The F-box protein FBXL-5 governs vitellogenesis and lipid homeostasis in C. elegans.

The molecular mechanisms that govern the metabolic commitment to reproduction, which often occurs at the expense of somatic reserves, remain poorly understood. We identified the Caenorhabditis elegans F-box protein FBXL-5 as a negative regulator of maternal provisioning of vitellogenin lipoproteins, which mediate the transfer of intestinal lipids to the germline. Mutations in fbxl-5 partially suppress the vitellogenesis defects observed in the heterochronic mutants lin-4 and lin-29, both of which ectopically express fbxl-5 at the adult developmental stage. FBXL-5 functions in the intestine to negatively regulate expression of the vitellogenin genes; and consistently, intestine-specific over-expression of FBXL-5 is sufficient to inhibit vitellogenesis, restrict lipid accumulation, and shorten lifespan. Our epistasis analyses suggest that fbxl-5 functions in concert with cul-6, a cullin gene, and the Skp1-related gene skr-3 to regulate vitellogenesis. Additionally, fbxl-5 acts genetically upstream of rict-1, which encodes the core mTORC2 protein Rictor, to govern vitellogenesis. Together, our results reveal an unexpected role for a SCF ubiquitin-ligase complex in controlling intestinal lipid homeostasis by engaging mTORC2 signaling.

The F-box protein FBXL-5 governs vitellogenesis and lipid homeostasis in C. elegans.

The molecular mechanisms that govern the metabolic commitment to reproduction, which often occurs at the expense of somatic reserves, remain poorly understood. We identified the C. elegans F-box protein FBXL-5 as a negative regulator of maternal provisioning of vitellogenin lipoproteins, which mediate the transfer of intestinal lipids to the germline. Mutations in fbxl-5 partially suppress the vitellogenesis defects observed in the heterochronic mutants lin-4 and lin-29, both of which ectopically express fbxl-5 at the adult developmental stage. FBXL-5 functions in the intestine to negatively regulate expression of the vitellogenin genes; and consistently, intestine-specific over-expression of FBXL-5 is sufficient to inhibit vitellogenesis, restrict lipid accumulation, and shorten lifespan. Our epistasis analyses suggest that fbxl-5 functions in concert with cul-6 , a cullin gene, and the Skp1-related gene skr-3 to regulate vitellogenesis. Additionally, fbxl-5 acts genetically upstream of rict-1 , which encodes the core mTORC2 protein Rictor, to govern vitellogenesis. Together, our results reveal an unexpected role for a SCF ubiquitin-ligase complex in controlling intestinal lipid homeostasis by engaging mTORC2 signaling.

The Evidence for Excess Risk of Cancer and Non-Cancer Disease at Low Doses and Dose Rates.

The question of whether there are excess radiation-associated health risks at low dose is controversial. We present evidence of excess cancer risks in a number of (largely pediatrically or in utero exposed) groups exposed to low doses of radiation (<0.1 Gy). Moreover, the available data on biological mechanisms do not provide support for the idea of a low-dose threshold or hormesis for any of these endpoints. There are emerging data suggesting risks of cardiovascular disease and cataract at low doses, but this is less well established. This large body of evidence does not suggest and, indeed, is not statistically compatible with any very large threshold in dose (>10 mGy), or with possible beneficial effects from exposures. The presented data suggest that exposure to low-dose radiation causes excess cancer risks and quite possibly also excess risks of various non-cancer endpoints.

Gamma-radiation levels outdoors in Great Britain based on K, Th and U geochemical data.

Gamma-rays from naturally occurring radionuclides are a major component of background radiation. They are an important tool for geology and are also important for radiation protection. In this paper we use over a quarter of a million geochemical measurements of concentrations of potassium, thorium and uranium in soils and in stream sediments to estimate outdoor gamma-ray dose rates across Great Britain. The soil concentrations are generally at a depth of 5-20 cm with some at 35-50 cm. Soil measurements will give spatially relatively precise estimates, but as soil data are not available for much of Scotland, stream sediment data are used there. Kriging methods are used to estimate surface concentrations of K, Th and U and dose rates are imputed from these concentrations. Our results are compared with measurement surveys of both outdoor and indoor gamma-ray dose rates. Recently there has been interest in exploring the carcinogenic risks of low dose radiation by investigating associations between childhood cancer rates and doses from natural background gamma radiation. To achieve adequate statistical power, such studies must be so large that it is impractical to assess exposures by direct measurements in the homes of study subjects. Instead the exposures must be modelled. The results presented here will be an important input to such work.

Noninvasive Venous Waveform Analysis Correlates With Pulmonary Capillary Wedge Pressure and Predicts 30-Day Admission in Patients With Heart Failure Undergoing Right Heart Catheterization.

BACKGROUND: Heart failure is the leading cause of hospitalization in the elderly and readmission is common. Clinical indicators of congestion may not precede acute congestion with enough time to prevent hospital admission for heart failure. Thus, there is a large and unmet need for accurate, noninvasive assessment of congestion. Noninvasive venous waveform analysis in heart failure (NIVAHF) is a novel, noninvasive technology that monitors intravascular volume status and hemodynamic congestion. The objective of this study was to determine the correlation of NIVAHF with pulmonary capillary wedge pressure (PCWP) and the ability of NIVAHF to predict 30-day admission after right heart catheterization. METHODS AND RESULTS: The prototype NIVAHF device was compared with the PCWP in 106 patients undergoing right heart catheterization. The NIVAHF algorithm was developed and trained to estimate the PCWP. NIVA scores and central hemodynamic parameters (PCWP, pulmonary artery diastolic pressure, and cardiac output) were evaluated in 84 patients undergoing outpatient right heart catheterization. Receiver operating characteristic curves were used to determine whether a NIVA score predicted 30-day hospital admission. The NIVA score demonstrated a positive correlation with PCWP (r = 0.92, n = 106, P < .0001). The NIVA score at the time of hospital discharge predicted 30-day admission with an AUC of 0.84, a NIVA score of more than 18 predicted admission with a sensitivity of 91% and specificity of 56%. Residual analysis suggested that no single patient demographic confounded the predictive accuracy of the NIVA score. CONCLUSIONS: The NIVAHF score is a noninvasive monitoring technology that is designed to provide an estimate of PCWP. A NIVA score of more than 18 indicated an increased risk for 30-day hospital admission. This noninvasive measurement has the potential for guiding decongestive therapy and the prevention of hospital admission in patients with heart failure.

Secondary Metabolic Profile as a Tool for Distinction and Characterization of Cultivars of Black Pepper (Piper nigrum L.) Cultivated in Pará State, Brazil.

This study evaluated the chemical compositions of the leaves and fruits of eight black pepper cultivars cultivated in Pará State (Amazon, Brazil). Hydrodistillation and gas chromatography-mass spectrometry were employed to extract and analyze the volatile compounds, respectively. Sesquiterpene hydrocarbons were predominant (58.5-90.9%) in the cultivars "Cingapura", "Equador", "Guajarina", "Iaçará", and "Kottanadan", and "Bragantina", "Clonada", and "Uthirankota" displayed oxygenated sesquiterpenoids (50.6-75.0%). The multivariate statistical analysis applied using volatile composition grouped the samples into four groups: γ-Elemene, curzerene, and δ-elemene ("Equador"/"Guajarina", I); δ-elemene ("Iaçará"/"Kottanadan"/"Cingapura", II); elemol ("Clonada"/"Uthirankota", III) and α-muurolol, bicyclogermacrene, and cubebol ("Bragantina", IV). The major compounds in all fruit samples were monoterpene hydrocarbons such as α-pinene, ß-pinene, and limonene. Among the cultivar leaves, phenolics content (44.75-140.53 mg GAE·g-1 FW), the enzymatic activity of phenylalanine-ammonia lyase (20.19-57.22 µU·mL-1), and carotenoids (0.21-2.31 µg·mL-1) displayed significant variations. Due to black pepper's susceptibility to Fusarium infection, a molecular docking analysis was carried out on Fusarium protein targets using each cultivar's volatile components. F. oxysporum endoglucanase was identified as the preferential protein target of the compounds. These results can be used to identify chemical markers related to the susceptibility degree of black pepper cultivars to plant diseases prevalent in Pará State.

Magnetic resonance imaging measurement of placental perfusion and oxygen saturation in early-onset fetal growth restriction.

OBJECTIVE: We hypothesised that a multi-compartment magnetic resonance imaging (MRI) technique that is sensitive to fetal blood oxygenation would identify changes in placental blood volume and fetal blood oxygenation in pregnancies complicated by early-onset fetal growth restriction (FGR). DESIGN: Case-control study. SETTING: London, UK. POPULATION: Women with uncomplicated pregnancies (estimated fetal weight [EFW] >10th centile for gestational age [GA] and normal maternal and fetal Doppler ultrasound, n = 12) or early-onset FGR (EFW <3rd centile with or without abnormal Doppler ultrasound <32 weeks GA, n = 12) were studied. METHODS: All women underwent MRI examination. Using a multi-compartment MRI technique, we quantified fetal and maternal blood volume and feto-placental blood oxygenation. MAIN OUTCOME MEASURES: Disease severity was stratified according to Doppler pulsatility index and the relationship to the MRI parameters was investigated, including the influence of GA at scan. RESULTS: The FGR group (mean GA 27+5  weeks, range 24+2 to 33+6  weeks) had a significantly lower EFW compared with the control group (mean GA 29+1  weeks; -705 g, 95% CI -353 to -1057 g). MRI-derived feto-placental oxygen saturation was higher in controls compared with FGR (75 ± 9.6% versus 56 ± 16.2%, P = 0.02, 95% CI 7.8-30.3%). Feto-placental oxygen saturation estimation correlated strongly with GA at scan in controls (r = -0.83). CONCLUSION: Using a novel multimodal MRI protocol we demonstrated reduced feto-placental blood oxygen saturation in pregnancies complicated by early-onset FGR. The degree of abnormality correlated with disease severity defined by ultrasound Doppler findings. Gestational age-dependent changes in oxygen saturation were also present in normal pregnancies. TWEETABLE ABSTRACT: MRI reveals differences in feto-placental oxygen saturation between normal and FGR pregnancy that is associated with disease severity.

Essential Oils as Antiviral Agents. Potential of Essential Oils to Treat SARS-CoV-2 Infection: An In-Silico Investigation.

Essential oils have shown promise as antiviral agents against several pathogenic viruses. In this work we hypothesized that essential oil components may interact with key protein targets of the 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A molecular docking analysis was carried out using 171 essential oil components with SARS-CoV-2 main protease (SARS-CoV-2 Mpro), SARS-CoV-2 endoribonucleoase (SARS-CoV-2 Nsp15/NendoU), SARS-CoV-2 ADP-ribose-1″-phosphatase (SARS-CoV-2 ADRP), SARS-CoV-2 RNA-dependent RNA polymerase (SARS-CoV-2 RdRp), the binding domain of the SARS-CoV-2 spike protein (SARS-CoV-2 rS), and human angiotensin-converting enzyme (hACE2). The compound with the best normalized docking score to SARS-CoV-2 Mpro was the sesquiterpene hydrocarbon (E)-ß-farnesene. The best docking ligands for SARS-CoV Nsp15/NendoU were (E,E)-α-farnesene, (E)-ß-farnesene, and (E,E)-farnesol. (E,E)-Farnesol showed the most exothermic docking to SARS-CoV-2 ADRP. Unfortunately, the docking energies of (E,E)-α-farnesene, (E)-ß-farnesene, and (E,E)-farnesol with SARS-CoV-2 targets were relatively weak compared to docking energies with other proteins and are, therefore, unlikely to interact with the virus targets. However, essential oil components may act synergistically, essential oils may potentiate other antiviral agents, or they may provide some relief of COVID-19 symptoms.

Validation of Regional Lymph Node Excisional Biopsy for Staging Oral and Maxillofacial Malignant Neoplasms in 97 Dogs and 10 Cats (2006-2016).

The objective of this retrospective clinical study was to confirm the validity of excisional biopsy of regional lymphocentrums for staging oral and maxillofacial neoplasms in a population of 97 dogs and 10 cats. Patients diagnosed with oral and maxillofacial malignant neoplasms underwent ipsilateral excisional biopsy of the mandibular, parotid, and medial retropharyngeal lymphocentrums that receive afferent drainage from the oral and maxillofacial region followed by curative intent surgery of the neoplasm. Biopsy specimens and the resected neoplasm were submitted to a commercial pathology laboratory for histopathologic assessment. The incidence of metastasis to one or more regional lymphocentrums was 14.0%. Of the cases with metastatic disease, 26.7% did not involve the mandibular lymphocentrum. Although the incidence of regional lymph node metastasis was less than reported previously, regional lymph node assessment is warranted in cases of oral and maxillofacial neoplasia.

Development and Pilot Testing of a Context-Relevant Safe Anesthesia Checklist for Cesarean Delivery in East Africa.

BACKGROUND: Maternal mortality rate in developing countries is 20 times higher than in developed countries. Detailed reports surrounding maternal deaths have noted an association between substandard management during emergency events and death. In parallel with these findings, there is increasing evidence for cognitive aids as a means to prevent errors during perioperative crises. However, previously published findings are not directly applicable to cesarean delivery in low-income settings. Our hypothesis was that the use of obstetric anesthesia checklists in the management of high-fidelity simulated obstetrical emergency scenarios would improve adherence to best practice guidelines in low- and middle-income countries. METHODS: Accordingly, with input from East African health care professionals, we created a context-relevant obstetric anesthesia checklist for cesarean delivery. Second, clinical observations were performed to assess in a real-world setting. Third, a pilot testing of the cognitive aid was undertaken. RESULTS: Clinical observation data highlighted significant deficiencies in the management of obstetric emergencies. The use of the cesarean delivery checklist during simulations of peripartum hemorrhage and preeclampsia showed significant improvement in the percentage of completed actions (pretraining 23% ± 6% for preeclampsia and 22% ± 13% for peripartum hemorrhage, posttraining 75% ± 9% for preeclampsia, and 69% ± 9% for peripartum hemorrhage [P < .0001, both scenarios; data as mean ± standard deviation]). CONCLUSIONS: We developed, evaluated, and begun implementation of a context-relevant checklist for the management of obstetric crisis in low- and middle-income countries. We demonstrated not only the need for this tool in a real-world setting but also confirmed its potential efficacy through a pilot simulation study.

Protein Targets of Frankincense: A Reverse Docking Analysis of Terpenoids from Boswellia Oleo-Gum Resins.

Background: Frankincense, the oleo-gum resin of Boswellia trees, has been used in traditional medicine since ancient times. Frankincense has been used to treat wounds and skin infections, inflammatory diseases, dementia, and various other conditions. However, in many cases, the biomolecular targets for frankincense components are not well established. Methods: In this work, we have carried out a reverse docking study of Boswellia diterpenoids and triterpenoids with a library of 16034 potential druggable target proteins. Results:Boswellia diterpenoids showed selective docking to acetylcholinesterase, several bacterial target proteins, and HIV-1 reverse transcriptase. Boswellia triterpenoids targeted the cancer-relevant proteins (poly(ADP-ribose) polymerase-1, tankyrase, and folate receptor ß), inflammation-relevant proteins (phospholipase A2, epoxide hydrolase, and fibroblast collagenase), and the diabetes target 11ß-hydroxysteroid dehydrogenase. Conclusions: The preferential docking of Boswellia terpenoids is consistent with the traditional uses and the established biological activities of frankincense.

Modelling the bimodal distribution of indoor gamma-ray dose-rates in Great Britain.

Gamma radiation from naturally occurring sources (including directly ionizing cosmic-rays) is a major component of background radiation. An understanding of the magnitude and variation of doses from these sources is important, and the ability to predict them is required for epidemiological studies. In the present paper, indoor measurements of naturally occurring gamma-rays at representative locations in Great Britain are summarized. It is shown that, although the individual measurement data appear unimodal, the distribution of gamma-ray dose-rates when averaged over relatively small areas, which probably better represents the underlying distribution with inter-house variation reduced, appears bimodal. The dose-rate distributions predicted by three empirical and geostatistical models are also bimodal and compatible with the distributions of the areally averaged dose-rates. The distribution of indoor gamma-ray dose-rates in the UK is compared with those in other countries, which also tend to appear bimodal (or possibly multimodal). The variation of indoor gamma-ray dose-rates with geology, socio-economic status of the area, building type, and period of construction are explored. The factors affecting indoor dose-rates from background gamma radiation are complex and frequently intertwined, but geology, period of construction, and socio-economic status are influential; the first is potentially most influential, perhaps, because it can be used as a general proxy for local building materials. Various statistical models are tested for predicting indoor gamma-ray dose-rates at unmeasured locations. Significant improvements over previous modelling are reported. The dose-rate estimates generated by these models reflect the imputed underlying distribution of dose-rates and provide acceptable predictions at geographical locations without measurements.

Natural Products as New Treatment Options for Trichomoniasis: A Molecular Docking Investigation.

Trichomoniasis, caused by the parasitic protozoan Trichomonas vaginalis, is the most common non-viral sexually-transmitted disease, and there can be severe complications from trichomoniasis. Antibiotic resistance in T. vaginalis is increasing, but there are currently no alternatives treatment options. There is a need to discover and develop new chemotherapeutic alternatives. Plant-derived natural products have long served as sources for new medicinal agents, as well as new leads for drug discovery and development. In this work, we have carried out an in silico screening of 952 antiprotozoal phytochemicals with specific protein drug targets of T. vaginalis. A total of 42 compounds showed remarkable docking properties to T. vaginalis methionine gamma-lyase (TvMGL) and to T. vaginalis purine nucleoside phosphorylase (TvPNP). The most promising ligands were polyphenolic compounds, and several of these showed docking properties superior to either co-crystallized ligands or synthetic enzyme inhibitors.

In-silico screening for anti-Zika virus phytochemicals.

Zika virus (ZIKV) is an arbovirus that has infected hundreds of thousands of people and is a rapidly expanding epidemic across Central and South America. ZIKV infection has caused serious, albeit rare, complications including Guillain-Barré syndrome and congenital microcephaly. There are currently no vaccines or antiviral agents to treat or prevent ZIKV infection, but there are several ZIKV non-structural proteins that may serve as promising antiviral drug targets. In this work, we have carried out an in-silico search for potential anti-Zika viral agents from natural sources. We have generated ZIKV protease, methyltransferase, and RNA-dependent RNA polymerase using homology modeling techniques and we have carried out molecular docking analyses of our in-house virtual library of phytochemicals with these protein targets as well as with ZIKV helicase. Overall, 2263 plant-derived secondary metabolites have been docked. Of these, 43 compounds that have drug-like properties have exhibited remarkable docking profiles to one or more of the ZIKV protein targets, and several of these are found in relatively common herbal medicines, suggesting promise for natural and inexpensive antiviral therapy for this emerging tropical disease.

Spatial prediction of naturally occurring gamma radiation in Great Britain.

Gamma radiation from natural sources is an important component of background radiation, and correlates with childhood leukaemia risk in Great Britain. The geographic variation of indoor gamma radiation dose-rates in Great Britain is explored using various geo-statistical methods. A multi-resolution Gaussian-process model using radial basis functions with 2, 4, or 8 components, is fitted via maximum likelihood, and a non-spatial model is also used, fitted by ordinary least squares. Because of the dataset size (N = 10,199), four other parametric spatial models are fitted by variogram-fitting. A randomly selected 70:30 split is used for fitting:validation. The models are evaluated based on their predictive performance as measured by Mean Absolute Error, Mean Squared Error, as well as Pearson correlation and rank-correlation between predicted and actual dose-rates. Each of the four parametric models (Matérn, Gaussian, Bessel, Spherical) fitted the empirical variogram well, and yielded similar predictions at >50 km separation, although with more substantial differences in predicted variograms at <50 km. The multi-resolution Gaussian-process model with 8 components had the best predictive accuracy among the models considered. The Spherical, Bessel, Matérn, Gaussian and ordinary least squares models had progressively worse predictive performance, the ordinary least squares model being particularly poor in this respect.

Alphavirus protease inhibitors from natural sources: A homology modeling and molecular docking investigation.

Alphaviruses such as Chikungunya virus (CHIKV), O'Nyong-Nyong virus (ONNV), Ross River virus (RRV), Eastern equine encephalitis virus (EEEV), Venezuelan equine encephalitis virus (VEEV), and Western equine encephalitis virus (WEEV), are mosquito-transmitted viruses that can cause fevers, rash, and rheumatic diseases (CHIKV, ONNV, RRV) or potentially fatal encephalitis (EEEV, VEEV, WEEV) in humans. These diseases are considered neglected tropical diseases for which there are no current antiviral therapies or vaccines available. The alphavirus non-structural protein 2 (nsP2) contains a papain-like protease, which is considered to be a promising target for antiviral drug discovery. In this work, molecular docking analyses have been carried out on a library of 2174 plant-derived natural products (290 alkaloids, 664 terpenoids, 1060 polyphenolics, and 160 miscellaneous phytochemicals) with the nsP2 proteases of CHIKV, ONNV, RRV, EEEV, VEEV, WEEV, as well as Aura virus (AURV), Barmah Forest Virus (BFV), Semliki Forest virus (SFV), and Sindbis virus (SINV) in order to identity structural scaffolds for inhibitor design or discovery. Of the 2174 phytochemicals examined, a total of 127 showed promising docking affinities and poses to one or more of the nsP2 proteases, and this knowledge can be used to guide experimental investigation of potential inhibitors.