bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma Citrate and Succinate Are Associated With Neurocognitive Impairment in Older People With HIV
Authors: Hileman Corrilynn O , Kalayjian Robert C , Azzam Sausan , Schlatzer Daniela , Wu Kunling , Tassiopoulos Katherine , Bedimo Roger , Ellis Ronald J , Erlandson Kristine M , Kallianpur Asha , Koletar Susan L , Landay Alan L , Palella Frank J , Taiwo Babafemi , Pallaki Muralidhar , Hoppel Charles L
Published: February 2021

Background

Neurocognitive impairment (NCI) is associated with monocyte activation in people with HIV (PWH). Activated monocytes increase glycolysis, reduce oxidative phosphorylation, and accumulate citrate and succinate, tricarboxylic acid (TCA) cycle metabolites that promote inflammation—this metabolic shift may contribute to NCI and slowed gait speed in PWH.

Methods

Plasma citrate and succinate were assayed by liquid chromatography–mass spectrometry from 957 participants upon entry to a multicenter, prospective cohort of older PWH. Logistic, linear, and mixed-effects linear regression models were used to examine associations between entry/baseline TCA cycle metabolites and cross-sectional and longitudinal NCI, neuropsychological test scores (NPZ-4), and gait speed.

Results

Median age was 51 (range 40–78) years. Each 1 standard deviation (SD) citrate increment was associated with 1.18 higher odds of prevalent NCI at baseline (P = .03), 0.07 SD lower time-updated NPZ-4 score (P = .01), and 0.02 m/s slower time-updated gait speed (P < .0001). Age accentuated these effects. In the oldest age-quartile, higher citrate was associated with 1.64 higher odds of prevalent NCI, 0.17 SD lower NPZ-4, and 0.04 m/s slower gait speed (P ≤ .01 for each). Similar associations were apparent with succinate in the oldest age-quintile, but not with gait speed. In participants without NCI at entry, higher citrate predicted a faster rate of neurocognitive decline.

Conclusions

Higher plasma citrate and succinate are associated with worse cross-sectional and longitudinal measures of neurocognitive function and gait speed that are age-dependent, supporting the importance of altered bioenergetic metabolism in the pathogenesis of NCI in older PWH.
Fine-tuning the cardiac O-GlcNAcylation regulatory enzymes governs the functional and structural phenotype of the diabetic heart
Authors: Prakoso Darnel , Lim Shiang Y , Erickson Jeffrey R , Wallace Rachel S , Lees Jarmon G , Tate Mitchel , Kiriazis Helen , Donner Daniel G , Henstridge Darren C , Davey Jonathan R , Qian Hongwei , Deo Minh , Parry Laura J , Davidoff Amy J , Gregorevic Paul , Chatham John C , De Blasio Miles J , Ritchie Rebecca H
Published: February 2021

Aims 

The glucose-driven enzymatic modification of myocardial proteins by the sugar moiety, β-N-acetylglucosamine (O-GlcNAc), is increased in pre-clinical models of diabetes, implicating protein O-GlcNAc modification in diabetes-induced heart failure. Our aim was to specifically examine cardiac manipulation of the two regulatory enzymes of this process on the cardiac phenotype, in the presence and absence of diabetes, utilising cardiac-targeted recombinant-adeno-associated viral-vector-6 (rAAV6)-mediated gene delivery.

Methods and results 

In human myocardium, total protein O-GlcNAc modification was elevated in diabetic relative to non-diabetic patients, and correlated with left ventricular (LV) dysfunction. The impact of rAAV6-delivered O-GlcNAc transferase (rAAV6-OGT, facilitating protein O-GlcNAcylation), O-GlcNAcase (rAAV6-OGA, facilitating de-O-GlcNAcylation), and empty vector (null) were determined in non-diabetic and diabetic mice. In non-diabetic mice, rAAV6-OGT was sufficient to impair LV diastolic function and induce maladaptive cardiac remodelling, including cardiac fibrosis and increased Myh-7 and Nppa pro-hypertrophic gene expression, recapitulating characteristics of diabetic cardiomyopathy. In contrast, rAAV6-OGA (but not rAAV6-OGT) rescued LV diastolic function and adverse cardiac remodelling in diabetic mice. Molecular insights implicated impaired cardiac PI3K(p110α)-Akt signalling as a potential contributing mechanism to the detrimental consequences of rAAV6-OGT in vivo. In contrast, rAAV6-OGA preserved PI3K(p110α)-Akt signalling in diabetic mouse myocardium in vivo and prevented high glucose-induced impairments in mitochondrial respiration in human cardiomyocytes in vitro.

Conclusion

Maladaptive protein O-GlcNAc modification is evident in human diabetic myocardium, and is a critical regulator of the diabetic heart phenotype. Selective targeting of cardiac protein O-GlcNAcylation to restore physiological O-GlcNAc balance may represent a novel therapeutic approach for diabetes-induced heart failure.
Tilt testing remains a valuable asset
Authors: Sutton Richard , Fedorowski Artur , Olshansky Brian , Gert van Dijk J , Abe Haruhiko , Brignole Michele , de Lange Frederik , Kenny Rose Anne , Lim Phang Boon , Moya Angel , Rosen Stuart D , Russo Vincenzo , Stewart Julian M , Thijs Roland D , Benditt David G
Published: February 2021

Head-up tilt test (TT) has been used for >50 years to study heart rate/blood pressure adaptation to positional changes, to model responses to haemorrhage, to assess orthostatic hypotension, and to evaluate haemodynamic and neuroendocrine responses in congestive heart failure, autonomic dysfunction, and hypertension. During these studies, some subjects experienced syncope due to vasovagal reflex. As a result, tilt testing was incorporated into clinical assessment of syncope when the origin was unknown. Subsequently, clinical experience supports the diagnostic value of TT. This is highlighted in evidence-based professional practice guidelines, which provide advice for TT methodology and interpretation, while concurrently identifying its limitations. Thus, TT remains a valuable clinical asset, one that has added importantly to the appreciation of pathophysiology of syncope/collapse and, thereby, has improved care of syncopal patients.
Smartphone electrocardiogram for detecting atrial fibrillation after a cerebral ischaemic event: a multicentre randomized controlled trial
Authors: Koh Keng Tat , Law Wan Chung , Zaw Win Moe , Foo Diana Hui Ping , Tan Chen Ting , Steven Anderson , Samuel Desmond , Fam Tem Lom , Chai Ching Hua , Wong Zhai Sing , Xaviar Sivaraj , Bhavnani Chandan Deepak , Tan Jason Seng Hong , Oon Yen Yee , Said Asri , Fong Alan Yean Yip , Ong Tiong Kiam
Published: February 2021

Aims

Atrial fibrillation (AF) is a preventable cause of ischaemic stroke but it is often undiagnosed and undertreated. The utility of smartphone electrocardiogram (ECG) for the detection of AF after ischaemic stroke is unknown. The aim of this study is to determine the diagnostic yield of 30-day smartphone ECG recording compared with 24-h Holter monitoring for detecting AF ≥30 s.

Methods and results

In this multicentre, open-label study, we randomly assigned 203 participants to undergo one additional 24-h Holter monitoring (control group, n = 98) vs. 30-day smartphone ECG monitoring (intervention group, n = 105) using KardiaMobile (AliveCor®, Mountain View, CA, USA). Major inclusion criteria included age ≥55 years old, without known AF, and ischaemic stroke or transient ischaemic attack (TIA) within the preceding 12 months. Baseline characteristics were similar between the two groups. The index event was ischaemic stroke in 88.5% in the intervention group and 88.8% in the control group (P = 0.852). AF lasting ≥30 s was detected in 10 of 105 patients in the intervention group and 2 of 98 patients in the control group (9.5% vs. 2.0%; absolute difference 7.5%; P = 0.024). The number needed to screen to detect one AF was 13. After the 30-day smartphone monitoring, there was a significantly higher proportion of patients on oral anticoagulation therapy at 3 months compared with baseline in the intervention group (9.5% vs. 0%, P = 0.002).

Conclusions

Among patients ≥55 years of age with a recent cryptogenic stroke or TIA, 30-day smartphone ECG recording significantly improved the detection of AF when compared with the standard repeat 24-h Holter monitoring.
Over-prescription of short-acting beta agonists in the treatment of asthma
Authors: Looijmans-van den Akker Ingrid , Werkhoven Anouk , Verheij Theo
Published: February 2021

Background

Despite a clear guideline for asthma medication, excessive use of short-acting β2-agonists (SABAs) is common in clinical practice. Previous research has shown that excessive use of SABAs is associated with poor asthma control.

Objective

This study examines current use of asthma medication in primary care and whether excessive use of SABAs is associated with exacerbations.

Methods

The study design was a retrospective analysis using information from electronical medical records from patients aged 18 and older of five Julius Health Centers located in Utrecht, the Netherlands, in the period of 1 July 2018 through 1 July 2019. Excessive SABA use was defined as ≥400 inhalations per year. An exacerbation was defined as an acute worsening of asthma symptoms with the need for systemic corticosteroids.

Results

A total of 1161 patients were included in the study. Of the patients using SABAs (n = 766), 193 (25%) overused SABAs. Among the patients with inappropriate SABA use (n = 193), 19% had an exacerbation compared with 7% of the appropriate SABA users. For patients using asthma medication the odds of having an exacerbation were 2.9 times higher if they used an inappropriate number of SABAs than if SABAs were used appropriately (odds ratio, 2.897; 95% confidence interval, 1.87–4.48).

Conclusions

This study shows that overuse of SABAs is still common and that it is associated with asthma exacerbations. It highlights that clinicians need to be aware of inappropriate SABA use as it is a sign of and can even contribute to poor asthma control.
Soil microbial composition and carbon mineralization are associated with vegetation type and temperature regime in mesocosms of a semiarid ecosystem
Authors: Avitia Morena , Barrón-Sandoval Alberto , Hernández-Terán Alejandra , Benítez Mariana , A. Barron-Gafford Greg , Dontsova Katerina , A. Pavao-Zuckerman Mitchell , E. Escalante Ana
Published: February 2021

Transition from historic grasslands to woody plants in semiarid regions has led to questions about impacts on soil functioning, where microorganisms play a primary role. Understanding the relationship between microbes, plant diversity and soil functioning is relevant to assess such impacts. We evaluate the effect that plant type change in semiarid ecosystems has for microbial diversity and composition, and how this is related to carbon mineralization (CMIN) as a proxy for soil functioning. We followed a mesocosm experiment during 2 years within the Biosphere 2 facility in Oracle, AZ, USA. Two temperature regimes were established with two types of plants (grass or mesquite). Soil samples were analyzed for physicochemical and functional parameters, as well as microbial community composition using 16S rRNA amplicon metagenomics (Illumina MiSeq). Our results show the combined role of plant type and temperature regime in CMIN, where CMIN in grass has lower values at elevated temperatures compared with the opposite trend in mesquite. We also found a strong correlation of microbial composition with plant type but not with temperature regime. Overall, we provide evidence of the major effect of plant type in the specific composition of microbial communities as a potential result of the shrub encroachment.
Will high-speed railway influence the healthcare seeking behaviour of patients? Quasi-experimental evidence from China
Authors: Liu Gordon G , Tang Chengxiang , Liu Yahong , Bu Tao , Tang Daisheng
Published: February 2021

This study examines the impacts of high-speed railway (HSR) transportation on the healthcare-seeking behaviour of patients along newly integrated areas of Sichuan province, China. The opening of the Cheng–Mian–Le intercity HSR is considered as quasi-experimental evidence from China, and we make a propensity score matching the difference in differences research design, using data from the monthly report database of the Sichuan Province health statistical data collection and Decision Support System from 2014 to 2015. We find that, first, the opening of the HSR resulted in significant healthcare-seeking behaviour with great heterogeneity. Second, patients are more likely to go to areas with high-density healthcare resources, in which case HSR may mitigate the diagnostic inaccuracies that patients face locally. Third, the ‘distance enhancement effect’ was present, and its marginal effect is more significant for long-distance patients. Fourth, the tiered-network healthcare policy has no significant restrictive impact on patients seeking high-level medical services. Our results show that HSR establishment has a substantial impact on the behaviour of people seeking medical treatment and medicine. Furthermore, we discuss the results’ policy implications for the allocation and integration of China’s healthcare market, and the accessibility of medical and health services.
Promoting lung cancer awareness, help-seeking and early detection: a systematic review of interventions
Authors: Saab Mohamad M , FitzGerald Serena , Noonan Brendan , Kilty Caroline , Collins Abigail , Lyng Áine , Kennedy Una , O’Brien Maidy , Hegarty Josephine
Published: February 2021

Lung cancer (LC) is the leading cause of cancer death. Barriers to the early presentation for LC include lack of symptom awareness, symptom misappraisal, poor relationship with doctors and lack of access to healthcare services. Addressing such barriers can help detect LC early. This systematic review describes the effect of recent interventions to improve LC awareness, help-seeking and early detection. This review was guided by the Cochrane Handbook for Systematic Reviews of Interventions. Electronic databases MEDLINE, CINAHL, ERIC, APA PsycARTICLES, APA PsycInfo and Psychology and Behavioral Sciences Collection were searched. Sixteen studies were included. Knowledge of LC was successfully promoted in most studies using educational sessions and campaigns. LC screening uptake varied with most studies successfully reducing decision conflicts using decision aids. Large campaigns, including UK-based campaign ‘Be Clear on Cancer’, were instrumental in enhancing LC awareness, promoting help-seeking and yielding an increase in chest X-rays and a decrease in the number of individuals diagnosed with advanced LC. Multimodal public health interventions, such as educational campaigns are best suited to raise awareness, reduce barriers to help-seeking and help detect LC early. Future interventions ought to incorporate targeted information using educational resources, face-to-face counselling and video- and web-based decision aids.
Polygenic risk score for alcohol drinking behavior improves prediction of inflammatory bowel disease risk
Authors: Di Narzo Antonio F , Hart Amy , Kosoy Roman , Peters Lauren , Stojmirovic Aleksandar , Cheng Haoxiang , Zhang Zhongyang , Shan Mingxu , Cho Judy , Kasarskis Andrew , Argmann Carmen , Peter Inga , Schadt Eric E , Hao Ke
Published: February 2021

Epidemiological studies have long recognized risky behaviors as potentially modifiable factors for the onset and flares of inflammatory bowel disease (IBD); yet, the underlying mechanisms are largely unknown. Recently, the genetic susceptibilities to cigarette smoking, alcohol and cannabis use [i.e. substance use (SU)] have been characterized by well-powered genome-wide association studies (GWASs). We aimed to assess the impact of genetic determinants of SU on IBD risk. Using Mount Sinai Crohn’s and Colitis Registry (MSCCR) cohort of 1058 IBD cases and 188 healthy controls, we computed the polygenic risk score (PRS) for SU and correlated them with the observed IBD diagnoses, while adjusting for genetic ancestry, PRS for IBD and SU behavior at enrollment. The results were validated in a pediatric cohort with no SU exposure. PRS of alcohol consumption (DrnkWk), smoking cessation and age of smoking initiation, were associated with IBD risk in MSCCR even after adjustment for PRSIBD and actual smoking status. One interquartile range decrease in PRSDrnkWk was significantly associated to higher IBD risk (i.e. inverse association) (with odds ratio = 1.65 and 95% confidence interval: 1.32, 2.06). The association was replicated in a pediatric Crohn’s disease cohort. Colocalization analysis identified a locus on chromosome 16 with polymorphisms in IL27, SULT1A2 and SH2B1, which reached genome-wide statistical significance in GWAS (P < 7.7e-9) for both alcohol consumption and IBD risk. This study demonstrated that the genetic predisposition to SU was associated with IBD risk, independent of PRSIBD and in the absence of SU behaviors. Our study may help further stratify individuals at risk of IBD.
Single-cell RNA sequencing reveals species-specific time spans of cell cycle transitions in early oogenesis
Authors: Zhao Zheng-Hui , Meng Tie-Gang , Zhang Hong-Yong , Hou Yi , Schatten Heide , Wang Zhen-Bo , Sun Qing-Yuan
Published: February 2021

Oogenesis is a highly regulated process and its basic cellular events are evolutionarily conserved. However, the time spans of oogenesis differ substantially among species. To explore these interspecies differences in oogenesis, we performed single-cell RNA-sequencing on mouse and monkey female germ cells and downloaded the single-cell RNA-sequencing data of human female germ cells. The cell cycle analyses indicate that the period and extent of cell cycle transitions are significantly different between the species. Moreover, hierarchical clustering of critical cell cycle genes and the interacting network of cell cycle regulators also exhibit distinguished patterns across species. We propose that differences in the regulation of cell cycle transitions may underlie female germ cell developmental allochrony between species. A better understanding of the cell cycle transition machinery will provide new insights into the interspecies differences in female germ cell developmental time spans.
Transportation noise and risk of stroke: a nationwide prospective cohort study covering Denmark
Authors: Sørensen Mette , Poulsen Aslak Harbo , Hvidtfeldt Ulla Arthur , Münzel Thomas , Thacher Jesse Daniel , Ketzel Matthias , Brandt Jørgen , Christensen Jesper H , Levin Gregor , Raaschou-Nielsen Ole
Published: February 2021

Background

Studies on transportation noise and incident stroke are few and inconclusive. We aimed to investigate associations between road-traffic and railway noise and the risk of incident stroke in the entire Danish population.

Methods

We estimated road-traffic and railway noise (Lden) at the most and least exposed façades for all residential addresses across Denmark (2.8 million) for the period 1990–2017. Based on this, we estimated the 10-year time-weighted mean noise exposure for 3.6 million Danes aged >35 years, of whom 184 523 developed incident stroke during follow-up from 2000 to 2017. Analyses were conducted using Cox proportional-hazards models, with adjustment for various individual- and area-level demographic and socio-economic covariates collected from registries and air pollution [fine particulate matter with particles with a diameter of ≤2.5 µm (PM2.5) and nitrogen dioxide (NO2)].

Results

A 10-dB increase in the 10-year mean road-traffic noise at the most exposed façade was associated with an incidence rate ratio (IRR) of 1.04 [95% confidence interval (CI): 1.03–1.05] for all strokes. For road-traffic noise at the least exposed façade, the IRR per 10 dB was 1.03 (95% CI: 1.02–1.04) for all strokes. Railway noise was not associated with a higher risk of stroke.

Conclusion

Road-traffic noise increased the risk of stroke. These findings add to the evidence of road-traffic noise as a cardiovascular risk factor.
Mycobacterium tuberculosis Peptidyl Prolyl Isomerase A Interacts With Host Integrin Receptor to Exacerbate Disease Progression
Authors: Dubey Neha , Khan Mehak Zahoor , Kumar Suresh , Sharma Aditya , Das Lahari , Bhaduri Asani , Singh Yogendra , Nandicoori Vinay Kumar
Published: February 2021

Attenuated intracellular survival of Mycobacterium tuberculosis (Mtb) secretory gene mutants exemplifies their role as virulence factors. Mtb peptidyl prolyl isomerase A (PPiA) assists in protein folding through cis/trans isomerization of prolyl bonds. Here, we show that PPiA abets Mtb survival and aids in disease progression by exploiting host-associated factors. While the deletion of PPiA has no discernable effect on bacillary survival in a murine infection model, it compromises the formation of granuloma-like lesions and promotes host cell death through ferroptosis. Overexpression of PPiA enhances the bacillary load and exacerbates pathology in mice lungs. Importantly, PPiA interacts with the integrin α5β1 receptor through a conserved surface-exposed RGD motif. The secretion of PPiA as well as interaction with integrin contributes to disease progression by upregulating multiple host matrix metalloproteinases. Collectively, we identified a novel nonchaperone role of PPiA that is critical in facilitating host–pathogen interaction and ensuing disease progression.
Whole-Proteome Differential Screening Identifies Novel Vaccine Candidates forSchistosomiasis japonica
Authors: Wu Hannah W , Park Sangshin , Pond-Tor Sunthorn , Stuart Ron , Zhou Sha , Hong Yang , Ruiz Amanda E , Acosta Luz , Jarilla Blanca , Friedman Jennifer F , Jiz Mario , Kurtis Jonathan D
Published: February 2021

Schistosomiasis remains a leading cause of chronic morbidity in endemic regions despite decades of widespread mass chemotherapy with praziquantel. Using our whole proteome differential screening approach, and plasma and epidemiologic data from a longitudinal cohort of individuals living in a Schistosoma japonicum–endemic region of the Philippines, we interrogated the parasite proteome to identify novel vaccine candidates for Schistosoma japonicum. We identified 16 parasite genes which encoded proteins that were recognized by immunoglobulin G or immunoglobulin E antibodies in the plasma of individuals who had developed resistance to reinfection, but were not recognized by antibodies in the plasma of individuals who remained susceptible to reinfection. Antibody levels to Sj6-8 and Sj4-1 measured in the entire cohort (N = 505) 1 month after praziquantel treatment were associated with significantly decreased risk of reinfection and lower intensity of reinfection over 18 months of follow-up.
Human SLC15A4 is crucial for TLR-mediated type I interferon production and mitochondrial integrity
Authors: Kobayashi Toshihiko , Nguyen-Tien Dat , Ohshima Daisuke , Karyu Hitomi , Shimabukuro-Demoto Shiho , Yoshida-Sugitani Reiko , Toyama-Sorimachi Noriko
Published: February 2021

Solute carrier family 15 member 4 (SLC15A4) is an endolysosome-resident amino acid transporter that regulates innate immune responses, and is genetically associated with inflammatory diseases such as systemic lupus erythematosus (SLE) and colitis. SLC15A4-deficient mice showed the amelioration of symptoms of these model diseases, and thus SLC15A4 is a promising therapeutic target of SLE and colitis. For developing a SLC15A4-based therapeutic strategy, understanding human SLC15A4’s properties is essential. Here, we characterized human SLC15A4 and demonstrated that human SLC15A4 possessed pH- and temperature-dependent activity for the transportation of dipeptides or tripeptides. Human SLC15A4 localized in LAMP1+ compartments and constitutively associated with Raptor and LAMTORs. We also investigated SLC15A4’s role in inflammatory responses using the human plasmacytoid dendritic cell line, CAL-1. Knock down (KD) of the SLC15A4 gene in CAL-1 (SLC15A4-KD CAL-1) impaired Toll-like receptor (TLR) 7/8 or TLR9-triggered type I interferon (IFN-I) production and mTORC1 activity, indicating that human SLC15A4 is critical for TLR7/8/9-mediated inflammatory signaling. We also examined SLC15A4’s role in the autophagy response since SLC15A4 loss caused the decrease of mTORC1 activity, which greatly influences autophagy. We found that SLC15A4 was not required for autophagy induction, but was critical for autophagy sustainability. Notably, SLC15A4-KD CAL-1 severely decreased mitochondrial membrane potential in starvation conditions. Our findings revealed that SLC15A4 plays a key role in mitochondrial integrity in human cells, which might benefit immune cells in fulfilling their functions in an inflammatory milieu.
Establishment of a research policy for supportive and palliative care in Japan
Authors: Zenda Sadamoto , Uchitomi Yosuke , Morita Tatsuya , Yamaguchi Takuhiro , Inoue Akira
Published: February 2021

Background

While several small groups in Japan have attempted to conduct prospective studies in the field of supportive and palliative care, development of exploratory research into multicentre confirmatory studies has been difficult. The main reason for this is the difference in clinical research methodology in supportive and palliative care compared with medical oncology in terms of the style of multidisciplinary approaches, study design and endpoints. Here, we establish a new research policy for cancer supportive and palliative care in Japan.

Methods

The first draft was developed by a policy working group within the Japanese Supportive, Palliative and Psychosocial Care Study Group. A provisional draft was subsequently developed after review by nine Japanese scientific societies (Japanese Association of Supportive Care in Cancer, Japanese Society of Medical Oncology, Japanese Society of Clinical Oncology, Japanese Society of Palliative Medicine, Japanese Society of Cancer Nursing, Japanese Society of Pharmaceutical Oncology (JASPO), Japan Cancer Association (JCA), Japanese Society of Therapeutic Radiation Oncology and Japanese Cancer Association) and receipt of public comments. The final research policy in the area of supportive and palliative care in Japan (Ver1.0) was completed in December 2018 and underwent its first revision (Ver1.1) in February, 2020.

Results

The policy includes the following components of clinical research: (i) objective of the research policy in the areas of supportive and palliative care; (ii) definitions of supportive care and palliative care; (iii) characteristics of supportive and palliative care research; (iv) target population for research; (v) research design; (vi) endpoints and assessment measures; (vii) handling of the deaths of subjects and (viii) operational structure and quality management.

Conclusions

We hope that studies conducted according to this policy will play important roles in the future development of the supportive and palliative field.
A multi-institutional randomized phase III study comparing weekly carboplatin plus nab-paclitaxel and daily low-dose carboplatin as regimens for concurrent chemoradiotherapy in elderly patients with unresectable locally advanced non-small cell lung cancer: Japan Clinical Oncology Group Study JCOG1914
Authors: Shimoyama Ryo , Omori Shota , Nomura Shogo , Kenmotsu Hirotsugu , Takahashi Toshiaki , Harada Hideyuki , Ishikura Satoshi , Mizutani Tomonori , Ando Masahiko , Kataoka Tomoko , Fukuda Haruhiko , Ohe Yuichiro ,   the Lung Cancer Study Group in the Japan Clinical Oncology Group
Published: February 2021

Daily low-dose carboplatin plus concurrent thoracic radiotherapy is the standard treatment for elderly patients with unresectable clinical stage (c-Stage) III non-small cell lung cancer (NSCLC) in Japan. However, a phase I study by Omori et al. suggests that weekly carboplatin and nab-paclitaxel plus concurrent thoracic radiotherapy have comparable efficacy outcomes with more manageable adverse events. In December 2020, we initiated a randomized controlled trial in Japan to confirm whether the weekly carboplatin plus nab-paclitaxel regimen is noninferior to the daily low-dose carboplatin regimen for concurrent chemoradiotherapy in elderly patients with unresectable c-Stage III NSCLC. We plan to enroll 166 patients from 50 institutions in 3.5 years. The primary endpoint is overall survival. The secondary endpoints are progression-free survival, response rate, proportion of patients starting maintenance durvalumab therapy, adverse events, site of progression, Functional Assessment of Cancer Therapy–Trial Outcome Index deterioration and Instrumental Activities of Daily Living deterioration.
Effect of the p53 P72R Polymorphism on Mutant TP53 Allele Selection in Human Cancer
Authors: De Souza Cristabelle , Madden Jill , Koestler Devin C , Minn Dennis , Montoya Dennis J , Minn Kay , Raetz Alan G , Zhu Zheng , Xiao Wen-Wu , Tahmassebi Neeki , Kathi Harikumara R , Nelson Nina , Karnezis Anthony N , Chien Jeremy
Published: February 2021

Background

TP53 mutations occur in more than 50% of cancers. We sought to determine the effect of the intragenic P72R single nucleotide polymorphism (SNP; rs1042522) on the oncogenic properties of mutant p53.

Methods

P72R allelic selection in tumors was determined from genotype calls and a Gaussian distributed mixture model. The SNP effect on mutant p53 was determined in p53-negative cancer cell lines. RNA-sequencing, chromatin immunoprecipitation, and survival analysis were performed to describe the SNP effect. All statistical tests were 2-sided.

Results

Among 409 patients with germline heterozygous P72R SNP who harbored somatic mutations in TP53, we observed a selection bias against missense TP53 mutants encoding the P72 SNP (P = 1.64 x 10-13). Exogenously expressed hotspot p53 mutants with the P72 SNP were negatively selected in cancer cells. Gene expression analyses showed the enrichment of p53 pathway genes and inflammatory genes in cancer cells transduced with mutants encoding P72 SNP. Immune gene signature is enriched in patients harboring missense TP53 mutations with homozygous P72 SNP. These patients have improved overall survival as compared with those with the R72 SNP (P = .04).

Conclusion

This is the largest study demonstrating a selection against the P72 SNP. Missense p53 mutants with the P72 SNP retain partial wild-type tumor-suppressive functions, which may explain the selection bias against P72 SNP across cancer types. Ovarian cancer patients with the P72 SNP have a better prognosis than with the R72 SNP. Our study describes a previously unknown role through which the rs1042522 SNP modifies tumor suppressor activities of mutant p53 in patients.
Effect of Early Palliative Care on Quality of Life of Advanced Head and Neck Cancer Patients: A Phase III Trial
Authors: Patil Vijay Maruti , Singhai Pankaj , Noronha Vanita , Bhattacharjee Atanu , Deodhar Jayita , Salins Naveen , Joshi Amit , Menon Nandini Sharrel , Abhyankar Anuja , Khake Ashwini , Dhumal Sachin Babanrao , Tambe Rupali , Muckaden Mary Ann , Prabhash Kumar
Published: February 2021

Background

Early palliative care (EPC) is an important aspect of cancer management but, to our knowledge, has never been evaluated in patients with head and neck cancer. Hence, we performed this study to determine whether the addition of EPC to standard therapy leads to an improvement in the quality of life (QOL), decrease in symptom burden, and improvement in overall survival.

Methods

Adult patients with squamous cell carcinoma of the head and neck region planned for palliative systemic therapy were allocated 1:1 to either standard systemic therapy without or with comprehensive EPC service referral. Patients were administered the revised Edmonton Symptom Assessment Scale and the Functional Assessment of Cancer Therapy for head and neck cancer (FACT-H&N) questionnaire at baseline and every 1 month thereafter for 3 months. The primary endpoint was a change in the QOL measured at 3 months after random assignment. All statistical tests were 2-sided.

Results

Ninety patients were randomly assigned to each arm. There was no statistical difference in the change in the FACT-H&N total score (P = .94), FACT-H&N Trial Outcome Index (P = .95), FACT-general total (P = .84), and Edmonton Symptom Assessment Scale scores at 3 months between the 2 arms. The median overall survival was similar between the 2 arms (hazard ratio for death = 1.01, 95% confidence interval = 0.74 to 1.35). There were 5 in-hospital deaths in both arms (5.6% for both, P = .99).

Conclusions

In this phase III study, the integration of EPC in head and neck cancer patients did not lead to an improvement in the QOL or survival.
Diurnal variation of transitory starch metabolism is regulated by plastid proteins WXR1/WXR3 in Arabidopsis young seedlings
Authors: Zou Wenjiao , Liu Kui , Gao Xueping , Yu Changjiang , Wang Xiaofei , Shi Junjie , Chao Yanru , Yu Qian , Zhou Gongke , Ge Lei
Published: February 2021

Transitory starch is the portion of starch that is synthesized during the day in the chloroplast and usually used for plant growth overnight. Here, we report altered metabolism of transitory starch in the wxr1/wxr3 (weak auxin response 1/3) mutants of Arabidopsis. WXR1/WXR3 were previously reported to regulate root growth of young seedlings and affect the auxin response mediated by auxin polar transport in Arabidopsis. In this study the wxr1/wxr3 mutants accumulated transitory starch in cotyledon, young leaf, and hypocotyl at the end of night. WXR1/WXR3 expression showed diurnal variation. Grafting experiments indicated that the WXRs in root were necessary for proper starch metabolism and plant growth. We also found that photosynthesis was inhibited and the transcription level of DIN1/DIN6 (Dark-Inducible 1/6) was reduced in wxr1/wxr3. The mutants also showed a defect in the ionic equilibrium of Na+ and K+, consistent with our bioinformatics data that genes related to ionic equilibrium were misregulated in wxr1. Loss of function of WXR1 also resulted in abnormal trafficking of membrane lipids and proteins. This study reveals that the plastid proteins WXR1/WXR3 play important roles in promoting transitory starch degradation for plant growth over night, possibly through regulating ionic equilibrium in the root.
A natural boundary of dark matter haloes revealed around the minimum bias and maximum infall locations
Authors: Fong Matthew , Han Jiaxin
Published: February 2021

We explore the boundary of dark matter haloes through their bias and velocity profiles. Using cosmological N-body simulations, we show that the bias profile exhibits a ubiquitous trough that can be interpreted as created by halo accretion that depletes material around the boundary. The inner edge of the active depletion region is marked by the location of the maximum mass inflow rate that separates a growing halo from the draining environment. This inner depletion radius can also be interpreted as the radius enclosing a highly complete population of splashback orbits, and matches the optimal exclusion radius in a halo model of the large-scale structure. The minimum of the bias trough defines a characteristic depletion radius, which is located within the infall region bounded by the inner depletion radius and the turnaround radius, while approaching the turnaround radius in low-mass haloes that have stopped mass accretion. The characteristic depletion radius depends the most on halo mass and environment. It is approximately 2.5 times the virial radius and encloses an average density of ∼40 times the background density of the universe, independent on halo mass but dependent on other halo properties. The inner depletion radius is smaller by 10–20 per cent and encloses an average density of ∼63 times the background density. These radii open a new window for studying the properties of haloes.
On the environments of giant radio galaxies
Authors: Lan 藍鼎文 Ting-Wen , Xavier Prochaska J
Published: February 2021

We test the hypothesis that environments play a key role in enabling the growth of enormous radio structures spanning more than 700 kpc, an extreme population of radio galaxies called giant radio galaxies (GRGs). To achieve this, we explore (1) the relationships between the occurrence of GRGs and the surface number density of surrounding galaxies, including satellite galaxies and galaxies from neighbouring haloes, and (2) the GRG locations towards large-scale structures. The analysis is done by making use of a homogeneous sample of 110 GRGs detected from the LOFAR Two-metre Sky Survey in combination with photometric galaxies from the DESI Legacy Imaging Surveys and a large-scale filament catalogue from the Sloan Digital Sky Survey. Our results show that the properties of galaxies around GRGs are similar with that around the two control samples, consisting of galaxies with optical colours and luminosity matched to the properties of the GRG host galaxies. Additionally, the properties of surrounding galaxies depend on neither their relative positions to the radio jet/lobe structures nor the sizes of GRGs. We also find that the locations of GRGs and the control samples with respect to the nearby large-scale structures are consistent with each other. These results demonstrate that there is no correlation between the GRG properties and their environments traced by stars, indicating that external galaxy environments are not the primary cause of the large sizes of the radio structures. Finally, regarding radio feedback, we show that the fraction of blue satellites does not correlate with the GRG properties, suggesting that the current epoch of radio jets has minimal influence on the nature of their surrounding galaxies.
Dust traps and the formation of cavities in transition discs: a millimetre to sub-millimetre comparison survey
Authors: Norfolk Brodie J , Maddison Sarah T , Pinte Christophe , van der Marel Nienke , Booth Richard A , Francis Logan , Gonzalez Jean-François , Ménard François , Wright Chris M , van der Plas Gerrit , Garg Himanshi
Published: February 2021

The origin of the inner dust cavities observed in transition discs remains unknown. The segregation of dust and size of the cavity is expected to vary depending on which clearing mechanism dominates grain evolution. We present the results from the Discs Down Under program, an 8.8-mm continuum Australia Telescope Compact Array (ATCA) survey targeting 15 transition discs with large (≳20 au) cavities and compare the resulting dust emission to Atacama Large millimetre/sub-millimetre Array (ALMA) observations. Our ATCA observations resolve the inner cavity for 8 of the 14 detected discs. We fit the visibilities and reconstruct 1D radial brightness models for 10 sources with a S/N > 5σ. We find that, for sources with a resolved cavity in both wavebands, the 8.8 mm and sub-mm brightness distributions peak at the same radius from the star. We suggest that a similar cavity size for 8.8 mm and sub-mm dust grains is due to a dust trap induced by the presence of a companion.
Probing frequency-dependent half-wave plate systematics for CMB experiments with full-sky beam convolution simulations
Authors: Duivenvoorden Adriaan J , Adler Alexandre E , Billi Matteo , Dachlythra Nadia , Gudmundsson Jon E
Published: February 2021

We study systematic effects from half-wave plates (HWPs) for cosmic microwave background (CMB) experiments using full-sky time-domain beam convolution simulations. Using an optical model for a fiducial spaceborne two-lens refractor telescope, we investigate how different HWP configurations optimized for dichroic detectors centred at 95 and 150 GHz impact the reconstruction of primordial B-mode polarization. We pay particular attention to possible biases arising from the interaction of frequency-dependent HWP non-idealities with polarized Galactic dust emission and the interaction between the HWP and the instrumental beam. To produce these simulations, we have extended the capabilities of the publicly available beamconv code. To our knowledge, we produce the first time-domain simulations that include both HWP non-idealities and realistic full-sky beam convolution. Our analysis shows how certain achromatic HWP configurations produce significant systematic polarization angle offsets that vary for sky components with different frequency dependence. Our analysis also demonstrates that once we account for interactions with HWPs, realistic beam models with non-negligible cross-polarization and sidelobes will cause significant B-mode residuals that will have to be extensively modelled in some cases.
CNN architecture comparison for radio galaxy classification
Authors: Becker Burger , Vaccari Mattia , Prescott Matthew , Grobler Trienko
Published: February 2021

The morphological classification of radio sources is important to gain a full understanding of galaxy evolution processes and their relation with local environmental properties. Furthermore, the complex nature of the problem, its appeal for citizen scientists, and the large data rates generated by existing and upcoming radio telescopes combine to make the morphological classification of radio sources an ideal test case for the application of machine learning techniques. One approach that has shown great promise recently is convolutional neural networks (CNNs). Literature, however, lacks two major things when it comes to CNNs and radio galaxy morphological classification. First, a proper analysis of whether overfitting occurs when training CNNs to perform radio galaxy morphological classification using a small curated training set is needed. Secondly, a good comparative study regarding the practical applicability of the CNN architectures in literature is required. Both of these shortcomings are addressed in this paper. Multiple performance metrics are used for the latter comparative study, such as inference time, model complexity, computational complexity, and mean per class accuracy. As part of this study, we also investigate the effect that receptive field, stride length, and coverage have on recognition performance. For the sake of completeness, we also investigate the recognition performance gains that we can obtain by employing classification ensembles. A ranking system based upon recognition and computational performance is proposed. MCRGNet, Radio Galaxy Zoo, and ConvXpress (novel classifier) are the architectures that best balance computational requirements with recognition performance.
The kinematics of globular cluster populations in the E-MOSAICS simulations and their implications for the assembly history of the Milky Way
Authors: Trujillo-Gomez Sebastian , Diederik Kruijssen J M , Reina-Campos Marta , Pfeffer Joel L , Keller Benjamin W , Crain Robert A , Bastian Nate , Hughes Meghan E
Published: February 2021

We present a detailed comparison of the Milky Way (MW) globular cluster (GC) kinematics with the 25 MW-mass cosmological simulations from the E-MOSAICS project. While the MW falls within the kinematic distribution of GCs spanned by the simulations, the relative kinematics of its metal-rich ($[\rm {Fe}/\rm {H}] \gt -1.2$) versus metal-poor ($[\rm {Fe}/\rm {H}] \lt -1.2$) and inner (r < 8 kpc) versus outer (r > 8 kpc) populations are atypical for its mass. To understand the origins of these features, we perform a comprehensive statistical analysis of the simulations, and find 18 correlations describing the assembly of L* galaxies and their dark matter haloes based on their GC population kinematics. The correlations arise because the orbital distributions of accreted and in situ GCs depend on the masses and accretion redshifts of accreted satellites, driven by the combined effects of dynamical fraction, tidal stripping, and dynamical heating. Because the kinematics of in situ/accreted GCs are broadly traced by the metal-rich/metal-poor and inner/outer populations, the observed GC kinematics are a sensitive probe of galaxy assembly. We predict that relative to the population of L* galaxies, the MW assembled its dark matter and stellar mass rapidly through a combination of in situ star formation, more than a dozen low-mass mergers, and 1.4 ± 1.2 early ($z$ = 3.1 ± 1.3) major mergers. The rapid assembly period ended early, limiting the fraction of accreted stars. We conclude by providing detailed quantitative predictions for the assembly history of the MW.
Engineering nucleosomes for generating diverse chromatin assemblies
Authors: Adhireksan Zenita , Sharma Deepti , Lee Phoi Leng , Bao Qiuye , Padavattan Sivaraman , Shum Wayne K , Davey Gabriela E , Davey Curt A
Published: February 2021

Structural characterization of chromatin is challenging due to conformational and compositional heterogeneity in vivo and dynamic properties that limit achievable resolution in vitro. Although the maximum resolution for solving structures of large macromolecular assemblies by electron microscopy has recently undergone profound increases, X-ray crystallographic approaches may still offer advantages for certain systems. One such system is compact chromatin, wherein the crystalline state recapitulates the crowded molecular environment within the nucleus. Here we show that nucleosomal constructs with cohesive-ended DNA can be designed that assemble into different types of circular configurations or continuous fibers extending throughout crystals. We demonstrate the utility of the method for characterizing nucleosome compaction and linker histone binding at near-atomic resolution but also advance its application for tackling further problems in chromatin structural biology and for generating novel types of DNA nanostructures. We provide a library of cohesive-ended DNA fragment expression constructs and a strategy for engineering DNA-based nanomaterials with a seemingly vast potential variety of architectures and histone chemistries.
Epstein-Barr virus inactivates the transcriptome and disrupts the chromatin architecture of its host cell in the first phase of lytic reactivation
Authors: Buschle Alexander , Mrozek-Gorska Paulina , Cernilogar Filippo M , Ettinger Andreas , Pich Dagmar , Krebs Stefan , Mocanu Bianca , Blum Helmut , Schotta Gunnar , Straub Tobias , Hammerschmidt Wolfgang
Published: February 2021

Epstein-Barr virus (EBV), a herpes virus also termed HHV 4 and the first identified human tumor virus, establishes a stable, long-term latent infection in human B cells, its preferred host. Upon induction of EBV’s lytic phase, the latently infected cells turn into a virus factory, a process that is governed by EBV. In the lytic, productive phase, all herpes viruses ensure the efficient induction of all lytic viral genes to produce progeny, but certain of these genes also repress the ensuing antiviral responses of the virally infected host cells, regulate their apoptotic death or control the cellular transcriptome. We now find that EBV causes previously unknown massive and global alterations in the chromatin of its host cell upon induction of the viral lytic phase and prior to the onset of viral DNA replication. The viral initiator protein of the lytic cycle, BZLF1, binds to >105 binding sites with different sequence motifs in cellular chromatin in a concentration dependent manner implementing a binary molar switch probably to prevent noise-induced erroneous induction of EBV’s lytic phase. Concomitant with DNA binding of BZLF1, silent chromatin opens locally as shown by ATAC-seq experiments, while previously wide-open cellular chromatin becomes inaccessible on a global scale within hours. While viral transcripts increase drastically, the induction of the lytic phase results in a massive reduction of cellular transcripts and a loss of chromatin-chromatin interactions of cellular promoters with their distal regulatory elements as shown in Capture-C experiments. Our data document that EBV’s lytic cycle induces discrete early processes that disrupt the architecture of host cellular chromatin and repress the cellular epigenome and transcriptome likely supporting the efficient de novo synthesis of this herpes virus.