Miracle-dz/UniFAR-FTUs huggingface dataset:
The Carcinogenome Project: In Vitro Gene Expression Profiling of Chemical Perturbations to Predict Long-Term Carcinogenicity

Background: Most chemicals in commerce have not been evaluated for their carcinogenic potential. The current de-facto gold-standard approach to carcinogen testing adopts the two-year rodent bioassay, a time consuming and costly procedure. Alternative approaches, such as high-throughput in-vitro assays, show promise in addressing the limitations in carcinogen screening. Objectives: We developed a screening process for predicting chemical carcinogenicity and genotoxicity and characterizing modes of actions (MoAs) using in-vitro gene expression assays. Methods: We generated a large toxicogenomics resource comprising ~6,000 expression profiles corresponding to 330 chemicals profiled in HepG2 cells at multiple doses and in replicates. Predictive models of carcinogenicity were built using a Random Forest classifier. Differential pathway enrichment analysis was performed to identify pathways associated with carcinogen exposure. Signatures of carcinogenicity and genotoxicity were compared with external data sources including Drugmatrix and the Connectivity Map. Results: Among profiles with sufficient bioactivity, our classifiers achieved 72.2% AUC for predicting carcinogenicity and 82.3% AUC for predicting genotoxicity. Our analysis showed that chemical bioactivity, as measured by the strength and reproducibility of the transcriptional response, is not significantly associated with long-term carcinogenicity, as evidenced by the many carcinogenic chemicals that did not elicit substantial changes in gene expression at doses up to 40 μM. However, sufficiently high transcriptional bioactivity is necessary for a chemical to be used for prediction of carcinogenicity. Pathway enrichment analysis revealed several pathways consistent with literature review of pathways that drive cancer, including DNA damage and DNA repair. These data are available for download via https://clue.io/CRCGN_ABC, and a web portal for interactive query and visualization of the data and results is accessible at https://carcinogenome.org. Conclusions: We demonstrated a short-term in-vitro screening approach using gene expression profiling to predict long-term carcinogenicity and infer MoAs of chemical perturbations.
Autophagy suppresses radiation damage by activating PARP-1 and attenuating reactive oxygen species in hepatoma cells

Abstract Purpose: To investigate the relationship between autophagy and radiation damage of human hepatoma cells and to explore the role of reactive oxygen species (ROS). Materials and methods: HepG2 cells were exposed to X-rays, then the protein expressions of microtubule-associated protein 1 light chain 3 (LC3) and poly ADP-ribose polymerase-1 (PARP-1) were measured by Western blot assay, the formation of autophagosomes was detected by an autophagy detection kit, the intracellular ROS level was measured by flow cytometer, and DNA damage was evaluated by the incidence of micronuclei (MN). A CCK-8 kit was used to measure the proliferation ability of irradiated cells with or without N-acetyl-l-cysteine (NAC) treatment. In some experiments, the hepatoma cells were transferred with LC3 siRNA or PARP-1 siRNA before irradiation. Results: The protein expressions of LC3 and PARP-1 and the inductions of autophagosomes and intracellular ROS were increased in the irradiated HepG2 cells. Pretreatment of cells with NAC relieved the irradiation-induced inhibition of cell proliferation. When HepG2 cells were transfected with the LC3 siRNA, the over-expression of PARP-1 was diminished in the irradiated cells. Compared with the control group, the inhibitions of LC3 and PARP-1 increased ROS level in the irradiated HepG2 cells and hence sensitized radiation responses of both proliferation inhibition and MN induction. Conclusion: Autophagy upregulates the expression of PARP-1 and relieves radiation damage by reducing the generation of ROS.
Intersegment contacts determine geometry of the open and closed states in P-loop channels

Abstract Despite impressive progress in experimental studies of ion channels, determinants of their state-dependent geometry are not completely understood. Previous studies of P-loop channels suggested that the gating mechanism involves coupled movement of the S4-S5 cuff and S6 bundle and emphasized importance of specific intersegment contacts in stabilizing different states. However, it is unclear whether or not such contacts are sufficient to computationally reproduce gating rearrangements. Here we analyzed X-ray and cryo-EM structures of several channels in different functional states and selected structures with the wide cuff (open-state Kv1.2) and narrow cuff (closed-state MlotiK1) for detailed analysis. We revealed three categories of inter-residue contacts within the pore domain: (i) state-dependent and state-independent contacts between helices S4-S5 and S5, which provide integrity and state-dependent dimensions of the S4-S5 cuff; (ii) state-independent contacts between helices S4-S5 and S6 that enable their coupled movement during gating and (iii) state-dependent contacts between S6s that stabilize the open and/or closed activation gate. We imposed these contacts to transform the channels from the open to closed state and vice versa using Monte Carlo energy minimizations. In all cases, the target structures were reached with a good precision. Thus, a limited set of inter-residue contacts can be used to predict computationally state-dependent geometry of the pore domain in P-loop channels. Effects of various engineered and naturally occurring mutations (channelopathies) on the channel gating can be rationalized in view of the contacts. Communicated by Ramaswamy H. Sarma
Targeting transcription factors in multiple myeloma: evolving therapeutic strategies

ABSTRACT Introduction: Transcription factors (TFs) are convergence points of signaling cascades that coordinate cell differentiation, proliferation, survival, and migration; and are commonly deregulated in solid and hematologic malignancies, including multiple myeloma (MM). Several recent studies indicate that the inhibition of TFs may lead to selective tumor cell death with little or no consequences for normal cells due to redundancy in signaling pathways. Nuclear hormone receptor (NHR)- TFs belong to the most common therapies in oncology today. In contrast, non-NHR-TFs have been considered ‘un- druggable’ until most recently. Areas covered: This review article summarizes advances of our knowledge on the complex composition of non-NHR-TFs and their binding to cognate DNA sequences that are propelling the development of novel strategies in MM. Expert opinion: Protein-protein and protein-DNA- binding inhibitors, proteolysis- targeting chimeric molecules, and chromatin remodeling/epigenetic reader inhibitors are among the most promising novel compounds with a potentially high therapeutic index; they are likely to once more advance MM treatment strategies and improve patient outcome in the near future.
Transmission-Blocking Vaccines: Old Friends and New Prospects

In the progression of the life cycle of Plasmodium falciparum, a small proportion of asexual parasites differentiate into male or female sexual forms called gametocytes. Just like their asexual counterparts, gametocytes are contained within the infected host’s erythrocytes (RBCs). ABSTRACT In the progression of the life cycle of Plasmodium falciparum, a small proportion of asexual parasites differentiate into male or female sexual forms called gametocytes. Just like their asexual counterparts, gametocytes are contained within the infected host’s erythrocytes (RBCs). However, unlike their asexual partners, they do not exit the RBC until they are taken up in a blood meal by a mosquito. In the mosquito midgut, they are stimulated to emerge from the RBC, undergo fertilization, and ultimately produce tens of thousands of sporozoites that are infectious to humans. This transmission cycle can be blocked by antibodies targeting proteins exposed on the parasite surface in the mosquito midgut, a process that has led to the development of candidate transmission-blocking vaccines (TBV), including some that are in clinical trials. Here we review the leading TBV antigens and highlight the ongoing search for additional gametocyte/gamete surface antigens, as well as antigens on the surfaces of gametocyte-infected erythrocytes, which can potentially become a new group of TBV candidates.
Annual environmental variation influences host tolerance to parasites

When confronted with a parasite or pathogen, hosts can defend themselves by resisting or tolerating the attack. While resistance can be diminished when resources are limited, it is unclear how robust tolerance is to changes in environmental conditions. Here, we investigate the sensitivity of tolerance in a single host population living in a highly variable environment. We manipulated the abundance of an invasive parasitic fly, Philornis downsi, in nests of Galápagos mockingbirds (Mimus parvulus) over four field seasons and measured host fitness in response to parasitism. Mockingbird tolerance to P. downsi varied significantly among years and decreased when rainfall was limited. Video observations indicate that parental provisioning of nestlings appears key to tolerance: in drought years, mockingbirds likely do not have sufficient resources to compensate for the effects of P. downsi. These results indicate that host tolerance is a labile trait and suggest that environmental variation plays a major role in mediating the consequences of host–parasite interactions.
Time and spatial variability in concentrations of selected metals and their species in water and bottom sediments of Dzierżno Duże (Poland)

Abstract Poland is an industrialized country in which industries (especially the heavy ones) have had a tremendous influence on the environment. It is particularly visible in the Upper Silesia region, where the observed air, soil and water pollution levels are the most highest. The aim of this study was to determine the time and spatial variability in: concentrations of selected metals (Co, Ni, Zn, Cr, Mn, Pb, Cd), and, to a limited extent, of Cu, V, Al and Sr; concentrations of inorganic ions (Cl–, SO42–, Na+, K+, Ca2+ and Mg2+) and values of pH, conductivity and redox potential. The enlisted parameters were determined for the water and bottom sediments of Dzierżno Duże, a water reservoir located in Poland (Upper Silesia region). Additionally, fractions of a few characteristic metals were determined in the bottom sediments of the discussed reservoir with the BCR method. The investigation was carried out in 2017. It showed that the reservoir surface water was not polluted with the determined metal contents. However, it was highly polluted with the inorganic ions. The metal contents determined in the bottom sediments were high. If the conditions for releasing them from the bottom sediments had been favorable, this situation could have posed a potentially considerable environmental threat.
Evaluation of a case of diffuse large B-cell lymphoma

Lymphomas are a group of malignant blood cell tumors that develop from lymphocytes representing 2.2% of all malignant neoplasms of the head and neck. Two main categories of lymphomas are Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL) of which 90% are of the NHL type. Several classification systems have existed for lymphomas, the objectives of which are to help in identification of homogeneous group of well-defined entities and facilitating the recognition of uncommon diseases that require further classification as it affects prognosis and therapeutic implications. Diffuse large B-cell lymphoma (DLBCL) is the most common NHL in the oral cavity involving Waldeyer's ring, base of the tongue, buccal mucosa and hard palate. DLBCL can be divided into germinal center B-cell-like, activated B-cell-like or type 3 gene expression profiles. This paper highlights a case report of DLBCL revisiting the intricacies and difficulties involved in establishing a diagnosis.
Partial Transphyseal Anterior Cruciate Ligament Reconstruction: Clinical, Functional, and Radiographic Outcomes

Background: With a steadily increasing rate of anterior cruciate ligament (ACL) injury and reconstruction in the pediatric population, disagreement remains regarding the optimal reconstruction technique for patients with ACL injury and ≥2 years of growth remaining. Purpose: This study aims to quantify the incidence of linear and angular growth disturbance of adolescents undergoing partial transphyseal ACL reconstruction (ACLR) while assessing graft failure rates, reoperation rates, and functional outcomes in the population. Study Design: Case series; Level of evidence, 4. Methods: Consecutive patients undergoing partial transphyseal ACLR by 2 surgeons were retrospectively reviewed. Radiographic outcomes, including bilateral limb length, mechanical axis deviation (MAD), mechanical lateral distal femoral angle (MLDFA), and medial proximal tibial angle (MPTA), were measured on long standing anterior-posterior view radiographs postoperatively. Growth disturbance was defined as ≥1-cm leg length discrepancy, ≥1-cm difference in MAD, or 5° difference in MLDFA or MPTA as compared with the nonoperative side and as MAD, MLDFA, or MPTA outside the established range of reference values. Clinical outcomes, including graft failure and reoperation, were recorded at each follow-up visit. Pediatric International Knee Documentation Committee (Pedi-IKDC) scores were collected electronically after last follow-up. Results: Twenty-four patients (mean ± SD age, 12.3 ± 0.9 years; 79.2% male) with a mean follow-up of 31.5 ± 17.1 months met inclusion criteria for the study. Overall postoperative growth disturbance incidence was 16.7% (4 of 24), but the incidence of growth disturbance was 66.7% (2 of 3) for those patients with >5 years of growth remaining. Seven patients (29.2%) required reoperation, most frequently for hardware removal. Two patients (8.3%) had graft failure with subsequent revision ACL reconstruction. One patient underwent bilateral medial distal femur hemiepiphysiodesis for genu valgum that was present before ACLR, but no other patients required guided growth procedures. In the subset of patients who completed a Pedi-IKDC questionnaire, the mean score was 94.8 ± 5.3. Conclusion: Overall, partial transphyseal ACLR has good functional outcomes and graft failure and reoperation rates, comparable with those seen with transphyseal and all-epiphyseal techniques. While postoperative growth disturbance occurred in 16.7% of the cohort, the severity was mild and well tolerated without necessitating secondary procedures. There is a high rate of growth disturbance of patients with >5 years of growth remaining (66.7%). Partial transphyseal ACLR represents a valid recommendation for adolescent patients with ACL injury and ≤5 years of growth remaining.
Hydrothermal synthesis of hierarchical flower-like α-CNTs/SnO2 architectures with enhanced photocatalytic activity

Abstract The hierarchical flower-like α-CNTs/SnO2 architectures composed of curved sheets are synthesized with hydrothermal method at 160 °C for 8 h. The α-CNTs/SnO2 composite was doped with α-CNTs during preparation, the photocatalytic activity of α-CNTs/SnO2 was evaluated by photodegradation of Rhodamine B (RhB) under simulated visible light. The results showed that the photocatalytic activity of α-CNTs/SnO2 for degradation of RhB was up to 90.35% within 120 min, which was much higher than that of pure compound. It was significantly found that the introduction of α-CNTs, which may suppressed the recombination of photogenerated electron-hole pairs on the interface of SnO2, leading to enhanced photocatalytic activity.
P‐1.11: A Compact Model of Current and Capacitance for Amorphous Indium Gallium Zinc Oxide Thin‐Film Transistors

In recent years, amorphous indium gallium zinc oxide (a‐IGZO) thin‐film transistors (TFTs) have shown outstanding performance in flexible circuit applications, active matrix display and so on. Therefore, they will play an increasingly important role in the future of electronic applications. At the same time, an analytical model that predicts the electrical characteristics of IGZO TFTs is also critical. In this paper, we present a current and capacitance compact model of a‐IGZO TFTs. The compact model can be applied to different channel lengths for a‐IGZO TFTs. Besides, it is capable of capturing device characteristics and of maintaining high computational efficiency. Its accuracy is validated through the extensive comparisons between model results and experimental data.
Utilization of Integrative Technique for Partial Recovery of Proteases from Soil Microbes

Aqueous two-phase system (ATPS) is an efficient, cost effective, fast, simple and ecofriendly method for the recovery of biomolecules. In the present study, an ATPS composed of polyethylene glycol and ammonium sulphate (NH4)2SO4 was used for the partial purification of proteases from microbial source. The effects of different parameters such as molecular weight of PEG (4000, 6000 and 10000), concentration of PEG (15, 17.5 and 20 %) and concentration of (NH4)2SO4 (7.5, 8.3, 9.1 and 9.9 %) on the partitioning behavior of proteases at room temperature were investigated. Generally, increasing the concentration of PEG and (NH4)2SO4 moved the protease to the top i.e., polymer-rich phase. Increasing the molecular weight of PEG from 4000 to 10000 the partition coefficient decreased subsequently. The highest partition coefficient i.e., 3.32 and maximum activity i.e., 16.06 soxhlet unit was found in an optimum system composed of 20 % PEG 4000 and 9.9 % (NH4)2SO4.
Impacts of household sources on air pollution at village and regional scales in India

Abstract. Approximately 3 billion people worldwide cook with solid fuels, such as wood, charcoal, and agricultural residues. These fuels, also used for residential heating, are often combusted in inefficient devices, producing carbonaceous emissions. Between 2.6 and 3.8 million premature deaths occur as a result of exposure to fine particulate matter from the resulting household air pollution (Health Effects Institute, 2018a; World Health Organization, 2018). Household air pollution also contributes to ambient air pollution; the magnitude of this contribution is uncertain. Here, we simulate the distribution of the two major health-damaging outdoor air pollutants (PM2.5 and O3) using state-of-the-science emissions databases and atmospheric chemical transport models to estimate the impact of household combustion on ambient air quality in India. The present study focuses on New Delhi and the SOMAARTH Demographic, Development, and Environmental Surveillance Site (DDESS) in the Palwal District of Haryana, located about 80 km south of New Delhi. The DDESS covers an approximate population of 200 000 within 52 villages. The emissions inventory used in the present study was prepared based on a national inventory in India (Sharma et al., 2015, 2016), an updated residential sector inventory prepared at the University of Illinois, updated cookstove emissions factors from Fleming et al. (2018b), and PM2.5 speciation from cooking fires from Jayarathne et al. (2018). Simulation of regional air quality was carried out using the US Environmental Protection Agency Community Multiscale Air Quality modeling system (CMAQ) in conjunction with the Weather Research and Forecasting modeling system (WRF) to simulate the meteorological inputs for CMAQ, and the global chemical transport model GEOS-Chem to generate concentrations on the boundary of the computational domain. Comparisons between observed and simulated O3 and PM2.5 levels are carried out to assess overall airborne levels and to estimate the contribution of household cooking emissions. Observed and predicted ozone levels over New Delhi during September 2015, December 2015, and September 2016 routinely exceeded the 8 h Indian standard of 100 µg m−3, and, on occasion, exceeded 180 µg m−3. PM2.5 levels are predicted over the SOMAARTH headquarters (September 2015 and September 2016), Bajada Pahari (a village in the surveillance site; September 2015, December 2015, and September 2016), and New Delhi (September 2015, December 2015, and September 2016). The predicted fractional impact of residential emissions on anthropogenic PM2.5 levels varies from about 0.27 in SOMAARTH HQ and Bajada Pahari to about 0.10 in New Delhi. The predicted secondary organic portion of PM2.5 produced by household emissions ranges from 16 % to 80 %. Predicted levels of secondary organic PM2.5 during the periods studied at the four locations averaged about 30 µg m−3, representing approximately 30 % and 20 % of total PM2.5 levels in the rural and urban stations, respectively.
Uncertainty Quantification in First-Principles Predictions of Harmonic Vibrational Frequencies of Molecules and Molecular Complexes

Accurate prediction of molecular vibrational frequencies is important to identify spectroscopic signatures and reaction thermodynamics. In this work, we develop a method to quantify the uncertainty associated with density functional theory-predicted harmonic vibrational frequencies using the built-in error estimation capabilities of the Bayesian error estimation functional with van der Waals exchange–correlation functional. The method is computationally efficient as it estimates the uncertainty at nearly the same computational cost as a single vibrational frequency calculation. We demonstrate the utility and robustness of the method by showing that the uncertainty estimates bound the self-consistent calculations of 6 exchange–correlation functionals for 10 small molecules, 10 rare-gas dimers, and molecular complexes from the S22 dataset. The rare-gas dimers and the S22 dataset provide a rigorous test, as they are systems with complicated vibrational motion and noncovalent interactions. Using the coefficie.
The 2 Gene Coding Sequence T807/A873 of the Platelet Collagen Receptor Integrin 2β1 Might Be a Genetic Risk Factor for the Development of Stroke in Younger Patients

The polymorphisms C807T and G873A of the platelet integrin 2β1 (collagen receptor glycoprotein [GP] Ia-IIa) are linked to the expression density of this receptor. The GPIa T807/A873 allele causes a higher receptor expression, enhancing platelet binding to collagen. This might present a genetic predisposition for the development of thromboembolic complications. In this case-control study, the genotypes of the GPIa C807T polymorphism and presence of conventional risk factors (hypertension, diabetes mellitus, and smoking) were compared in stroke patients and patients without cerebrovascular disease (non-CVD patients) ≤50 years of age (n = 45 and 41, respectively) and in stroke patients and non-CVD patients more than 50 years of age (n = 182 and 129, respectively. In patients ≤50 years of age, the T807 allele was the only overrepresented variable ( P = .023; odds ratio, 3.02; 95% confidence interval, 1.20 to 7.61) and an independent risk factor, whereas the presence of conventional risk factors was similar between stroke patients ≤50 years of age and non-CVD patients ≤50 years of age. Large epidemiological studies should prove whether the platelet collagen receptor GPIa-IIa T807 allele is an independent risk factor for the development of stroke in younger patients.