Miracle-dz/UniFAR-FTUs huggingface dataset:
Estrogen therapy induces an unfolded protein response to drive cell death in ER+ breast cancer

Estrogens have been shown to elicit anticancer effects against estrogen receptor α (ER)‐positive breast cancer. We sought to determine the mechanism underlying the therapeutic response. Response to 17β‐estradiol was assessed in ER+ breast cancer models with resistance to estrogen deprivation: WHIM16 patient‐derived xenografts, C7‐2‐HI and C4‐HI murine mammary adenocarcinomas, and long‐term estrogen‐deprived MCF‐7 cells. As another means to reactivate ER, the anti‐estrogen fulvestrant was withdrawn from fulvestrant‐resistant MCF‐7 cells. Transcriptional, growth, apoptosis, and molecular alterations in response to ER reactivation were measured. 17β‐estradiol treatment and fulvestrant withdrawal induced transcriptional activation of ER, and cells adapted to estrogen deprivation or fulvestrant were hypersensitive to 17β‐estradiol. ER transcriptional response was followed by an unfolded protein response and apoptosis. Such apoptosis was dependent upon the unfolded protein response, p53, and JNK signaling. Anticancer effects were most pronounced in models exhibiting genomic amplification of the gene encoding ER (ESR1), suggesting that engagement of ER at high levels is cytotoxic. These data indicate that long‐term adaptation to estrogen deprivation or ER inhibition alters sensitivity to ER reactivation. In such adapted cells, 17β‐estradiol treatment and anti‐estrogen withdrawal hyperactivate ER, which drives an unfolded protein response and subsequent growth inhibition and apoptosis. 17β‐estradiol treatment should be considered as a therapeutic option for anti‐estrogen‐resistant disease, particularly in patients with tumors harboring ESR1 amplification or ER overexpression. Furthermore, therapeutic strategies that enhance an unfolded protein response may increase the therapeutic effects of ER reactivation.
A Secure and Efficient Data Sharing and Searching Scheme in Wireless Sensor Networks

Wireless sensor networks (WSN) generally utilize cloud computing to store and process sensing data in real time, namely, cloud-assisted WSN. However, the cloud-assisted WSN faces new security challenges, particularly outsourced data confidentiality. Data Encryption is a fundamental approach but it limits target data retrieval in massive encrypted data. Public key encryption with keyword search (PEKS) enables a data receiver to retrieve encrypted data containing some specific keyword in cloud-assisted WSN. However, the traditional PEKS schemes suffer from an inherent problem, namely, the keyword guessing attack (KGA). KGA includes off-line KGA and on-line KGA. To date, the existing literature on PEKS cannot simultaneously resist both off-line KGA and on-line KGA performed by an external adversary and an internal adversary. In this work, we propose a secure and efficient data sharing and searching scheme to address the aforementioned problem such that our scheme is secure against both off-line KGA and on-line KGA performed by external and internal adversaries. We would like to stress that our scheme simultaneously achieves document encryption/decryption and keyword search functions. We also prove our scheme achieves keyword security and document security. Furthermore, our scheme is more efficient than previous schemes by eliminating the pairing computation.
Development of a haptic feedback device to reduce syringe substitution and drug overdosage error

Despite use of colour‐coded labels, syringe substitution (syringe swap) error of anaesthetic drugs remains a frequent and potentially serious cause of iatrogenic harm. We explored the novel concept of using a simple device which can be fitted to existing syringes, and employs colour and raised elements (detents) to provide visual, haptic and auditory cues to supplement the visual cues provided by standard drug labelling, and particularly helps to differentiate, for example, syringes containing vaso‐active drugs from other syringes. We produced six different embodiments of the device, and performed a randomised unblinded study with 14 volunteers to identify the functional characteristics which met with the approval of the majority of participants, and the mechanical characteristics which produced adequate haptic feedback without excessive resistance to injection. The optimal design was identified, which required the user to exert a mean (SD) force of ~20 (7) N to overcome the resistance of the detents in the syringe. The majority of volunteers felt that a device of this type would be helpful in reducing the incidence of syringe substitution error; however, further research is needed to assess the efficacy of this innovation in the clinical environment.
Feed utilization and lactational performance of Friesian cows fed beet tops silage treated with lactic acid bacteria as a replacement for corn silage

Abstract Thirty multiparous lactating Friesian cows were used to study the effect of partial or complete replacement of corn silage with lactic acid bacteria (LAB), molasses and calcium carbonate ensiled sugar beet tops for 3 months in a complete randomized experimental design with repeated measures. A week after parturition, cows were grouped into three treatments of 10 cows each and fed a control treatment containing corn silage at 300 g/kg DM. In the other treated diets, 50% or 100% of the control corn silage was substituted with beet tops silage treated with LAB included at 150 g or 300 g per kg diet. Ensiling of beet tops with LAB decreased its contents of oxalic acid and neutral detergent and acid detergent fibers but increased its contents of non-structural carbohydrate and calcium. Without affecting daily milk production and feed efficiency, beet tops silage treated with LAB diets decreased (p < 0.05) feed intake, total ruminal volatile fatty acids, acetate and propionate concentrations, energy-corrected milk yield and concentrations of milk total solids, fat, protein and energy. In conclusion, beet tops silage treated with LAB can replace corn silage in diets of lactating cows. An inclusion rate of 15% of beet tops silage treated with LAB (replacing 50% of corn silage) in the diet was the most suitable level for lactating cows under the current experimental conditions.
Guidelines on the Use of Therapeutic Apheresis in Clinical Practice – Evidence‐Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue

The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating and categorizing indications for the evidence‐based use of therapeutic apheresis (TA) in human disease. Since the 2007 JCA Special Issue (Fourth Edition), the committee has incorporated systematic review and evidence‐based approaches in the grading and categorization of apheresis indications. This Eighth Edition of the JCA Special Issue continues to maintain this methodology and rigor in order to make recommendations on the use of apheresis in a wide variety of diseases/conditions. The JCA Eighth Edition, like its predecessor, continues to apply the category and grading system definitions in fact sheets. The general layout and concept of a fact sheet that was introduced in the Fourth Edition, has largely been maintained in this edition. Each fact sheet succinctly summarizes the evidence for the use of TA in a specific disease entity or medical condition. The Eighth Edition comprises 84 fact sheets for relevant diseases and medical conditions, with 157 graded and categorized indications and/or TA modalities. The Eighth Edition of the JCA Special Issue seeks to continue to serve as a key resource that guides the utilization of TA in the treatment of human disease.
Health Care Disparities Among U.S. Women of Reproductive Age by Level of Psychological Distress.

Purpose: Reproductive-age women have a high rate of contact with the health care system for reproductive health care. Yet, beyond pregnancy, little is known about psychological distress and unmet health care needs among these women. We examined reasons for delayed medical care and types of foregone care by level of psychological distress. Methods: We used a nationally representative sample of U.S. women aged 18-49, from the 2015-2016 National Health Interview Survey. Using the K6 screening tool for nonspecific psychological distress, we examined differences in reasons for delayed care and types of care foregone due to cost by level of psychological distress (none, moderate psychological distress [MPD], and severe psychological distress [SPD]). Results: Overall, 20% of U.S. women aged 18-49 had MPD (16%) or SPD (4%), equating to nearly 13 million women of reproductive age living with psychological distress. Women with SPD or MPD are more likely to have delayed and foregone care. Notably, women with SPD have higher odds of needing but not receiving mental health care (adjusted odds ratios [AOR] = 12.4, 95% confidence interval [CI] 8.4-18.4), specialist care (AOR = 3.6, 95% CI 2.6-5.1), and follow-up care (AOR = 3.5, 95% CI 2.4-5.1) due to cost than women with no psychological distress. Cost is the greatest barrier to timely medical care for women with MPD and SPD. Conclusions: Women of reproductive age with psychological distress face considerable structural and cost-related barriers to accessing health care, which may be exacerbated by their psychological state. Despite recent policy advances such as the Affordable Care Act, additional efforts by policymakers and providers are crucial to address the needs of this population.
Capture, immobilization, and Global Positioning System collaring of olive baboons (Papio anubis) and vervets (Chlorocebus pygerythrus): Lessons learned and suggested best practices

As the value of Global Positioning System (GPS) technology in addressing primatological questions becomes more obvious, more studies will include capturing and collaring primates, with concomitant increased risk of adverse consequences to primate subjects. Here we detail our experiences in capturing, immobilizing, and placing GPS collars on six olive baboons (Papio anubis) in four groups and 12 vervet monkeys (Chlorocebus pygerythrus) in five groups in Kenya. We captured baboons with cage traps and vervets with box traps, immobilized them, and attached GPS collars that were to be worn for 1 year. Adverse consequences from the trapping effort included incidental death of two nonsubjects (an adult female and her dependent infant), temporary rectal prolapse in one baboon, superficial wounds on the crown of the head in two vervets, and failure to recapture/remove collars from two baboons and two vervets. Obvious negative effects from wearing collars were limited to abrasions around the neck of one vervet. A possible, and if so, serious, adverse effect was greater mortality for collared adult female vervets compared with known uncollared adult female vervets, largely due to leopard (Panthera pardus) predation. Collared animals could be more vulnerable to predation because trapping favors bolder individuals, who may also be more vulnerable to predation, or because collars could slow them down or make them more noticeable to predators. Along with recommendations made by others, we suggest that future studies diversify trapping bait to minimize the risk of rectal prolapse, avoid capturing the first individuals to enter traps, test the movement speeds of collared versus noncollared animals, include a release system on the collars to avoid retrapping failure, and publish both positive and negative effects of capturing, immobilizing, and collaring.
Seroprevalence of Leptospira spp. Infection in Cattle from Central and Northern Madagascar

Leptospirosis is a zoonotic disease of global importance, especially in tropical countries. The current Leptospira spp. seroprevalence in cattle from central and northern Madagascar is unknown. Thus, the aim of this study was to determine the seroprevalence resulting from infections with pathogenic Leptospira spp. in zebu cattle from these areas. Serum samples from 194 animals were tested by microscopic agglutination test (MAT) using a panel of 12 serovars as antigens. Samples with a titer of ≥1:100 were considered positive. The overall seroprevalence was 59.3% (95% CI; 52.0–66.2%) with titers ranging from 1:100 to 1:1600. Among the seropositive animals, the most frequent antibody reactions were against serovar L. Tarassovi (serogroup L. Tarassovi) with 40.2% (33.3–47.5%), followed by L. Hardjo (L. Sejroe) with 13.9% (9.5–19.8%), L. Grippotyphosa (L. Grippotyphosa) with 9.8% (6.2–15.1%), L. Pomona (L. Pomona) with 7.7% (4.5–12.7%) and L. Autumnalis (L. Autumnalis) with 5.2% (2.6–9.5%). Less than 5% of the samples reacted positively against the remaining serovars. These results indicate a very high exposure of Malagasy cattle to Leptospira spp. which, consequently, poses a definite risk for people working with cattle acquiring this zoonotic infection.
Spatial proteomics reveal that the protein phosphatase PTP1B interacts with and may modify tyrosine phosphorylation of the rhomboid protease RHBDL4

Rhomboid-like proteins are evolutionarily conserved, ubiquitous polytopic membrane proteins, including the canonical rhomboid intramembrane serine proteases and also others that have lost protease activity during evolution. We still have much to learn about their cellular roles, and evidence suggests that some may have more than one function. For example, RHBDL4 (rhomboid-like protein 4) is an endoplasmic reticulum (ER)–resident protease that forms a ternary complex with ubiquitinated substrates and p97/VCP (valosin-containing protein), a major driver of ER-associated degradation (ERAD). RHBDL4 is required for ERAD of some substrates, such as the pre–T-cell receptor α chain (pTα) and has also been shown to cleave amyloid precursor protein to trigger its secretion. In another case, RHBDL4 enables the release of full-length transforming growth factor α in exosomes. Using the proximity proteomic method BioID, here we screened for proteins that interact with or are in close proximity to RHBDL4. Bioinformatics analyses revealed that BioID hits of RHBDL4 overlap with factors related to protein stress at the ER, including proteins that interact with p97/VCP. PTP1B (protein-tyrosine phosphatase nonreceptor type 1, also called PTPN1) was also identified as a potential proximity factor and interactor of RHBDL4. Analysis of RHBDL4 peptides highlighted the presence of tyrosine phosphorylation at the cytoplasmic RHBDL4 C terminus. Site-directed mutagenesis targeting these tyrosine residues revealed that their phosphorylation modifies binding of RHBDL4 to p97/VCP and Lys63-linked ubiquitinated proteins. Our work lays a critical foundation for future mechanistic studies of the roles of RHBDL4 in ERAD and other important cellular pathways.
Definitions of post-coronary artery bypass grafting myocardial infarction: variations in incidence and prognostic significance.

OBJECTIVES Using data from the CORONARY trial (n = 4752), we evaluated the incidence and prognostic significance of myocardial infarction (MI) applying different definitions based on peak postoperative creatine kinase-MB isoenzyme and cardiac troponin levels. We then aimed to identify the peak cardiac troponin during the first 3 postoperative days that was independently associated with a 2-fold increase in 30-day mortality. METHODS To combine different assays, we analysed cardiac troponins in multiples of their respective upper limit of normal (ULN). We identified the lowest threshold with a hazard ratio (HR) >2 for 30-day mortality independent of EuroSCORE and on- versus off-pump surgery. RESULTS Depending on the definition used based on creatine kinase-MB, the incidence of MI after coronary artery bypass grafting (CABG) ranged from 0.6% to 19% and the associated HRs for 30-day mortality ranged from 2.7 to 6.9. Using cardiac troponin (1528 patients), the incidence of MI ranged from 1.7% to 13% depending on the definition used with HRs for 30-day mortality ranging from 5.1 to 7.2. The first cardiac troponin threshold we evaluated, 180xULN, was associated with an adjusted HR for 30-day mortality of 7.6 [95% confidence interval (CI) 3.4-17.1] when compared to <130xULN. The next independent threshold was 130xULN with an adjusted HR for 30-day mortality of 7.8 (95% CI 2.3-26.1). The next cardiac troponin tested threshold (70xULN) did not meet criteria for significance. CONCLUSIONS Our results illustrate that the incidence and prognosis of a post-CABG MI varies based on the definition used. Validated post-CABG MI diagnostic criteria formulated from their independent association with important clinical outcomes are needed.
Real-world effectiveness of medications on survival in patients with COPD-heart failure overlap

The appropriate treatment for patients with coexistent chronic obstructive pulmonary disease (COPD) and heart failure (HF) remains unclear. Data from the Taiwan National Health Insurance Research Database was used for this retrospective cohort study. Patients diagnosed with both diseases between 1997 and 2012 were enrolled as the COPD-heart failure overlap cohort. Patients were categorized as non-users and users of specific COPD and HF medications. Medication prescriptions in each 3-month and 1-year period served as time-dependent covariates. The primary endpoint was cumulative survival. The validation study confirmed the accuracy of definitions of COPD (94.0% sensitivity) and HF (96.3% sensitivity). The study included 275,436 patients with COPD-heart failure overlap, with a mean follow-up period of 9.32 years. The COPD-heart failure overlap cohort had more medical service use and higher mortality than did the COPD alone cohort. Use of inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) combinations, long-acting muscarinic antagonist (LAMA), angiotensin receptor blockers (ARBs), β blockers, aldosterone antagonists, and statins reduced mortality risk compared with non-use. Sensitivity and subgroup analyses confirmed the consistency and robustness of results. ICS/LABA combinations, LAMA, ARBs, β blockers, aldosterone antagonists, and statins use was associated with a lower mortality risk in patients with COPD-heart failure overlap.
Multimodal imaging reveals a complex pattern of dysfunction in corticolimbic pathways in major depressive disorder

Major depressive disorder (MDD) is highly prevalent and associated with considerable morbidity, yet its pathophysiology remains only partially understood. While numerous studies have investigated the neurobiological correlates of MDD, most have used only a single neuroimaging modality. In particular, diffusion tensor imaging (DTI) studies have failed to yield uniform results. In this context, examining key tracts and using information from multiple neuroimaging modalities may better characterize potential abnormalities in the MDD brain. This study analyzed data from 30 participants with MDD and 26 healthy participants who underwent DTI, magnetic resonance spectroscopy (MRS), resting‐state functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG). Tracts connecting the subgenual anterior cingulate cortex (sgACC) and the left and right amygdala, as well as connections to the left and right hippocampus and thalamus, were examined as target areas. Reduced fractional anisotropy (FA) was observed in the studied tracts. Significant differences in the correlation between medial prefrontal glutamate concentrations and FA were also observed between MDD and healthy participants along tracts connecting the sgACC and right amygdala; healthy participants exhibited a strong correlation but MDD participants showed no such relationship. In the same tract, a correlation was observed between FA and subsequent antidepressant response to ketamine infusion in MDD participants. Exploratory models also suggested group differences in the relationship between DTI, fMRI, and MEG measures. This study is the first to combine MRS, DTI, fMRI, and MEG data to obtain multimodal indices of MDD and antidepressant response and may lay the foundation for similar future analyses.
Strengthening behavioral clinical trials with online qualitative research methods

Qualitative methods are integral to the systematic development of effective health behavioral interventions, as noted in recent translational models, such as the Obesity-Related Behavioral Intervention Trials model. To our knowledge, however, no scholarly literature describes how online qualitative research methods can be used to benefit the development and conduct of behavioral clinical trials. We emphasize the value of qualitative methodologies to behavioral clinical trial research more broadly and provide an introductory overview of online qualitative research methods. We highlight the specific affordances of these methods in maximizing the quality of behavioral clinical trials as well as note their potential limitations. Finally, we argue that online qualitative research methods ought to be incorporated in behavioral trial development and call for future research in this area.
Disentangling Heterogeneity in Alzheimer's Disease: Two Empirically-Derived Subtypes.

BACKGROUND Clinical-pathological Alzheimer's disease (AD) subtypes may help distill heterogeneity in patient presentation. To date, no studies have utilized neuropsychological and biological markers to identify preclinical subtypes with longitudinal stability. OBJECTIVE The objective of this study was to empirically derive AD endophenotypes using a combination of cognitive and biological markers. METHODS Hierarchical cluster analysis grouped dementia-free older adults using memory, executive and language abilities, and cerebrospinal fluid amyloid-β and phosphorylated tau. Brain volume differences, neuropsychological trajectory, and progression to dementia were compared, controlling for age, gender, education, and apolipoprotein E4 (ApoE4). RESULTS Subgroups included asymptomatic-normal (n = 653) with unimpaired cognition and subthreshold biomarkers, typical AD (TAD; n = 191) showing marked memory decline, high ApoE4 rates and abnormal biomarkers, and atypical AD (AAD; n = 132) with widespread cognitive decline, intermediate biomarker levels, older age, less education and more white matter lesions. Cognitive profiles showed longitudinal stability with corresponding patterns of cortical atrophy, despite nearly identical rates of progression to AD dementia. CONCLUSION Two clinical-pathological AD subtypes are identified with potential implications for preventative efforts.
In situ spectroscopic analysis of Lactobacillus rhamnosus GG flow on an abiotic surface reveals a role for nutrients in biofilm development

Abstract In this work, infrared spectroscopy was used to monitor the changes in the biochemical composition of biofilms of the probiotic bacterium Lactobacillus rhamnosus GG (LGG) in three nutritive media (10-fold diluted MRS, AOAC, and mTSB), in situ and under flow conditions. Epifluorescence microscopy was used to observe the shape of LGG cells and their distribution on the surface. Spectroscopic fingerprints recorded as a function of time revealed a medium-dependent content of nucleic acids, phospholipids and polysaccharides in the biofilms. In addition, time-dependent synthesis of lactic acid was observed in MRS/10 and AOAC/10. Polysaccharides were produced to the highest extent in mTSB/10, and the biofilms obtained were the densest in this medium. The rod shape of the cells was preserved in MRS/10, whereas acidic stress induced in AOAC/10 and the nutritional quality of mTSB/10 led to strong morphological changes. These alterations due to the nutritive environment are important to consider in research and use of LGG biofilms.