Miracle-dz/UniFAR-FTUs huggingface dataset:
Single Nucleotide Variant in FAS Associates With Organ Failure and Soluble Fas Cell Surface Death Receptor in Critical Illness

OBJECTIVES: Multiple organ failure in critically ill patients is associated with poor prognosis, but biomarkers contributory to pathogenesis are unknown. Previous studies support a role for Fas cell surface death receptor (Fas)-mediated apoptosis in organ dysfunction. Our objectives were to test for associations between soluble Fas and multiple organ failure, identify protein quantitative trait loci, and determine associations between genetic variants and multiple organ failure. DESIGN: Retrospective observational cohort study. SETTING: Four academic ICUs at U.S. hospitals. PATIENTS: Genetic analyses were completed in a discovery (n = 1,589) and validation set (n = 863). Fas gene expression and flow cytometry studies were completed in outpatient research participants (n = 250). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In discovery and validation sets of critically ill patients, we tested for associations between enrollment plasma soluble Fas concentrations and Sequential Organ Failure Assessment score on day 3. We conducted a genome-wide association study of plasma soluble Fas (discovery n = 1,042) and carried forward a single nucleotide variant in the FAS gene, rs982764, for validation (n = 863). We further tested whether the single nucleotide variant in FAS (rs982764) was associated with Sequential Organ Failure Assessment score, FAS transcriptional isoforms, and Fas cell surface expression. Higher plasma soluble Fas was associated with higher day 3 Sequential Organ Failure Assessment scores in both the discovery (β = 4.07; p < 0.001) and validation (β = 6.96; p < 0.001) sets. A single nucleotide variant in FAS (rs982764G) was associated with lower plasma soluble Fas concentrations and lower day 3 Sequential Organ Failure Assessment score in meta-analysis (–0.21; p = 0.02). Single nucleotide variant rs982764G was also associated with a lower relative expression of the transcript for soluble as opposed to transmembrane Fas and higher cell surface expression of Fas on CD4+ T cells. CONCLUSIONS: We found that single nucleotide variant rs982764G was associated with lower plasma soluble Fas concentrations in a discovery and validation population, and single nucleotide variant rs982764G was also associated with lower organ dysfunction on day 3. These findings support further study of the Fas pathway as a potential mediator of organ dysfunction in critically ill patients.
Enhanced liver fibrosis score as a surrogate of liver-related complications and mortality in primary biliary cholangitis

Abstract The presence of bridging fibrosis predicts survival of primary biliary cholangitis (PBC). This study aimed to compare serum parameters for the estimation of liver fibrosis and prediction of clinical outcomes in PBC. Out of 392 patients with PBC, 102 who underwent liver biopsy and in whom fibrosis indices, platelet count, hyaluronic acid, type IV collagen 7 second domain, procollagen type III amino-terminal peptide, tissue inhibitor of metalloproteinases 1, Mac-2 binding protein glycosylation isomer, N-terminal type III collagen propeptide levels; fibrosis index based on 4 factors, aspartate aminotransferase-to-platelet ratio index, and enhanced liver fibrosis (ELF) score were determined, were included. The correlation of histological stages based on both Scheuer and Nakanuma classifications with fibrosis indices was investigated. The Nakanuma system comprises grading for liver fibrosis and bile duct loss. Diagnostic performances of 10 fibrosis indices were evaluated to identify patients with poor prognosis. Moreover, correlations of those with PBC clinical manifestation and survival were also investigated. Enhances liver fibrosis (ELF) score had the highest correlation coefficient for liver fibrosis evaluated according to either the Scheuer or Nakanuma classification among 10 serum fibrosis indices. It also had the highest diagnostic performance in estimating Scheuer stage III and Nakanuma fibrosis score 2, both of which represent portal-bridging fibrosis. Patients with an ELF score of ≥10.0 had shorter survival and presented more frequently clinical complications than those with an ELF score of <10.0. ELF score determines the severity of liver fibrosis and predicts the occurrence of complications and survival in patients with PBC.
Effect of prophylactic administration of vitamin C in chickens with staphylococcal septic arthritis

Abstract Background Septic arthritis (SA) due to Staphylococcus aureus is a major cause of lameness in poultry with improper response to antimicrobial therapy. Objectives The study evaluates the effect of prophylactic administration of vitamin C on SA induced by methicillin resistant S. aureus in chickens. Methods One hundred and twenty chickens were randomly assigned into four groups: I. Negative control (NC), II. Positive control (PC) with SA induced at the age of 35 days by intra articular injection of S. aureus. III. Vehicle control (VC) and IV. Arthritic vitamin C‐treated (VitC) group (15 g/100 L of drinking water from day 25 to the end of the experiment). Samplings were performed on day 44 (sampling 1) and day 54 (sampling 2) of age. Results Arthritic birds showed an obvious decrease in body weight with severe clinical arthritis and lameness which were not significantly affected by vitamin C administration at both samplings. Moreover, marked increase in serum malondialdehyde (MDA) concentration of the PC group was observed in sampling 1. Administration of vitamin C successfully reduced MDA concentration at both samplings. In sampling 2, birds in the VitC group showed significantly higher total antioxidant capacity (TAC) than NC birds (p < 0.05). Interleukin‐6 concentration in synovial fluid of chickens remained statistically similar among groups in both samplings, while histopathological changes were ameliorated in the VitC group in sampling 2. Conclusions Prophylactic administration of vitamin C especially for relatively longer period can ameliorate oxidative stress and histopathological changes due to staphylococcal arthritis in chickens, although it is not associated with a significant effect on clinical manifestations of the disease.
Interpretation of Enhanced Fecal and Urinary Plutonium Excretion Data under a 2-y Regular DTPA Treatment Started Months after Intake

Abstract In a worker who had internalized plutonium, most likely through inhalation of a somewhat soluble compound, an extensive diethylenetriaminepentaacetate (DTPA) treatment regimen was initiated several months after contamination. Numerous radiotoxicological analyses were performed in both fecal and urinary specimens collected, sometimes for three consecutive days after DTPA administration. Activity measurements showed the continued effectiveness of DTPA intravenous infusions in removing plutonium from tissues of retention even if the treatment regimen started very belatedly after contamination. In the present case, the activity excreted through urine within the first 24-h after a DTPA infusion contributed only about half of that activity excreted within the first three days (i.e., the cumulative activity of the first three 24-h urine collections). In addition, the careful study of the data revealed that DTPA-induced excretion of plutonium via fecal pathway significantly contributed to the overall decorporation. The intracellular chelation of plutonium may be responsible for this enhanced excretion of activity in feces as well as for the delayed and sustained increased clearance of activity in urine. The authors would suggest that the occupational physicians offer to individuals who internalized moderately soluble or soluble plutonium compounds undergo a long-term DTPA treatment, especially when it is not initiated promptly after intake. Under this scenario, measurements of plutonium in successive urine and fecal collections after treatment should be required to get a better estimate of the therapeutic benefit. Also, intracellular chelation and fecal route should be taken into account for better interpretation of radiotoxicological data and modeling of plutonium kinetics under delayed DTPA treatment.
Factors related to instrumental activities of daily living in persons with chronic thromboembolic pulmonary hypertension

Instrumental activities of daily living (IADL) are significantly related to quality of life and mortality among individuals with heart disease. However, few reports have examined IADL in persons with chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to clarify factors related to IADL in persons with CTEPH. This retrospective, observational study enrolled 163 persons with CTEPH (mean ± standard deviation age = 65 ± 13 years; 68% female) admitted to the Department of Cardiology at Keio University Hospital between January 2015 and July 2019. The Frenchay Activities Index (FAI) was used to assess IADL. Age, sex, body mass index, World Health Organization functional class (WHO-FC), cardiac function (mean pulmonary arterial pressure, mean right atrial pressure, pulmonary capillary wedge pressure, and cardiac index), pulmonary function (percentage vital capacity, percentage forced expiratory volume in 1 s, diffusion capacity of carbon monoxide (DLCO)/alveolar volume (VA)), physical function (knee extension strength and walking speed), and 6-min walking distance (6MWD) were assessed. Multiple regression analysis was performed to identify factors significantly associated with FAI. Mean FAI was 25 ± 8. Univariate analysis showed that sex, WHO-FC, DLCO/VA, walking speed, and 6MWD were correlated with FAI. Multiple regression analysis showed that 6MWD (sβ = 0.338, 95% CI 0.014–0.034, p < .001), sex (sβ = 0.268, 95% CI 2.238–7.165, p < .001), and DLCO/VA (sβ = 0.257, 95% CI 1.011–3.528, p < .001) were significantly correlated with FAI (R2 = 0.261). IADL were associated with exercise tolerance, sex, and DLCO/VA in persons with CTEPH. In the future, more details of IADL are expected to be clarified by analyzing individual components of IADL and investigating social background characteristics, including living environment.
The effect of antiretroviral therapy initiation time and baseline CD4+ cell counts on AIDS-related mortality among former plasma donors in China: a 20-Year retrospective cohort study

Background: To estimate the influence of antiretroviral therapy (ART) initiation time， baseline CD4+ cell counts and other prognostic factors on AIDS-related death among former plasma donors patients (FPD). Methods: A retrospective cohort study was conducted involving 11,905 HIV/AIDS patients in a high-risk area of illicit blood donation of Henan province in China between 1995 and 2016. Demographic and clinical characteristics information was collected. Hazard Ratios (HRs) for AIDS-related mortality by categories of baseline CD4+ cell counts and ART initiation time, were determined using competing risk model. Competing risk model also was used to evaluate the prognostic factors of AIDS-related mortality. The model performance was assessed by time-dependent receiver operating characteristic curve. Results: Patients who initiated ART within 90 days of HIV/AIDS diagnosis (sHR: 0.24, 95% CI: 0.22-0.27) and baseline CD4+ cell counts of ≥500 cells/μL (sHR: 0.23, 95% CI: 0.19-0.28) were associated with lower AIDS-related mortality risk. ART initiation time >1 year and CD4+ counts >350 (sHR: 4.42, 95% CI: 3.30-5.91) had a higher AIDS-related mortality risk than ART initiation time >90 days and CD4+ counts ≤350 (sHR: 4.33, 95% CI: 3.58-5.23). Male (sHR: 1.32, 95% CI: 1.22-1.43), older age (sHR: 1.97, 95% CI: 1.59-2.46), and infection by blood transmission (sHR: 1.57, 95% CI: 1.37-1.80) were risk factors.Conclusions: Early ART should be promoted to improve the survival of HIV/AIDS patients regardless of baseline CD4+ cell counts, especially elders, males, and infected through blood transmission. Key words: HIV/AIDS; antiretroviral therapy; treatment initiation; CD4+ cell counts; AIDS-related mortality; competing risk model
Computational modeling identifies multitargeted kinase inhibitors as effective therapies for metastatic, castration-resistant prostate cancer

Significance Metastatic, castration-resistant prostate cancer (mCRPC) is an advanced prostate cancer with limited therapeutic options and poor patient outcomes. To investigate whether multitargeted kinase inhibitors (KIs) represent an opportunity for mCRPC drug development, we applied machine learning–based functional screening and identified two KIs, PP121 and SC-1, which demonstrated strong suppression of CRPC growth in vitro and in vivo. Furthermore, we show the marked ability of these KIs to improve on standard-of-care chemotherapy in both tumor response and survival, suggesting that combining multitargeted KIs with chemotherapy represents a promising avenue for mCRPC treatment. Overall, our findings demonstrate the application of a multidisciplinary strategy that blends bench science with machine-learning approaches for rapidly identifying KIs that result in desired phenotypic effects. Castration-resistant prostate cancer (CRPC) is an advanced subtype of prostate cancer with limited therapeutic options. Here, we applied a systems-based modeling approach called kinome regularization (KiR) to identify multitargeted kinase inhibitors (KIs) that abrogate CRPC growth. Two predicted KIs, PP121 and SC-1, suppressed CRPC growth in two-dimensional in vitro experiments and in vivo subcutaneous xenografts. An ex vivo bone mimetic environment and in vivo tibia xenografts revealed resistance to these KIs in bone. Combining PP121 or SC-1 with docetaxel, standard-of-care chemotherapy for late-stage CRPC, significantly reduced tibia tumor growth in vivo, decreased growth factor signaling, and vastly extended overall survival, compared to either docetaxel monotherapy. These results highlight the utility of computational modeling in forming physiologically relevant predictions and provide evidence for the role of multitargeted KIs as chemosensitizers for late-stage, metastatic CRPC.
Vaccine Videos and Information Sharing: The Effects of Framing, Evidence Type, and Speaker Expertise

YouTube videos have been used to inform and misinform the public about the safety of vaccines related to health threats such as measles and COVID-19. Understanding how such videos can promote the sharing of accurate vaccine safety information is of the utmost importance if health researchers are to combat the spread of misinformation and encourage widespread uptake of vaccines. Through the lens of prospect theory, this study conducted a 2 (framing: loss v. gain) x 2 (evidence type: episodic v. thematic) x 2 (speaker expertise: expert v. non-expert) between-subject factorial experiment in which a sample of N = 400 US adults over the age of 18 recruited through MTurk were asked their intention to share vaccine safety information with others after watching a manipulated YouTube video. The results showed that loss framing was associated with perceived MMR severity which was, in turn, associated with the likelihood that participants would share MMR vaccine information with others, via any means. However, this process varied depending on the type of evidence delivered, and the expertise of the speaker. Results and limitations are discussed in the context of vaccine communication and social media.
Targeted Protein Acetylation in Cells Using Heterobifunctional Molecules

Protein acetylation is a central event in orchestrating diverse cellular processes. However, current strategies to investigate protein acetylation in cells are often non-specific or lack temporal and magnitude control. Here, we developed an acetylation tagging system, AceTAG, to induce acetylation of targeted proteins. The AceTAG system utilizes bifunctional molecules to direct the lysine acetyltransferase p300/CBP to proteins fused with the small protein tag FKBP12F36V, resulting in their induced acetylation. Using AceTAG, we induced targeted acetylation of a diverse array of proteins in cells, specifically histone H3.3, the NF-κB subunit p65/RelA, and the tumor suppressor p53. We demonstrate that targeted acetylation with the AceTAG system is rapid, selective, reversible, and can be controlled in a dose-dependent fashion. AceTAG represents a useful strategy to modulate protein acetylation and will enable the exploration of targeted acetylation in basic biological and therapeutic contexts.
Nano-scale characterization of the formation of silver layers during electroless deposition on polymeric surfaces

We report here a quantitative method of Transmission Electron Microscopy (TEM) to measure the shapes, sizes and volumes of nanoparticles which are responsible for their properties. Gold nanoparticles (Au NPs) acting as nucleating agents for the electroless deposition of silver NPs on SU-8 polymers were analyzed in this project. The atomic-number contrast (Z-contrast) imaging technique reveals the height and effective diameter of each Au NP and a volume distribution is obtained. Varying the reducing agents produced Au NPs of different sizes which were found both on the polymer surface and in some cases buried several nanometers below the surface. The morphology of Au NPs is an important factor for systems that use surface-bound nanoparticles as nucleation sites as in electroless metallization. Electrolessly deposited silver layers reduced by hydroquinone on SU-8 polymer are analyzed in this project.
sEH promotes macrophage phagocytosis and lung clearance of Streptococcus pneumoniae.

Epoxyeicosatrienoic acids (EETs) have potent anti-inflammatory properties. Hydrolysis of EETs by soluble epoxide hydrolase (sEH/EPHX2) to less active diols attenuates their anti-inflammatory effects. Macrophage activation is critical to many inflammatory responses; however, the role of EETs and sEH in regulating macrophage function remains unknown. Lung bacterial clearance of S. pneumoniae was impaired in Ephx2-deficient (Ephx2-/-) mice and in mice treated with an sEH inhibitor. The EET receptor antagonist, EEZE, restored lung clearance of S. pneumoniae in Ephx2-/- mice. Ephx2-/- mice had normal lung Il-1β, Il-6 and Tnfα expression and macrophage recruitment to lungs during S. pneumoniae infection; however, Ephx2 disruption attenuated proinflammatory cytokine induction, Tlr2 and Pgylrp1 receptor upregulation and Rac1/2 and Cdc42 activation in PGN-stimulated macrophages. Consistent with these observations, Ephx2-/-macrophages displayed reduced phagocytosis of S. pneumoniae in vivo and in vitro. Heterologous overexpression of TLR2 and PGLYRP1 in Ephx2-/- macrophages restored macrophage activation and phagocytosis. Human macrophage function was similarly regulated by EETs. Together, these results demonstrate that EETs reduce macrophage activation and phagocytosis of S. pneumoniae through down-regulation of TLR2 and PGLYRP1 expression. Defining the role of EETs and sEH in macrophage function may lead to development of new therapeutic approaches for bacterial diseases.
From cells to atoms: Cryo‐EM as an essential tool to investigate pathogen biology, host–pathogen interaction, and drug discovery

Electron cryo‐microscopy (cryo‐EM) has lately emerged as a powerful method in structural biology and cell biology. While cryo‐EM single‐particle analysis (SPA) is now routinely delivering structures of purified proteins and protein complexes at near‐atomic resolution, the use of electron cryo‐tomography (cryo‐ET), together with subtomogram averaging, is allowing visualization of macromolecular complexes in their native cellular environment, at unprecedented resolution. The unique ability of cryo‐EM to provide information at many spatial resolution scales from ångströms to microns makes it an invaluable tool that bridges the classic “resolution‐gap” between structural biology and cell biology domains. Like in many other fields of biology, in recent years, cryo‐EM has revolutionized our understanding of pathogen biology, host–pathogen interaction and has made significant strides toward structure‐based drug discovery. In a very recent example, during the ongoing coronavirus disease (COVID‐19) pandemic, the structure of the stabilized severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike protein was deciphered by SPA. This led to the development of multiple vaccines. Alongside, cryo‐ET provided key insights into the structure of the native virion, mechanism of its entry, replication, and budding; demonstrating the unrivaled power of cryo‐EM in investigating pathogen biology, host–pathogen interaction, and drug discovery. In this review, we showcase a few examples of how different imaging modalities within cryo‐EM have enabled the study of microbiology and host–pathogen interaction.
Raman spectroscopic analysis of cataract lens: A compendious review

ABSTRACT Age-related cataracts is a pressing health issue with the increase in elderly populations. This creates an imminent demand for the development of an early, noninvasive method of cataracts diagnosis. Early detection of cataracts will improve quality of life and may prevent morbidity associated with advanced cataracts and surgery. Raman spectrum of proteins provides characteristic information regarding molecular interactions of peptide residues. Hence Raman spectroscopy is a promising tool for the study of protein-related diseases, such as cataracts. We surveyed the literature to assess the use of Raman technology in the studies of human lens and animal models. These studies included analysis of amino acids (i.e., cysteine, tryptophan, and tyrosine, etc.) and secondary protein structures (i.e., α-helix and β-sheet) in various Raman profiles. Other studies used Raman spectroscopy to analyze and monitor the development of cataracts in lens. Technological advances in the instrumentation of laser Raman spectroscopy, including Fourier transform Raman spectroscopy, Raman microspectroscopy, and confocal Raman microspectroscopy have improved the performance of Raman spectroscopic analysis. How to take advantage of these developments and make it closer to reality using Raman spectroscopic methods to diagnose cataracts in a timely manner is a key challenge for the scientific community of Raman spectroscopy.
Developing OurSleepKit: A Couple-focused mHealth Tool to Support Adherence to Positive Airway Pressure Treatment

ABSTRACT Background and Aim Existing interventions promoting positive airway pressure (PAP) adherence focus only on the diagnosed individual, despite the fact that partners are often the most impacted by obstructive sleep apnea (OSA), and are delivered mostly by health professionals, with limited success. The goal of this work is to develop a prototype of OurSleepKit, a couple-focused mobile health (mHealth) tool to coach mutual engagement and promote adherence to PAP treatment. Methods We used an iterative participatory approach working with future end users of OurSleepKit to support the development of this prototype. We conducted a total of 14 semi-structured in-depth open-ended dyadic interviews with OSA patients and their partners. Phase 1 of the development was to inform key functions of an engaging tool. Phase 2 focused on developing functions to engage positive conversation in the dyad and obtained feedback for this initial prototype. Results The OurSleepKit prototype was developed and demonstrated high acceptability and engagement. Three key functions included periodic assessments based on developmental stages of PAP treatment, a Coaching Board which provides customized and dynamically updated support content – primarily brief story-telling videos featuring real-life couples’ experiences – and timely tailored prompts (for action, learning, and conversation) through push notifications in the evening to facilitate positive conversation in the dyad and offer in-the-moment support for PAP use. Conclusions Going beyond the traditional and prevailing view of PAP use as an individual phenomenon, OurSleepKit is a novel mHealth intervention engaging both the patient and partner holding great promise to promote PAP adherence.