Miracle-dz/UniFAR-FTUs huggingface dataset:
Major failings of trial procedures and quality of screening fatally compromise the results of the Canadian National Breast Screening Studies

Despite overwhelming evidence of a major reduction in deaths, the debate about the efficacy of breast cancer screening has continued for over 50 years. The poor results in the Canadian National Breast Screening Studies (CNBSS) have been used to challenge the benefits shown by the other randomized, controlled trials. They continue to be used in assessing the value of breast cancer screening despite their unblinded allocation process, which first identified women with breast abnormalities and then assigned them on open lists allowing for nonrandom assignment, compromising the trials and rendering their results unreliable. There were, statistically significantly, more women with advanced cancers who were assigned to the screening arm in CNBSS1. The early results for CNBSS1 showed an excess of women dying in the screening arm, and an (otherwise inexplicable) greater than 90%, 5-year survival for the control women. The failure of random assignment also explains why the clinically evident cancers were larger in the screening arms than the cancers in the “usual care” arms, despite the fact that the screened women underwent very intense clinical breast examinations each year by highly skilled examiners. The claim that balanced demographic factors prove random assignment is also false. Nonrandom allocation of a hundred or more women with clinically evident abnormalities would have no detectable influence on the distribution of demographic factors. In summary, policy decisions about mammography should not be influenced by the results of the CNBSS.
An innovative standard for LC‐MS‐based HCP profiling and accurate quantity assessment: Application to batch consistency in viral vaccine samples

Biotherapeutics, molecules produced from biological systems, require rigorous purification steps to remove impurities including host cell proteins (HCPs). Regulatory guidelines require manufacturers to monitor process‐related impurities along the purification workflow. Mass spectrometry (MS) has recently been considered as a complementary method to the well‐established ELISA for HCPs quantification, since it has the advantage of unambiguously identifying individual HCP. In this study, we developed an innovative standard dedicated to MS‐based HCP profiling analysis in order to monitor the consistency of viral vaccine intermediate purification samples. This standard, termed the HCP‐PROFILER standard, is composed of a water‐soluble bead (READYBEADS technology) which, after being added into the sample, releases unlabeled peptides in controlled amounts. The standard meets three desired criteria: (1) it is composed of multiple peptides, at different concentration levels, allowing construction of a calibration curve covering the dynamic range of HCPs present in the target sample, ensuring quantification accuracy; (2) it demonstrates high batch‐to‐batch reproducibility, ensuring quantification robustness and consistency over time; and (3) it is easy to use and avoids user‐induced analytical biases. In this study, we present the use of the HCP‐PROFILER standard for vaccine batches comparison and downstream process performance studies.
Stressors, coping styles, and anxiety & depression in pediatric nurses with different lengths of service in six tertiary hospitals in Chengdu, China

Background The level of stress experienced by nurses is related to their length of service. In the current study, we investigated the potential correlations among stressors, coping styles, and anxiety and depression in pediatric nurses with different lengths of service in six tertiary hospitals in Chengdu, Sichuan, China. Methods Between January and June 2018, we enrolled 500 pediatric nurses from 6 tertiary hospitals in Chengdu using a convenience sampling method. A cross-sectional survey was carried out using the Chinese Nurses’ Occupational Stressor Scale (NOSS), the Simplified Coping Style Questionnaire (SCSQ), and Zung’s Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS). Results Statistically significant differences were found in the average scores of NOSS and scores of various dimensions, SAS and SDS, and Simple Coping Style score among pediatric nurses with different lengths of service (all P<0.05). Nurses with 8–12 years of service had the highest average score for stressors. Anxiety and depression were both prevalent among nurses with 4–7 years of service. The average overall stress scores of nurses with different lengths of service were negatively correlated with positive coping style (P<0.05), were not significantly correlated with negative coping style (P>0.05), and were positively correlated with anxiety score and depression score (P<0.05). The positive coping style score showed negative correlations with anxiety score and depression score (both P<0.05). The negative coping style score was positively correlated with the scores for anxiety and depression (all P<0.05), except in nurses with 4–7 years of service, for whom the negative coping style score showed no significant correlation with the depression score. Conclusions Pediatric nurses with different lengths of service in tertiary hospitals in Chengdu experience different levels of workplace stress. Pediatric nurses with 4–7 and 8–12 years of service have higher levels of workplace stress and are more likely to experience anxiety and depression.
Fusidic acid derivatives from the endophytic fungus Acremonium pilosum F47

Abstract Fusidic acid, a representative member of fungal fusidane triterpenoids, has been clinically used as an antibiotic. In the present study, fusidic acid (1), and its known analogs 16-desacetylfusidic acid (2) and 3β,20-dihydroxy-protosta-16,24-dien-29-oic acid (4), together with one new derivative acremonidiol A (3), were isolated from the endophytic fungus, Acremonium pilosum F47. Their structures were determined by MS and NMR. The spectroscopic data of 2 are firstly reported here. The antibacterial efficacies of 1-4 were evaluated against four selected Gram-positive or Gram-negative bacteria. As expected, only compound 1 showed strong inhibitory effect on Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis. Graphical abstract
Genetic and Environmental Influences of Dietary Indices in a UK Female Twin Cohort

Abstract A healthy diet is associated with the improvement or maintenance of health parameters, and several indices have been proposed to assess diet quality comprehensively. Twin studies have found that some specific foods, nutrients and food patterns have a heritable component; however, the heritability of overall dietary intake has not yet been estimated. Here, we compute heritability estimates of the nine most common dietary indices utilized in nutritional epidemiology. We analyzed 2590 female twins from TwinsUK (653 monozygotic [MZ] and 642 dizygotic [DZ] pairs) who completed a 131-item food frequency questionnaire (FFQ). Heritability estimates were computed using structural equation models (SEM) adjusting for body mass index (BMI), smoking status, Index of Multiple Deprivation (IMD), physical activity, menopausal status, energy and alcohol intake. The AE model was the best-fitting model for most of the analyzed dietary scores (seven out of nine), with heritability estimates ranging from 10.1% (95% CI [.02, .18]) for the Dietary Reference Values (DRV) to 42.7% (95% CI [.36, .49]) for the Alternative Healthy Eating Index (A-HEI). The ACE model was the best-fitting model for the Healthy Diet Indicator (HDI) and Healthy Eating Index 2010 (HEI-2010) with heritability estimates of 5.4% (95% CI [−.17, .28]) and 25.4% (95% CI [.05, .46]), respectively. Here, we find that all analyzed dietary indices have a heritable component, suggesting that there is a genetic predisposition regulating what you eat. Future studies should explore genes underlying dietary indices to further understand the genetic disposition toward diet-related health parameters.
Safety and tolerability of sacubitril-valsartan: a systematic review and meta-analysis

ABSTRACT Introduction: Sacubitril-valsartan is a recently approved drug. However, there are few data regarding safety issues. We aimed to summarize the available evidence regarding sacubitril-valsartan’s safety and tolerability. Methods: We conducted a systematic review with meta-analysis of randomized controlled trials (RCTs) enrolling patients receiving sacubitril-valsartan for any condition, compared with standard therapy or placebo. Database search was performed in October 2019. Outcomes were adverse events (AEs), serious AEs (SAEs), discontinuation due to AEs, and five AEs of special interest. Data were reported using risk ratio (RR) and 95% confidence interval (95%CI). Results: We included 20 RCTs (22510 participants). When compared with active controls, there were no differences in SAEs (RR=0.93, 95%CI 0.86–1.01) and AEs (RR=1.00, 95%CI 0.97–1.03). However, sacubitril-valsartan resulted in an 8% risk reduction in discontinuation due to AEs (95%CI 0.85–0.99) and an increased risk of hypotension (RR=1.45, 95%CI 1.27–1.67). The risk of angioedema was higher with follow-ups greater than 12 months (RR=2.36, 95%CI 1.29–4.33). There were no further significant differences in the remaining AEs' risk. Conclusions: Sacubitril-valsartan was at least as safe and tolerable as active control, with a similar need of administration cautiousness, except for a higher risk of hypotension. However, one should consider the study’s limitations.
Formin homology domains of Daam1 bind to Fascin and collaboratively promote pseudopodia formation and cell migration in breast cancer

Cancer cell migration to secondary organs remains an essential cause of death among breast cancer (BrCa) patients. Cell motility mainly relies on actin dynamics. Our previous reports verified that dishevelled‐associated activator of morphogenesis 1 (Daam1) regulates invadopodia extension and BrCa cell motility. However, how Daam1 is involved in actin filament assembly and promotes pseudopodia formation in BrCa cells remains unclear.
EARRINGS: an efficient and accurate adapter trimmer entails no a priori adapter sequences

MOTIVATION Cross-sample comparisons or large-scale meta-analyses based on the next generation sequencing (NGS) involve replicable and universal data preprocessing, including removing adapter fragments in contaminated reads (i.e., adapter trimming). While modern adapter trimmers require users to provide candidate adapter sequences for each sample, which are sometimes unavailable or falsely documented in the repositories (such as GEO or SRA), large-scale meta-analyses are therefore jeopardized by suboptimal adapter trimming. RESULTS Here we introduce a set of fast and accurate adapter detection and trimming algorithms that entail no a priori adapter sequences. These algorithms were implemented in modern C ++ with SIMD and multithreading to accelerate its speed. Our experiments and benchmarks show that the implementation (i.e., EARRINGS), without being given any hint of adapter sequences, can reach comparable accuracy and higher throughput than that of existing adapter trimmers. EARRRINGS is particularly useful in meta-analyses of a large batch of datasets and can be incorporated in any sequence analysis pipelines in all scales. AVAILABILITY AND IMPLEMENTATION EARRINGS is open-source software and is available at https://github.com/jhhung/EARRINGS. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
Familial Hypercholesterolaemia in the Malaysian Community: Prevalence, Under-Detection and Under-Treatment

Aim: Familial hypercholesterolaemia (FH) is the most common autosomal dominant lipid disorder, leading to severe hypercholesterolaemia. Early detection and treatment with lipid-lowering medications may reduce the risk of premature coronary artery disease in FH patients. However, there is scarcity of data on FH prevalence, detection rate, treatment and control with lipid-lowering therapy in the Malaysian community. Methods: Community participants ( n =5130) were recruited from all states in Malaysia. Blood samples were collected for lipid profiles and glucose analyses. Personal and family medical histories were collected by means of assisted questionnaire. Physical examination for tendon xanthomata and premature corneal arcus were conducted on-site. FH were clinically screened using Dutch Lipid Clinic Network Criteria. Results: Out of 5130 recruited community participants, 55 patients were clinically categorised as potential (Definite and Probable) FH, making the prevalence FH among the community as 1:100. Based on current total population of Malaysia (32 million), the estimated number of FH patients in Malaysia is 320,000, while the detection rates are estimated as 0.5%. Lipid-lowering medications were prescribed to 54.5% and 30.5% of potential and possible FH patients, respectively, but none of them achieved the therapeutic LDL-c target. Conclusion: Clinically diagnosed FH prevalence in Malaysian population is much higher than most of the populations in the world. At community level, FH patients are clinically under-detected, with majority of them not achieving target LDL-c level for high-risk patients. Therefore, public health measures are warranted for early detection and treatment, to enhance opportunities for premature CAD prevention.
The Arabidopsis R‐SNARE VAMP714 is essential for polarisation of PIN proteins and auxin responses

Summary The plant hormone auxin and its directional intercellular transport play a major role in diverse aspects of plant growth and development. The establishment of auxin gradients requires the asymmetric distribution of members of the auxin efflux carrier PIN‐FORMED (PIN) protein family to the plasma membrane. An endocytic pathway regulates the recycling of PIN proteins between the plasma membrane and endosomes, providing a mechanism for dynamic localisation. N‐Ethylmaleimide‐sensitive factor adaptor protein receptors (SNAP receptors, SNAREs) mediate fusion between vesicles and target membranes and are classed as Q‐ or R‐SNAREs based on their sequence. We analysed gain‐ and loss‐of‐function mutants, dominant‐negative transgenics and localisation of the Arabidopsis R‐SNARE VAMP714 protein to understand its function. We demonstrate that VAMP714 is essential for the insertion of PINs into the plasma membrane, for polar auxin transport, root gravitropism and morphogenesis. VAMP714 gene expression is upregulated by auxin, and the VAMP714 protein co‐localises with endoplasmic reticulum and Golgi vesicles and with PIN proteins at the plasma membrane. It is proposed that VAMP714 mediates the delivery of PIN‐carrying vesicles to the plasma membrane, and that this forms part of a positive regulatory loop in which auxin activates a VAMP714‐dependent PIN/auxin transport system to control development.
Organoboron ion conductive materials for target cation transport

A variety of organoboron ion conductive materials were prepared via hydroboration, dehydrocoupling reaction, imidazole-borane complex formation and so forth. By using mesitylborane, defined organoboron polymer electrolytes bearing an alkylborane or boric ester unit were conveniently prepared. The polymers obtained showed ionic conductivity of 3.39×10−5∼2.11×10−6 S/cm at 50°C. The lithium transference number of these polymers was significantly higher than that for polyethers without organoboron units. Alkylborane type polymer electrolytes showed especially improved selectivity of lithium ion conduction because of stronger Lewis acidity of the alkylborane unit. Novel imidazolium molten salts bearing an organoboron anion receptor were also prepared by hydroboration of 1-allyl-3-ethylimidazolium bromide and subsequent ion exchange reaction. From the lithium transference number observed, it was demonstrated that anion trapping of organoboron unit works much efficiently in molten salt systems than was in polyet.
N-myc downstream-regulated gene 2 promotes the protein stability of estrogen receptor beta via inhibition of ubiquitin-protein ligase E3A to suppress colorectal cancer.

Background N-myc downstream-regulated gene 2 (NDRG2) and estrogen receptor beta (ERβ) both play key roles in cellular differentiation in colorectal cancer (CRC). Previous studies have demonstrated that ERβ co-locates with and directly transactivates NDRG2. However, the effect of NDRG2 on ERβ and its underlying mechanism remain largely unknown. Our aim of the study is to explore the effect of NDRG2 on ERβ and their contributions to progression of CRC. Methods The Cancer Genome Atlas (TCGA) database was first utilized to validate the clinical significance of ERβ and NDRG2 in CRC. MTT and scratch migration assays were carried out to verify the role of ERβ and NDRG2 in CRC cells. Western blotting and polymerase chain reaction were performed to analyze the effect of NDRG2 on ERβ, and an immunoprecipitation assay was conducted to explore the protein-protein interaction. Results ERβ and NDRG2 were both found to be significantly down-regulated in tumor tissues from the TCGA-CRC database. NDRG2 was also observed to enhance the protein stability of ERβ while could not change messenger RNA (mRNA) level of ESR2 (encoding ERβ). A positive relationship was found to exist between the two proteins in CRC cells, with NDRG2 prolonging the half-life of ERβ and improving its nuclear translocation. Through detecting expression of ERβ downstream genes (such as TP53 and JNK) and performing related function experiment, we demonstrated that NDRG2 could promote transcriptional activation of ERβ target genes and enhance the function of tumor suppressors when the ERβ agonist diarylpropionitrile (DPN). The immunoprecipitation assay showed that NDRG2 could affect the complex components of ubiquitin-protein ligase E3A (UBE3A, known as E6AP) and ERβ, reducing the ubiquitin-mediated proteasome degradation of ERβ. Conclusions In the current study, we found that NDRG2 could bind with UBE3A to hinder the binding of UBE3A with ERβ. Moreover, a positive feedback loop was discovered between NDRG2 and ERβ, which provides a novel insight and therapeutic target for CRC.
Glucocorticoids attenuate interleukin‐6‐induced c‐Fos and Egr1 expression and impair neuritogenesis in PC12 cells

Interleukin‐6 (IL‐6) is a cytokine primarily known for immune regulation. There is also growing evidence that IL‐6 triggers neurogenesis and impacts neural development, both life‐long occurring processes that can be impaired by early‐life and adult stress. Stress induces the release of glucocorticoids by activation of the hypothalamic–pituitary–adrenal (HPA) axis. On the cellular level, glucocorticoids act via the ubiquitously expressed glucocorticoid receptor. Thus, we aimed to elucidate whether glucocorticoids affect IL‐6‐induced neural development. Here, we show that IL‐6 signalling induces neurite outgrowth in adrenal pheochromocytoma PC12 cells in a mitogen‐activated protein kinase (MAPK) pathway‐dependent manner, since neurite outgrowth was diminished upon Mek‐inhibitor treatment. Using quantitative biochemical approaches, such as qRT‐PCR analysis of Hyper‐IL‐6 treated PC12 cells, we show that neurite outgrowth induced by IL‐6 signalling is accompanied by early and transient MAPK‐dependent mRNA expression of immediate early genes coding for proteins such as early growth response protein 1 (Egr1) and c‐Fos. This correlates with reduced proliferation and prolonged G0/G1 cell cycle arrest as determined by monitoring the cellular DNA content using flow cytometry. These results indicate for IL‐6 signalling‐induced neural differentiation. Interestingly, the glucocorticoid Dexamethasone impairs early IL‐6 signalling‐induced mRNA expression of c‐Fos and Egr1 and restrains neurite outgrowth. Impaired Egr1 and c‐Fos expression in neural development is implicated in the aetiology of neuropathologies. Thus, it appears likely that stress‐induced release of glucocorticoids, as well as therapeutically administered glucocorticoids, contribute to the development of neuropathologies by reducing the expression of Egr1 and c‐Fos, and by restraining IL‐6‐dependent neural differentiation.
Regulation of temozolomide resistance in glioma cells via the RIP2/NF‐κB/MGMT pathway

Temozolomide (TMZ) is a first‐line chemotherapy drug for the treatment of malignant glioma and resistance to it poses a major challenge. Receptor‐interacting protein 2 (RIP2) is associated with the malignant character of cancer cells. However, it remains unclear whether RIP2 is involved in TMZ resistance in glioma.
Biological sex, not reproductive cycle, influences peripheral blood immune cell prevalence in mice

Traditionally the female sex, compared with the male sex, has been perceived as having greater variability in many physiological traits, including within the immune system. We investigated effects of biological sex and the female reproductive cycle on numbers of circulating leukocytes in C57BL/6J mice. We show that biological sex, but not female reproductive cyclicity, has a significant effect on peripheral blood immune cell prevalence and variability, and that sex differences were not consistent amongst common inbred laboratory mouse strains. We found that male C57BL/6J mice, compared with female mice, have greater variability in peripheral blood immunophenotype, and that this was influenced by body weight. We created summary tables for researchers to facilitate experiment planning and sample size calculations for peripheral immune cells that consider the effects of biological sex.
Population structure of Erysiphe necator on domesticated and wild vines in the Middle East raises questions on the origin of the grapevine powdery mildew pathogen.

Plant pathogens usually originate and diversify in geographical regions where hosts and pathogens co-evolve. Erysiphe necator, the causal agent of grape powdery mildew, is a destructive pathogen of grapevines worldwide. Although Eastern US is considered the center of origin and diversity of E. necator, previous reports on resistant native wild and domesticated Asian grapevines suggest Asia as another possible origin of the pathogen. By using multi-locus sequencing, microsatellites and a novel application of amplicon sequencing (AmpSeq), we show that the population of E. necator in Israel is composed of three genetic groups: Groups A and B that are common worldwide, and a new group IL, which is genetically differentiated from any known group in Europe and Eastern US. Group IL showed distinguished ecological characteristics: it was dominant on wild and traditional vines (95%); its abundance increased along the season; and was more aggressive than A and B isolates on both wild and domesticated vines. The low genetic diversity within group IL suggests that it has invaded Israel from another origin. Therefore, we suggest that the Israeli E. necator population was founded by at least two invasions, of which one could be from a non-East American source, possibly from Asian origin. This article is protected by copyright. All rights reserved.
Phase Topology and Growth of Single Domains in Lipid Bilayers

The time-dependent topology of domains in supported phospholipid bilayers of a binary mixture of dioleoylphosphatidylcholine and dipalmitoylphosphatidylcholine under a buffer solution has been studied by atomic force microscopy. We observe a transient regime of the phase separation until 45 min after a temperature quench from a miscible state of the system into the gel−liquid crystal coexistence region with the earliest observation after 20 min showing large gel-phase domains (containing ∼104−106 molecules) of irregular shapes. The transient regime is characterized by a power law for the growth rate of the domain size (A) with n = 3.0 ± 0.4 in A ∝ t2/n. After 45 min, an asymptotic power law with n = 20 ± 10 is observed and is linked to an inhibited domain growth. The evolution of individual domains suggests that domain growth in the transient regime is governed by a ripening mechanism. The growth inhibition is linked to the observation that the gel domains in each leaflet of the bilayer must grow simultan.