bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peripheral blood RNA biomarkers for cardiovascular disease from bench to bedside: a position paper from the EU-CardioRNA COST action CA17129
Authors: Vanhaverbeke Maarten , Attard Ritienne , Bartekova Monika , Ben-Aicha Soumaya , Brandenburger Timo , de Gonzalo-Calvo David , Emanueli Costanza , Farrugia Rosienne , Grillari Johannes , Hackl Matthias , Kalocayova Barbora , Martelli Fabio , Scholz Markus , Wettinger Stephanie Bezzina , Devaux Yvan 
Published: October 2021

Abstract
Despite significant advances in the diagnosis and treatment of cardiovascular diseases, recent calls have emphasized the unmet need to improve precision-based approaches in cardiovascular disease. Although some studies provide preliminary evidence of the diagnostic and prognostic potential of circulating coding and non-coding RNAs, the complex RNA biology and lack of standardization have hampered the translation of these markers into clinical practice. In this position paper of the CardioRNA COST action CA17129, we provide recommendations to standardize the RNA development process in order to catalyse efforts to investigate novel RNAs for clinical use. We list the unmet clinical needs in cardiovascular disease, such as the identification of high-risk patients with ischaemic heart disease or heart failure who require more intensive therapies. The advantages and pitfalls of the different sample types, including RNAs from plasma, extracellular vesicles, and whole blood, are discussed in the sample matrix, together with their respective analytical methods. The effect of patient demographics and highly prevalent comorbidities, such as metabolic disorders, on the expression of the candidate RNA is presented and should be reported in biomarker studies. We discuss the statistical and regulatory aspects to translate a candidate RNA from a research use only assay to an in-vitro diagnostic test for clinical use. Optimal planning of this development track is required, with input from the researcher, statistician, industry, and regulatory partners.
Neutrophil extracellular traps: from physiology to pathology
Authors: Hidalgo Andres , Libby Peter , Soehnlein Oliver , Aramburu Iker Valle , Papayannopoulos Venizelos , Silvestre-Roig Carlos 
Published: October 2021

AbstractAt the frontline of the host defence response, neutrophil antimicrobial functions have adapted to combat infections and injuries of different origins and magnitude. The release of web-like DNA structures named neutrophil extracellular traps (NETs) constitutes an important mechanism by which neutrophils prevent pathogen dissemination or deal with microorganisms of a bigger size. At the same time, nuclear and granule proteins with microbicidal activity bind to these DNA structures promoting the elimination of entrapped pathogens. However, these toxic properties may produce unwanted effects in the host, when neutrophils uncontrollably release NETs upon persistent inflammation. As a consequence, NET accumulation can produce vessel occlusion, tissue damage, and prolonged inflammation associated with the progression and exacerbation of multiple pathologic conditions. This review outlines recent advances in understanding the mechanisms of NET release and functions in sterile disease. We also discuss mechanisms of physiological regulation and the importance of neutrophil heterogeneity in NET formation and composition.
Hypochloraemia following admission to hospital with heart failure is common and associated with an increased risk of readmission or death: a report from OPERA-HF
Authors: Cuthbert J J , Brown O I , Urbinati A , Pan D , Pellicori P , Dobbs K , Bulemfu J , Kazmi S , Sokoreli I , Pauws S C , Riistama J M , Cleland J G F , Clark A L 
Published: October 2021

Abstract

Aims
Hypochloraemia is common in patients hospitalized with heart failure (HF) and associated with a high risk of adverse outcomes during admission and following discharge. We assessed the significance of changes in serum chloride concentrations in relation to serum sodium and bicarbonate concentrations during admission in a cohort of 1002 consecutive patients admitted with HF and enrolled into an observational study based at a single tertiary centre in the UK.

Methods and results
Hypochloraemia (&lt;96 mmol/L), hyponatraemia (&lt;135 mmol/L), and metabolic alkalosis (bicarbonate &gt;32 mmol/L) were defined by local laboratory reference ranges. Outcomes assessed were all-cause mortality, all-cause mortality or all-cause readmission, and all-cause mortality or HF readmission. Cox regression and Kaplan–Meier curves were used to investigate associations with outcome. During a median follow-up of 856 days (interquartile range 272–1416), discharge hypochloraemia, regardless of serum sodium, or bicarbonate levels was associated with greater all-cause mortality [hazard ratio (HR) 1.44, 95% confidence interval (CI) 1.15–1.79; P = 0.001], all-cause mortality or all-cause readmission (HR 1.26, 95% CI 1.04–1.53; P = 0.02), and all-cause mortality or HF readmission (HR 1.41, 95% CI 1.14–1.74; P = 0.002) after multivariable adjustment. Patients with concurrent hypochloraemia and natraemia had lower haemoglobin and haematocrit, suggesting congestion; those with hypochloraemia and normal sodium levels had more metabolic alkalosis, suggesting decongestion.

Conclusion
Hypochloraemia is common at discharge after a hospitalization for HF and is associated with worse outcome subsequently. It is an easily measured clinical variables that is associated with morbidity or mortality of any cause.
Bitter taste receptors
Authors: Wooding Stephen P , Ramirez Vicente A , Behrens Maik 
Published: October 2021

AbstractBitter taste perception plays vital roles in animal behavior and fitness. By signaling the presence of toxins in foods, particularly noxious defense compounds found in plants, it enables animals to avoid exposure. In vertebrates, bitter perception is initiated by TAS2Rs, a family of G protein-coupled receptors expressed on the surface of taste buds. There, oriented toward the interior of the mouth, they monitor the contents of foods, drinks and other substances as they are ingested. When bitter compounds are encountered, TAS2Rs respond by triggering neural pathways leading to sensation. The importance of this role placed TAS2Rs under selective pressures in the course of their evolution, leaving signatures in patterns of gene gain and loss, sequence polymorphism, and population structure consistent with vertebrates' diverse feeding ecologies. The protective value of bitter taste is reduced in modern humans because contemporary food supplies are safe and abundant. However, this is not always the case. Some crops, particularly in the developing world, retain surprisingly high toxicity and bitterness remains an important measure of safety. Bitter perception also shapes health through its influence on preference driven behaviors such as diet choice, alcohol intake and tobacco use. Further, allelic variation in TAS2Rs is extensive, leading to individual differences in taste sensitivity that drive these behaviors, shaping susceptibility to disease. Thus, bitter taste perception occupies a critical intersection between ancient evolutionary processes and modern human health.
Simultaneous calibration of instrument scale factor and drift rate in network adjustment for continental-scale gravity survey campaign
Authors: Wang Linhai , Chen Shi , Zhuang Jiancang , Xu Weimin 
Published: October 2021

SUMMARY
The scale factor of each relative gravimeter must be calibrated both before and after the fieldwork of a terrestrial gravity survey, to reduce uncertainties and ensure high precision. Conventionally, such calibration is a time-consuming process performed following well-established baselines. We propose a new Bayesian method to estimate the scale factor in a hybrid gravity network that includes several absolute gravity observation stations. In this approach, the scale factor is estimated as a hyperparameter using the Akaike Bayesian information criterion and using known absolute gravity stations in the network or/and calibrated instruments as constraints. Testing the sensitivity of the gravity values and the residuals of the gravity difference between two successive stations to the change of the scale factor demonstrates the robustness of this method. We also test the sensitivity of the estimated scale factor in the presence of Gaussian noise and the non-linear instrumental drift rate. Moreover, if the maximum absolute gravity interval is greater than 60 per cent of the range of gravity values in the network, or if the known scale factors of calibrated gravimeters are well calibrated, this approach can provide reasonable estimates of the daily drift rate and the unknown scale factors, where the latter has an error of &lt;3 × 10−5. We apply this approach to real gravity campaign data from Yunnan in China and use a cross-validation method to compare estimated gravity values and corresponding gravity values obtained from absolute gravity observations at the same stations, to validate how the proposed method improves estimation accuracy of the gravity value at each station.
The adeno-associated virus 2 genome and Rep 68/78 proteins interact with cellular sites of DNA damage
Authors: Boftsi Maria , Whittle Fawn B , Wang Juexin , Shepherd Phoenix , Burger Lisa R , Kaifer Kevin A , Lorson Christian L , Joshi Trupti , Pintel David J , Majumder Kinjal 
Published: October 2021

Abstract
Nuclear DNA viruses simultaneously access cellular factors that aid their life cycle while evading inhibitory factors by localizing to distinct nuclear sites. Adeno-associated viruses (AAVs), which are Dependoviruses in the family Parvovirinae, are non-enveloped icosahedral viruses, which have been developed as recombinant AAV vectors to express transgenes. AAV2 expression and replication occur in nuclear viral replication centers (VRCs), which relies on cellular replication machinery as well as coinfection by helper viruses such as adenoviruses or herpesviruses, or exogenous DNA damage to host cells. AAV2 infection induces a complex cellular DNA damage response (DDR), in response to either viral DNA or viral proteins expressed in the host nucleus during infection, where VRCs co-localized with DDR proteins. We have previously developed a modified iteration of a viral chromosome conformation capture (V3C-seq) assay to show that the autonomous parvovirus minute virus of mice localizes to cellular sites of DNA damage to establish and amplify its replication. Similar V3C-seq assays to map AAV2 show that the AAV2 genome co-localized with cellular sites of DNA damage under both non-replicating and replicating conditions. The AAV2 non-structural protein Rep 68/78, also localized to cellular DDR sites during both non-replicating and replicating infections, and also when ectopically expressed. Ectopically expressed Rep could be efficiently re-localized to DDR sites induced by micro-irradiation. Recombinant AAV2 gene therapy vector genomes derived from AAV2 localized to sites of cellular DNA damage to a lesser degree, suggesting that the inverted terminal repeat origins of replication were insufficient for targeting.
Differential impact of Kv8.2 loss on rod and cone signaling and degeneration
Authors: Inamdar Shivangi M , Lankford Colten K , Poria Deepak , Laird Joseph G , Solessio Eduardo , Kefalov Vladimir J , Baker Sheila A 
Published: October 2021

Abstract
Heteromeric Kv2.1/Kv8.2 channels are voltage-gated potassium channels localized to the photoreceptor inner segment. They carry IKx, which is largely responsible for setting the photoreceptor resting membrane potential. Mutations in Kv8.2 result in childhood-onset cone dystrophy with supernormal rod response (CDSRR). We generated a Kv8.2 knockout (KO) mouse and examined retinal signaling and photoreceptor degeneration to gain deeper insight into the complex phenotypes of this disease. Using electroretinograms, we show that there were delayed or reduced signaling from rods depending on the intensity of the light stimulus, consistent with reduced capacity for light-evoked changes in membrane potential. The delayed response was not seen ex vivo where extracellular potassium levels were controlled by the perfusion buffer, so we propose the in vivo alteration is influenced by genotype-associated ionic imbalance. We observed mild retinal degeneration. Signaling from cones was reduced but there was no loss of cone density. Loss of Kv8.2 altered responses to flickering light with responses attenuated at high frequencies and altered in shape at low frequencies. The Kv8.2 KO line on an all-cone retina background had reduced cone-driven ERG b wave amplitudes and underwent degeneration. Altogether, we provide insight into how a deficit in the dark current affects the health and function of photoreceptors.
Expanded practice for rural community pharmacy: what are we waiting for?
Authors: Taylor Selina M , Cairns Alice , Glass Beverley D 
Published: October 2021

Abstract

Objective
To synthesise stakeholder (consumer, pharmacist and health professional) perspectives of expanded pharmacy practice in rural and remote community pharmacy.

Methods
Comparison of perspectives of stakeholder groups identified by four studies has highlighted the expected outcomes and anticipated barriers to expanded pharmacy practice. Aligning the studies has identified priority areas of health for which pharmacists may be able to provide expanded service delivery.

Key findings
Expanded pharmacy services are supported by consumers, pharmacists and health professionals and are expected to improve health outcomes for rural and remote populations. Barriers will need to be overcome for expanded services to be sustainable in the future.

Conclusion
The pharmacy profession will need to undertake a paradigm shift to professional practice and work towards this should begin to reduce the health inequality for rural populations.
Comorbid insomnia among breast cancer survivors and its prediction using machine learning: a nationwide study in Japan
Authors: Ueno Taro , Ichikawa Daisuke , Shimizu Yoichi , Narisawa Tomomi , Tsuji Katsunori , Ochi Eisuke , Sakurai Naomi , Iwata Hiroji , Matsuoka Yutaka J 
Published: October 2021

AbstractObjectiveInsomnia is an increasingly recognized major symptom of breast cancer which can seriously disrupt the quality of life during and many years after treatment. Sleep problems have also been linked with survival in women with breast cancer. The aims of this study were to estimate the prevalence of insomnia in breast cancers survivors, clarify the clinical characteristics of their sleep difficulties and use machine learning techniques to explore clinical insights.MethodsOur analysis of data, obtained in a nationwide questionnaire survey of breast cancer survivors in Japan, revealed a prevalence of suspected insomnia of 37.5%. With the clinical data obtained, we then used machine learning algorithms to develop a classifier that predicts comorbid insomnia. The performance of the prediction model was evaluated using 8-fold cross-validation.ResultsWhen using optimal hyperparameters, the L2 penalized logistic regression model and the XGBoost model provided predictive accuracy of 71.5 and 70.6% for the presence of suspected insomnia, with areas under the curve of 0.76 and 0.75, respectively. Population segments with high risk of insomnia were also extracted using the RuleFit algorithm. We found that cancer-related fatigue is a predictor of insomnia in breast cancer survivors.ConclusionsThe high prevalence of sleep problems and its link with mortality warrants routine screening. Our novel predictive model using a machine learning approach offers clinically important insights for the early detection of comorbid insomnia and intervention in breast cancer survivors.
From Traction to Treaty-Bound: Jus Cogens, Erga Omnes and Corporate Subjectivity in International Investment Arbitration
Authors: Crow Kevin , Lorenzoni-Escobar Lina 
Published: October 2021

Abstract
This article suggests that the arbitral use of jus cogens and erga omnes is slowly producing a ‘presumption of applicability’ in investor–state arbitration tribunals tasked with determining whether international law applies to investors. Looking backward from two recent counterclaims at tribunals established under investor–state dispute settlement (ISDS) clauses in international investment agreements that support our claim, the article first analyses the evolution and use of jus cogens in attaching rights-claims to non-State subjects of international law. Secondly, it explores the origins and uses of obligations erga omnes in attaching obligations-claims to non-State subjects of international law. It attempts to define the contours of jus cogens and erga omnes as they are deployed in recent ISDS case law and highlights the limits of each concept. The article concludes that there is a potential for a presumption of applicability in international investment arbitration for investor obligations and that this presumption can be sourced from general international law.
Endoscopic transorbital management of frontal sinus mucocele: a case report and review of the literature
Authors: Alaraifi Abdulaziz K , Alrusayyis Danah F , Alzuwayed Abdullah , Alobaid Fahad , AlRajeh Mohammed , Alhedaithy Riyadh 
Published: October 2021

AbstractThe frontal sinus is the most common site for paranasal mucoceles, resulting in potentially threatening intraorbital or intracranial complications. Surgical drainage of mucoceles is the mainstay of treatment, which can be achieved usually through open or endoscopic transnasal approaches. Transorbital endoscopic surgery is a relatively novel approach to selective skull base lesions with limited data in the literature. It could be utilized as a safe and effective alternative approach in managing frontal sinus lesions when the endoscopic transnasal access alone is insufficient or inadequate. Here, we present a case of an isolated lateral left frontal mucocele that was managed successfully using an endoscopic transorbital approach alone with complete resolution of symptoms during a 10-month follow-up period.
Accretion of tidally disrupted asteroids on to white dwarfs: direct accretion versus disc processing
Authors: Li Daohai , Mustill Alexander J , Davies Melvyn B 
Published: October 2021

ABSTRACT
Atmospheric heavy elements have been observed in more than a quarter of white dwarfs (WDs) at different cooling ages, indicating ongoing accretion of asteroidal material, whilst only a few per cent of the WDs possess a dust disc, and all these WDs are accreting metals. Here, assuming that a rubble-pile asteroid is scattered inside a WD’s Roche lobe by a planet, we study its tidal disruption and the long-term evolution of the resulting fragments. We find that after a few pericentric passages, the asteroid is shredded into its constituent particles, forming a flat, thin ring. On a time-scale of Myr, tens of per cent of the particles are scattered on to the WD, and are therefore directly accreted without first passing through a circularized close-in disc. Fragment mutual collisions are most effective for coplanar fragments, and are thus only important in 103−104 yr before the orbital coplanarity is broken by the planet. We show that for a rubble pile asteroid with a size frequency distribution of the component particles following that of the near earth objects, it has to be roughly at least 10 km in radius such that enough fragments are generated and $\ge 10{{\ \rm per\ cent}}$ of its mass is lost to mutual collisions. At relative velocities of tens of km s−1, such collisions grind down the tidal fragments into smaller and smaller dust grains. The WD radiation forces may shrink those grains’ orbits, forming a dust disc. Tidal disruption of a monolithic asteroid creates large km-size fragments, and only parent bodies ≥100 km are able to generate enough fragments for mutual collisions to be significant. Hence, those large asteroids experience a disc phase before being accreted.
Enhancer architecture-dependent multilayered transcriptional regulation orchestrates RA signaling-induced early lineage differentiation of ESCs
Authors: Su Guangsong , Wang Wenbin , Zhao Xueyuan , Chen Jun , Zheng Jian , Liu Man , Bi Jinfang , Guo Dianhao , Chen Bohan , Zhao Zhongfang , Shi Jiandang , Zhang Lei , Lu Wange 
Published: October 2021

Abstract
Signaling pathway-driven target gene transcription is critical for fate determination of embryonic stem cells (ESCs), but enhancer-dependent transcriptional regulation in these processes remains poorly understood. Here, we report enhancer architecture-dependent multilayered transcriptional regulation at the Halr1–Hoxa1 locus that orchestrates retinoic acid (RA) signaling-induced early lineage differentiation of ESCs. We show that both homeobox A1 (Hoxa1) and Hoxa adjacent long non-coding RNA 1 (Halr1) are identified as direct downstream targets of RA signaling and regulated by RARA/RXRA via RA response elements (RAREs). Chromosome conformation capture-based screens indicate that RA signaling promotes enhancer interactions essential for Hoxa1 and Halr1 expression and mesendoderm differentiation of ESCs. Furthermore, the results also show that HOXA1 promotes expression of Halr1 through binding to enhancer; conversely, loss of Halr1 enhances interaction between Hoxa1 chromatin and four distal enhancers but weakens interaction with chromatin inside the HoxA cluster, leading to RA signaling-induced Hoxa1 overactivation and enhanced endoderm differentiation. These findings reveal complex transcriptional regulation involving synergistic regulation by enhancers, transcription factors and lncRNA. This work provides new insight into intrinsic molecular mechanisms underlying ESC fate determination during RA signaling-induced early differentiation.
FAN1’s protection against CGG repeat expansion requires its nuclease activity and is FANCD2-independent
Authors: Zhao Xiaonan , Lu Huiyan , Usdin Karen 
Published: October 2021

Abstract
The Repeat Expansion Diseases, a large group of human diseases that includes the fragile X-related disorders (FXDs) and Huntington's disease (HD), all result from expansion of a disease-specific microsatellite via a mechanism that is not fully understood. We have previously shown that mismatch repair (MMR) proteins are required for expansion in a mouse model of the FXDs, but that the FANCD2 and FANCI associated nuclease 1 (FAN1), a component of the Fanconi anemia (FA) DNA repair pathway, is protective. FAN1’s nuclease activity has been reported to be dispensable for protection against expansion in an HD cell model. However, we show here that in a FXD mouse model a point mutation in the nuclease domain of FAN1 has the same effect on expansion as a null mutation. Furthermore, we show that FAN1 and another nuclease, EXO1, have an additive effect in protecting against MSH3-dependent expansions. Lastly, we show that the loss of FANCD2, a vital component of the Fanconi anemia DNA repair pathway, has no effect on expansions. Thus, FAN1 protects against MSH3-dependent expansions without diverting the expansion intermediates into the canonical FA pathway and this protection depends on FAN1 having an intact nuclease domain.