECs, despite the close resemblance of the Kif11 CKO phenotype to that caused by EC-specific reductions in beta-catenin signaling. Based on prior work, defective beta-catenin signaling had been the only known mechanism responsible for monogenic human disorders of retinal hypovascularization. The present study implies that retinal hypovascularization can arise from a second and mechanistically distinct cause.
Educational and health outcomes of children and adolescents receiving antidepressant medication: Scotland-wide retrospective record linkage cohort study of 766 237 schoolchildren
Authors: Fleming Michael , Fitton Catherine A , Steiner Markus F C , McLay James S , Clark David , King Albert , Mackay Daniel F , Pell Jill P
Published: January 2020

Background

Childhood depression is relatively common, under-researched and can impact social and cognitive function and self-esteem.

Methods

Record linkage of routinely collected Scotland-wide administrative databases covering prescriptions [prescribing information system (PIS)], hospitalizations (Scottish Morbidity Records 01 and 04), maternity records (Scottish Morbidity Records 02), deaths (National Records of Scotland), annual pupil census, school absences/exclusions, special educational needs (Scottish Exchange of Educational Data; ScotXed), examinations (Scottish Qualifications Authority) and (un)employment (ScotXed) provided data on 766 237 children attending Scottish schools between 2009 and 2013 inclusively. We compared educational and health outcomes of children receiving antidepressant medication with their peers, adjusting for confounders (socio-demographic, maternity and comorbidity) and explored effect modifiers and mediators.

Results

Compared with peers, children receiving antidepressants were more likely to be absent [adjusted incidence rate ratio (IRR) 1.90, 95% confidence interval (CI) 1.85–1.95] or excluded (adjusted IRR 1.48, 95% CI 1.29–1.69) from school, have special educational needs [adjusted odds ratio (OR) 1.77, 95% CI 1.65–1.90], have the lowest level of academic attainment (adjusted OR 3.00, 95% CI 2.51–3.58) and be unemployed after leaving school (adjusted OR 1.88, 95% CI 1.71–2.08). They had increased hospitalization [adjusted hazard ratio (HR) 2.07, 95% CI 1.98–2.18] and mortality (adjusted HR 2.73, 95% CI 1.73–4.29) over 5 years’ follow-up. Higher absenteeism partially explained poorer attainment and unemployment. Treatment with antidepressants was less common among boys than girls (0.5% vs 1.0%) but the associations with special educational need and unemployment were stronger in boys.

Conclusions

Children receiving antidepressants fare worse than their peers across a wide range of education and health outcomes. Interventions to reduce absenteeism or mitigate its effects should be investigated.
Drug Resistance Assessment Following Administration of Respiratory Syncytial Virus (RSV) Fusion Inhibitor Presatovir to Participants Experimentally Infected With RSV
Authors: Stray Kirsten , Perron Michel , Porter Danielle P , Anderson Francisco , Lewis Sandra A , Perry Jason , Miller Michael , Cihlar Tomas , DeVincenzo John , Chien Jason W , Jordan Robert
Published: January 2020

Background

Presatovir is an oral respiratory syncytial virus (RSV) fusion inhibitor targeting RSV F protein. In a double-blind, placebo-controlled study in healthy adults experimentally infected with RSV (Memphis-37b), presatovir significantly reduced viral load and clinical disease severity in a dose-dependent manner.

Methods

Viral RNA from nasal wash samples was amplified and the F gene sequenced to monitor presatovir resistance. Effects of identified amino acid substitutions on in vitro susceptibility to presatovir, viral fitness, and clinical outcome were assessed.

Results

Twenty-eight treatment-emergent F substitutions were identified. Of these, 26 were tested in vitro; 2 were not due to lack of recombinant virus recovery. Ten substitutions did not affect presatovir susceptibility, and 16 substitutions reduced RSV susceptibility to presatovir (2.9- to 410-fold). No substitutions altered RSV susceptibility to palivizumab or ribavirin. Frequency of phenotypically resistant substitutions was higher with regimens containing lower presatovir dose and shorter treatment duration. Participants with phenotypic presatovir resistance had significantly higher nasal viral load area under the curve relative to those without, but substitutions did not significantly affect peak viral load or clinical manifestations of RSV disease.

Conclusions

Emergence of presatovir-resistant RSV occurred during therapy but did not significantly affect clinical efficacy in participants with experimental RSV infection.
Protection From Natural Immunity Against Enteric Infections and Etiology-Specific Diarrhea in a Longitudinal Birth Cohort
Authors: Rogawski McQuade Elizabeth T , Liu Jie , Kang Gagandeep , Kosek Margaret N , Lima Aldo A M , Bessong Pascal O , Samie Amidou , Haque Rashidul , Mduma Estomih R , Shrestha Sanjaya , Leite Jose Paulo , Bodhidatta Ladaporn , Iqbal Najeeha , Page Nicola , Kiwelu Ireen , Bhutta Zulfiqar , Ahmed Tahmeed , Houpt Eric R , Platts-Mills James A
Published: January 2020

Background

The degree of protection conferred by natural immunity is unknown for many enteropathogens, but it is important to support the development of enteric vaccines.

Methods

We used the Andersen-Gill extension of the Cox model to estimate the effects of previous infections on the incidence of subsequent subclinical infections and diarrhea in children under 2 using quantitative molecular diagnostics in the MAL-ED cohort. We used cross-pathogen negative control associations to correct bias due to confounding by unmeasured heterogeneity of exposure and susceptibility.

Results

Prior rotavirus infection was associated with a 50% lower hazard (calibrated hazard ratio [cHR], 0.50; 95% confidence interval [CI], 0.41–0.62) of subsequent rotavirus diarrhea. Strong protection was evident against Cryptosporidium diarrhea (cHR, 0.32; 95% CI, 0.20–0.51). There was also protection due to prior infections for norovirus GII (cHR against diarrhea, 0.67; 95% CI, 0.49–0.91), astrovirus (cHR, 0.62; 95% CI, 0.48–0.81), and Shigella (cHR, 0.79; 95% CI, 0.65–0.95). Minimal protection was observed for other bacteria, adenovirus 40/41, and sapovirus.

Conclusions

Natural immunity was generally stronger for the enteric viruses than bacteria, potentially due to less antigenic diversity. Vaccines against major causes of diarrhea may be feasible but likely need to be more immunogenic than natural infection.
Should they stay or should they go? Climate migrants and local conflicts
Authors: Bosetti Valentina , Cattaneo Cristina , Peri Giovanni
Published: January 2020

There is extensive evidence that higher temperatures increase the probability of local conflict. There is also evidence that emigration represents an important margin of adaptation to a warming climate. In this article, we analyse whether migration influences the link between warming and conflicts by either attenuating this connection in countries of origin and/or by exacerbating it in countries of destination. We find that in countries where the propensity to emigrate—as measured by past diaspora—is higher, increases in temperature have smaller effects on the probability of armed conflict, compared to countries with lower migration propensity. This is consistent with emigration functioning as ‘escape valve’ for local tensions. We find no evidence that climate-induced migration increased the probability of conflict in receiving countries.
Melanoma Prognosis: Accuracy of the American Joint Committee on Cancer Staging Manual Eighth Edition
Authors: Bajaj Shirin , Donnelly Douglas , Call Melissa , Johannet Paul , Moran Una , Polsky David , Shapiro Richard , Berman Russell , Pavlick Anna , Weber Jeffrey , Zhong Judy , Osman Iman
Published: January 2020

Background

The American Joint Committee on Cancer (AJCC) maintains that the eighth edition of its Staging Manual (AJCC8) has improved accuracy compared with the seventh (AJCC7). However, there are concerns that implementation may disrupt analysis of active clinical trials for stage III patients. We used an independent cohort of melanoma patients to test the extent to which AJCC8 has improved prognostic accuracy compared with AJCC7.

Methods

We analyzed a cohort of 1315 prospectively enrolled patients. We assessed primary tumor and nodal classification of stage I–III patients using AJCC7 and AJCC8 to assign disease stages at diagnosis. We compared recurrence-free (RFS) and overall survival (OS) using Kaplan-Meier curves and log-rank tests. We then compared concordance indices of discriminatory prognostic ability and area under the curve of 5-year survival to predict RFS and OS. All statistical tests were two-sided.

Results

Stage IIC patients continued to have worse outcomes than stage IIIA patients, with a 5-year RFS of 26.5% (95% confidence interval [CI] = 12.8% to 55.1%) vs 56.0% (95% CI = 37.0% to 84.7%) by AJCC8 (P = .002). For stage I, removing mitotic index as a T classification factor decreased its prognostic value, although not statistically significantly (RFS concordance index [C-index] = 0.63, 95% CI = 0.56 to 0.69; to 0.56, 95% CI = 0.49 to 0.63, P = .07; OS C-index = 0.48, 95% CI = 0.38 to 0.58; to 0.48, 95% CI = 0.41 to 0.56, P = .90). For stage II, prognostication remained constant (RFS C-index = 0.65, 95% CI = 0.57 to 0.72; OS C-index = 0.61, 95% CI = 0.50 to 0.72), and for stage III, AJCC8 yielded statistically significantly enhanced prognostication for RFS (C-index = 0.65, 95% CI = 0.60 to 0.70; to 0.70, 95% CI = 0.66 to 0.75, P = .01).

Conclusions

Compared with AJCC7, we demonstrate that AJCC8 enables more accurate prognosis for patients with stage III melanoma. Restaging a large cohort of patients can enhance the analysis of active clinical trials.
Trends in Late Mortality Among Adolescent and Young Adult Cancer Survivors
Authors: Anderson Chelsea , Nichols Hazel B
Published: January 2020

Background

Over the past several decades, treatment of cancer in adolescents and young adults (AYAs) has evolved substantially, leading to steady improvements in estimated 5-year survival at diagnosis. However, the impact on late mortality in this population is largely unexamined. We investigated temporal trends in mortality among 5-year AYA cancer survivors.

Methods

The Surveillance, Epidemiology, and End Results database was used to identify AYAs (age 15–39 years) diagnosed with cancer during 1975–2011 who survived at least 5 years beyond diagnosis. Survival months were accrued from 5 years postdiagnosis until death or the end of 2016. Cumulative mortality from all causes, the primary cancer, other cancers, and noncancer or nonexternal causes (ie, excluding accidents, suicide, homicide) were estimated according to diagnosis era.

Results

Among 282 969 five-year AYA cancer survivors, 5-year mortality (ie, from 5 through 10 years postdiagnosis) from all-causes decreased from 8.3% (95% confidence interval = 8.0% to 8.6%) among those diagnosed in 1975–1984 to 5.4% (95% confidence interval = 5.3% to 5.6%) among those diagnosed in 2005–2011. This was largely explained by decreases in mortality from the primary cancer (6.8% to 4.2%) between these periods. However, for specific cancer types, including colorectal, bone, sarcomas, cervical/uterine, and bladder, cumulative mortality curves demonstrated little improvement in primary cancer mortality over time. Some reduction in late mortality from noncancer or nonexternal causes was apparent for Hodgkin lymphoma, leukemia, kidney cancer, head and neck cancers, and trachea, lung, and bronchus cancers.

Conclusion

Over the past four decades, all-cause and cancer-specific mortality have decreased among 5-year AYA cancer survivors overall, but several cancer types have not shared in these improvements.
Symplasmic isolation marks cell fate changes during somatic embryogenesis
Authors: Godel-Jedrychowska Kamila , Kulinska-Lukaszek Katarzyna , Horstman Anneke , Soriano Mercedes , Li Mengfan , Malota Karol , Boutilier Kim , Kurczynska Ewa U
Published: January 2020

Cell-to-cell signalling is a major mechanism controlling plant morphogenesis. Transport of signalling molecules through plasmodesmata is one way in which plants promote or restrict intercellular signalling over short distances. Plasmodesmata are membrane-lined pores between cells that regulate the intercellular flow of signalling molecules through changes in their size, creating symplasmic fields of connected cells. Here we examine the role of plasmodesmata and symplasmic communication in the establishment of plant cell totipotency, using somatic embryo induction from Arabidopsis explants as a model system. Cell-to-cell communication was evaluated using fluorescent tracers, supplemented with histological and ultrastructural analysis, and correlated with expression of a WOX2 embryo reporter. We showed that embryogenic cells are isolated symplasmically from non-embryogenic cells regardless of the explant type (immature zygotic embryos or seedlings) and inducer system (2,4-dichlorophenoxyacetic acid or the BABY BOOM (BBM) transcription factor), but that the symplasmic domains in different explants differ with respect to the maximum size of molecule capable of moving through the plasmodesmata. Callose deposition in plasmodesmata preceded WOX2 expression in future sites of somatic embryo development, but later was greatly reduced in WOX2-expressing domains. Callose deposition was also associated with a decrease DR5 auxin response in embryogenic tissue. Treatment of explants with the callose biosynthesis inhibitor 2-deoxy-D-glucose supressed somatic embryo formation in all three systems studied, and also blocked the observed decrease in DR5 expression. Together these data suggest that callose deposition at plasmodesmata is required for symplasmic isolation and establishment of cell totipotency in Arabidopsis.
The Jewish Fusgeyer Migration Movement from Early Twentieth-Century Romania as Transcultural Rhetorical Tool in US Memorial Literary Culture
Authors: Mihăilescu Dana
Published: January 2020

From 1900 to 1907, a so-called fusgeyer phenomenon was the most salient characteristic of Jewish emigration from Romania, given the high number of impoverished, desperate Jews who were on the brink of starvation and started to go on foot in the attempt to leave the country. My essay considers the literary representation of this fusgeyer movement over time as a conduit upholding transcultural networks of memory work in the United States. To that end, I will examine the representation of fusgeyers in the literature produced by immigrant fusgeyers to the United States immediately after emigration (M. E. Ravage’s 1917 An American in the Making: The Life Story of an Immigrant and Jacob Finkelstein’s 1942 “Memoirs of a Fusgeyer from Romania to America”) and in the literature created in contemporary times in the United States (Stuart Tower’s 2003 historical novel The Wayfarers). In my analysis, I rely on Astrid Erll’s demonstration that literature can be a powerful conduit of cultural memory by its use of “four modes of a ‘rhetoric of collective memory’: the experiential, the mythical, the antagonistic, and the reflexive mode.” I will show which of these modes of rhetoric apply to the literary works I consider and how they highlight a dynamic movement toward a transcultural type of rhetoric shaping Jewish memory forms in contemporary US literature.
Mass determinations of the three mini-Neptunes transiting TOI-125
Authors: Nielsen L D , Gandolfi D , Armstrong D J , Jenkins J S , Fridlund M , Santos N C , Dai F , Adibekyan V , Luque R , Steffen J H , Esposito M , Meru F , Sabotta S , Bolmont E , Kossakowski D , Otegi J F , Murgas F , Stalport M , Rodler F , Díaz M R , Kurtovic N T , Ricker G , Vanderspek R , Latham D W , Seager S , Winn J N , Jenkins J M , Allart R , M. Almenara J , Barrado D , Barros S C C , Bayliss D , Berdiñas Z M , Boisse I , Bouchy F , Boyd P , Brown D J A , Bryant E M , Burke C , Cochran W D , Cooke B F , Demangeon O D S , Díaz R F , Dittman J , Dorn C , Dumusque X , García R A , González-Cuesta L , Grziwa S , Georgieva I , Guerrero N , Hatzes A P , Helled R , Henze C E , Hojjatpanah S , Korth J , Lam K W F , Lillo-Box J , Lopez T A , Livingston J , Mathur S , Mousis O , Narita N , Osborn H P , Palle E , Rojas P A Peña , Persson C M , Quinn S N , Rauer H , Redfield S , Santerne A , dos Santos L A , Seidel J V , Sousa S G , Ting E B , Turbet M , Udry S , Vanderburg A , Van Eylen V , Vines J I , Wheatley P J , Wilson P A
Published: January 2020

The Transiting Exoplanet Survey Satellite, TESS, is currently carrying out an all-sky search for small planets transiting bright stars. In the first year of the TESS survey, a steady progress was made in achieving the mission’s primary science goal of establishing bulk densities for 50 planets smaller than Neptune. During that year, the TESS’s observations were focused on the southern ecliptic hemisphere, resulting in the discovery of three mini-Neptunes orbiting the star TOI-125, a V = 11.0 K0 dwarf. We present intensive HARPS radial velocity observations, yielding precise mass measurements for TOI-125b, TOI-125c, and TOI-125d. TOI-125b has an orbital period of 4.65 d, a radius of 2.726 ± 0.075 RE, a mass of 9.50 ± 0.88 ME, and is near the 2:1 mean motion resonance with TOI-125c at 9.15 d. TOI-125c has a similar radius of 2.759 ± 0.10 RE and a mass of 6.63 ± 0.99 ME, being the puffiest of the three planets. TOI-125d has an orbital period of 19.98 d and a radius of 2.93 ± 0.17 RE and mass 13.6 ± 1.2 ME. For TOI-125b and d, we find unusual high eccentricities of 0.19 ± 0.04 and $0.17^{+0.08}_{-0.06}$, respectively. Our analysis also provides upper mass limits for the two low-SNR planet candidates in the system; for TOI-125.04 (RP = 1.36 RE, P = 0.53 d), we find a 2σ upper mass limit of 1.6 ME, whereas TOI-125.05 ($R_P=4.2^{+2.4}_{-1.4}$ RE, P = 13.28 d) is unlikely a viable planet candidate with an upper mass limit of 2.7 ME. We discuss the internal structure of the three confirmed planets, as well as dynamical stability and system architecture for this intriguing exoplanet system.
Global Site Selection for Astronomy
Authors: Aksaker N , Yerli S K , Erdoğan M A , Kurt Z , Kaba K , Bayazit M , Yesilyaprak C
Published: January 2020

A global site selection for astronomy was performed with 1 km spatial resolution (∼1 gigapixel in size) using long-term and up-to-date datasets to classify the entire terrestrial surface of the Earth. Satellite instruments are used to get the following datasets of geographical information system (GIS) layers: cloud coverage, digital elevation model, artificial light, precipitable water vapour, aerosol optical depth, wind speed, and land use and land cover. A multi-criteria decision analysis (MCDA) technique is applied to these datasets, creating four different series where each layer will have a specific weight. We introduce for the first time a suitability index for astronomical sites (SIAS). This index can be used to find suitable locations and to compare different sites or observatories. The midwestern Andes in South America and the Tibetan Plateau in western China were found to be the best in all SIAS series. Considering all the series, less than 3 per cent of all terrestrial surfaces are found to be the best regions to establish an astronomical observatory. In addition to this, only approximately 10 per cent of all current observatories are located in good locations in all SIAS series. Amateurs, institutions or countries aiming to construct an observatory could create a shortlist of potential site locations using a layout of SIAS values for each country without spending time and budget. The outcomes and datasets of this study have been made available through a website, the Astro GIS Database, at www.astrogis.org.
IQ-TREE 2: New Models and Efficient Methods for Phylogenetic Inference in the Genomic Era
Authors: Minh Bui Quang , Schmidt Heiko A , Chernomor Olga , Schrempf Dominik , Woodhams Michael D , von Haeseler Arndt , Lanfear Robert
Published: January 2020

IQ-TREE (http://www.iqtree.org, last accessed February 6, 2020) is a user-friendly and widely used software package for phylogenetic inference using maximum likelihood. Since the release of version 1 in 2014, we have continuously expanded IQ-TREE to integrate a plethora of new models of sequence evolution and efficient computational approaches of phylogenetic inference to deal with genomic data. Here, we describe notable features of IQ-TREE version 2 and highlight the key advantages over other software.
Reducing the structure bias of RNA-Seq reveals a large number of non-annotated non-coding RNA
Authors: Boivin Vincent , Reulet Gaspard , Boisvert Olivier , Couture Sonia , Elela Sherif Abou , Scott Michelle S
Published: January 2020

The study of RNA expression is the fastest growing area of genomic research. However, despite the dramatic increase in the number of sequenced transcriptomes, we still do not have accurate estimates of the number and expression levels of non-coding RNA genes. Non-coding transcripts are often overlooked due to incomplete genome annotation. In this study, we use annotation-independent detection of RNA reads generated using a reverse transcriptase with low structure bias to identify non-coding RNA. Transcripts between 20 and 500 nucleotides were filtered and crosschecked with non-coding RNA annotations revealing 111 non-annotated non-coding RNAs expressed in different cell lines and tissues. Inspecting the sequence and structural features of these transcripts indicated that 60% of these transcripts correspond to new snoRNA and tRNA-like genes. The identified genes exhibited features of their respective families in terms of structure, expression, conservation and response to depletion of interacting proteins. Together, our data reveal a new group of RNA that are difficult to detect using standard gene prediction and RNA sequencing techniques, suggesting that reliance on actual gene annotation and sequencing techniques distorts the perceived architecture of the human transcriptome.
Cooperation of the NEIL3 and Fanconi anemia/BRCA pathways in interstrand crosslink repair
Authors: Li Niu , Wang Jian , Wallace Susan S , Chen Jing , Zhou Jia , D’Andrea Alan D
Published: January 2020

The NEIL3 DNA glycosylase is a base excision repair enzyme that excises bulky base lesions from DNA. Although NEIL3 has been shown to unhook interstrand crosslinks (ICL) in Xenopus extracts, how NEIL3 participants in ICL repair in human cells and its corporation with the canonical Fanconi anemia (FA)/BRCA pathway remain unclear. Here we show that the NEIL3 and the FA/BRCA pathways are non-epistatic in psoralen-ICL repair. The NEIL3 pathway is the major pathway for repairing psoralen-ICL, and the FA/BRCA pathway is only activated when NEIL3 is not present. Mechanistically, NEIL3 is recruited to psoralen-ICL in a rapid, PARP-dependent manner. Importantly, the NEIL3 pathway repairs psoralen-ICLs without generating double-strand breaks (DSBs), unlike the FA/BRCA pathway. In addition, we found that the RUVBL1/2 complex physically interact with NEIL3 and function within the NEIL3 pathway in psoralen-ICL repair. Moreover, TRAIP is important for the recruitment of NEIL3 but not FANCD2, and knockdown of TRAIP promotes FA/BRCA pathway activation. Interestingly, TRAIP is non-epistatic with both NEIL3 and FA pathways in psoralen-ICL repair, suggesting that TRAIP may function upstream of the two pathways. Taken together, the NEIL3 pathway is the major pathway to repair psoralen-ICL through a unique DSB-free mechanism in human cells.
Synergistic defects in pre-rRNA processing from mutations in the U3-specific protein Rrp9 and U3 snoRNA
Authors: Clerget Guillaume , Bourguignon-Igel Valérie , Marmier-Gourrier Nathalie , Rolland Nicolas , Wacheul Ludivine , Manival Xavier , Charron Christophe , Kufel Joanna , Méreau Agnès , Senty-Ségault Véronique , Tollervey David , Lafontaine Denis L J , Branlant Christiane , Rederstorff Mathieu
Published: January 2020

U3 snoRNA and the associated Rrp9/U3-55K protein are essential for 18S rRNA production by the SSU-processome complex. U3 and Rrp9 are required for early pre-rRNA cleavages at sites A0, A1 and A2, but the mechanism remains unclear. Substitution of Arg 289 in Rrp9 to Ala (R289A) specifically reduced cleavage at sites A1 and A2. Surprisingly, R289 is located on the surface of the Rrp9 β-propeller structure opposite to U3 snoRNA. To understand this, we first characterized the protein-protein interaction network of Rrp9 within the SSU-processome. This identified a direct interaction between the Rrp9 β-propeller domain and Rrp36, the strength of which was reduced by the R289A substitution, implicating this interaction in the observed processing phenotype. The Rrp9 R289A mutation also showed strong synergistic negative interactions with mutations in U3 that destabilize the U3/pre-rRNA base-pair interactions or reduce the length of their linking segments. We propose that the Rrp9 β-propeller and U3/pre-rRNA binding cooperate in the structure or stability of the SSU-processome. Additionally, our analysis of U3 variants gave insights into the function of individual segments of the 5′-terminal 72-nt sequence of U3. We interpret these data in the light of recently reported SSU-processome structures.
Cas3/I-C mediated target DNA recognition and cleavage during CRISPR interference are independent of the composition and architecture of Cascade surveillance complex
Authors: Nimkar Siddharth , Anand B
Published: January 2020

In type I CRISPR-Cas system, Cas3—a nuclease cum helicase—in cooperation with Cascade surveillance complex cleaves the target DNA. Unlike the Cascade/I-E, which is composed of five subunits, the Cascade/I-C is made of only three subunits lacking the CRISPR RNA processing enzyme Cas6, whose role is assumed by Cas5. How these differences in the composition and organization of Cascade subunits in type I-C influence the Cas3/I-C binding and its target cleavage mechanism is poorly understood. Here, we show that Cas3/I-C is intrinsically a single-strand specific promiscuous nuclease. Apart from the helicase domain, a constellation of highly conserved residues—which are unique to type I-C—located in the uncharacterized C-terminal domain appears to influence the nuclease activity. Recruited by Cascade/I-C, the HD nuclease of Cas3/I-C nicks the single-stranded region of the non-target strand and positions the helicase motor. Powered by ATP, the helicase motor reels in the target DNA, until it encounters the roadblock en route, which stimulates the HD nuclease. Remarkably, we show that Cas3/I-C supplants Cas3/I-E for CRISPR interference in type I-E in vivo, suggesting that the target cleavage mechanism is evolutionarily conserved between type I-C and type I-E despite the architectural difference exhibited by Cascade/I-C and Cascade/I-E.
A prospective study of pre-employment psychological testing amongst police recruits
Authors: Marshall R E , Milligan-Saville J S , Steel Z , Bryant R A , Mitchell P B , Harvey S B
Published: January 2020

Background

Pre-employment psychological screening to detect psychological vulnerability is common amongst emergency service organizations worldwide, yet the evidence for its ability to predict poor mental health outcomes is limited with published studies looking at post-recruitment research data rather than data collected by the organizations themselves.

Aims

The present study sought to investigate the ability of pre-employment screening to predict later psychological injury-related absenteeism amongst police officers.

Methods

A nested case–control study using prospective data was conducted. One hundred and fifty police officers with a liability-accepted psychological injury were matched to a control group of 150 psychologically healthy officers. Conditional logistic regression was used to examine associations between Minnesota Multiphasic Personality Inventory-2 (MMPI-2) scales measuring factors research has shown to predict psychological injury (Neuroticism, Psychoticism, Introversion, Disconstraint and Aggressiveness) and psychopathology (Depression, Anxiety and post-traumatic stress disorder [PTSD]) with subsequent psychological injury.

Results

Contrary to expectations, we were unable to demonstrate any association between validated pre-employment measures of personality and psychopathology with mental health outcomes amongst newly recruited police officers over a 7-year follow-up.

Conclusions

Other measures may be better able to predict future mental health problems in police recruits.