Miracle-dz/UniFAR-FTUs huggingface dataset:
Historical perspective on the department of energy mortality studies: focus on the collection and storage of individual worker data

Abstract Purpose To present how the Department of Energy’s (DOE) Comprehensive Epidemiologic Data Resource (CEDR) is integrated into the Million Person Study of Low Dose Health Effects (MPS). The history of DOE’s worker health surveillance and its epidemiology program are described. Methods and materials A standard protocol is used to extract data from CEDR for use in the MPS. The data files are pulled from CEDR to form the basis for the cohort analyzed in the MPS. The previous study data are reviewed to formulate the protocol for the MPS study cohort. The activities needed to update the data to construct the new analytic files are carried out in parallel. The primary efforts relate to updating the vital status, retrieving cause of death information and calculating annual radiation doses for the specific organs of interest. Working data files containing the updated data are produced for construction of analytic data files used in the biostatistical analysis. At study completion the working and analytic data files are placed into CEDR for use by other researchers. Results The use of CEDR to study the scientific and maintenance workers at the Los Alamos National Laboratory which is currently underway is used to demonstrate the process. Conclusions There is a pressing need to answer the question of the health risk of exposure to chronic low-level exposure to ionizing radiation. Using CEDR as the starting point to identify new cohorts to include in the MPS is a cost-effective and a time efficient way to expedite answering this question.
Perceived Parental Control, Restructuring Ability, and Leisure Motivation: A Cross-Cultural Comparison

ABSTRACT Leisure is viewed worldwide as an important developmental context for adolescents. As leisure research and programs are shared across nations, it is crucial to examine the cultural equivalence of leisure-related constructs and how they are related. Grounded in self-determination theory, this study explored the influence of perceived parental control and leisure restructuring ability on leisure motivation (amotivation and autonomous motivation) using samples of eighth grade adolescents in the United States and South Africa. Results of multiple-group structural equation modeling showed that the measurement model of the constructs was equivalent across the two samples, but the determinants of leisure motivation differed between the two samples. The findings provide implications for future cross-cultural research in leisure and offer insights on design and adaptation of leisure-based intervention and education programs in different cultural contexts.
Employment and health after retirement in Japanese men

Abstract Objective To estimate the average treatment effect of working past the current retirement age on the health of Japanese men. Methods We used publicly available data from the National Survey of Japanese Elderly, extracting a sample of 1288 men who were 60 years or older. Survey respondents were followed-up for at most 15 years for the onset of four health outcomes: death, cognitive decline, stroke and diabetes. By using the propensity score method, we adjusted for the healthy worker effect by incorporating economic, sociodemographic and health data in the form of independent variables. By calculating the differences in times to a health outcome between those in employment and those not employed, we estimated the average treatment effects on health of being in paid work past retirement age. Findings Compared with those not employed, those in employment lived 1.91 years longer (95% confidence interval, CI: 0.70 to 3.11), had an additional 2.22 years (95% CI: 0.27 to 4.17) before experiencing cognitive decline, and had a longer period before the onset of diabetes and stroke of 6.05 years (95% CI: 4.44 to 7.65) and 3.35 years (95% CI: 1.42 to 5.28), respectively. We also observed differences between employees and the self-employed: the self-employed had longer life expectancies than employees. In terms of years to onset of diabetes or stroke, however, we only observed significant benefits to health of being an employee but not self-employed. Conclusion Our study found that being in employment past the current age of retirement had a positive impact on health.
miR-155-5p is Negatively Associated with Acute Pancreatitis and Inversely Regulates Pancreatic Acinar Cell Progression by Targeting Rela and Traf3

Background/Aims: Acute pancreatitis contributes to high mortality in pancreatitis patients, and miRNAs play a vital role in the development of acute pancreatitis (AP), however, its precise biological role remains largely elusive. Methods: To clarify the potential mechanisms of miRNAs in AP, we built mouse models of mild acute pancreatitis (MAP) and moderate/ severe acute pancreatitis (SAP). MiRNA microarray analysis and Real-time quantitative PCR (qRT-PCR) were used to analyze the expression of miRNA in MAP/SAP. TargetScan software, dual-luciferase gene reporter assays and Western blotting were used to assess the target genes of miR-155-5p in AP. Results: miR-155-5p was significantly decreased in MAP/SAP mice compared to controls. In pancreatic acinar AR42J cells transfected with miR-155-5p mimic, the expression of Rela and Traf3 notably decreased in both the caerulein- and TLC-S-induced groups compared with the negative control (NC); however, the expression of Rela and Traf3 notably increased after transfection with miR-155-5p inhibitor. Combined analysis using the TargetScan software and dual-luciferase gene reporter assays indicated that Rela and Traf3 were both targeted by miR-155-5p. Meanwhile, the expression of Ptgs2 also decreased after transfection of the AR42J cells with miR-155-5p mimic. The opposite results were found when miR-155-5p inhibitor was transfected into the AR42J cells. In addition, we treated caerulein- and TLC-S-induced AR42J cells with the Rela inhibitor helenalin and found that the expression of Rela, Traf3 and Ptgs2 decreased compared with the NC, while the expression of miR-155-5p did not show any significant difference. Furthermore, we found that miR-155-5p was significantly down-regulated in pancreatitis patients. Conclusion: miR-155-5p inversely regulated AP development through the Rela/Traf3/Ptgs2 signaling pathway.
The Ralstonia solanacearum effector RipN suppresses plant PAMP‐triggered immunity, localizes to the endoplasmic reticulum and nucleus, and alters the NADH/NAD+ ratio in Arabidopsis

Summary Ralstonia solanacearum, one of the most destructive plant bacterial pathogens, delivers an array of effector proteins via its type III secretion system for pathogenesis. However, the biochemical functions of most of these proteins remain unclear. RipN is a type III effector with unknown function(s) from the pathogen R. solanacearum. Here, we demonstrate that RipN is a conserved type III effector found within the R. solanacearum species complex that contains a putative Nudix hydrolase domain and has ADP‐ribose/NADH pyrophosphorylase activity in vitro. Further analysis shows that RipN localizes to the endoplasmic reticulum (ER) and nucleus in Nicotiana tabacum leaf cells and Arabidopsis protoplasts, and truncation of the C‐terminus of RipN results in a loss of nuclear and ER targeting. Furthermore, the expression of RipN in Arabidopsis suppresses callose deposition and the transcription of pathogen‐associated molecular pattern (PAMP)‐triggered immunity (PTI) marker genes under flg22 treatment, and promotes bacterial growth in planta. In addition, the expression of RipN in plant cells alters NADH/NAD+, but not GSH/GSSG, ratios, and its Nudix hydrolase activity is indispensable for such biochemical function. These results suggest that RipN acts as a Nudix hydrolase, alters the NADH/NAD+ ratio of the plant and contributes to R. solanacearum virulence by suppression of PTI of the host.
The Burden of Facilitating Collaboration: Towards Estimation of Teacher Orchestration Load using Eye-Tracking Measures

Teacher facilitation of CSCL activities is widely recognized as one of the main factors affecting student learning outcomes in formal face-to-face settings. However, the orchestration load that such facilitation represents for the teacher, within the constraints of an authentic classroom, remains under-researched. This paper presents a novel method to estimate the cognitive load of teachers during facilitation of CSCL sessions, using mobile eye-tracking techniques. Throughout three studies of increasing authenticity, we demonstrate the feasibility of this approach, and extract insights about classroom usability challenges in CSCL practice: the increased load of class-level facilitation, or the real-time monitoring of students’ progress. This new instrument in the CSCL researcher’s toolkit can help focus our attention in critical, fine-grained classroom usability episodes, to make more informed design decisions.
Risk factors for Plasmodium falciparum infection in the Kenyan Highlands: a cohort study

Abstract Background Malaria transmission in African highland areas can be prone to epidemics, with minor fluctuations in temperature or altitude resulting in highly heterogeneous transmission. In the Kenyan Highlands, where malaria prevalence has been increasing, characterising malaria incidence and identifying risk factors for infection is complicated by asymptomatic infection. Methods This all-age cohort study, one element of the Malaria Transmission Consortium, involved monthly follow-up of 3155 residents of the Kisii and Rachuonyo South districts during June 2009–June 2010. Participants were tested for malaria using rapid diagnostic testing at every visit, regardless of symptoms. Results The incidence of Plasmodium falciparum infection was 0.2 cases per person, although infections were clustered within individuals and over time, with the majority of infections detected in the last month of the cohort study. Overall, incidence was higher in the Rachuonyo district and infections were detected most frequently in 5–10-year-olds. The majority of infections were asymptomatic (58%). Travel away from the study area was a notable risk factor for infection. Conclusions Identifying risk factors for malaria infection can help to guide targeting of interventions to populations most likely to be exposed to malaria.
Human DNA ligase IV is able to use NAD+ as an alternative adenylation donor for DNA ends ligation

Abstract All the eukaryotic DNA ligases are known to use adenosine triphosphate (ATP) for DNA ligation. Here, we report that human DNA ligase IV, a key enzyme in DNA double-strand break (DSB) repair, is able to use NAD+ as a substrate for double-stranded DNA ligation. In the in vitro ligation assays, we show that the recombinant Ligase IV can use both ATP and NAD+ for DNA ligation. For NAD+-mediated ligation, the BRCA1 C-terminal (BRCT) domain of Ligase IV recognizes NAD+ and facilitates the adenylation of Ligase IV, the first step of ligation. Although XRCC4, the functional partner of Ligase IV, is not required for the NAD+-mediated adenylation, it regulates the transfer of AMP moiety from Ligase IV to the DNA end. Moreover, cancer-associated mutation in the BRCT domain of Ligase IV disrupts the interaction with NAD+, thus abolishes the NAD+-mediated adenylation of Ligase IV and DSB ligation. Disrupting the NAD+ recognition site in the BRCT domain impairs non-homologous end joining (NHEJ) in cell. Taken together, our study reveals that in addition to ATP, Ligase IV may use NAD+ as an alternative adenylation donor for NHEJ repair and maintaining genomic stability.
A scoping review of published literature on chikungunya virus

Chikungunya virus (CHIKV) has caused several major epidemics globally over the last two decades and is quickly expanding into new areas. Although this mosquito-borne disease is self-limiting and is not associated with high mortality, it can lead to severe, chronic and disabling arthritis, thereby posing a heavy burden to healthcare systems. The two main vectors for CHIKV are Aedes aegypti and Aedes albopictus (Asian tiger mosquito); however, many other mosquito species have been described as competent CHIKV vectors in scientific literature. With climate change, globalization and unfettered urban planning affecting many areas, CHIKV poses a significant public health risk to many countries. A scoping review was conducted to collate and categorize all pertinent information gleaned from published scientific literature on a priori defined aspects of CHIKV and its competent vectors. After developing a sensitive and specific search algorithm for the research question, seven databases were searched and data was extracted from 1920 relevant articles. Results show that CHIKV research is reported predominantly in areas after major epidemics have occurred. There has been an upsurge in CHIKV publications since 2011, especially after first reports of CHIKV emergence in the Americas. A list of hosts and vectors that could potentially be involved in the sylvatic and urban transmission cycles of CHIKV has been compiled in this scoping review. In addition, a repository of CHIKV mutations associated with evolutionary fitness and adaptation has been created by compiling and characterizing these genetic variants as reported in scientific literature.
In silico identification and experimental validation of hits active against KPC-2 β-lactamase

Bacterial resistance has become a worldwide concern, particularly after the emergence of resistant strains overproducing carbapenemases. Among these, the KPC-2 carbapenemase represents a significant clinical challenge, being characterized by a broad substrate spectrum that includes aminothiazoleoxime and cephalosporins such as cefotaxime. Moreover, strains harboring KPC-type β-lactamases are often reported as resistant to available β-lactamase inhibitors (clavulanic acid, tazobactam and sulbactam). Therefore, the identification of novel non β-lactam KPC-2 inhibitors is strongly necessary to maintain treatment options. This study explored novel, non-covalent inhibitors active against KPC-2, as putative hit candidates. We performed a structure-based in silico screening of commercially available compounds for non-β-lactam KPC-2 inhibitors. Thirty-two commercially available high-scoring, fragment-like hits were selected for in vitro validation and their activity and mechanism of action vs the target was experimentally evaluated using recombinant KPC-2. N-(3-(1H-tetrazol-5-yl)phenyl)-3-fluorobenzamide (11a), in light of its ligand efficiency (LE = 0.28 kcal/mol/non-hydrogen atom) and chemistry, was selected as hit to be directed to chemical optimization to improve potency vs the enzyme and explore structural requirement for inhibition in KPC-2 binding site. Further, the compounds were evaluated against clinical strains overexpressing KPC-2 and the most promising compound reduced the MIC of the β-lactam antibiotic meropenem by four-fold.
Targeting LINC00673 expression triggers cellular senescence in lung cancer

ABSTRACT Aberrant expression of noncoding RNAs plays a critical role during tumorigenesis. To uncover novel functions of long non-coding RNA (lncRNA) in lung adenocarcinoma, we used a microarray-based screen identifying LINC00673 with elevated expression in matched tumor versus normal tissue. We report that loss of LINC00673 is sufficient to trigger cellular senescence, a tumor suppressive mechanism associated with permanent cell cycle arrest, both in lung cancer and normal cells in a p53-dependent manner. LINC00673-depleted cells fail to efficiently transit from G1- to S-phase. Using a quantitative proteomics approach, we confirm the modulation of senescence-associated genes as a result of LINC00673 knockdown. In addition, we uncover that depletion of p53 in normal and tumor cells is sufficient to overcome LINC00673-mediated cell cycle arrest and cellular senescence. Furthermore, we report that overexpression of LINC00673 reduces p53 translation and contributes to the bypass of Ras-induced senescence. In summary, our findings highlight LINC00673 as a crucial regulator of proliferation and cellular senescence in lung cancer.
Quantitative collision‐induced unfolding differentiates model antibody–drug conjugates

Antibody–drug conjugates (ADCs) are antibody‐based therapeutics that have proven to be highly effective cancer treatment platforms. They are composed of monoclonal antibodies conjugated with highly potent drugs via chemical linkers. Compared to cysteine‐targeted chemistries, conjugation at native lysine residues can lead to a higher degree of structural heterogeneity, and thus it is important to evaluate the impact of conjugation on antibody conformation. Here, we present a workflow involving native ion mobility (IM)‐MS and gas‐phase unfolding for the structural characterization of lysine‐linked monoclonal antibody (mAb)–biotin conjugates. Following the determination of conjugation states via denaturing Liquid Chromatography‐Mass Spectrometry (LC–MS) measurements, we performed both size exclusion chromatography (SEC) and native IM‐MS measurements in order to compare the structures of biotinylated and unmodified IgG1 molecules. Hydrodynamic radii (Rh) and collision cross‐sectional (CCS) values were insufficient to distinguish the conformational changes in these antibody–biotin conjugates owing to their flexible structures and limited instrument resolution. In contrast, collision induced unfolding (CIU) analyses were able to detect subtle structural and stability differences in the mAb upon biotin conjugation, exhibiting a sensitivity to mAb conjugation that exceeds native MS analysis alone. Destabilization of mAb–biotin conjugates was detected by both CIU and differential scanning calorimetry (DSC) data, suggesting a previously unknown correlation between the two measurement tools. We conclude by discussing the impact of IM‐MS and CIU technologies on the future of ADC development pipelines.
Expression of PD-1 by T Cells in Malignant Glioma Patients Reflects Exhaustion and Activation

Purpose: Glioblastoma (GBM) is the most common primary malignant tumor in the central nervous system. Our recent preclinical work has suggested that PD-1/PD-L1 plays an important immunoregulatory role to limit effective antitumor T-cell responses induced by active immunotherapy. However, little is known about the functional role that PD-1 plays on human T lymphocytes in patients with malignant glioma. Experimental Design: In this study, we examined the immune landscape and function of PD-1 expression by T cells from tumor and peripheral blood in patients with malignant glioma. Results: We found several differences between PD-1+ tumor-infiltrating lymphocytes (TIL) and patient-matched PD-1+ peripheral blood T lymphocytes. Phenotypically, PD-1+ TILs exhibited higher expression of markers of activation and exhaustion than peripheral blood PD-1+ T cells, which instead had increased markers of memory. A comparison of the T-cell receptor variable chain populations revealed decreased diversity in T cells that expressed PD-1, regardless of the location obtained. Functionally, peripheral blood PD-1+ T cells had a significantly increased proliferative capacity upon activation compared with PD-1− T cells. Conclusions: Our evidence suggests that PD-1 expression in patients with glioma reflects chronically activated effector T cells that display hallmarks of memory and exhaustion depending on its anatomic location. The decreased diversity in PD-1+ T cells suggests that the PD-1–expressing population has a narrower range of cognate antigen targets compared with the PD-1 nonexpression population. This information can be used to inform how we interpret immune responses to PD-1–blocking therapies or other immunotherapies.
Distinct Alterations in the Composition of Mucosal Innate Lymphoid Cells in Newly Diagnosed and Established Crohn’s Disease and Ulcerative Colitis

Background and Aims Innate lymphoid cells [ILC] have been suggested to play a role in inflammatory bowel disease [IBD]. Here, we investigated the ILC compartment in intestinal biopsies and blood from distinct patient groups with Crohn's disease [CD] and ulcerative colitis [UC], either newly diagnosed or with disease established for at least 1 year. This approach allowed us to simultaneously investigate temporal, disease-specific, and tissue-specific changes in ILC composition in IBD. Methods ILC subset frequencies, phenotype, and transcription factor profile in blood and intestinal biopsies were investigated by multi-parameter flow cytometry analysis. Endoscopic disease severity was judged using the ulcerative colitis endoscopic index of severity and the simple endoscopic score for Crohn's disease. Results The frequency of NKp44+ILC3 was decreased in inflamed tissue, both in patients with CD and those with UC, already at the time of diagnosis, and correlated with disease severity. Simultaneously, the frequency of ILC1 was increased in patients with CD, whereas the frequency of ILC2 was increased in patients with UC. However, in patients with established UC or CD, both ILC1 and ILC2 were increased. In contrast to the ILC composition in inflamed tissue, ILC in non-inflamed tissue or blood were unchanged compared with non-IBD controls. Finally, in patients undergoing treatment with an anti-α4β7 antibody the frequencies of ILC in peripheral blood remained unchanged. Conclusions We report both shared and distinct changes in ILC composition depending on diagnosis and disease duration. The alterations in ILC composition in IBD occur selectively at inflamed sites in the gut.
Photothermal treatment of port-wine stains using erythrocyte-derived particles doped with indocyanine green: a theoretical study

Abstract. Pulsed dye laser irradiation in the wavelength range of 585 to 600 nm is currently the gold standard for treatment of port-wine stains (PWSs). However, this treatment method is often ineffective for deeply seated blood vessels and in individuals with moderate to heavy pigmentation. Use of optical particles doped with the FDA-approved near-infrared (NIR) absorber, indocyanine green (ICG), can potentially provide an effective method to overcome these limitations. Herein, we theoretically investigate the effectiveness of particles derived from erythrocytes, which contain ICG, in mediating photothermal destruction of PWS blood vessels. We refer to these particles as NIR erythrocyte-derived transducers (NETs). Our theoretical model consists of a Monte Carlo algorithm to estimate the volumetric energy deposition, a finite elements approach to solve the heat diffusion equation, and a damage integral based on an Arrhenius relationship to quantify tissue damage. The model geometries include simulated PWS blood vessels as well as actual human PWS blood vessels plexus obtained by the optical coherence tomography. Our simulation results indicate that blood vessels containing micron- or nano-sized NETs and irradiated at 755 nm have higher levels of photothermal damage as compared to blood vessels without NETs irradiated at 585 nm. Blood vessels containing micron-sized NETs also showed higher photothermal damage than blood vessels containing nano-sized NETs. The theoretical model presented can be used in guiding the fabrication of NETs with patient-specific optical properties to allow for personalized treatment based on the depth and size of blood vessels as well as the pigmentation of the individual’s skin.