Miracle-dz/UniFAR-FTUs huggingface dataset:
Spatial Coupling Tunes NMDA Receptor Responses via Ca2+ Diffusion

In the CNS, NMDA receptors generate large and highly regulated Ca2+ signals, which are critical for synaptic development and plasticity. They are highly clustered at postsynaptic sites and along dendritic arbors, but whether this spatial arrangement affects their output is unknown. Synaptic NMDA receptor currents are subject to Ca2+-dependent inactivation (CDI), a type of activity-dependent inhibition that requires intracellular Ca2+ and calmodulin (CaM). We asked whether Ca2+ influx through a single NMDA receptor influences the activity of nearby NMDA receptors, as a possible coupling mechanism. Using cell-attached unitary current recordings from GluN1–2a/GluN2A receptors expressed in human HEK293 cells and from NMDA receptors native to hippocampal neurons from male and female rats, we recorded unitary currents from multichannel patches and used a coupled Markov model to determine the extent of signal coupling (κ). In the absence of extracellular Ca2+, we observed no cooperativity (κ < 0.1), whereas in 1.8 mm external Ca2+, both recombinant and native channels showed substantial negative cooperativity (κ = 0.27). Intracellular Ca2+ chelation or overexpression of a Ca2+-insensitive CaM mutant, reduced coupling, which is consistent with CDI representing the coupling mechanism. In contrast, cooperativity increased substantially (κ = 0.68) when overexpressing the postsynaptic scaffolding protein PSD-95, which increased receptor clustering. Together, these new results demonstrate that NMDA receptor currents are negatively coupled through CDI, and the degree of coupling can be tuned by the distance between receptors. Therefore, channel clustering can influence the activity-dependent reduction in NMDA receptor currents. SIGNIFICANCE STATEMENT At central synapses, NMDA receptors are a major class of excitatory glutamate-gated channels and a source of activity-dependent Ca2+ influx. In turn, fluxed Ca2+ ions bind to calmodulin-primed receptors and reduce further entry, through an autoinhibitory mechanism known as Ca2+ -dependent inactivation (CDI). Here, we show that the diffusion of fluxed Ca2+ between active channels situated within submicroscopic distances amplified receptor inactivation. Thus, calmodulin-mediated gating modulation, an evolutionarily conserved regulatory mechanism, endows synapses with sensitivity to both the temporal sequence and spatial distribution of Ca2+ signals. Perturbations in this mechanism, which coordinates the activity of NMDA receptors within a cluster, may cause signaling alterations that contribute to neuropsychiatric conditions.
Social Drinking Contexts and Their Influence on Problematic Drinking at Age 30

Abstract Aims: Understanding the social contexts in which problematic drinking occurs can inform prevention strategies. In this article, we investigate gender-specific social contexts associated with problematic drinking and depression among adults aged 30 years. Because depression has been consistently linked with harmful alcohol consumption, we will also examine its association with drinking contexts. Methods: We used data from 2490 young adults who completed the 30-year follow-up phase of the Mater-University of Queensland Study of Pregnancy and its Outcomes, a prospective study commenced in 1981. Exploratory and confirmatory factor analyses were used to identify latent constructs of drinking contexts stratified by gender, with subsequent regression analysis to assess the role of these contexts in problematic drinking (measured using the Alcohol Use Disorders Identification Test). Results: Six distinct drinking contexts were identified, which differed by gender, three for men and three for women. For both men and women, “social drinking”, was associated with problematic drinking. “Home drinking” was also common to men and women but associations with problematic drinking differed, being risky only among men. “Daytime drinking” (women) was associated with risk but “work-related drinking” (men) was not. Both “home drinking” (men) and “daytime drinking” (women) were linked to depression symptoms. Conclusion: Specific contexts appeared to be associated with problematic drinking for both sexes. Among both men and women, “social drinking” was associated with problematic drinking. Both “home drinking” (men) and “daytime drinking” (women) contexts, were associated with problematic drinking and depressive symptoms. Targeted alcohol-focused interventions need to address co-occurring mental health issues.
Applications of amyloid, tau, and neuroinflammation PET imaging to Alzheimer's disease and mild cognitive impairment

Alzheimer's disease (AD) is a devastating and progressive neurodegenerative disease for which there is no cure. Mild cognitive impairment (MCI) is considered a prodromal stage of the disease. Molecular imaging with positron emission tomography (PET) allows for the in vivo visualisation and tracking of pathophysiological changes in AD and MCI. PET is a very promising methodology for differential diagnosis and novel targets of PET imaging might also serve as biomarkers for disease‐modifying therapeutic interventions. This review provides an overview of the current status and applications of in vivo molecular imaging of AD pathology, specifically amyloid, tau, and microglial activation. PET imaging studies were included and evaluated as potential biomarkers and for monitoring disease progression. Although the majority of radiotracers showed the ability to discriminate AD and MCI patients from healthy controls, they had various limitations that prevent the recommendation of a single technique or tracer as an optimal biomarker. Newer research examining amyloid, tau, and microglial PET imaging in combination suggest an alternative approach in studying the disease process.
Sedation versus general anaesthesia in endovascular therapy for anterior circulation acute ischaemic stroke: the multicentre randomised controlled AMETIS trial study protocol

Introduction Endovascular thrombectomy is the standard of care for anterior circulation acute ischaemic stroke (AIS) secondary to emergent large vessel occlusion in patients who qualify. General anaesthesia (GA) or conscious sedation (CS) is usually required to ensure patient comfort and avoid agitation and movement during thrombectomy. However, the question of whether the use of GA or CS might influence functional outcome remains debated. Indeed, conflicting results exist between observational studies with better outcomes associated with CS and small monocentric randomised controlled trials favouring GA. Therefore, we aim to evaluate the effect of CS versus GA on functional outcome and periprocedural complications in endovascular mechanical thrombectomy for anterior circulation AIS. Methods and analysis Anesthesia Management in Endovascular Therapy for Ischemic Stroke (AMETIS) trial is an investigator initiated, multicentre, prospective, randomised controlled, two-arm trial. AMETIS trial will randomise 270 patients with anterior circulation AIS in a 1:1 ratio, stratified by centre, National Institutes of Health Stroke Scale (≤15 or >15) and association of intravenous thrombolysis or not to receive either CS or GA. The primary outcome is a composite of functional independence at 3 months and absence of perioperative complication occurring by day 7 after endovascular therapy for anterior circulation AIS. Functional independence is defined as a modified Rankin Scale score of 0–2 by day 90. Perioperative complications are defined as intervention-associated arterial perforation or dissection, pneumonia or myocardial infarction or cardiogenic acute pulmonary oedema or malignant stroke evolution occurring by day 7. Ethics and dissemination The AMETIS trial was approved by an independent ethics committee. Study began in august 2017. Results will be published in an international peer-reviewed medical journal. Trial registration number NCT03229148.
Neutrophil Extracellular Traps Drive Mitochondrial Homeostasis in Tumors to Augment Growth.

Neutrophil infiltration and neutrophil extracellular traps (NETs) in solid cancers are associated with poorer prognosis but the mechanisms are incompletely understood. We hypothesized that NETs enhance mitochondrial function in tumor cells providing extra energy for accelerated growth. Metastatic colorectal cancer tissue showed increased intratumoral NETs and supranormal preoperative serum MPO-DNA, a NET marker. Higher MPO-DNA correlated with shorter survival. In mice, subcutaneous tumor implants and hepatic metastases grew slowly in PAD4-KO mice, genetically incapable of NETosis. In parallel experiments, human cancer cell lines grew slower in nu/nu mice treated with DNAse, which disassembles NETs. PAD4-KO tumors manifested decreased proliferation, increased apoptosis and increased evidence of oxidative stress. PAD4-KO tumors had decreased mitochondrial density, mitochondrial DNA, a lesser degree of ATP production, along with significantly decreased mitochondrial biogenesis proteins PGC-1α, TFAM and NRF-1. In vitro, cancer cells treated with NETs upregulated mitochondrial biogenesis associated genes, increased mitochondrial density, increased ATP production, enhanced the percentage of cancer cells with reduced mitochondrial membrane potential and increased the oxygen consumption rate. Furthermore, NETs increased cancer cell's expression of fission and fusion associated proteins, DRP-1 and MFN-2, and mitophagy-linked proteins, PINK1 and Parkin. All of which were decreased in PAD4-KO tumors. Mechanistically, neutrophil elastase (NE) released from NETs activated TLR-4 on cancer cells leading to PGC-1α upregulation, increased mitochondrial biogenesis and accelerated growth. Taken together, NETs can directly alter the metabolic programming of cancer cells to increase tumor growth. NETs represent a promising therapeutic target to halt cancer progression.
What are the challenges for nurses when providing end-of-life care in intensive care units?

AIM this literature review aimed to explore qualitative studies in which nurses discussed the challenges they face when delivering end-of-life care in intensive care units (ICUs). Analysis and discussion of the studies' findings aimed to contribute to the current evidence base surrounding the subject. METHOD a systematic search of academic databases was conducted to source relevant studies. An inductive process using grounded theory was undertaken to elicit suitable themes to address the review question. FINDINGS six relevant studies were identified with four main themes emerging from analysis. The themes were a lack of nurse involvement in end-of-life care decision-making, a lack of nursing knowledge in providing end-of-life care, the dilemma of prioritising care between the patient and family, and the nature of providing end-of-life care within an ICU environment. CONCLUSION the provision of end-of-life care in ICUs requires nurses to be involved in interdisciplinary communication. ICU-specific end-of-life care education, training and guidelines need to be implemented to ensure patients receive high-quality, patient-centred care.
Association Between Power Morcellation and Mortality in Women With Unexpected Uterine Cancer Undergoing Hysterectomy or Myomectomy.

PURPOSE Despite concerns that power morcellation may adversely affect prognosis of patients with occult uterine cancer, empirical evidence has been limited and inconclusive. In this study, we aimed to determine whether uncontained power morcellation at the time of hysterectomy or myomectomy is associated with increased mortality risk in women with occult uterine cancer. METHODS By linking statewide hospital discharge records with cancer registry data in New York, we identified 843 women with occult endometrial carcinoma and 334 women with occult uterine sarcoma who underwent a hysterectomy or myomectomy for presumed benign indications during the period October 1, 2003, through December 31, 2013. Within this cohort, we compared disease-specific and all-cause mortality of women who underwent laparoscopic supracervical hysterectomy/laparoscopic myomectomy (LSH/LM), a surrogate indicator for uncontained power morcellation, with women who underwent supracervical abdominal hysterectomy and total abdominal hysterectomy (TAH), which did not involve power morcellation. Multivariable Cox regressions and propensity score method were used to adjust for patient characteristics. RESULTS Among women with occult uterine sarcoma, LSH/LM was associated with a higher risk for disease-specific mortality than TAH (adjusted hazard ratio [aHR], 2.66, 95% CI, 1.11 to 6.37; adjusted difference in 5-year disease-specific survival, -19.4%, 95% CI, -35.8% to -3.1%). In the subset of women with leiomyosarcoma, LSH/LM was associated with an increased risk for disease-specific mortality compared with supracervical abdominal hysterectomy (aHR, 3.64, 95% CI, 1.50 to 8.86; adjusted difference in 5-year disease-specific survival, -31.2%, 95% CI, -50.0% to -12.3%) and TAH (aHR, 4.66, 95% CI, 1.97 to 11.00; adjusted difference in 5-year disease-specific survival, -37.3%, 95% CI, -54.2% to -20.3%). Among women with occult endometrial carcinoma, there was no significant association between surgical approach and disease-specific mortality. CONCLUSION Uncontained power morcellation was associated with higher mortality risk in women with occult uterine sarcoma, especially in those with occult leiomyosarcoma.
Validity of six consumer-level activity monitors for measuring steps in patients with chronic heart failure

Introduction Although numerous activity trackers have been validated in healthy populations, validation is lacking in chronic heart failure patients who normally walk at a slower pace, making it difficult for researchers and clinicians to implement activity monitors during physical activity interventions. Methods Six consumer-level activity monitors were validated in a 3-day field study in patients with chronic heart failure and healthy individuals under free living conditions. Furthermore, the same devices were evaluated in a lab-based study during treadmill walking at speeds of 2.4, 3.0, 3.6, and 4.2 km·h-1. Concordance correlation coefficients (CCC) were used to evaluate the agreement between the activity monitors and the criterion, and mean absolute percentage errors (MAPE) were calculated to assess differences between each device and the criterion (MAPE <10% was considered as a threshold for validity). Results In the field study of healthy individuals, all but one of the activity monitors showed a substantial correlation (CCC ≥0.95) with the criterion device and MAPE <10%. In patients with heart failure, the correlation of only two activity monitors (Garmin vívofit 3 and Withings Go) was classified as at least moderate (CCC ≥0.90) and none of the devices had MAPE <10%. In the lab-based study at speeds 4.2 and 3.6 km·h-1, all activity monitors showed substantial to almost perfect correlations (CCC ≥0.95) with the criterion and MAPE in the range 1%-3%. However, at slower speeds of 3.0 and 2.4 km·h-1, the accuracy of all devices substantially deteriorated: their correlation with the criterion decreased below 90% and their MAPE increased to 4–8% and 10–45%, respectively. Conclusions Even though none of the tested activity monitors fall within arbitrary thresholds for validity, most of them perform reasonably well enough to be useful tools that clinicians can use to simply motivate chronic heart failure patients to walk more.
Learning Drug Functions from Chemical Structures with Convolutional Neural Networks and Random Forests

Empirical testing of chemicals for drug efficacy costs many billions of dollars every year. The ability to predict the action of molecules in silico would greatly increase the speed and decrease the cost of prioritizing drug leads. Here, we asked whether drug function, defined as MeSH “therapeutic use” classes, can be predicted from only a chemical structure. We evaluated two chemical-structure-derived drug classification methods, chemical images with convolutional neural networks and molecular fingerprints with random forests, both of which outperformed previous predictions that used drug-induced transcriptomic changes as chemical representations. This suggests that the structure of a chemical contains at least as much information about its therapeutic use as the transcriptional cellular response to that chemical. Furthermore, because training data based on chemical structure is not limited to a small set of molecules for which transcriptomic measurements are available, our strategy can leverage more training data to significantly improve predictive accuracy to 83–88%. Finally, we explore use of these models for prediction of side effects and drug-repurposing opportunities and demonstrate the effectiveness of this modeling strategy for multilabel classification.
Humans Perceive Binocular Rivalry and Fusion in a Tristable Dynamic State

Human vision combines inputs from the two eyes into one percept. Small differences “fuse” together, whereas larger differences are seen “rivalrously” from one eye at a time. These outcomes are typically treated as mutually exclusive processes, with paradigms targeting one or the other and fusion being unreported in most rivalry studies. Is fusion truly a default, stable state that only breaks into rivalry for non-fusible stimuli? Or are monocular and fused percepts three sub-states of one dynamical system? To determine whether fusion and rivalry are separate processes, we measured human perception of Gabor patches with a range of interocular orientation disparities. Observers (10 female, 5 male) reported rivalrous, fused, and uncertain percepts over time. We found a dynamic “tristable” zone spanning from ∼25–35° of orientation disparity where fused, left-eye-, or right-eye-dominant percepts could all occur. The temporal characteristics of fusion and non-fusion periods during tristability matched other bistable processes. We tested statistical models with fusion as a higher-level bistable process alternating with rivalry against our findings. None of these fit our data, but a simple bistable model extended to have three states reproduced many of our observations. We conclude that rivalry and fusion are multistable substates capable of direct competition, rather than separate bistable processes. SIGNIFICANCE STATEMENT When inputs to the two eyes differ, they can either fuse together or engage in binocular rivalry, where each eye's view is seen exclusively in turn. Visual stimuli have often been tailored to produce either fusion or rivalry, implicitly treating them as separate mutually-exclusive perceptual processes. We have found that some similar-but-different stimuli can result in both outcomes over time. Comparing various simple models with our results suggests that rivalry and fusion are not independent processes, but compete within a single multistable system. This conceptual shift is a step toward unifying fusion and rivalry, and understanding how they both contribute to the visual system's production of a unified interpretation of the conflicting images cast on the retina by real-world scenes.
Comparison and Characterization of Mutations Induced by Gamma-Ray and Carbon-Ion Irradiation in Rice (Oryza sativa L.) Using Whole-Genome Resequencing

Gamma-rays are the most widely used mutagenic radiation in plant mutation breeding, but detailed characteristics of mutated DNA sequences have not been clarified sufficiently. In contrast, newly introduced physical mutagens, e.g., heavy-ion beams, have attracted geneticists’ and breeders’ interest and many studies on their mutation efficiency and mutated DNA characteristics have been conducted. In this study, we characterized mutations induced by gamma rays and carbon(C)-ion beams in rice (Oryza sativa L.) mutant lines at M5 generation using whole-genome resequencing. On average, 57.0 single base substitutions (SBS), 17.7 deletions, and 5.9 insertions were detected in each gamma-ray-irradiated mutant, whereas 43.7 single SBS, 13.6 deletions, and 5.3 insertions were detected in each C-ion-irradiated mutant. The structural variation (SV) analysis detected 2.0 SVs (including large deletions or insertions, inversions, duplications, and reciprocal translocations) on average in each C-ion-irradiated mutant, while 0.6 SVs were detected on average in each gamma-ray-irradiated mutant. Furthermore, complex SVs presumably having at least two double-strand breaks (DSBs) were detected only in C-ion-irradiated mutants. In summary, gamma-ray irradiation tended to induce larger numbers of small mutations than C-ion irradiation, whereas complex SVs were considered to be the specific characteristics of the mutations induced by C-ion irradiation, which may be due to their different radiation properties. These results could contribute to the application of radiation mutagenesis to plant mutation breeding.
Elevated Hexokinase II Expression Confers Acquired Resistance to 4-Hydroxytamoxifen in Breast Cancer Cells*

Development of drug resistance is a challenge in tamoxifen-based breast cancer therapy. By assessing the differential expression of kinase proteins in drug-resistant and parental breast cancer cells, we discover that elevated expression of hexokinase 2 (HK2) and the ensuing inhibition of mTOR contribute to tamoxifen resistance, suggesting HK2 as a potential target for overcoming tamoxifen resistance. Graphical Abstract Highlights LC-PRM-based targeted kinome analysis led to the quantification of 315 kinases in parental and tamoxifen-resistant MCF-7 breast cancer cells. Hexokinase 2 and mTOR were up-regulated in tamoxifen-resistant MCF-7 cells, which was accompanied with elevated glycolysis rate. Augmented expression of HK2 promotes autophagy through inhibition of the mTOR-S6K signaling pathway and results in resistance of MCF-7 cells to tamoxifen. HK2 is a potential drug target for overcoming tamoxifen resistance. Tamoxifen has been clinically used in treating estrogen receptor (ER)-positive breast cancer for over 30 years. The most challenging aspect associated with tamoxifen therapy is the development of resistance in initially responsive breast tumors. We applied a parallel-reaction monitoring (PRM)-based quantitative proteomic method to examine the differential expression of kinase proteins in MCF-7 and the isogenic tamoxifen-resistant (TamR) cells. We were able to quantify the relative protein expression levels of 315 kinases, among which hexokinase 2 (HK2) and mTOR were up-regulated in TamR MCF-7 cells. We also observed that the TamR MCF-7 cells exhibited elevated rate of glycolysis than the parental MCF-7 cells. In addition, we found that phosphorylation of S6K - a target of mTOR - was much lower in TamR MCF-7 cells, and this phosphorylation level could be restored upon genetic depletion or pharmacological inhibition of HK2. Reciprocally, the level of S6K phosphorylation was diminished upon overexpression of HK2 in MCF-7 cells. Moreover, we observed that HK2 interacts with mTOR, and this interaction inhibits mTOR activity. Lower mTOR activity led to augmented autophagy, which conferred resistance of MCF-7 cells toward tamoxifen. Together, our study demonstrates that elevated expression of HK2 promotes autophagy through inhibiting the mTOR-S6K signaling pathway and results in resistance of MCF-7 breast cancer cells toward tamoxifen; thus, our results uncovered, for the first time, HK2 as a potential therapeutic target for overcoming tamoxifen resistance.