Novel drug-target interactions via link prediction and network embedding

BACKGROUND: As many interactions between the chemical and genomic space remain undiscovered, computational methods able to identify potential drug-target interactions (DTIs) are employed to accelerate drug discovery and reduce the required cost. Predicting new DTIs can leverage drug repurposing by identifying new targets for approved drugs. However, developing an accurate computational framework that can efficiently incorporate chemical and genomic spaces remains extremely demanding. A key issue is that most DTI predictions suffer from the lack of experimentally validated negative interactions or limited availability of target 3D structures. RESULTS: We report DT2Vec, a pipeline for DTI prediction based on graph embedding and gradient boosted tree classification. It maps drug-drug and protein–protein similarity networks to low-dimensional features and the DTI prediction is formulated as binary classification based on a strategy of concatenating the drug and target embedding vectors as input features. DT2Vec was compared with three top-performing graph similarity-based algorithms on a standard benchmark dataset and achieved competitive results. In order to explore credible novel DTIs, the model was applied to data from the ChEMBL repository that contain experimentally validated positive and negative interactions which yield a strong predictive model. Then, the developed model was applied to all possible unknown DTIs to predict new interactions. The applicability of DT2Vec as an effective method for drug repurposing is discussed through case studies and evaluation of some novel DTI predictions is undertaken using molecular docking. CONCLUSIONS: The proposed method was able to integrate and map chemical and genomic space into low-dimensional dense vectors and showed promising results in predicting novel DTIs. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12859-022-04650-w

First Top-Down Estimates of Anthropogenic NO_x Emissions Using High-Resolution Airborne Remote Sensing Observations

A number of satellite‐based instruments have become an essential part of monitoring emissions. Despite sound theoretical inversion techniques, the insufficient samples and the footprint size of current observations have introduced an obstacle to narrow the inversion window for regional models. These key limitations can be partially resolved by a set of modest high‐quality measurements from airborne remote sensing. This study illustrates the feasibility of nitrogen dioxide (NO_2) columns from the Geostationary Coastal and Air Pollution Events Airborne Simulator (GCAS) to constrain anthropogenic NO_x emissions in the Houston‐Galveston‐Brazoria area. We convert slant column densities to vertical columns using a radiative transfer model with (i) NO_2 profiles from a high‐resolution regional model (1 × 1 km^2) constrained by P‐3B aircraft measurements, (ii) the consideration of aerosol optical thickness impacts on radiance at NO_2 absorption line, and (iii) high‐resolution surface albedo constrained by ground‐based spectrometers. We characterize errors in the GCAS NO_2 columns by comparing them to Pandora measurements and find a striking correlation (r > 0.74) with an uncertainty of 3.5 × 10^(15) molecules cm^(−2). On 9 of 10 total days, the constrained anthropogenic emissions by a Kalman filter yield an overall 2–50% reduction in polluted areas, partly counterbalancing the well‐documented positive bias of the model. The inversion, however, boosts emissions by 94% in the same areas on a day when an unprecedented local emissions event potentially occurred, significantly mitigating the bias of the model. The capability of GCAS at detecting such an event ensures the significance of forthcoming geostationary satellites for timely estimates of top‐down emissions

Online teacher training in a context for forced immobility: the Case of Gaza, Palestine

This article discusses an action research study that involved the design and delivery of an online training course for teachers of Arabic to speakers of other languages in the Gaza Strip (Palestine). Grounded in Freirean pedagogy, the course aimed to respond to the employment needs of university graduates by creating opportunities for online language teaching. The action research study explored the dynamics at play within the online educational environment, to evidence elements that challenged and/or facilitated effective collaboration between trainers and trainees. This article retraces and discusses the processes through which the course moved from didacticism to engaged critical pedagogy

Global retrieval of stratospheric and tropospheric BrO columns from the Ozone Mapping and Profiler Suite Nadir Mapper (OMPS-NM) on board the Suomi-NPP satellite

Quantifying the global bromine monoxide (BrO) budget is essential to understand ozone chemistry better. In particular, the tropospheric BrO budget has not been well characterized. Here, we retrieve nearly a decade (February 2012–July 2021) of stratospheric and tropospheric BrO vertical columns from the Ozone Mapping and Profiling Suite Nadir Mapper (OMPS-NM) on board the Suomi National Polar-orbiting Partnership (Suomi-NPP) satellite. In quantifying tropospheric BrO enhancements from total slant columns, the key aspects involve segregating them from stratospheric enhancements and applying appropriate air mass factors. To address this concern and improve upon the existing methods, our study proposes an approach that applies distinct BrO vertical profiles based on the presence or absence of tropospheric BrO enhancement at each pixel, identifying it dynamically using a satellite-derived stratospheric-ozone–BrO relationship. We demonstrate good agreement for both stratosphere (r = 0.81–0.83) and troposphere (r = 0.50–0.70) by comparing monthly mean BrO vertical columns from OMPS-NM with ground-based observations from three stations (Lauder, Utqiaġvik, and Harestua). Although algorithm performance is primarily assessed at high latitudes, the OMPS-NM BrO retrievals successfully capture tropospheric enhancements not only in polar regions but also in extrapolar areas, such as the Rann of Kutch and the Great Salt Lake. We also estimate random uncertainties in the retrievals pixel by pixel, which can assist in quantitative applications of the OMPS-NM BrO dataset. Our BrO retrieval algorithm is designed for cross-sensor applications and can be adapted to other space-borne ultraviolet spectrometers, contributing to the creation of continuous long-term satellite BrO observation records.</p

First Top-Down Estimates of Anthropogenic NO_x Emissions Using High-Resolution Airborne Remote Sensing Observations

A number of satellite‐based instruments have become an essential part of monitoring emissions. Despite sound theoretical inversion techniques, the insufficient samples and the footprint size of current observations have introduced an obstacle to narrow the inversion window for regional models. These key limitations can be partially resolved by a set of modest high‐quality measurements from airborne remote sensing. This study illustrates the feasibility of nitrogen dioxide (NO_2) columns from the Geostationary Coastal and Air Pollution Events Airborne Simulator (GCAS) to constrain anthropogenic NO_x emissions in the Houston‐Galveston‐Brazoria area. We convert slant column densities to vertical columns using a radiative transfer model with (i) NO_2 profiles from a high‐resolution regional model (1 × 1 km^2) constrained by P‐3B aircraft measurements, (ii) the consideration of aerosol optical thickness impacts on radiance at NO_2 absorption line, and (iii) high‐resolution surface albedo constrained by ground‐based spectrometers. We characterize errors in the GCAS NO_2 columns by comparing them to Pandora measurements and find a striking correlation (r > 0.74) with an uncertainty of 3.5 × 10^(15) molecules cm^(−2). On 9 of 10 total days, the constrained anthropogenic emissions by a Kalman filter yield an overall 2–50% reduction in polluted areas, partly counterbalancing the well‐documented positive bias of the model. The inversion, however, boosts emissions by 94% in the same areas on a day when an unprecedented local emissions event potentially occurred, significantly mitigating the bias of the model. The capability of GCAS at detecting such an event ensures the significance of forthcoming geostationary satellites for timely estimates of top‐down emissions

Validation of OMPS Suomi NPP and OMPS NOAA‐20 Formaldehyde Total Columns With NDACC FTIR Observations

We validate formaldehyde (HCHO) vertical column densities (VCDs) from Ozone Mapping and Profiler Suite Nadir Mapper (OMPS-NM) instruments onboard the Suomi National Polar-orbiting Partnership (Suomi NPP) satellite for 2012–2020 and National Oceanic and Atmospheric Administration-20 (NOAA-20) satellite for 2018–2020, hereafter referred to as OMPS-NPP and OMPS-N20, with ground-based Fourier-Transform Infrared (FTIR) observations of the Network for the Detection of Atmospheric Composition Change (NDACC). OMPS-NPP/N20 HCHO products reproduce seasonal variability at 24 FTIR sites. Monthly variability of OMPS-NPP/N20 has a very good agreement with FTIR, showing correlation coefficients of 0.83 and 0.88, respectively. OMPS-NPP (N20) biases averaged over all sites are −0.9 (4) ± 3 (6)%. However, at clean sites (with VCDs 4.0 × 10$^{15}$ molecules cm$^{−2}$, negative biases of −15% ± 4% appear for OMPS-NPP, but OMPS-N20 shows smaller bias of 0.5% ± 6% due to its smaller ground pixel footprints. Therefore, smaller satellite footprint sizes are important in distinguishing small-scale plumes. In addition, we discuss a bias correction and provide lower limit for the monthly uncertainty of OMPS-NPP/N20 HCHO products. The total uncertainty for OMPS-NPP (N20) at clean sites is 0.7 (0.8) × 10$^{15}$ molecules cm$^{−2}$, corresponding to a relative uncertainty of 32 (30)%. In the case of HCHO VCDs > 4.0 × 10$^{15}$ molecules cm$^{−2}$, however, the relative uncertainty in HCHO VCDs for OMPS-NPP (N20) decreases to 31 (18)%

Revisiting the mechanism of coagulation factor XIII activation and regulation from a structure/functional perspective

The activation and regulation of coagulation Factor XIII (FXIII) protein has been the subject of active research for the past three decades. Although discrete evidence exists on various aspects of FXIII activation and regulation a combinatorial structure/functional view in this regard is lacking. In this study, we present results of a structure/function study of the functional chain of events for FXIII. Our study shows how subtle chronological submolecular changes within calcium binding sites can bring about the detailed transformation of the zymogenic FXIII to its activated form especially in the context of FXIIIA and FXIIIB subunit interactions. We demonstrate what aspects of FXIII are important for the stabilization (first calcium binding site) of its zymogenic form and the possible modes of deactivation (thrombin mediated secondary cleavage) of the activated form. Our study for the first time provides a structural outlook of the FXIIIA 2 B 2 heterotetramer assembly, its association and dissociation. The FXIIIB subunits regulatory role in the overall process has also been elaborated upon. In summary, this study provides detailed structural insight into the mechanisms of FXIII activation and regulation that can be used as a template for the development of future highly specific therapeutic inhibitors targeting FXIII in pathological conditions like thrombosis

Efficacy and safety of percutaneous mitral balloon valvotomy in patients with mitral stenosis: A systematic review and meta-analysis

Aims: Percutaneous mitral balloon valvotomy PMBV is an acceptable alternative to Mitral valve surgery for patients with mitral stenosis. The purpose of this study was to explore the immediate results of PMBV with respect to echocardiographic changes, outcomes, and complications, using a meta-analysis approach. Methods: MEDLINE, and EMBASE databases were searched (01/2012 to 10/2018) for original research articles regarding the efficacy and safety of PMBV. Two reviewers independently screened references for inclusion and abstracted data including article details and echocardiographic parameters before and 24–72 h after PMBV, follow-up duration, and acute complications. Disagreements were resolved by third adjudicator. Quality of all included studies was evaluated using the Newcastle-Ottawa Scale NOS. Results: 44/990 references met the inclusion criteria representing 6537 patients. Our findings suggest that PMBV leads to a significant increase in MVA (MD = 0.81 cm2; 0.76–0.87, p < 0.00001), LVEDP (MD = 1.89 mmHg; 0.52–3.26, p = 0.007), LVEDV EDV (MD = 5.81 ml; 2.65–8.97, p = 0.0003) and decrease in MPG (MD = 7.96 mmHg; 8.73 to 7.20, p < 0.00001), LAP (MD = 10.09 mmHg; 11.06 to 9.12, p < 0.00001), and SPAP (MD = 15.55 mmHg; 17.92 to 13.18, p < 0.00001). On short term basis, the pooled overall incidence estimates of repeat PMBV, mitral valve surgery, post-PMBV severe MR, and post- PMBV stroke, and systemic thromboembolism were 0.5%, 2%, 1.4%, 0.4%, and 0.7% respectively. On long term basis, the pooled overall incidence estimates of repeat PMBV, mitral valve surgery, post-PMBV severe MR, and post-PMBV stroke, systemic thromboembolism were 5%, 11.5%, 5.5%, 2.7%, and 1.7% respectively Conclusion: PMBV represents a successful approach for patients with mitral stenosis as evidenced by improvement in echocardiographic parameters and low rate of complications.The authors received no financial support for the research, authorship and publication of this article

The role of acyl-coenzyme A carboxylase complex in lipstatin biosynthesis of Streptomyces toxytricini

Streptomyces toxytricini produces lipstatin, a specific inhibitor of pancreatic lipase, which is derived from two fatty acid moieties with eight and 14 carbon atoms. The pccB gene locus in 10.6 kb fragment of S. toxytricini chromosomal DNA contains three genes for acyl-coenzyme A carboxylase (ACCase) complex accA3, pccB, and pccE that are presumed to be involved in secondary metabolism. The pccB gene encoding a β subunit of ACCase [carboxyltransferase (CT)] was identified upstream of pccE gene for a small protein of ε subunit. The accA3 encoding the α subunit of ACCase [biotin carboxylase (BC)] was also identified downstream of pccB gene. When the pccB and pccE genes were inactivated by homologous recombination, the lipstatin production was reduced as much as 80%. In contrast, the accumulation of another compound, tetradeca-5.8-dienoic acid (the major lipstatin precursor), was 4.5-fold increased in disruptant compared with wild-type. It implies that PccB of S. toxytricini is involved in the activation of octanoic acid to hexylmalonic acid for lipstatin biosynthesis

Association of waterpipe smoking and road traffic crashes

<p>Abstract</p> <p>Background</p> <p>The purpose of this research was to examine whether waterpipe smokers experience increased risk of motor vehicle crashes.</p> <p>Methods</p> <p>In a telephone survey, a random sample of Iranian drivers were asked to report their age, gender, vehicle age, whether their vehicles were equipped with anti-lock braking system (ABS), average daily drive time (DDT), whether they smoked cigarette or waterpipe, whether they had diabetes mellitus (DM), number of traffic crashes during the last calendar year and whether the crash involved a pedestrian or another vehicle.</p> <p>Results</p> <p>A total of 2070 motor vehicle owners with the mean age of 41.6 ± 11.45 were interviewed. The annual incidence of Road Traffic Crashes (RTC) was 14.9%; 14.0% involved a collision/s with other vehicles and 0.9% with pedestrians. There was an association between the RTC and male gender, DDT, being a cigarette smoker, being a waterpipe smoker and DM in univariable analysis. The association between RTC and being a waterpipe smoker and also cigarette smoker was significant in multivariable analysis after adjustment for DDT.</p> <p>Conclusions</p> <p>Being waterpipe and/or cigarette smoker and DDT were the independent predictors of the number of traffic crashes in Poisson regression model. If the increased risk of RTC among waterpipe or cigarette smokers is seen in other studies, it would be beneficial to promote tobacco cessation and control strategies through injury prevention initiatives.</p