Miracle-dz/UniFAR-FTUs huggingface dataset:
Chemical structure-guided design of dynapyrazoles, cell-permeable dynein inhibitors with a unique mode of action

Cytoplasmic dyneins are motor proteins in the AAA+ superfamily that transport cellular cargos toward microtubule minus-ends. Recently, ciliobrevins were reported as selective cell-permeable inhibitors of cytoplasmic dyneins. As is often true for first-in-class inhibitors, the use of ciliobrevins has in part been limited by low potency. Moreover, suboptimal chemical properties, such as the potential to isomerize, have hindered efforts to improve ciliobrevins. Here, we characterized the structure of ciliobrevins and designed conformationally constrained isosteres. These studies identified dynapyrazoles, inhibitors more potent than ciliobrevins. At single-digit micromolar concentrations dynapyrazoles block intraflagellar transport in the cilium and lysosome motility in the cytoplasm, processes that depend on cytoplasmic dyneins. Further, we find that while ciliobrevins inhibit both dynein's microtubule-stimulated and basal ATPase activity, dynapyrazoles strongly block only microtubule-stimulated activity. Together, our studies suggest that chemical-structure-based analyses can lead to inhibitors with improved properties and distinct modes of inhibition. DOI: http://dx.doi. org/10.7554/eLife.25174. 001
Predicting the risk of hypertension using machine learning algorithms: A cross sectional study in Ethiopia

Background and objectives Hypertension (HTN), a major global health concern, is a leading cause of cardiovascular disease, premature death and disability, worldwide. It is important to develop an automated system to diagnose HTN at an early stage. Therefore, this study devised a machine learning (ML) system for predicting patients with the risk of developing HTN in Ethiopia. Materials and methods The HTN data was taken from Ethiopia, which included 612 respondents with 27 factors. We employed Boruta-based feature selection method to identify the important risk factors of HTN. The four well-known models [logistics regression, artificial neural network, random forest, and extreme gradient boosting (XGB)] were developed to predict HTN patients on the training set using the selected risk factors. The performances of the models were evaluated by accuracy, precision, recall, F1-score, and area under the curve (AUC) on the testing set. Additionally, the SHapley Additive exPlanations (SHAP) method is one of the explainable artificial intelligences (XAI) methods, was used to investigate the associated predictive risk factors of HTN. Results The overall prevalence of HTN patients is 21.2%. This study showed that XGB-based model was the most appropriate model for predicting patients with the risk of HTN and achieved the accuracy of 88.81%, precision of 89.62%, recall of 97.04%, F1-score of 93.18%, and AUC of 0. 894. The XBG with SHAP analysis reveal that age, weight, fat, income, body mass index, diabetes mulitas, salt, history of HTN, drinking, and smoking were the associated risk factors of developing HTN. Conclusions The proposed framework provides an effective tool for accurately predicting individuals in Ethiopia who are at risk for developing HTN at an early stage and may help with early prevention and individualized treatment.
The brassinosteroid‐responsive protein OCTOPUS is a novel regulator of Arabidopsis thaliana immune signaling

Abstract Phloem is a critical tissue for transport of photosynthates and extracellular signals in vascular plants. However, it also represents an ideal environment for pathogens seeking access to valuable host nutrients. Although many vascular pathogens induce economically relevant crop damage, there is still little known about the mechanisms by which immune signaling operates through the phloem. An existing phosphoproteomic dataset was mined to identify proteins that were both phosphorylated in response to the defense‐elicitor flagellin (flg22) and expressed in vascular cells. A single candidate, OCTOPUS (OPS), is polarly associated with the plasma membrane of sieve element cells and has been characterized as an inhibitor of brassinosteroid insensitive‐2 in promotion of brassinosteroid‐related phytohormone signaling. The observation that OPS is differentially phosphorylated in response to flg22 led us to the examine whether OPS may also regulate flg22‐induced immune signaling. Two independent alleles of ops exhibited enhanced immunity outputs across multiple signaling branches of PAMP‐triggered immunity (PTI), constitutively and in response to flg22 treatment. Together with our observation that interactions between OPS and brassinosteroid insensitive‐2 were disrupted by induction of salicylic acid and depletion of brassinosteriod, these data support a model whereby OPS modulates brassinolide and immune signaling to control downstream responses. We present OPS as a novel addition to the list of proteins with documented roles in PAMP‐PTI signaling. These results further indicate that immune signaling in the phloem may be a significant and unique component of the host detection and response to pathogens in vascular plants.
Efficacy of Wex-cide 128 disinfectant against multiple prion strains

Prion diseases are transmissible, fatal neurologic diseases that include Creutzfeldt-Jakob Disease (CJD) in humans, chronic wasting disease (CWD) in cervids, bovine spongiform encephalopathy (BSE) in cattle and scrapie in sheep. Prions are extremely difficult to inactivate and established methods to reduce prion infectivity are often dangerous, caustic, expensive, or impractical. Identifying viable and safe methods for treating prion contaminated materials is important for hospitals, research facilities, biologists, hunters, and meat-processors. For three decades, some prion researchers have used a phenolic product called Environ LpH (eLpH) to inactivate prions. ELpH has been discontinued, but a similar product, Wex-cide 128, containing the similar phenolic chemicals as eLpH is now available. In the current study, we directly compared the anti-prion efficacy of eLpH and Wex-cide 128 against prions from four different species (hamster 263K, cervid CWD, mouse 22L and human CJD). Decontamination was performed on either prion infected brain homogenates or prion contaminated steel wires and mouse bioassay was used to quantify the remaining prion infectivity. Our data show that both eLpH and Wex-cide 128 removed 4.0–5.5 logs of prion infectivity from 22L, CWD and 263K prion homogenates, but only about 1.25–1.50 logs of prion infectivity from human sporadic CJD. Wex-cide 128 is a viable substitute for inactivation of most prions from most species, but the resistance of CJD to phenolic inactivation is a concern and emphasizes the fact that inactivation methods should be confirmed for each target prion strain.
Development of Strategies for SNP Detection in RNA-Seq Data: Application to Lymphoblastoid Cell Lines and Evaluation Using 1000 Genomes Data

Next-generation RNA sequencing (RNA-seq) maps and analyzes transcriptomes and generates data on sequence variation in expressed genes. There are few reported studies on analysis strategies to maximize the yield of quality RNA-seq SNP data. We evaluated the performance of different SNP-calling methods following alignment to both genome and transcriptome by applying them to RNA-seq data from a HapMap lymphoblastoid cell line sample and comparing results with sequence variation data from 1000 Genomes. We determined that the best method to achieve high specificity and sensitivity, and greatest number of SNP calls, is to remove duplicate sequence reads after alignment to the genome and to call SNPs using SAMtools. The accuracy of SNP calls is dependent on sequence coverage available. In terms of specificity, 89% of RNA-seq SNPs calls were true variants where coverage is >10X. In terms of sensitivity, at >10X coverage 92% of all expected SNPs in expressed exons could be detected. Overall, the results indicate that RNA-seq SNP data are a very useful by-product of sequence-based transcriptome analysis. If RNA-seq is applied to disease tissue samples and assuming that genes carrying mutations relevant to disease biology are being expressed, a very high proportion of these mutations can be detected.
Clinical dosage of lidocaine does not impact the biomedical outcome of sepsis-induced acute respiratory distress syndrome in a porcine model

Background Sepsis is a common disease in intensive care units worldwide, which is associated with high morbidity and mortality. This process is often associated with multiple organ failure including acute lung injury. Although massive research efforts have been made for decades, there is no specific therapy for sepsis to date. Early and best treatment is crucial. Lidocaine is a common local anesthetic and used worldwide. It blocks the fast voltage-gated sodium (Na+) channels in the neuronal cell membrane responsible for signal propagation. Recent studies show that lidocaine administered intravenously improves pulmonary function and protects pulmonary tissue in pigs under hemorrhagic shock, sepsis and under pulmonary surgery. The aim of this study is to show that lidocaine inhalative induces equivalent effects as lidocaine intravenously in pigs in a lipopolysaccharide (LPS)-induced sepsis with acute lung injury. Methods After approval of the local State and Institutional Animal Care Committee, to induce the septic inflammatory response a continuous infusion of lipopolysaccharide (LPS) was administered to the pigs in deep anesthesia. Following induction and stabilisation of sepsis, the study medication was randomly assigned to one of three groups: (1) lidocaine intravenously, (2) lidocaine per inhalation and (3) sham group. All animals were monitored for 8 h using advanced and extended cardiorespiratory monitoring. Postmortem assessment included pulmonary mRNA expression of mediators of early inflammatory response (IL-6 & TNF-alpha), wet-to-dry ratio and lung histology. Results Acute respiratory distress syndrome (ARDS) was successfully induced after sepsis-induction with LPS in all three groups measured by a significant decrease in the PaO2/FiO2 ratio. Further, septic hemodynamic alterations were seen in all three groups. Leucocytes and platelets dropped statistically over time due to septic alterations in all groups. The wet-to-dry ratio and the lung histology showed no differences between the groups. Additionally, the pulmonary mRNA expression of the inflammatory mediators IL-6 and TNF-alpha showed no significant changes between the groups. The proposed anti-inflammatory and lung protective effects of lidocaine in sepsis-induced acute lung injury could not be proven in this study.
A feasibility study to evaluate a purposeful walk intervention with a distance goal using a commercially available activity monitor in elderly people post total hip replacement surgery

Introduction Total hip replacement (THR) is performed in an increasing number of individuals around the world and while improvements in pain reduction and long-term enhancement of muscle strength are well documented, the improvement in daily activity does not follow the same trend. This study aimed to determine the feasibility of a 5-week intervention where a personalised outdoor walking distance is monitored using a commercial activity monitor (Fitbit Charge 4). Method Data was collected on gait and activities of daily living using patient reported outcome measures. Following the completion of the intervention period, participants took part in a semi-structured interview to voice their opinion on the use of the activity monitor, their experiences, and any challenges in order to assess the feasibility of the intervention. All quantitative data were presented descriptively, using appropriate summary statistics. Interviews were analysed using thematic analysis. Results Five participants who had undergone total hip replacement surgery within the postoperative period of 3 to 6 months were recruited from the local community. Conclusion The findings suggest that the intervention was feasible and that it encouraged all participants to increase their daily activity. Therefore, it can be concluded that a follow-up effectiveness trial is warranted.
Chloromethylisothiazolinone induces ER stress-induced stress granule formation in human keratinocytes

ABSTRACT Chloromethylisothiazolinone (CMIT), a humidifier disinfectant, is known to be toxic to the respiratory system. While the toxic effect of CMIT on the lungs has been widely investigated, its effect on the skin is well unknown. In this study, we examined stress granule (SG) formation to investigate the cytotoxic effects of CMIT on human keratinocytes. We assessed the viability of the cells following CMIT exposure and performed immunofluorescence microscopy and immunoblot analyses to determine SG formation and downstream pathways. The IC50 values in human keratinocyte HaCaT cells after CMIT exposure for 1 and 24 h were 11 and 8 μg/mL, respectively, showing no significant difference. As determined using immunofluorescence microscopy, SG formation was effectively induced after CMIT exposure. Moreover, the phosphorylation of eukaryotic initiation factor-2α (eIF2α), a translation initiation factor, and protein kinase R-like endoplasmic reticulum (ER) kinase, which plays a role in the ER stress-mediated eIF2α phosphorylation, was confirmed by CMIT exposure. These results suggest that exposure to CMIT can have detrimental effects on the skin, even briefly, by inducing SG formation through ER stress in keratinocytes.
Mechanical Properties of 3D-Printed Occlusal Splint Materials

Data regarding the mechanical properties of three-dimensionally (3D) printed materials for occlusal splint manufacturing are scarce. The aim of the present study was to evaluate the flexural strength and surface hardness of modern 3D-printed occlusal splint materials and compare them with two control groups, namely, milled and conventional cold-polymerized occlusal splint materials. A total of 140 rectangular specimens were manufactured for the present study. The specimens were prepared in accordance with the International Organization for Standardization standards (ISO 20795-1:2013). Five 3D-printed (NextDent Ortho Rigid, Dental LT Clear, Dentona Flexisplint, Cosmos Bite Splint, and ProArt Print Splint), one milled (ProArt CAD Splint), and one cold-polymerized (ProBase Cold) occlusal splint materials were used to determine flexural strength and surface hardness values. The three-point flexure test was used for the determination of flexural strength values, while Vickers hardness was measured to determine surface hardness. Ten specimens (n = 10) of each material were tested using these procedures. One-way ANOVA and Tukey’s post-hoc test were used to analyze the obtained results (α = 0.05). The values of flexural strength ranged from 46.1 ± 8.2 MPa to 106 ± 8.3 MPa. The Vickers hardness values ranged from 4.9 ± 0.5 VHN to 20.6 ± 1.3 VHN. Significant differences were found among the tested materials (p < 0.0001). The milled and cold-polymerized materials yielded higher values for both flexural strength (only one 3D-printed resin had comparable results to cold-polymerized acrylics) and surface hardness. There are differences in the mechanical properties of the various tested occlusal splint materials. The flexural strength of most of the 3D-printed materials and their surface hardness values are still inferior when compared to the milled or cold-polymerized materials.
Remote Sensing for Ecology and Conservation: A Handbook of Techniques

Preface Acronyms List 1. Introduction: Why Ecologists and Conservation Biologists Use Remote Sensing 2. When to Use Remote Sensing 3. Working with Images 4. Measuring and Monitoring Land Cover, Land Use, and Vegetation Characteristics 5. Terrain and Soils 6. Marine and Coastal Environments 7. Wetlands-Estuaries, Inland Wetlands, and Freshwater Lakes 8. Atmosphere and Climate 9. Disturbances: Fires and Floods 10. Landscape Fragmentation 11. Human Interfaces and Urban Change 12. Protected Area Design and Monitoring 13. Integrating Field Data 14. Linking Remote Sensing with Modeling 15. Global Conservation Appendix 1 The Electromagnetic Spectrum Appendix 2 Image Processing Software Appendix 3 Open Source Software Appendix 4 Satellites and Sensors Appendix 5 Visual Interpretation Appendix 6 Systems for Observing Climate and Atmospheric Phenomena References Index
Therapeutic targeting of nuclear export and import receptors in cancer and their potential in combination chemotherapy

Systemic modalities are crucial in the management of disseminated malignancies and liquid tumours. However, patient responses and tolerability to treatment are generally poor and those that enter remission often return with refractory disease. Combination therapies provide a methodology to overcome chemoresistance mechanisms and address dose‐limiting toxicities. A deeper understanding of tumorigenic processes at the molecular level has brought a targeted therapy approach to the forefront of cancer research, and novel cancer biomarkers are being identified at a rapid rate, with some showing potential therapeutic benefits. The Karyopherin superfamily of proteins is soluble receptors that mediate nucleocytoplasmic shuttling of proteins and RNAs, and recently, nuclear transport receptors have been recognized as novel anticancer targets. Inhibitors against nuclear export have been approved for clinical use against certain cancer types, whereas inhibitors against nuclear import are in preclinical stages of investigation. Mechanistically, targeting nucleocytoplasmic shuttling has shown to abrogate oncogenic signalling and restore tumour suppressor functions through nuclear sequestration of relevant proteins and mRNAs. Hence, nuclear transport inhibitors display broad spectrum anticancer activity and harbour potential to engage in synergistic interactions with a wide array of cytotoxic agents and other targeted agents. This review is focussed on the most researched nuclear transport receptors in the context of cancer, XPO1 and KPNB1, and highlights how inhibitors targeting these receptors can enhance the therapeutic efficacy of standard of care therapies and novel targeted agents in a combination therapy approach. Furthermore, an updated review on the therapeutic targeting of lesser characterized karyopherin proteins is provided and resistance to clinically approved nuclear export inhibitors is discussed.
Determination of Sea Surface Temperature with N-ROSS (Navy-Remote Ocean Sensing System).

Abstract : The all-weather, global determination of sea surface temperature (SST) was identified as a requirement needed to support Navy operations. The acceptable SST accuracy is + or - 1.0 K with a surface resolution of 25 km. Investigations of the phenomenology and technology of remote passive microwave sensing of the ocean environment over the past decade beginning with the Navy specification of the Remote Ocean-surface Measurement System, through the NASA launched Scanning Multichannel Microwave Radiometer flown on both SEASAT and NIMBUS-7 to the planning by NASA of the Large Antenna Multichannel Microwave Radiometer, and development of the Mission Sensor Microwave/Imager (SSM/I) to be flown in 1985 by the Navy/Air Force, have demonstrated that this objective is presently attainable. Preliminary specifications and trade-off studies have been conducted to define the frequency, polarization, scan geometry, antenna size and other essential parameters, as well as the retrieval algorithms and spacecraft interface requirements, of the Low Frequency Microwave Radiometer (LFMR). As presently planned, the LFMR will be a stand alone system completely independent of the SSM/I but with a 30 rpm conical scan at 53.1 deg incidence angle identical to the SSM/I. It will be a dual-frequency system at 5.2 and 10.4 GHz using a 5.9 meter deployable mesh surface antenna. It is to be flown on the Navy-Remote Ocean Sensing System satellite scheduled to be launched in late 1988. (Author)
Predictors of outcomes in mild pulmonary hypertension according to 2022 ESC/ERS Guidelines: the EVIDENCE-PAH UK study

Abstract Background and Aims Interventional studies in pulmonary arterial hypertension completed to date have shown to be effective in symptomatic patients with significantly elevated mean pulmonary artery pressure (mPAP) (≥25 mmHg) and pulmonary vascular resistance (PVR) > 3 Wood Unit (WU). However, in health the mPAP does not exceed 20 mmHg and PVR is 2 WU or lower, at rest. The ESC/ERS guidelines have recently been updated to reflect this. There is limited published data on the nature of these newly defined populations (mPAP 21–24 mmHg and PVR >2–≤3 WU) and the role of comorbidity in determining their natural history. With the change in guidelines, there is a need to understand this population and the impact of the ESC/ERS guidelines in greater detail. Methods A retrospective nationwide evaluation of the role of pulmonary haemodynamics and comorbidity in predicting survival among patients referred to the UK pulmonary hypertension (PH) centres between 2009 and 2017. In total, 2929 patients were included in the study. Patients were stratified by mPAP (<21 mmHg, 21–24 mmHg, and ≥25 mmHg) and PVR (≤2 WU, > 2–≤3 WU, and >3 WU), with 968 (33.0%) in the mPAP <21 mmHg group, 689 (23.5%) in the mPAP 21–24 mmHg group, and 1272 (43.4%) in the mPAP ≥25 mmHg group. Results Survival was negatively correlated with mPAP and PVR in the population as a whole. Survival in patients with mildly elevated mPAP (21–24 mmHg) or PVR (>2–≤3WU) was lower than among those with normal pressures (mPAP <21 mmHg) and normal PVR (PVR ≤ 2WU) independent of comorbid lung and heart disease [hazard ratio (HR) 1.36, 95% confidence interval (CI) 1.14–1.61, P = . 0004 for mPAP vs. HR 1.28, 95% CI 1.10–1.49, P = . 0012 for PVR]. Among patients with mildly elevated mPAP, a mildly elevated PVR remained an independent predictor of survival when adjusted for comorbid lung and heart disease (HR 1.33, 95% CI 1.01–1.75, P = .042 vs. HR 1.4, 95% CI 1.06–1.86, P = .019). 68.2% of patients with a mPAP 21–24 mmHg had evidence of underlying heart or lung disease. Patients with mildly abnormal haemodynamics were not more symptomatic than patients with normal haemodynamics. Excluding patients with heart and lung disease, connective tissue disease was associated with a poorer survival among those with PH. In this subpopulation evaluating those with a mPAP of 21–24 mmHg, survival curves only diverged after 5 years. Conclusions This study supports the change in diagnostic category of the ESC/ERS guidelines in a PH population. The newly included patients have an increased mortality independent of significant lung or heart disease. The majority of patients in this new category have underlying heart or lung disease rather than an isolated pulmonary vasculopathy. Mortality is higher if comorbidity is present. Rigorous phenotyping will be pivotal to determine which patients are at risk of progressive vasculopathic disease and in whom surveillance and recruitment to studies may be of benefit. This study provides an insight into the population defined by the new guidelines.