Quantum circuits with many photons on a programmable nanophotonic chip.

Growing interest in quantum computing for practical applications has led to a surge in the availability of programmable machines for executing quantum algorithms1,2. Present-day photonic quantum computers3-7 have been limited either to non-deterministic operation, low photon numbers and rates, or fixed random gate sequences. Here we introduce a full-stack hardware-software system for executing many-photon quantum circuit operations using integrated nanophotonics: a programmable chip, operating at room temperature and interfaced with a fully automated control system. The system enables remote users to execute quantum algorithms that require up to eight modes of strongly squeezed vacuum initialized as two-mode squeezed states in single temporal modes, a fully general and programmable four-mode interferometer, and photon number-resolving readout on all outputs. Detection of multi-photon events with photon numbers and rates exceeding any previous programmable quantum optical demonstration is made possible by strong squeezing and high sampling rates. We verify the non-classicality of the device output, and use the platform to carry out proof-of-principle demonstrations of three quantum algorithms: Gaussian boson sampling, molecular vibronic spectra and graph similarity8. These demonstrations validate the platform as a launchpad for scaling photonic technologies for quantum information processing.

Climate-Change-Induced Weather Events and Implications for Urban Water Resource Management in the Free State Province of South Africa.

Current climate projections for Southern Africa indicate an increase in the incidence of extreme weather events in the future. Even though South Africa does not rank among the highest on the world multi-hazard index list, the country is prone to multiple climate-related extreme events which pose substantial human and ecological impacts. Consequently, such climate extremes have serious negative effects on regional water resources, public health, biodiversity, food security, natural systems, and infrastructure. The main aim of this study is to review the literature on climate-change-induced weather events and the implications for urban water resource management in South Africa particularly focusing on QwaQwa. The study reviewed 122 documents which include books, peer-reviewed articles, conference papers, newspaper articles, institutional and government reports, and one news broadcast video. Findings revealed that QwaQwa experiences increasing water challenges as demand for water increases and both quantity and quality decrease to critical levels. This study, therefore, provides preliminary suggestions of strategies to build resilience in this climate change context, such as investment in climate-resilient water infrastructure, effective and transparent management of public resources with accountability, strengthening resilience through addressing poverty and marginalisation, nature-based solutions, and education and awareness. Furthermore, conducting hazard, exposure, and resilience analyses is necessary in order to inform the development of relevant disaster risk reduction strategies. The findings contribute to the literature on climate change impacts on water resource planning in South Africa and similar climate change contexts. The findings could; therefore, be valuable to researchers and applied practitioners such as policymakers, water resource management professionals, and urban planners.

Satellite-based application in drought disaster assessment using terra MOD13Q1 data across free state province, South Africa.

Terra MOD13Q1 satellite data were used to assess drought disaster events and its spatiotemporal patterns over the Free State Province, South Africa between 2001 and 2019. Moderate Resolution Imaging Spectroradiometer (MODIS) products and climate data downloaded from Application for Extracting and Exploring Analysis Ready Samples" (AppEEARS) and NASA: Prediction of Worldwide Energy Resource databases, respectively were used in the study area. After acquiring MODIS data with the area of interest extracted using field sample and the layers of interest: using Enhanced Vegetation Index (EVI) and pixel reliability and defining the output as GeoTIFF with geographic projection, R programming was used for the analysis. This study also evaluated Standardized Precipitation Index (SPI) to further identify meteorological drought, computed at various time scales utilising information acquired from the Global Drought Observatory database. The results show and identify the years that are water-stressed in the study area, which indicated that low vegetation abundance and high temperature in the Free State Province occurred in 2000, 2008, and 2009. The result also shows that the summer season over large parts of the study region is characterized by moderate to extreme drought while winter seasons have light drought conditions during the same time. Seasonal and inter-annual comparisons of drought events outlined in the Vegetation Condition Index (VCI) provided a useful tool for analysing the temporal and spatial evolution of regional drought and for estimating potential environmental impacts. Drought events occurrence in the study area is less frequent and milder in winter months while summer droughts of different years were more severe. The results of this study can also be used as a tool for monitoring droughts and support for decision making in the evaluation and management of regional drought, for disaster preparedness.

Drought disaster monitoring using MODIS derived index for drought years: A space-based information for ecosystems and environmental conservation.

Drought disaster is one of the major factors restricting the development of vegetation across a wide variety of environments. Monitoring the temporal and spatial dynamics of drought episodes in the study area is crucial for environmental and ecosystem conservation. This study assesses drought disaster by utilising space-based data and R programming for drought years 2003, 2007, 2012 and 2019 in the Free State Province, South Africa. Results revealed that the study area witnessed drought events in the year 2003 where March, August, September, October, November and December were more affected by drought disaster events. It was further observed that February and March were affected by extreme drought conditions in the year 2007. In year 2012, January, October, November and December, there exist moderate to severe drought conditions in the study area where some regions were more affected than the other. Finally, year 2019 witnessed variations in drought event distributions across the months with January, October and November witnessing severe to extreme drought conditions from about 0 to 30% drought values. Overall, this study shows that the 16-day Terra-MODIS composite and EVI products are sensitive to stressors associated with drought. The Vegetation Condition Monitoring Index (VCI) based on MODIS is suited for monitoring drought disasters. The technique used in this study revealed the suitability of MODIS data for assessing drought conditions and their potential environmental impacts.

Drought conditions appraisal using geoinformatics and multi-influencing factors.

The world including South Africa is faced with unprecedented environmental changes, which can be linked to climate-related disasters such as drought and extreme heat. Several studies have indicated that these changes are likely to accelerate in the future and cause an adverse impact on the environment. The Eastern Cape Province of South Africa, especially Amathole District Municipality (ADM), has recorded a high number of climate change-related disasters including prolonged drought conditions witnessed during the winter season of 2008, 2009, 2014 and 2015 among others. Consequently, this study aimed at exploring remote sensing information to assess and document drought occurrences in the ADM from 2007 to 2017. To accomplish the aim, the Normalized Difference Vegetation Index, Land Surface Temperature and Precipitation were utilised to access drought spatiotemporal variations. For the analysis, a total of 396 satellite imageries (MODIS and TRMM) were used. The results revealed that different correlations exist between the three variables. The significance of correlations differed from one season to another. Furthermore, it was revealed that the drought conditions in the district differed in the spatial distribution. The study accurately identified the drought episodes that occurred in the ADM in the years 2008, 2009, 2014, 2015 and 2016. The chosen methodology and variables proved to be suitable for analysing drought conditions offering space and temporal variation dimension, which is vital in monitoring drought events.

Efficacy and safety of brodalumab in patients with psoriasis who had inadequate responses to ustekinumab: subgroup analysis of two randomized phase III trials.

BACKGROUND: Brodalumab, a fully human anti-interleukin-17 receptor A monoclonal antibody, has demonstrated superior efficacy and safety over ustekinumab as induction therapy for moderate-to-severe psoriasis. OBJECTIVES: To evaluate the efficacy and safety of brodalumab through week 52 in patients who had inadequate responses to ustekinumab. METHODS: A subgroup analysis of the phase III AMAGINE-2/-3 double-blind randomized controlled trials was performed. Participants were aged 18-75 years and had a Psoriasis Area and Severity Index (PASI) ≥ 12, static Physician's Global Assessment score ≥ 3 and involvement of ≥ 10% body surface area. The studies were registered at ClinicalTrials.gov: AMAGINE-2, NCT01708603; AMAGINE-3, NCT01708629. RESULTS: At baseline, patients with or without prior biologic experience who had an adequate response at week 16 on ustekinumab or brodalumab had lower rates of involved body surface area, PASI, prior biologic use, psoriatic arthritis and body mass index than patients who experienced inadequate response at or after week 16. Among patients who experienced inadequate response to ustekinumab, those rescued with brodalumab had PASI ≥ 75%, ≥ 90% and 100% improvement response rates of 72·6%, 58·1% and 36·3%, respectively, at week 52 compared with 61·7%, 25·5% and 5·4%, respectively, in patients who continued ustekinumab. Exposure-adjusted rates of treatment-emergent adverse events were similar among patients rescued with brodalumab (377·3 adverse events per 100 patient-years) and those who remained on ustekinumab (389·9 adverse events per 100 patient-years). CONCLUSIONS: Among patients who experienced inadequate responses to ustekinumab, rescue with brodalumab improved skin clearance outcomes compared with continuing ustekinumab.

Impact of previous biologic use on the efficacy and safety of brodalumab and ustekinumab in patients with moderate-to-severe plaque psoriasis: integrated analysis of the randomized controlled trials AMAGINE-2 and AMAGINE-3.

BACKGROUND: Biologics are being used increasingly to treat moderate-to-severe psoriasis. Efficacy may differ in patients with previous exposure to biologics. OBJECTIVES: To investigate the impact of previous biologic exposure on the efficacy and safety of brodalumab and ustekinumab in patients with moderate-to-severe plaque psoriasis. METHODS: Two placebo- and ustekinumab-controlled phase III clinical trials. There was an initial 12-week induction phase where patients were treated with brodalumab [210 mg or 140 mg every 2 weeks (Q2W)], ustekinumab or placebo. Efficacy end points included ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and static Physician's Global Assessment (score of 0 or 1) vs. placebo, PASI 100 vs. ustekinumab, Dermatology Life Quality Index and Psoriasis Symptom Inventory. Adverse events were monitored throughout. RESULTS: In total, 493 patients [334 (27%) brodalumab 210 mg Q2W and 159 (26%) ustekinumab] had received prior biologics; 150 (12%) and 62 (10%), respectively, reported previously failed treatment with a biologic. Brodalumab efficacy in patients with or without previous exposure to biologics was statistically equivalent: 40·9% and 39·5% of biologic-naive and -experienced patients achieved PASI 100 at week 12, compared with 21·1% and 17·0% with ustekinumab (both P < 0·001). In patients where prior biologics had been successful or failed, 41·7% and 32·0% achieved PASI 100, compared with 21·1% and 11·3% with ustekinumab. Tolerability was similar, and did not appear to be influenced by previous treatment with biologics. CONCLUSIONS: The efficacy of brodalumab 210 mg Q2W was similar regardless of prior biological therapy (P = 0·31, 0·32 and 0·64 for PASI 75, 90 and 100, respectively). Almost twice as many patients achieved PASI 100 or complete clearance with brodalumab at week 12 compared with ustekinumab; the differences were most noticeable where previous biologics had failed. Both treatments were well tolerated.

Improvement in itch and other psoriasis symptoms with brodalumab in phase 3 randomized controlled trials.

BACKGROUND: Patients with psoriasis have lesional symptoms, including itch, which can reduce quality of life. The efficacy and safety of brodalumab, an interleukin-17 receptor A antagonist, in treating moderate-to-severe psoriasis have been reported in three randomized, controlled, phase 3 trials (AMAGINE-1/-2/-3). OBJECTIVE: The effect of brodalumab on lesional symptoms was assessed using the psoriasis symptom inventory (PSI), a validated patient-reported instrument. METHODS: Patients were randomized to receive brodalumab (140 or 210 mg every 2 weeks [Q2W]), placebo (AMAGINE-1/-2/-3), or ustekinumab (AMAGINE-2/-3) during a 12-week induction phase, followed by a maintenance phase through week 52. Patients electronically rated the severity of PSI items (itch, burning, stinging, pain, redness, scaling, cracking and flaking) during the previous 24 h on a scale of 0 (not at all severe) to 4 (very severe). At each visit, the PSI total score responder status was assessed, with responders defined as having an average weekly total inventory score ≤8 with no item score >1 at week 12. RESULTS: Across AMAGINE-1/-2/-3, brodalumab was associated with improvements in PSI total scores and itch scores vs. placebo from week 2 through week 12 (P < 0.001 in both domains). In AMAGINE-2/-3, brodalumab 210 mg Q2W demonstrated faster onset of PSI total score and itch responses (week 2, 22.1% and 36.4%, respectively) vs. ustekinumab (week 2, 6.9% and 17.1%, respectively) and was associated with improved itch responses vs. ustekinumab after 52 weeks of constant treatment. CONCLUSION: Brodalumab demonstrated rapid, robust improvements in symptoms assessed by the PSI, including itch, vs. placebo and ustekinumab.

Repeat Rifaximin for Irritable Bowel Syndrome: No Clinically Significant Changes in Stool Microbial Antibiotic Sensitivity.

BACKGROUND: Rifaximin has demonstrated efficacy and safety for diarrhea-predominant irritable bowel syndrome (IBS-D). AIM: To determine the rifaximin repeat treatment effect on fecal bacterial antibiotic susceptibility. METHODS: Patients with IBS in Trial 3 (TARGET 3) study who responded to open-label rifaximin 550 mg three times daily for 2 weeks, with symptom recurrence within 18 weeks, were randomized to double-blind treatment: two 2-week repeat courses of rifaximin or placebo, separated by 10 weeks. Prospective stool sample collection occurred before and after open-label rifaximin, before and after the first repeat course, and at the end of the study. Susceptibility testing was performed with 11 antibiotics, including rifaximin and rifampin, using broth microdilution or agar dilution methods. RESULTS: Of 103 patients receiving open-label rifaximin, 73 received double-blind rifaximin (n = 37) or placebo (n = 36). A total of 1429 bacterial and yeast isolates were identified, of which Bacteroidaceae (36.7%) and Enterobacteriaceae (33.9%) were the most common. In the double-blind phase, Clostridium difficile was highly susceptible to rifaximin [minimum inhibitory concentration (MIC) range 0.008-1 µg/mL] and rifampin (MIC range 0.004-0.25 µg/mL). Following double-blind rifaximin treatment, Staphylococcus isolates remained susceptible to rifaximin at all visits (MIC50 range ≤0.06-32 µg/mL). Rifaximin exposure was not associated with long-term cross-resistance of Bacteroidaceae, Enterobacteriaceae, and Enterococcaceae to rifampin or nonrifamycin antibiotics tested. CONCLUSIONS: In this study, short-term repeat treatment with rifaximin has no apparent long-term effect on stool microbial susceptibility to rifaximin, rifampin, and nonrifamycin antibiotics. CLINICALTRIALS. GOV IDENTIFIER: NCT01543178.

Comparative Study on the Antimicrobial Activities and Metabolic Profiles of Five Usnea Species from the Philippines.

The rapid emergence of resistant bacteria is occurring worldwide, endangering the efficacy of antibiotics. Hence, there is a need to search for new sources of antibiotics that either exhibit novel structures or express a new mechanism of action. The lichen Usnea, with its wide range of unique, biologically potent secondary metabolites, may solve this problem. In this study, Usnea species were collected in the Northern Philippines, identified through combined morphological and biochemical characterization, and tested for antimicrobial activities against the multidrug-resistant ESKAPE pathogens, i.e., Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae, two standard antibiotic-sensitive test bacteria, and a yeast. A total of 46 lichen specimens were collected and later identified as Usnea baileyi (10), U. diffracta (10), U. glabrata (12), U. longissima (4), and U. rubicunda (10). The results show that the crude extracts of the Usnea species exhibited promising in vitro inhibitory activities against standard antibiotic-sensitive (E. faecalis ATCC 29212) and multidrug-resistant (methicillin-resistant S. aureus and E. faecalis) Gram-positive bacteria. Additionally, lichen compounds of representative specimens per species were identified and profiled using thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC). The detection of lichen acids (LA) via HPLC showed the presence of 24 peaks of lichen acids. TLC-bioautography identified the bioactive lichen acids as alectronic acid, connorstictic acid, consalazinic acid, diffractaic acid, echinocarpic acid, erythrin acid, galbinic acid, hypoconstictic acid, hyposalazinic acid, hypostictic acid, lobaric acid, menegazzaic acid, micareic acid, pannarin, salazinic acid, stictic acid, and usnic acid. Our study highlighted the wide spectrum of opportunities for using lichens for the discovery of potential antimicrobial agents.

Attenuation of Lipopolysaccharide-Induced Inflammatory Responses through Inhibition of the NF-κB Pathway and the Increased NRF2 Level by a Flavonol-Enriched n-Butanol Fraction from Uvaria alba.

Pathologic hyperreactive inflammatory responses occur when there is excessive activation of a proinflammatory NF-κB pathway and a reduced cytoprotective NRF2 cascade. The noncytotoxic, highly selective COX-2 inhibitory flavonol-enriched butanol fraction (UaB) from Uvaria alba (U. alba) was investigated for its inflammatory modulating potential by targeting NF-κB activation and NRF2 activity. Enzyme-linked immunosorbent assay was initially performed to measure levels of proinflammatory mediators [nitric oxide (NO), prostaglandin E2, and reactive oxygen species (ROS)] and cytokines [tumor necrosis factor-alpha (TNF-α), IL-1ß, and IL-6], followed by reverse transcription-polymerase chain reaction and western blotting to determine mRNA and protein expression, respectively. Using immunofluorescence staining combined with western blot analysis, the activation of NF-κB was further investigated. NRF2 activity was also measured using a luciferase reporter assay. UaB abrogated protein and mRNA expressions of inducible nitric oxide synthase (iNOS), COX-2, TNF-α, IL-1ß, and IL-6 in RAW 264.7 macrophages, thereby suppressing the production of proinflammatory mediators and cytokines. This was further validated when a concentration-dependent decrease in NO and ROS production was observed in zebrafish (Danio rerio) larvae. UaB also increased NRF2 activity in HaCaT/ARE cell line and attenuated NF-κB activation by inhibiting the nuclear translocation of transcription factor p65 in RAW 264.7 macrophages. Nontargeted LC-MS analysis of UaB revealed the presence of the flavonols quercitrin (1), quercetin (2), rutin (3), kaempferol (4), and kaempferol 3-O-rutinoside (5). Molecular docking indicates that major flavonol aglycones have high affinity toward COX-2 NSAID-binding sites, TNF-α, and TNF-α converting enzyme, while the glycosylated flavonoids showed strong binding toward iNOS and IKK-all possessing dynamic stability when performing molecular dynamics simulations at 140 ns. This is the first report to have elucidated the mechanistic anti-inflammatory potential of the Philippine endemic plant U. alba.

Observational study on efficacy of negative expiratory pressure test proposed as screening for obstructive sleep apnea syndrome among commercial interstate bus drivers--protocol study.

BACKGROUND: Obstructive sleep apnea (OSA) is a respiratory disease characterized by the collapse of the extrathoracic airway and has important social implications related to accidents and cardiovascular risk. The main objective of the present study was to investigate whether the drop in expiratory flow and the volume expired in 0.2 s during the application of negative expiratory pressure (NEP) are associated with the presence and severity of OSA in a population of professional interstate bus drivers who travel medium and long distances. METHODS/DESIGN: An observational, analytic study will be carried out involving adult male subjects of an interstate bus company. Those who agree to participate will undergo a detailed patient history, physical examination involving determination of blood pressure, anthropometric data, circumference measurements (hips, waist and neck), tonsils and Mallampati index. Moreover, specific questionnaires addressing sleep apnea and excessive daytime sleepiness will be administered. Data acquisition will be completely anonymous. Following the medical examination, the participants will perform a spirometry, NEP test and standard overnight polysomnography. The NEP test is performed through the administration of negative pressure at the mouth during expiration. This is a practical test performed while awake and requires little cooperation from the subject. In the absence of expiratory flow limitation, the increase in the pressure gradient between the alveoli and open upper airway caused by NEP results in an increase in expiratory flow. DISCUSSION: Despite the abundance of scientific evidence, OSA is still underdiagnosed in the general population. In addition, diagnostic procedures are expensive, and predictive criteria are still unsatisfactory. Because increased upper airway collapsibility is one of the main determinants of OSA, the response to the application of NEP could be a predictor of this disorder. With the enrollment of this study protocol, the expectation is to encounter predictive NEP values for different degrees of OSA in order to contribute toward an early diagnosis of this condition and reduce its impact and complications among commercial interstate bus drivers. TRIAL REGISTRATION: Registro Brasileiro de Ensaios Clinicos (local acronym RBEC) [Internet]: Rio de Janeiro (RJ): Instituto de Informaçao Cientifica e Tecnologica em Saude (Brazil); 2010 - Identifier RBR-7dq5xx. Cross-sectional study on efficacy of negative expiratory pressure test proposed as screening for obstructive sleep apnea syndrome among commercial interstate bus drivers; 2011 May 31 [7 pages]. Available from http://www.ensaiosclinicos.gov.br/rg/RBR-7dq5xx/.

Systematic mapping of disaster risk management research and the role of innovative technology.

Globally, disaster risk management (DRM) has gone through a criterion transpose from static to a technology-based proactive approach in managing disasters including natural and anthropogenic disasters. This study aimed at exploring this research niche and to identify the main topical issues currently underway, such as the most disaster risk management techniques and prevalent geographical locations using scientometrics techniques. The result reveals that studies on DRM during the period of investigation witnessed an increase from early 2000 and peaking in 2017 followed by 2016 with a Kolmogorov-Smirnoff goodness-of-fit of 0.9672. More so, there exists a decline in year 2018 with about 144 published articles on DRM. However, research output fluctuated during the survey period between 1990 and 2004; for instance, the result shows that the research published on DRM in year 1990, 1991, 1992, 1993, 1994 and 1995 are six, seven, five, seven, three and seven articles, respectively. In this study, the contribution of different nations and country collaboration to different sub-categories of disasters was examined. Global distributions of scientific articles tailored to DRM research across different environmental and disaster issues that demonstrate the development of analytical tools used to detect them and the researchers' production from various nations in both developed and developing countries were evaluated. Despite the recurrence of climate-related disasters in some parts of the world, relevant studies, disaster impacts and support systems remain poorly understood and not well explored.

Preventing or controlling periodontitis reduces the occurrence of osteonecrosis of the jaw (ONJ) in rice rats (Oryzomys palustris).

INTRODUCTION: Osteonecrosis of the jaw (ONJ) is an adverse event that requires association of both systemic risk factors, such as powerful anti-resorptives (pARs; e.g. zoledronic acid [ZOL]), and local oral risk factors (e.g. tooth extraction, periodontitis). Whereas optimal oral health prior to initiate pARs is recognized as critically important for minimizing ONJ risk, the efficacy of preventive/maintenance measures in patients who are taking pARs is understudied. Rice rats fed a standard diet (STD), rich in insoluble fiber, develop localized periodontitis. STD-rats with localized periodontitis treated with ZOL for 18-24 wk develop ONJ. Hence, we hypothesized that controlling/preventing localized periodontitis in the ZOL-treated rats, reduces ONJ occurrence. METHODS: We used two approaches to attempt reducing periodontitis prevalence: 1) periodontal cleaning (PC); and 2) replacing the STD-diet with a nutritionally-equivalent diet high in soluble fiber (SF). 75 four-week-old male rats were weight-randomized into five groups (n = 15) in a 24-week experiment. Three groups ate the STD-diet and two the high SF-diet. STD-diet groups received intravenous (IV) vehicle (VEH) q4wks (STD + VEH), 80 µg/kg ZOL q4wks IV (STD + ZOL), or ZOL plus PC q2wks (STD + ZOL + PC). The SF-diet groups received VEH (SF + VEH) or ZOL (SF + ZOL). Jaws were processed for histopathology and evaluated for ONJ prevalence and tissue-level periodontitis. RESULTS: 1) 40% of STD + VEH rats developed maxillary localized periodontitis with no ONJ; 2) 50% of STD + ZOL rats developed ONJ; 3) 7% of STD + ZOL + PC rats developed ONJ (p < 0.01 vs. STD + ZOL); and 4) one SF + ZOL rat developed localized periodontitis, and no SF + VEH or SF + ZOL rats developed ONJ (p < 0.001 vs. STD + ZOL). CONCLUSIONS: 1) Periodontal cleaning in ZOL-treated rats decreases localized periodontitis severity and reduces ONJ prevalence; and 2) feeding a SF-diet to ZOL-treated rats reduces both incidence of localized periodontitis and ONJ. Our data indicates strong oral microbial community shifts according to oral health condition and trends in the shifts associated with diet.

Anti-HIV reverse transcriptase plant polyphenolic natural products with in silico inhibitory properties on seven non-structural proteins vital in SARS-CoV-2 pathogenesis.

BACKGROUND: Accessing COVID-19 vaccines is a challenge despite successful clinical trials. This burdens the COVID-19 treatment gap, thereby requiring accelerated discovery of anti-SARS-CoV-2 agents. This study explored the potential of anti-HIV reverse transcriptase (RT) phytochemicals as inhibitors of SARS-CoV-2 non-structural proteins (nsps) by targeting in silico key sites in the structures of SARS-CoV-2 nsps. One hundred four anti-HIV phytochemicals were subjected to molecular docking with nsp3, 5, 10, 12, 13, 15, and 16. Top compounds in complex with the nsps were investigated further through molecular dynamics. The drug-likeness and ADME (absorption, distribution, metabolism, and excretion) properties of the top compounds were also predicted using SwissADME. Their toxicity was likewise determined using OSIRIS Property Explorer. RESULTS: Among the top-scoring compounds, the polyphenolic functionalized natural products comprised of biflavones 1, 4, 11, 13, 14, 15; ellagitannin 9; and bisisoquinoline alkaloid 19 were multi-targeting and exhibited strongest binding affinities to at least two nsps (binding energy = - 7.7 to - 10.8 kcal/mol). The top ligands were stable in complex with their target nsps as determined by molecular dynamics. Several top-binding compounds were computationally druggable, showed good gastrointestinal absorptive property, and were also predicted to be non-toxic. CONCLUSIONS: Twenty anti-HIV RT phytochemicals showed multi-targeting inhibitory potential against SARS-CoV-2 non-structural proteins 3, 5, 10, 12, 13, 15, and 16. Our results highlight the importance of polyhydroxylated aromatic substructures for effective attachment in the binding/catalytic sites of nsps involved in post-translational mechanism pathways. As such with the nsps playing vital roles in viral pathogenesis, our findings provide inspiration for the design and discovery of novel anti-COVID-19 drug prototypes.

Virtual screening-driven drug discovery of SARS-CoV2 enzyme inhibitors targeting viral attachment, replication, post-translational modification and host immunity evasion infection mechanisms.

The novel coronavirus SARS-CoV2, the causative agent of the pandemic disease COVID-19, emerged in December 2019 forcing lockdown of communities in many countries. The absence of specific drugs and vaccines, the rapid transmission of the virus, and the increasing number of deaths worldwide necessitated the discovery of new substances for anti-COVID-19 drug development. With the aid of bioinformatics and computational modelling, ninety seven antiviral secondary metabolites from fungi were docked onto five SARS-CoV2 enzymes involved in viral attachment, replication, post-translational modification, and host immunity evasion infection mechanisms followed by molecular dynamics simulation and in silico ADMET prediction (absorption, distribution, metabolism, excretion and toxicity) of the hit compounds. Thus, three fumiquinazoline alkaloids scedapin C (15), quinadoline B (19) and norquinadoline A (20), the polyketide isochaetochromin D1 (8), and the terpenoid 11a-dehydroxyisoterreulactone A (11) exhibited high binding affinities on the target proteins, papain-like protease (PLpro), chymotrypsin-like protease (3CLpro), RNA-directed RNA polymerase (RdRp), non-structural protein 15 (nsp15), and the spike binding domain to GRP78. Molecular dynamics simulation was performed to optimize the interaction and investigate the stability of the top-scoring ligands in complex with the five target proteins. All tested complexes were found to have dynamic stability. Of the five top-scoring metabolites, quinadoline B (19) was predicted to confer favorable ADMET values, high gastrointestinal absorptive probability and poor blood-brain barrier crossing capacities.Communicated by Ramaswamy H. Sarma.

Anti-vascular endothelial growth factor antibody monotherapy causes destructive advanced periodontitis in rice rats (Oryzomys palustris).

OBJECTIVE: Angiogenesis inhibitors (AgI) are commonly used in combination chemotherapy protocols to treat cancer, and have been linked to osteonecrosis of the jaw (ONJ). However, it is unknown if AgI therapy alone is sufficient to induce ONJ. We have previously established an ONJ model in rice rats with localized periodontitis that receive zoledronic acid (ZOL). The purpose of this study was to use this model to determine the role of anti-vascular endothelial growth factor A (anti-VEGF) antibody treatment of rice rats with localized maxillary periodontitis. We hypothesized that rice rats with localized maxillary periodontitis given anti-VEGF monotherapy will develop oral lesions that resemble ONJ, defined by exposed, necrotic alveolar bone. METHODS: At age 4 weeks, 45 male rice rats were randomized into three groups (n = 15): 1) VEH (saline), 2) ZOL (80 µg/kg body weight, intravenously once monthly), and 3) anti-VEGF (5 mg B20-4.1.1/kg body weight, subcutaneously twice weekly). After 24 weeks, rats were euthanized, jaws were excised and a high-resolution photograph of each quadrant was taken to assign a severity grade based on gross appearance. Jaws were then fixed, scanned by MicroCT, decalcified and sectioned for histopathologic and immunohistochemical analyses. RESULTS: 40-80% of the rats in the three groups developed gross oral lesions. 50% of ZOL rats developed ONJ. In contrast, 80% of the anti-VEGF rats developed destructive advanced periodontitis that was characterized by extreme alveolar bone loss and fibrosis. Anti-VEGF rats never developed exposed, necrotic bone. Furthermore, only anti-VEGF rats developed mild to severe mandibular periodontitis. Compared to VEH rats, more T-cells were found in periodontal lesions of anti-VEGF rats and more cells of the monocyte lineage were found in ONJ lesions of ZOL rats. CONCLUSIONS: Anti-VEGF monotherapy administered to a validated rodent model of ONJ caused a destructive advanced form of periodontitis that differed significantly from ONJ.

Reversal of opioid-induced bladder dysfunction by intravenous naloxone and methylnaltrexone.

Peripheral mechanisms may be involved in opioid actions on the urinary bladder. This double-blind study investigated whether opioid inhibition of bladder function is reversed by methylnaltrexone, a peripheral opioid antagonist. Thirteen healthy male volunteers received an intravenous (i.v.) infusion of remifentanil, 0.15 mcg/kg/min, then a single i.v. dose of study medication (methylnaltrexone 0.3 mg/kg, naloxone 0.01 mg/kg, or saline). Urodynamics were measured with indwelling bladder and rectal catheters, and pupil size was assessed with infrared pupillometry. Remifentanil decreased detrusor pressure in 21/25 sessions and caused complete urinary retention in 18/25. Voiding was possible in 7/7, 5/12, and 0/6 sessions after naloxone, methylnaltrexone, and saline, respectively (P=0.0013). Remifentanil caused marked miosis that was reversed by naloxone, but not methylnaltrexone or placebo (P<0.0001). The pupil data confirm that methylnaltrexone did not reverse central opioid effects. Reversal of urinary retention by methylnaltrexone indicates that peripheral mechanisms may play a role in opioid-induced bladder dysfunction.

Effect of polyethylene pretreatments on the biomimetic deposition and adhesion of calcium phosphate films.

The effect of ultraviolet irradiation and glow discharge (GD) processing of the polyethylene (PE) substrates on deposition of calcium phosphate (CaP) films from supersaturated aqueous calcium phosphate solutions was investigated in this study. CaP coatings deposited on the PE substrates were comprised of elongated clusters of spherical particles and 100% of the free surface area of nearly all of the substrates was covered with a porous CaP film after a 3 day immersion. Nano-scratch tests determined that PE-CaP adhesion was most improved when PE substrates were subjected to 50W GD treatments. As determined by contact angle measurements, the GD-treated PE samples had the highest electron donor parameter of surface energy, suggesting that enhancing the electron donor parameter of PE leads to improved adhesion with the biomimetic CaP coating.