Toward an integrated multi-gigahertz ionizing particle diagnostic.

Needs arising at both current and future accelerator facilities call for the development of radiation-hardened position-sensing diagnostics that can operate with multi-GHz repetition rates. Such instruments are likely to also have applications in the diagnosis of rapid plasma behavior. Building on the recent work of our Advanced Accelerator Diagnostics Collaboration, we are exploring the development of integrated multi-GHz ionizing particle detection systems based on chemical-vapor deposition diamond sensors, with the initial goal of producing a quadrant detector that can determine the intensity and centroid position of a particle beam at a repetition rate between 5 and 10 GHz. Results from our initial high-speed characterization work are presented, including those from a single-channel sensor with a GHz response. Approaches to achieving multi-GHz (5-10 GHz) rate capability, including the design of a dedicated Application Specific Integrated Circuit and the use of 3D RF-solver computer aided design software, are presented and discussed in more detail. 3D RF simulations suggest clean pulses of duration less than 250 ps (FWHM less than 125 ps) can be achieved with the approaches developed by this work.

Optimization of diastereomeric dihydropyridines as antimalarials.

The increase in research funding for the development of antimalarials since 2000 has led to a surge of new chemotypes with potent antimalarial activity. High-throughput screens have delivered several thousand new active compounds in several hundred series, including the 4,7-diphenyl-1,4,5,6,7,8-hexahydroquinolines, hereafter termed dihydropyridines (DHPs). We optimized the DHPs for antimalarial activity. Structure-activity relationship studies focusing on the 2-, 3-, 4-, 6-, and 7-positions of the DHP core led to the identification of compounds potent (EC50 < 10 nM) against all strains of P. falciparum tested, including the drug-resistant parasite strains K1, W2, and TM90-C2B. Evaluation of efficacy of several compounds in vivo identified two compounds that reduced parasitemia by >75 % in mice 6 days post-exposure following a single 50 mg/kg oral dose. Resistance acquisition experiments with a selected dihydropyridine led to the identification of a single mutation conveying resistance in the gene encoding for Plasmodium falciparum multi-drug resistance protein 1 (PfMDR1). The same dihydropyridine possessed transmission blocking activity. The DHPs have the potential for the development of novel antimalarial drug candidates.

Indoloquinoline Alkaloids as Antimalarials: Advances, Challenges, and Opportunities.

Malaria infections affect almost half of the world's population, with over 200 million cases reported annually. Cryptolepis sanguinolenta, a plant native to West Africa, has long been used across various regions of Africa for malaria treatment. Chemical analysis has revealed that the plant is abundant in indoloquinolines, which have been shown to possess antimalarial properties. Cryptolepine, neocryptolepine, and isocryptolepine are well-studied indoloquinoline alkaloids known for their potent antimalarial activity. However, their structural rigidity and associated cellular toxicity are major drawbacks for preclinical development. This review focuses on the potential of indoloquinoline alkaloids (cryptolepine, neocryptolepine, and isocryptolepine) as scaffolds in drug discovery. The article delves into their antimalarial effects in vitro and in vivo, as well as their proposed mechanisms of action and structure-activity relationship studies. Several studies aim to improve these leads by reducing cytotoxicity while preserving or enhancing antimalarial activity and gaining insights into their mechanisms of action. These investigations highlight the potential of indoloquinolines as a scaffold for developing new antimalarial drugs.

Porous Organic Polymers for Efficient and Selective SO2 Capture from CO2-rich Flue Gas.

The quest for effective technologies to reduce SO2 pollution is crucial due to its adverse effects on the environment and human health. Markedly, removing a ppm level of SO2 from CO2-containing waste gas is a persistent challenge, and current technologies suffer from low SO2/CO2 selectivity and energy-intensive regeneration processes. Here using the molecular building blocks approach and theoretical calculation, we constructed two porous organic polymers (POPs) encompassing pocket-like structures with exposed imidazole groups, promoting preferential interactions with SO2 from CO2-containing streams. Markedly, the evaluated POPs offer outstanding SO2/CO2 selectivity, high SO2 capacity, and an easy regeneration process, making it one of the best materials for SO2 capture. To gain better structural insights into the notable SO2 selectivity of the POPs, we used dynamic nuclear polarization NMR spectroscopy (DNP) and molecular modelling to probe the interactions between SO2 and POP adsorbents. The newly developed materials are poised to offer an energy-efficient and environment-friendly SO2 separation process while we are obliged to use fossil fuels for our energy needs.

Harnessing the potential of pigeonpea and maize feedstock biochar for carbon sequestration, energy generation, and environmental sustainability.

Crop residues in agriculture pose disposal challenges and contribute to air pollution when burned. This study aims to use pigeonpea and maize stalks to produce biochar at different pyrolysis temperatures. Biochar can serve in carbon sequestration, as a soil amendment, and as an alternative fuel source. Pyrolysis was conducted at 400, 500, and 600 °C to examine the effects on physicochemical properties, fuel, and energy related properties. Increase in temperatures resulted in decrease of biochar yield, volatile matter, and O/C and H/C atomic ratios, while ash content and essential nutrients increased. Yield was observed to be higher in pigeonpea stalks derived biochar compared to maize stalks derived biochar at same pyrolysis temperatures. The yields of pigeonpea stalks derived biochar at 400 °C, 500 °C, and 600 °C are 34, 33 and 29%, respectively, and the yields of maize biomass-derived biochar at 400 °C, 500 °C, and 600 °C are 29, 28, and 26%, respectively. The organic carbon content is found to be higher in the biochar samples prepared at 600 °C, i.e., 10.44%, and 10.39% for pigeonpea and maize-derived biochar, respectively. The essential elements of biochar were increased with an increase in pyrolysis temperature except nitrogen which is conversely related to temperature. The biochar obtained through pyrolysis at 400 °C demonstrated superior characteristics compared to biochar produced at other temperatures. It exhibited a higher biochar yield, with approximately 84.60% for pigeonpea and 64.85% for maize fixed carbon content. Additionally, the energy retention efficiency was higher, reaching 67.33% for pigeonpea and 42.70% for maize-derived biochar at a pyrolysis temperature of 400 °C. The fixed carbon recovery efficiency was also notable at around 200.44% for PPS and 142.37% for maize biochar which is higher compared to biochar produced at other temperatures. Furthermore, the higher heating value (HHV) was approximately 30.75 MJ kg-1 for both the biochars, indicating their suitability as alternative solid fuels. A significant CO2 reduction potential of 84 CO2 eq kg-1 and 55 CO2 eq kg-1 was observed for pigeonpea and maize biochar, respectively. Hence, biochar is a promising and effective option for carbon sequestration, offering environmental benefits.

Major sources of sinking particulate organic matter in the western Bay of Bengal.

Impacts of river discharge on coastal ocean processes are multi-dimensional. Studies on sinking particle fluxes, composition and their seasonal variability in coastal oceans are very limited. In this study, we investigated the impact of river discharge on seasonal variability in sinking fluxes of total mass, biogenic and lithogenic material in a river-dominated continental margin, western coastal Bay of Bengal. Higher POC, lithogenic and total mass fluxes were found during early southwest monsoon, and are decoupled with peak river discharge and elevated primary production. It is attributed to cross-shelf transport of re-suspended surface sediments from shelf region. Peak river discharge followed by elevated chlorophyll-a suggest nutrients supply though river discharge support primary production. Elemental C:N ratios, δ13C and δ15N results likely suggest that both marine and terrestrial sources contributed to sinking POM, . Overall, higher sinking fluxes during southwest monsoon than rest of the year suggest that seasonal river discharge exerts considerable impact on sinking fluxes in the western coastal Bay of Bengal.

In Vitro Antimalarial Activity of Trichothecenes against Liver and Blood Stages of Plasmodium Species.

Trichothecenes (TCNs) are a large group of tricyclic sesquiterpenoid mycotoxins that have intriguing structural features and remarkable biological activities. Herein, we focused on three TCNs (anguidine, verrucarin A, and verrucarol) and their ability to target both the blood and liver stages of Plasmodium species, the parasite responsible for malaria. Anguidine and verrucarin A were found to be highly effective against the blood and liver stages of malaria, while verrucarol had no effect at the highest concentration tested. However, these compounds were also found to be cytotoxic and, thus, not selective, making them unsuitable for drug development. Nonetheless, they could be useful as chemical probes for protein synthesis inhibitors due to their direct impact on parasite synthesis processes.

Impact of Effortful Swallow with Progressive Resistance on Swallow Safety, Efficiency and Quality of Life in Individuals with Post-Stroke Dysphagia: Analysis Using DIGEST- FEES and SWAL-QOL.

Introduction: Effortful swallow with progressive resistance has a potential clinical implication in improving the oro-muscular strength, swallow safety, and efficiency in elderly individuals. But to date, no studies have explored its benefits in training individuals with post-stroke dysphagia. Aim: The present study investigated the long- term effect of effortful swallow with progressive resistance on swallow safety, efficiency and quality of life in persons with dysphagia following stroke. Method: The study consisted of 5 males (mean age: 41.80yrs ± 9.6yrs) diagnosed with dysphagia post-stroke.  The participants underwent 20 sessions (5 days/week) of intensive effortful swallow with progressive training spread across four weeks. In the first two weeks, the participants performed 10 × 3 sets of effortful swallows with a 50% of resistance load, which was further increased to 15 × 3 sets with a 70% resistance load. Results: DIGEST-FEES safety and overall swallow quality of life significantly improved post-therapy, whereas DIGEST-FEES efficiency and overall swallow grades showed no significant changes. Inter-rater reliability of DIGEST-FEES revealed substantial agreement between judges. Conclusion: The results are promising as the technique improved swallow safety, and swallow quality of life in persons with dysphagia following stroke.

Shotgun Kinetic Target-Guided Synthesis Approach Enables the Discovery of Small-Molecule Inhibitors against Pathogenic Free-Living Amoeba Glucokinases.

Pathogenic free-living amoebae (pFLA) can cause life-threatening central nervous system (CNS) infections and warrant the investigation of new chemical agents to combat the rise of infection from these pathogens. Naegleria fowleri glucokinase (NfGlck), a key metabolic enzyme involved in generating glucose-6-phosphate, was previously identified as a potential target due to its limited sequence similarity with human Glck (HsGlck). Herein, we used our previously demonstrated multifragment kinetic target-guided synthesis (KTGS) screening strategy to identify inhibitors against pFLA glucokinases. Unlike the majority of previous KTGS reports, our current study implements a "shotgun" approach, where fragments were not biased by predetermined binding potentials. The study resulted in the identification of 12 inhibitors against 3 pFLA glucokinase enzymes─NfGlck, Balamuthia mandrillaris Glck (BmGlck), and Acanthamoeba castellanii Glck (AcGlck). This work demonstrates the utility of KTGS to identify small-molecule binders for biological targets where resolved X-ray crystal structures are not readily accessible.

Theoretical insight on the optical centred electrical properties of guanidinium isophthalate NLO crystal for electro-optic Q switches.

Guanidinium isophthalate single crystals with dimensions 16 × 4 x 2 mm3 were prepared by the low temperature solvent evaporation method and growth kinetics with interfacial tension was discussed to bring out the growth parameters of guanidinium isophthalate single crystals. The harvested single crystals were utilized for various characterization studies like powder X-ray diffraction, optical transmission, photoluminescence, laser damage study and optical limiting studies. The visualization of varying potential regions on the surfaces to quantify short contacts were generated by Hirshfeld surface analysis. 2D fingerprint plots were analyzed, in which H ….H contact was found to be the most significant with 54.1%. Growth kinetics of the crystalline material was studied to reveal the nucleation process. Crystal samples prepared with reference to the solubility data were found to be free of inclusions and cracks and had maximum transmittance in the complete visible region. The electronic disorder of the crystal sample was reported in the form of Urbach energy. The PL spectra with the emission intensity provide the emission characteristic of the title compound. The major fundamental optical limit for a crystal material is experimentally measured and presented in the picosecond regime. Thus the present work contributes to the understanding of growth, structural, optical and electronic characteristics of the title guanidinium isophthalate single crystals for the fabrication of electro-optic devices in photonic industry.

A Tailored COF for Visible-Light Photosynthesis of 2,3-Dihydrobenzofurans.

Heterogeneous photocatalysis is considered as an ecofriendly and sustainable approach for addressing energy and environmental persisting issues. Recently, heterogeneous photocatalysts based on covalent organic frameworks (COFs) have gained considerable attention due to their remarkable performance and recyclability in photocatalytic organic transformations, offering a prospective alternative to homogeneous photocatalysts based on precious metal/organic dyes. Herein, we report Hex-Aza-COF-3 as a metal-free, visible-light-activated, and reusable heterogeneous photocatalyst for the synthesis of 2,3-dihydrobenzofurans, as a pharmaceutically relevant structural motif, via the selective oxidative [3+2] cycloaddition of phenols with olefins. Moreover, we demonstrate the synthesis of natural products (±)-conocarpan and (±)-pterocarpin via the [3+2] cycloaddition reaction as an important step using Hex-Aza-COF-3 as a heterogeneous photocatalyst. Interestingly, the presence of phenazine and hexaazatriphenylene as rigid heterocyclic units in Hex-Aza-COF-3 strengthens the covalent linkages, enhances the absorption in the visible region, and narrows the energy band, leading to excellent activity, charge transport, stability, and recyclability in photocatalytic reactions, as evident from theoretical calculations and real-time information on ultrafast spectroscopic measurements.

Anti-inflammatory effect of wedelolactone on DSS induced colitis in rats: IL-6/STAT3 signaling pathway.

BACKGROUND: Wedelolactone, main active constituent of Wedelia calendulace and Eclipta alba plants which has been traditionally used to treat various chronic inflammatory conditions. However, its mechanism of action of anti-inflammatory effect on ulcerative colitis is yet to be established. OBJECTIVE: In the present study, the effect of the wedelolactone on the myeloperoxidase activities and in the production of proinflammatory cytokines involved in the pathogenesis of chronic inflammation was assessed. MATERIALS AND METHODS: Wistar rats were randomly divided into four groups containing six animals per group. Group I (Vehicle control): tap water and vehicle; Group II (DSS control): tap water containing 5% (w/v) of DSS over 7 days, and vehicle; Group III (treatment group): Wedelolactone 50 mg/kg/day, and tap water containing 5% DSS over 7 days, Group IV (treatment group): Wedelolactone 100 mg/kg/day and tap water containing 5% DSS over 7 days over the experiment. RESULTS: Study revealed that wedelolactone treatment dramatically decrease the release of IL-1a, IL-1b, IL-2, TNF, INFγ, STAT3 and CCL-5 in colons treated with DSS. In summary, these results suggest that the inhibition of IL-6/STAT3 signaling is a potential mechanism by which wedelolactone is used in the treatment of ulcerative colitis. CONCLUSION: Oral administration of Wedelolactone (100 mg/kg) significantly attenuated pathological colonic damage and inhibited inflammatory infiltration, myeloperoxidase activities. In summary, Wedelolactone showed anti-inflammatory effect by down regulation of the IL-6/STAT3 inflammatory signaling pathway. These findings provide new insights into the pharmacological actions of wedelolactone as a potential therapeutic agent for colitis.

Use of diamond sensors for a high-flux, high-rate X-ray pass-through diagnostic.

X-ray free-electron lasers (XFELs) deliver pulses of coherent X-rays on the femtosecond time scale, with potentially high repetition rates. While XFELs provide high peak intensities, both the intensity and the centroid of the beam fluctuate strongly on a pulse-to-pulse basis, motivating high-rate beam diagnostics that operate over a large dynamic range. The fast drift velocity, low X-ray absorption and high radiation tolerance properties of chemical vapour deposition diamonds make these crystals a promising candidate material for developing a fast (multi-GHz) pass-through diagnostic for the next generation of XFELs. A new approach to the design of a diamond sensor signal path is presented, along with associated characterization studies performed in the XPP endstation of the LINAC Coherent Light Source (LCLS) at SLAC. Qualitative charge collection profiles (collected charge versus time) are presented and compared with those from a commercially available detector. Quantitative results on the charge collection efficiency and signal collection times are presented over a range of approximately four orders of magnitude in the generated electron-hole plasma density.

Structure-activity and structure-property relationship studies of spirocyclic chromanes with antimalarial activity.

Malaria is a prevalent and lethal disease. The fast emergence and spread of resistance to current therapies is a major concern and the development of a novel line of therapy that could overcome, the problem of drug resistance, is imperative. Screening of a set of compounds with drug/natural product-based sub-structural motifs led to the identification of spirocyclic chroman-4-one 1 with promising antimalarial activity against the chloroquine-resistant Dd2 and chloroquine-sensitive 3D7 strains of the parasite. Extensive structure-activity and structure-property relationship studies were conducted to identify the essential features necessary for its activity and properties.

Total synthesis of (±)-decursivine via BINOL-phosphoric acid catalyzed tandem oxidative cyclization.

The synthesis of tetracyclic indole alkaloid (±)-decursivine was accomplished using BINOL-phosphoric acid catalyzed tandem oxidative cyclization as a key step with (bis(trifluoroacetoxy)iodo)benzene (PIFA) as an oxidizing agent. This represents one of the shortest and highest yielding routes for the synthesis of (±)-decursivine from readily available starting materials.

Aminoalkoxycarbonyloxymethyl Ether Prodrugs with a pH-Triggered Release Mechanism: A Case Study Improving the Solubility, Bioavailability, and Efficacy of Antimalarial 4(1H)-Quinolones with Single Dose Cures.

Preclinical and clinical development of numerous small molecules is prevented by their poor aqueous solubility, limited absorption, and oral bioavailability. Herein, we disclose a general prodrug approach that converts promising lead compounds into aminoalkoxycarbonyloxymethyl (amino AOCOM) ether-substituted analogues that display significantly improved aqueous solubility and enhanced oral bioavailability, restoring key requirements typical for drug candidate profiles. The prodrug is completely independent of biotransformations and animal-independent because it becomes an active compound via a pH-triggered intramolecular cyclization-elimination reaction. As a proof-of-concept, the utility of this novel amino AOCOM ether prodrug approach was demonstrated on an antimalarial compound series representing a variety of antimalarial 4(1H)-quinolones, which entered and failed preclinical development over the last decade. With the amino AOCOM ether prodrug moiety, the 3-aryl-4(1H)-quinolone preclinical candidate was shown to provide single-dose cures in a rodent malaria model at an oral dose of 3 mg/kg, without the use of an advanced formulation technique.

Distal Transradial Access for Diagnostic Cerebral Angiography and Neurointervention: Systematic Review and Meta-analysis.

BACKGROUND: Radial artery access for cerebral angiography is traditionally performed in the wrist. Distal transradial access in the anatomic snuffbox is an alternative with several advantages. PURPOSE: Our aim was to review the safety and efficacy of distal transradial access for diagnostic cerebral angiography and neurointerventions. DATA SOURCES: We performed a comprehensive search of the literature using PubMed, Scopus, and EMBASE. STUDY SELECTION: The study included all case series of at least 10 patients describing outcomes associated with distal transradial access for diagnostic cerebral angiography or a neurointervention. DATA ANALYSIS: Random-effects models were used to obtain pooled rates of procedural success and complications. DATA SYNTHESIS: A total of 7 studies comprising 348 (75.8%) diagnostic cerebral angiograms and 111 (24.2%) interventions met the inclusion criteria. The pooled success rate was 95% (95% CI, 91%-98%; I2 = 74.33). The pooled minor complication rate was 2% (95% CI, 1%-4%; I2 = 0. No major complications were reported. For diagnostic procedures, the combined mean fluoroscopy time was 13.53 [SD, 8.82] minutes and the mean contrast dose was 74.9 [SD, 35.6] mL. LIMITATIONS: A small number of studies met the inclusion criteria, all of them were retrospective, and none compared outcomes with proximal transradial or femoral access. CONCLUSIONS: Early experience with distal transradial access suggests that it is a safe and effective alternative to proximal radial and femoral access for performing diagnostic cerebral angiography and interventions. Additional studies are needed to establish its efficacy and compare it with other access sites.

Characterization of community-wide transmission of SARS-CoV-2 in congregate living settings and local public health-coordinated response during the initial phase of the COVID-19 pandemic.

BACKGROUND: Clusters of COVID-19 cases amplify the pandemic and are critical targets for intervention, but comprehensive cluster-level data are not collected systematically by federal or most state public health entities. This analysis characterizes COVID-19 clusters among vulnerable populations housed in congregate living settings across an entire community and describes early mitigation efforts. METHODS: The Cuyahoga County Board of Health identified and interviewed COVID-19 cases and exposed contacts, assessing possible connections to congregate living facilities within its jurisdiction from March 7, 2020, to May 15, 2020, during the first phase of the pandemic, while state of Ohio stay-at-home orders were in effect. A multi-disciplinary team-based response network was mobilized to support active case finding and develop facility-focused containment strategies. RESULTS: We identified a cascade of 45 COVID-19 clusters across community facilities (corrections, nursing, assisted living, intermediate care, extended treatment, shelters, group homes). Attack rates were highest within small facilities (P < .01) and large facilities requiring extensive support to implement effective containment measures. For 25 clusters, we identified an index case who frequently (88%) was a healthcare worker. Engagement of clinical, community, and government partners through public health coordination efforts created opportunities to rapidly develop and coordinate effective response strategies to support the facilities facing the dawning impact of the pandemic. CONCLUSIONS: Active cluster investigations can uncover the dynamics of community transmission affecting both residents of congregate settings and their caregivers and help to target efforts toward populations with ongoing challenges in access to detection and control resources.

Pharmacokinetic and pharmacodynamic evaluation of Solid self-nanoemulsifying delivery system (SSNEDDS) loaded with curcumin and duloxetine in attenuation of neuropathic pain in rats.

The present investigation is focused on improving oral bioavailability of poorly soluble and lipophilic drugs, curcumin (CRM) and duloxetine (DXH), through the solid self-nanoemulsifying drug delivery system (S-SNEDDS) and identifying their potential against attenuation of NP in chronic constriction injury (CCI)-induced rats through the solid self-nanoemulsifying drug delivery system (S-SNEDDS). The optimized batch of S-SNEDDS reported was containing CRM and DXH (30 mg each), castor oil (20% w/w), tween-80 (40% w/w), transcutol-P (40% w/w), and syloid 244 FP (1 g). The high dose of each of naïve CRM (NCH), naïve DXH (NDH), physical mixture of DXH and CRM (C-NCM-DXH), S-SNEDDS-CRM (SCH), S-SNEDDS-DXH (SDH), and S-SNEDDS-CRM-DXH (C-SCH-SDH) was subjected for MTT assay. The developed formulations were subjected to pharmacokinetic studies and results showed about 8 to 11.06 and 2-fold improvement in oral bioavailability of CRM and DXH through S-SNEDDS. Furthermore, CCI-induced male Wistar rats were treated with SSNEDDS containing CRM and DXH, S-SNEDDS containing individual drug, individual naïve forms, and their combination from the day of surgery for 14 days and evaluated for behavioral at pre-determined time intervals. On the terminal day, animals were sacrificed to assess tissue myeloperoxidase, superoxide anion, protein, tumor necrosis factor-α, total calcium levels, and histopathological changes. Pronounced effect was observed in rats treated with S-SNEDDS containing both drugs with respect to rats receiving any of other treatments owing to enhanced oral bioavailability through S-SNEDDS. Therefore, it can be concluded that S-SNEDDS of both drugs and their coadministration can accelerate the prevention of NP.

Benthic foraminifera as potential ecological proxies for environmental monitoring in coastal regions: A study on the Beypore estuary, Southwest coast of India.

The benthic foraminiferal diversity index was computed from Beypore estuary sediments. The abundance and diversity of Quinqueloculina lata, Textularia agglutinans, Haplophagmoides canariensis, and Quinqueloculina stelligera were dominated by stress-tolerant taxa such as Ammonia tepida, A.parkinsoniana, Nonion grateloupi, and N. scaphum in the estuary. The small-size foraminifera probably perished in a juvenile stage because of the high temperature and low salinity that prevailed in the ecosystem. The dominance of stress tolerant benthic foraminifera and absence of Elphidium species in the estuary suggest the prevalence of hypoxic (low-oxygen) conditions. The consistent low-diversity index of foraminifera indicates that the ecosystem is moderate to highly stressed ecologically in the Beypore estuary. The application of benthic foraminifera as a bioindicator for assessing the environmental stress in the Beypore estuary is key in monitoring these fragile coastal ecosystems.