Miracle-dz/UniFAR-FTUs huggingface dataset:
Chespa: Streamlining Expansive Chemical Space Evaluation of Molecular Sets

Thousands of chemical properties can be calculated for small molecules, which can be used to place the molecules within the context of a broader "chemical space. " These definitions vary based on compounds of interest and the goals for the given chemical space definition. Here, we introduce a customizable Python module, chespa, built to easily assess different chemical space definitions through clustering of compounds in these spaces and visualizing trends of these clusters. To demonstrate this, chespa currently streamlines prediction of various molecular descriptors (predicted chemical properties, molecular substructures, AI-based chemical space, and chemical class ontology) in order to test six different chemical space definitions. Furthermore, we investigated how these varying definitions trend with mass spectrometry (MS)-based observability, that is, the ability of a molecule to be observed with MS (e.g., as a function of the molecule ionizability), using an example data set from the U.S. EPA's nontargeted analysis collaborative trial, where blinded samples had been analyzed previously, providing 1398 data points. Improved understanding of observability would offer many advantages in small-molecule identification, such as (i) a priori selection of experimental conditions based on suspected sample composition, (ii) the ability to reduce the number of candidate structures during compound identification by removing those less likely to ionize, and, in turn, (iii) a reduced false discovery rate and increased confidence in identifications. Factors controlling observability are not fully understood, making prediction of this property nontrivial and a prime candidate for chemical space analysis. Chespa is available at github.com/pnnl/chespa.
System-level factors shaping the implementation of “hub and spoke” systems to expand MOUD in rural areas

Background Hub and spoke systems (HSS) are increasingly promoted as a systems-level intervention to expand access to medication for opioid use disorders (MOUD), particularly in rural areas with limited treatment options. The HSS model consists of sub-systems in which “hubs” deliver specialized expertise to a regional network of office-based opioid treatment (OBOT) providers in “spokes,” who together create a continuum of acute and chronic care. Yet, little is known about system-level factors (e.g., system structure, financing) that influence HSS implementation and sustainability in rural areas. Methods For this case study, we conducted semi-structured interviews with substance use disorder treatment providers (N = 26) and system-level stakeholders (N = 16) in five rural HSS sub-systems throughout one state. We undertook iterative textual analysis of interview transcripts, identifying and coding themes related to key implementation constructs associated with the Exploration, Preparation, Implementation and Sustainability (EPIS) framework. Results California policy-makers adopted HSS to expand rural access to opioid treatment programs (OTPs, i.e., providers of methadone and other medications for opioid use disorder). However, stakeholders questioned the model's fit for rural regions featuring few established OTPs that could function as hubs and critiqued its treatment-focused approach, felt to sideline harm reduction service providers. Contracts to serve rural regions were awarded entirely to for-profit methadone providers, contributing to stigma and distrust among many buprenorphine providers whose organizations were later recruited as spokes. While hubs offered financial resources enabling some spokes to expand MOUD, the needs of spokes varied considerably. Relationships between hubs and spokes to facilitate the care continuum under HSS were restricted by limited behavioral health resources and the large distances characterizing rural California. Conclusions This case study reveals how rural contextual factors such as geography and behavioral healthcare resource availability can dramatically influence differential HSS implementation.
Robust Permutation Test for Equality of Distributions under Covariate-Adaptive Randomization

Though stratified randomization achieves more balance on baseline covariates than pure randomization, it does affect the way we conduct inference. This paper considers the classical two-sample goodness-of-fit testing problem in randomized controlled trials (RCTs) when the researcher employs a particular type of stratified randomization— covariate-adaptive randomization (CAR). When testing the null hypothesis of equality of distributions between experimental groups in this setup, we first show that stratification leaves a mark on the test statistic’s limit distribution, making it difficult, if not impossible, to obtain critical values. We instead propose an alternative approach to conducting inference based on a permutation test that i) is asymptotically exact in the sense that the limiting rejection probability under the null hypothesis equals the nominal α level, ii) is applicable under relatively weak assumptions commonly satisfied in practice, and iii) works for randomization schemes that are popular among empirically oriented researchers, such as stratified permuted block randomization. The proposed test’s main idea is that by transforming the original statistic by one minus its bootstrap p-value, it becomes asymptotically uniformly distributed on [0, 1]. Thus, the transformed test statistic—also called prepivoted—has a fixed limit distribution that is free of unknown parameters, effectively removing the effect of stratification. Consequently, a permutation test based on the prepivoted statistic produces a test whose limiting rejection probability equals the nominal level. We present further numerical evidence of the proposed test’s advantages in a Monte Carlo exercise, showing our permutation test outperforms the existing alternatives. We illustrate our method’s empirical relevance by revisiting a field experiment by Butler and Broockman (2011) on the effect of race on state legislators’ responsiveness to help their constituents register to vote during elections in the United States. Lastly, we provide the companion RATest R package to facilitate and encourage applying our test in empirical research.
Amyloid‐β impairs the phagocytosis of dystrophic synapses by astrocytes in Alzheimer's disease

Reactive astrocytes and dystrophic neurites, most aberrant presynaptic elements, are found surrounding amyloid‐β plaques in Alzheimer's disease (AD). We have previously shown that reactive astrocytes enwrap, phagocytose, and degrade dystrophic synapses in the hippocampus of APP mice and AD patients, but affecting less than 7% of dystrophic neurites, suggesting reduced phagocytic capacity of astrocytes in AD. Here, we aimed to gain insight into the underlying mechanisms by analyzing the capacity of primary astrocyte cultures to phagocytose and degrade isolated synapses (synaptoneurosomes, SNs) from APP (containing dystrophic synapses and amyloid‐β peptides), Tau (containing AT8‐ and AT100‐positive phosphorylated Tau) and WT (controls) mice. We found highly reduced phagocytic and degradative capacity of SNs‐APP, but not AT8/AT100‐positive SNs‐Tau, as compared with SNs‐WT. The reduced astrocyte phagocytic capacity was verified in hippocampus from 12‐month‐old APP mice, since only 1.60 ± 3.81% of peri‐plaque astrocytes presented phagocytic structures. This low phagocytic capacity did not depend on microglia‐mediated astrocyte reactivity, because removal of microglia from the primary astrocyte cultures abrogated the expression of microglia‐dependent genes in astrocytes, but did not affect the phagocytic impairment induced by oligomeric amyloid‐β alone. Taken together, our data suggest that amyloid‐β, but not hyperphosphorylated Tau, directly impairs the capacity of astrocytes to clear the pathological accumulation of oligomeric amyloid‐β, as well as of peri‐plaque dystrophic synapses containing amyloid‐β, perhaps by reducing the expression of phagocytosis receptors such as Mertk and Megf10, thus increasing neuronal damage in AD. Therefore, the potentiation or recovery of astrocytic phagocytosis may be a novel therapeutic avenue in AD.
The Impact of Obesity in End of Life Care in Patients With End Stage Liver Disease: An Observational Study

Background: Both obesity and end stage liver disease (ESLD) are increasing. Obesity’s impact on hospice and palliative care in patients with ESLD is unknown. Methods: We retrospectively evaluated patients admitted to an academic, Midwestern, tertiary center between January 2016 and May 2019 with a diagnosis of ESLD. Body Mass Index and MELD Na were calculated for each patient’s first admission during the study period. Patients with MELD Na scores ≥ 21 or 18-20 with additional criteria were considered potentially eligible for hospice and palliative care referrals. Results: Of 3863 patients admitted with ESLD, 1556 (40%) were potentially eligible for hospice and palliative care referrals. Of these, 703 (45%) were obese. Comorbidity burden was higher in obese patients (15.6% of obese patients had a Charlson Comorbidity Index ≥ 5, while 5% of non-obese patients had a comorbidity index of ≥ 5 (p < 0.001). Referral rates to hospice and palliative services in obese patients were 10.1% and 16.4% respectively. Hospice and palliative referral rates among non-obese patients were similar (10.1% and 15.5%). Among patients who died within 6 months of the first hospitalization, the mean time to referral to hospice or palliative care from index admission was longer in obese patients. Conclusion: Obesity is common in patients hospitalized with ESLD who may be approaching the end of life. Referral rates to hospice and palliative care services are low and similar regardless of BMI and despite higher co-morbidity burdens in obese patients. Obesity may delay referrals to hospice and palliative care.
Charlson comorbidity index as a predictor of short-term outcomes after pulmonary resection

Background The objective of this retrospective study is to evaluate the impact of the CCI on short-term outcomes in pulmonary resection. Methods We retrospectively analyzed 1,309 patients who underwent pulmonary surgery consecutively in our hospital. Results All patients were divided into complication group and non-complication group. CCI (P=0.012), blood loss (P=0.015) and type of surgery (P<0.001) were an independent risk factors for complications in multivariate analysis. Assuming a threshold of 3 for defining poor outcomes for pulmonary resection, the sensitivity and specificity were 87.9% and 44.2%, respectively. The area under the curve for CCI was 0.711 (P<0.001). There were 918 (70.1%) patients in the CCI ≤3 group and 391 (29.9%) patients in the CCI ≤3 group. The rate of poor outcome was 3.3% in the CCI ≤3 group, and 9.2% in the CCI >3 group (P<0.001). Conclusions The main finding of the present study was that CCI >3 was associated with a poor short-term outcome. For patients with CCI >3, it was suggested that the experienced surgical team should perform pulmonary resection in the shortest time and preserving the lung function as much as possible.
Characterization of Chemically Prepared Magnetite Nanoparticles

Magnetite (Fe3O4) nanoparticles are being extensively researched as potential building blocks for nanoscaled structures, devices and systems. They exhibit many unique properties due to their dimension that lies in the mesoscopic scale (in between atomic scale and microscopic scale). In addition, it is possible to fine tune the properties of magnetite particles prepared by wet chemical techniques simply by varying the synthesis parameters. Thus, they are widely considered for various applications in fields such as electronics, optoelectronics, biomedicine and medical diagnostics. However, in order to be widely utilized for biomedical and commercial applications, these particles have to be produced at a large scale with low cost, high yield and high reproducibility. Moreover, the particles have to possess uniform properties and narrow size distribution. In this paper, Fe3O4 nanoparticles are prepared under non‐oxidized environment using co‐precipitation of Fe2+ and Fe3+ with an alkaline base. The effect of preparation variables, such as the stirring rate, stirring period and reaction temperature, on the properties of the nanoparticles are compared using TEM, VSM and XRD.
Reevaluation of the average prompt neutron emission multiplicity (nubar) values from fission of uranium and transuranium nuclides

In response to a need of the safeguards community, we have begun an evaluation effort to upgrade the recommended values of the prompt neutron emission multiplicity distribution, P/sub nu/ and its average value, nubar. This paper will report on progress achieved thus far. The evaluation of the uranium, plutonium, americium and curium nuclide's nubar values will be presented. The recommended values will be given and discussed. 61 references.
Influence of extracellular polymeric substances on microbial activity and cell hydrophobicity in biofilms

BACKGROUND: Over the last few decades, the emphasis in studies on extracellular polymeric substances (EPS) has been on the extraction and quantitative analysis methods relating to activated sludge. However, little is currently known about the relationship between EPS and microbial activity and cell hydrophobicity in heterogeneous biofilms. This paper aims to reveal the relationship between them. RESULTS: Experimental results indicated that EPS content and components varied with depth in the aerobic biofilter. Protein was the main component of EPS at all depths within the biofilter, and the ratio of protein to polysaccharide was higher in the upper media than that in the lower media. Most active biomass was present in the bottom 25% of the biofilter near the inlet. By means of repeatedly washing intact cells, a sharp decline of EPS content of washed cells was obtained, while active biomass rarely decreased. Microbial activity as well as cell hydrophobicity at different filter depths decreased with the decline of EPS. CONCLUSION: Results indicated that EPS on cell surfaces are essential for microbial metabolism as well as for the formation and stability of biofilm, and it is possible to take EPS into consideration for biofilter control and microbial activity assessment. Copyright © 2007 Society of Chemical Industry
Inventory of Youth Adaptation to Loss (IYAL): Psychometric Testing of a New Instrument for Bereaved Youth to Assess Social Support and Coping

The Inventory of Youth Adaptation to Loss (IYAL) was developed to understand the feelings and social supports experienced by bereaved youth to develop an evidence-base for bereavement interventions. The sample included 400 youth ages 9–17, permitting robust psychometric testing of the IYAL. To evaluate the reliability of the IYAL, the sample framework was national in scope, encompassed a range of different types of youth bereavement programs, and purposively sought diversity in the sample. Exploratory factor analysis identified five factors with distinct sub-scales indicating that the IYAL is a valid and reliable assessment instrument of youth coping with grief and their social support relationships.
Androgen‐dependent miR‐125a‐5p targets LYPLA1 and regulates global protein palmitoylation level in late‐onset hypogonadism males

Late‐onset hypogonadism (LOH) is defined as a clinical and biochemical syndrome with multiple symptoms caused by testosterone deficiency in aging males. An in‐depth exploration of the molecular mechanism underlying LOH development is insufficient. We previously identified miR‐125a‐5p as a dysregulated microRNA in LOH patients and potential diagnostic biomarker for LOH. The present study demonstrated that plasma miR‐125a‐5p was upregulated after testosterone supplementation in both LOH patients and castrated mice, and positively associated with the testosterone concentrations, suggesting direct regulation of miR‐125a‐5p expression by testosterone. Androgen response element in the promoter of miR‐125a‐5p was subsequently identified. Target gene screening and confirmation verified that LYPLA1, encoding acyl‐protein thioesterase 1 which catalyzed protein depalmitoylation process, was a target gene of miR‐125a‐5p. Furthermore, in cells cultured with testosterone deprivation and organs from castrated mice, testosterone deficiency led to decreased global protein palmitoylation level. In aging males, global protein palmitoylation in peripheral blood showed a notable decline in LOH patients contrast to the normal elderly males. And the palmitoylation level was positively correlative with serum testosterone concentrations. Our results suggested that testosterone could regulate global palmitoylation level through miR‐125a‐5p/LYPLA1 signaling pathway. Given that protein palmitoylation is pivotal for protein function and constitutes the pathogenesis of various diseases, testosterone/miR‐125a‐5p/LYPLA1 may contribute to the molecular mechanism underlying multiple symptoms caused by testosterone deficiency in LOH patients, and aberrant global palmitoylation could be a potential biomarker for LOH.
Is Touch in Romantic Relationships Universally Beneficial for Psychological Well-Being? The Role of Attachment Avoidance

Affectionate touch is crucial for well-being. However, attachment avoidance is associated with negative attitudes toward touch. We tested two preregistered hypotheses about how attachment avoidance influences the association between touch in romantic couples and psychological well-being. We examined whether greater attachment avoidance is associated with a reduced link between touch and well-being, and/or whether reduced touch mediates the relationship between attachment avoidance and lower well-being. Across three studies, including two dyadic ones, we measured retrospective self-reports (Studies 1 and 2), laboratory observations (Study 2), and daily experiences (Study 3) of touch. Touch and well-being were positively associated, and attachment avoidance was associated with lower well-being and less frequent touch. Touch was associated with greater well-being regardless of level of attachment avoidance, and less frequent touch mediated the negative association between attachment avoidance and well-being in most analyses. This underscores the importance of touch, even for those valuing distance and autonomy.
Quantitation and predictors of short-term mortality following extrapleural pneumonectomy, pleurectomy/decortication, and nonoperative management for malignant pleural mesothelioma

Background For malignant pleural mesothelioma (MPM), the benefit of resection, as well as the optimal surgical technique, remain controversial. In efforts to better refine patient selection, this retrospective observational cohort study queried the National Cancer Database in an effort to quantify and evaluate predictors of 30- and 90-day mortality between extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D), as well as nonoperative management. Methods After applying selection criteria, cumulative incidences of mortality by treatment paradigm were graphed for the unadjusted and propensity-matched populations, as well as for six a priori age-based intervals (≤60, 61–65, 66–70, 71–75, 76–80, and ≥81 years). The interaction between age and hazard ratio (HR) for mortality between treatment paradigms was also graphed. Cox multivariable analysis ascertained factors independently associated with 30- and 90-day mortality. Results Of 10,723 patients, 2,125 (19.8%) received resection (n=438 EPP, n=1,687 P/D) and 8,598 (80.2%) underwent nonoperative management. The unadjusted 30/90-day mortality for EPP, P/D, and all operated cases was 3.0%/8.0%, 5.4%/14.1%, and 4.9%/12.8%, respectively. There were no short-term mortality differences between EPP and P/D following propensity-matching, within each age interval, or between age subgroups on interaction testing (P>0.05 for all). Nonoperative patients had a crude 30- and 90-day mortality of 9.9% and 24.6%, respectively. Several variables were identified as predictors of short-term mortality, notably patient age (HR 1.022, P<0.001), Charlson-Deyo comorbidity index (HR 1.882, P<0.001), receipt of treatment at high-volume centers (HR 0.834, P=0.032) and induction chemotherapy (HR 1.735, P=0.025), among others. The patient (yearly) incremental increase in age conferred 2.0% (30 day) and 2.2% (90 day) increased risk of mortality (P<0.001). Conclusions Quantitative estimates of age-associated 30- and 90-day mortality of EPP and P/D should be considered when potentially operable patients are counseled regarding the risks and benefits of resection.
Cell-Cell Junction Signaling Regulating DNA Double-Strand Break Repair In Breast Cells

IV LIST OF FIGURES. IX INTRODUCTION.1 EXTRACELLULAR MATRIX (ECM). 2 INTEGRINS.8 INTEGRINS AND CADHERINS . 11 E-CADHERIN PATHWAY . 13 DOUBLE STRAND BREAK REPAIR AND CELL-CELL JUNCTIONS.16 HUMAN BREAST EPITHELIAL CELL LINE MODEL.22 EFFECT OF ECM ON HR IN JUNCTIONED CELLS.27 EFFECT OF ECM ON HR IN SINGLE CELLS.27 HYPOTHESIS . 32 METHODS AND MATERIALS.33 CELLS USED . 34 PLASMIDS AND siRNA USED AND THEIR TRANSFECTION . 34 ANTIBODIES.35 INDIRECT IMMUNOFLUORESCENCE.35 WESTERN BLOTTING.37 RESULTS.40 EFFECT OF E-CADHERIN ON DNA REPAIR PROTEINS IN PROLIFERATIVE CELLS . 45
Pterostilbene alleviates Aβ1-42 -induced cognitive dysfunction via inhibition of oxidative stress by activating Nrf2 signaling pathway.

SCOPE In the present study, we investigated effect of pterostilbene on Aβ1-42 induced cognitive impairment in mice and explored its possible mechanism of action. METHODS AND RESULTS The behavior results showed that pterostilbene alleviated Aβ1-42 -induced cognitive dysfunction assessed using the Y-maze test, novel object recognition task, Morris water maze test, and passive avoidance test. Pterostilbene alleviated neuron loss and accumulation of reactive oxygen species (ROS) in Aβ1-42 treated mouse brain. Additionally, pterostilbene promoted Nrf2 nuclear translocation and enhanced the transcription and expression of antioxidant genes such as HO-1 and SOD both in vivo and in vitro. Nrf2 inhibitor ML385 reversed the antioxidant function of pterostilbene in SH-SY5Y cells. Nrf2 is the master regulator of oxidative homeostasis and can be activated by p62. Pterostilbene promoted the binding of Keap1 and p62 which enhanced activation of Nrf2. CONCLUSION The present study reported that pterostilbene alleviated Aβ1-42 -induced cognitive dysfunction in mice. The mechanism of pterostilbene can be associated to the inhibition of oxidative stress through the Nrf2 signaling pathway. This article is protected by copyright. All rights reserved.