Early Release Science of the exoplanet WASP-39b with JWST NIRSpec PRISM.

Transmission spectroscopy1-3 of exoplanets has revealed signatures of water vapour, aerosols and alkali metals in a few dozen exoplanet atmospheres4,5. However, these previous inferences with the Hubble and Spitzer Space Telescopes were hindered by the observations' relatively narrow wavelength range and spectral resolving power, which precluded the unambiguous identification of other chemical species-in particular the primary carbon-bearing molecules6,7. Here we report a broad-wavelength 0.5-5.5 µm atmospheric transmission spectrum of WASP-39b8, a 1,200 K, roughly Saturn-mass, Jupiter-radius exoplanet, measured with the JWST NIRSpec's PRISM mode9 as part of the JWST Transiting Exoplanet Community Early Release Science Team Program10-12. We robustly detect several chemical species at high significance, including Na (19σ), H2O (33σ), CO2 (28σ) and CO (7σ). The non-detection of CH4, combined with a strong CO2 feature, favours atmospheric models with a super-solar atmospheric metallicity. An unanticipated absorption feature at 4 µm is best explained by SO2 (2.7σ), which could be a tracer of atmospheric photochemistry. These observations demonstrate JWST's sensitivity to a rich diversity of exoplanet compositions and chemical processes.

The Importance of Social Determinants of Health for Cancer Patients in the Era of COVID-19.

The COVID-19 pandemic has proven to be a challenge for public health professionals, researchers, clinicians, and patients. One group that has experienced significant difficulties during this time is cancer patients. Data regarding this vulnerable population is scarce, despite novel information about vaccine efficacy, therapeutics, mutations, and comorbidities. In this article, we discuss the need for a greater study of social determinants of health (SDOH) for cancer patients in the context of the COVID-19 pandemic. The effects of SDOH on population health are generally well-understood, but their effects on cancer patients are poorly understood. We further pose questions that may be starting points for the investigation of SDOH in cancer patients during this time. Using SDOH as a tool for more effective clinical care will promote the development of targeted interventions to study and improve outcomes in this population.

Concurrent Nephrotoxicity and Neurotoxicity Induced by Oral Valacyclovir in a Patient With Previously Normal Kidney Function.

Drug-induced nephrotoxicity and neurotoxicity are commonly encountered problems in clinical practice. We describe a case of concurrent valacyclovir-induced nephrotoxicity and neurotoxicity in a 64-year-old man with no history of renal disease who developed acute renal injury and neurological symptoms after he received two weeks of the standard dose of oral valacyclovir for herpes zoster meningitis. His clinical condition improved significantly after the initiation of hemodialysis. Although nephrotoxicity due to intravenous infusion of valacyclovir and/or acyclovir is not uncommon, oral valacyclovir therapy is rarely associated with nephrotoxicity in patients with no history of renal insufficiency. Additionally, concurrent nephrotoxicity and neurotoxicity due to valacyclovir and/or acyclovir are rarely reported. Clinicians should be aware of these adverse events as immediate recognition and intervention are necessary to prevent morbidity.

Social Determinants of Health in Oncology: Towards a More Personalized and Equitable Delivery of Cancer Care.

Social determinants of health (SDOH) are defined as the set of modifiable social and physical risk factors that affect health. It is known that SDOH directly influence the population's overall health, but their effects on patients with cancer are considerably less elucidated. Here, we review the literature describing the effects of SDOH outlined by the Healthy People 2020 framework on patients diagnosed with cancer. We have found that while some SDOH are well-defined in cancer patients, evidence surrounding several variables is scarce. In addition, we have found that many SDOH are associated with disparities at the screening stage, indicating that upstream interventions are necessary before addressing the clinical outcomes themselves. Further investigation is warranted to understand how SDOH affect screenings and outcomes in multiple disciplines of oncology and types of cancers as well as explore how SDOH affect the treatments sought by these vulnerable patients.

State-of-the-Art Data Management: Improving the Reproducibility, Consistency, and Traceability of Structural Biology and in Vitro Biochemical Experiments.

Efficient and comprehensive data management is an indispensable component of modern scientific research and requires effective tools for all but the most trivial experiments. The LabDB system developed and used in our laboratory was originally designed to track the progress of a structure determination pipeline in several large National Institutes of Health (NIH) projects. While initially designed for structural biology experiments, its modular nature makes it easily applied in laboratories of various sizes in many experimental fields. Over many years, LabDB has transformed into a sophisticated system integrating a range of biochemical, biophysical, and crystallographic experimental data, which harvests data both directly from laboratory instruments and through human input via a web interface. The core module of the system handles many types of universal laboratory management data, such as laboratory personnel, chemical inventories, storage locations, and custom stock solutions. LabDB also tracks various biochemical experiments, including spectrophotometric and fluorescent assays, thermal shift assays, isothermal titration calorimetry experiments, and more. LabDB has been used to manage data for experiments that resulted in over 1200 deposits to the Protein Data Bank (PDB); the system is currently used by the Center for Structural Genomics of Infectious Diseases (CSGID) and several large laboratories. This chapter also provides examples of data mining analyses and warnings about incomplete and inconsistent experimental data. These features, together with its capabilities for detailed tracking, analysis, and auditing of experimental data, make the described system uniquely suited to inspect potential sources of irreproducibility in life sciences research.

Efficacy of Ibrexafungerp (SCY-078) against Candida auris in an In Vivo Guinea Pig Cutaneous Infection Model.

Candida auris has been shown to have a high risk of skin colonization in hospitalized patients, possibly contributing to nosocomial spread. In a guinea pig skin model, animals were evaluated for clinical appearance, tissue fungal burden, histology, and pharmacokinetics. Oral dosing with 10 mg/kg ibrexafungerp (IBX) reduced the severity of lesions and significantly reduced the C. auris fungal burden in infected animals compared with untreated controls. This indicates promise for use of IBX in controlling skin infection and colonization of hospitalized patients.

Albumin-Based Transport of Nonsteroidal Anti-Inflammatory Drugs in Mammalian Blood Plasma.

Every day, hundreds of millions of people worldwide take nonsteroidal anti-inflammatory drugs (NSAIDs), often in conjunction with multiple other medications. In the bloodstream, NSAIDs are mostly bound to serum albumin (SA). We report the crystal structures of equine serum albumin complexed with four NSAIDs (ibuprofen, ketoprofen, etodolac, and nabumetone) and the active metabolite of nabumetone (6-methoxy-2-naphthylacetic acid, 6-MNA). These compounds bind to seven drug-binding sites on SA. These sites are generally well-conserved between equine and human SAs, but ibuprofen binds to both SAs in two drug-binding sites, only one of which is common. We also compare the binding of ketoprofen by equine SA to binding of it by bovine and leporine SAs. Our comparative analysis of known SA complexes with FDA-approved drugs clearly shows that multiple medications compete for the same binding sites, indicating possibilities for undesirable physiological effects caused by drug-drug displacement or competition with common metabolites. We discuss the consequences of NSAID binding to SA in a broader scientific and medical context, particularly regarding achieving desired therapeutic effects based on an individual's drug regimen.

Molstack: A platform for interactive presentations of electron density and cryo-EM maps and their interpretations.

In the Special Issue on Tools for Protein Science in 2018, we presented Molstack: a concept of a cloud-based platform for sharing electron density maps and their interpretations. Molstack is a web platform that allows the interactive visualization of density maps through the simultaneous presentation of multiple datasets and models in a way that allows for easy pairwise comparison. We anticipated that the users of this conceptually simple platform would find many different uses for their projects, and we were not mistaken. We have observed researchers use Molstack to present experimental evidence for their models in the form of electron density maps, omit maps, and anomalous difference density maps. Users also employed Molstack to present alternative interpretations of densities, including rerefinements and speculative interpretations. While we anticipated these types of projects to be the main use cases, we were pleased to see Molstack used to display superpositions of different models, as a tool for story-driven presentations, and for collaboration as well. Here, we present developments in the platform that were driven by user feedback, highlight several cases that used Molstack to enhance the publication, and discuss possible directions for the platform.

Activity of a novel 1,3-beta-D-glucan Synthase Inhibitor, Ibrexafungerp (formerly SCY-078), Against Candida glabrata.

Ibrexafungerp (formerly SCY-078), a novel glucan synthase inhibitor with oral availability, was evaluated for activity against Candida glabrata Susceptibility of clinical strains to Ibrexafungerp was determined by microdilution and time kill assays. The MIC range against wild type strains was 1-2 µg/mL. IBX was also active against the majority of echinocandin-resistant strains. Time kill studies showed a 4 to 6-log reduction in growth at concentrations of 0.25 to 4 µg/ml at 24 and 48 hr.

A Novel 1,3-Beta-d-Glucan Inhibitor, Ibrexafungerp (Formerly SCY-078), Shows Potent Activity in the Lower pH Environment of Vulvovaginitis.

Ibrexafungerp (IBX) (formerly SCY-078) is a novel glucan synthase inhibitor whose oral availability is being evaluated for efficacy against vulvovaginal candidiasis (VVC). Bioavailability and in vitro activity are important efficacy indicators, but accepted susceptibility methods do not always accurately predict activity in an acidic environment, such as the vagina. Studies were 3-fold, as follows: (i) pharmacokinetic study following oral administration in a murine model; (ii) susceptibility testing of isolates from a phase 2 VVC clinical trial by CLSI M27-A4 methodology; and (iii) susceptibility testing of Candida albicans and Candida glabrata isolates obtained from this trial group in RPMI 1640 adjusted to 3 different pH values, 7.0, 5.72, and 4.5, compared to susceptibility testing for micafungin and fluconazole. IBX readily accumulated in vaginal tissues and secretions following oral administration. Potent in vitro activity was demonstrated against Candida strains obtained at baseline and end of study visits. Moreover, the geometric mean (GM) values for IBX at pH 4.5 were dramatically lower than those at pH 7.0 and 5.72. The MIC90 values of micafungin remained the same regardless of pH value, while those of fluconazole tended to increase with lower pH values. IBX is able to reach target tissues following oral administration at pharmacologically meaningful levels. IBX demonstrated potent in vitro activity, with no development of resistance, following repeated exposure over the course of the clinical trial. Importantly, activity of IBX in an acidic medium suggests a therapeutic advantage of this novel antifungal in the treatment of vaginal Candida infections.

Testosterone meets albumin - the molecular mechanism of sex hormone transport by serum albumins.

Serum albumin is the most abundant protein in mammalian blood plasma and is responsible for the transport of metals, drugs, and various metabolites, including hormones. We report the first albumin structure in complex with testosterone, the primary male sex hormone. Testosterone is bound in two sites, neither of which overlaps with the previously suggested Sudlow site I. We determined the binding constant of testosterone to equine and human albumins by two different methods: tryptophan fluorescence quenching and ultrafast affinity extraction. The binding studies and similarities between residues comprising the binding sites on serum albumins suggest that testosterone binds to the same sites on both proteins. Our comparative analysis of albumin complexes with hormones, drugs, and other biologically relevant compounds strongly suggests interference between a number of compounds present in blood and testosterone transport by serum albumin. We discuss a possible link between our findings and some phenomena observed in human patients, such as low testosterone levels in diabetic patients.

Evaluation of the Antifungal Activity of the Novel Oral Glucan Synthase Inhibitor SCY-078, Singly and in Combination, for the Treatment of Invasive Aspergillosis.

Invasive aspergillosis remains a major cause of death among the immunocompromised population and those receiving long-term immunosuppressive therapy. In light of increased azole resistance, variable outcomes with existing echinocandin monotherapy and combination therapy, and persistent high mortality rates, new antifungal agents for the treatment of invasive aspergillosis are clearly needed. SCY-078 is the first-in-class triterpenoid antifungal, a novel class of glucan synthase inhibitors with broad in vitro and in vivo activity against a broad spectrum of Candida and Aspergillus species. In vitro testing of clinical strains of Aspergillus fumigatus and non-fumigatus Aspergillus strains showed that SCY-078 had potent fungistatic activity (minimum effective concentration for 90% of strains tested = 0.125 µg/ml) compared with the activities of amphotericin B (MIC90 = 8 µg/ml) and voriconazole (MIC90 = 2 µg/ml). Testing of SCY-078 in combination with isavuconazole or voriconazole demonstrated synergistic activity against the majority of the azole-susceptible strains tested, and SCY-078 in combination with amphotericin B was synergistic against the azole-susceptible strains, as well as one known resistant cyp51A mutant. SCY-078 may be an important additional antifungal for first-line or salvage monotherapy or combination treatment of invasive aspergillosis.

Does proteinura in preeclampsia have enough value to predict pregnancy outcome?

OBJECTIVE: Preeclampsia is defined by the new onset of elevated blood pressure and protienuria after 20 weeks of gestation. Protienuria is one of the essential criteria for the clinical definition of preeclampsia. The authors investigated the predictive value of proteinuria in the outcome of pregnancies with preeclampsia. MATERIALS AND METHODS: In this retrospective cohort study, they entered all pregnant women who were admitted with diagnosis of preeclampsia in Yahyanejad Hospital from 1998 to 2008. Patients' data such as age, gestational age, level of 24-hour urine protein, liver enzyme, blood urea nitrogen (BUN), creatinine, and other laboratory test. Also, prenatal and maternal outcome were studied. The data analyzed and compare with each other. RESULTS: Out of 289 patients, 5.9% (17) women had placental abruption, 13.1% (28) patients had intrauterine growth retardation (IUGR), 32.2% (96) had respiratory distress, and 26.6% (77) of the patients' infants were transferred to neonatal intensive care unit (NICU). Although the present study showed proteinurea cannot be a sufficient predictor for adverse consequences of preeclampsia, however, the incidence of pregnancy adverse effects increased in the patients with elevated 24-hour proteinuria. CONCLUSION: The authors concluded that proteinuria in patients with preeclampsia is associated with adverse outcome in pregnancy, although it is not an adequate predictor.

Does vaginal pH affect the efficacy of dinoprostone in cervical ripening/labor duration?

BACKGROUND: Prostaglandins are effective in the ripening of the cervix and facilitating labor induction. Vaginal pH is probably an important factor in the effectiveness of vaginal prostaglandins. The aim of this study was to evaluate the effect of vaginal pH on the function of prostaglandin vaginal tablet during labor. METHODS: This is a double-blinded clinical trial study of 147 pregnant primigravid trated in the Yahyanejad Hospital of Babol (Iran) from January 2006 to December 2007. Initial pH was measured during vaginal examination with nitrazin paper and the Bishop score was determined. All women received vaginal dinoprostone inserted in the posterior fornix of the vagina for cervical ripening and the second dose was administered if the uterine contractions were inadequate. Reassessment of the Bishop score after 12 hours, duration of latent and active phases, and also the duration of the second stage of labor were compared between the two groups with low or high vaginal pH. RESULTS: The incidence of Cesarean section was lower in women with high vaginal pH but was not statistically significant. The Bishop score after 12 hours, latent phase, and second stage durations were not different in the two groups of high or low vaginal pH, but active phase duration in patients with high pH was significantly shorter than those with low pH (p = 0.019). CONCLUSION: High vaginal pH influences the function of prostaglandin tablet as a reduction in duration of the active phase of labor.

Application of sensory and microbial analysis to assess quality of fish in Siliguri city of West Bengal, India.

Sensory and certain microbial analyses were applied to assess the quality of raw fish sold at a market in Siliguri cityof West Bengal, India. In regular surveys undertaken during June to August 2008, a particular fish species was randomly selected, its source was noted and a sensory analysis, the quality index method (QIM) was applied to assess its quality Raw fish samples were also collected and a small quantity (about 1 g) of scales oran upper layer of the skin surface (forscale-less fish samples), gill, liverand a portion of gut with gut-contents were aseptically removed for enumeration of the total aerobic heterotrophic bacteria, Aeromonas spp., Pseudomonas spp., Salmonella spp. and coliform counts. Oreochromis mossambicus and Tenulosa ilisha recorded significantly higher QIM scores, compared to other species (p<0.05). Riverine fish, Lepidocephalichthys guntea and Channa punctatus scored the lowest QIM scores (0) while scores for Puntius ticto and Mystus vittatus and pond cultured species like Cirrhinus mrigala, Catla catla, Labeo rohita, Labeo bata and Cyprinus carpio were very marginal (p<0.05). Aeromonas spp., Salmonella spp. and total coliforms were recorded from all the studied species while Pseudomonas spp. was isolated from only seven species. Among the tissues examined, the lowest counts of total heterotrophic bacteria, Aeromonas spp., Pseudomonas spp., Salmonella spp. and total coliforms were recorded from the skin in every fish species. Highest counts of pathogenic bacteria (except Pseudomonas spp.) were recorded in Tenulosa ilisha for all the tissues except liver. Since fish are properly cooked in Bengali households, the risk of disease from fish consumption is relatively less. However, some tribes residing in the region are known to consume undercooked fish and proper cooking methods should be followed in view of the present findings to avoid health risks. Besides, utmost care should be taken while handling fish.

Kinetics and rat locomotor activity following cocaine and lidocaine administration.

Cocaine abuse is a widespread problem in the USA. Illicit cocaine is usually never found in pure form but is adulterated with other agents, among which are the local anesthetics such as lidocaine. Adulteration of cocaine with another active agent allows the potential for various drug-drug interactions to occur. The presence of an additional active agent in illicit cocaine samples can complicate the pharmacological and toxicological responses elicited and possibly the mode of emergency medical care thereafter. When studying drug interactions, both the kinetic and dynamic aspects of each agent must be considered. This study investigated the plasma time course and tissue distribution of cocaine and lidocaine alone and in combination following a 5 mg kg(-1) intravenous injection in rats. The plasma time course of cocaine and lidocaine in combination did not differ from that seen when each drug was alone. Tissue contents were without change when administered alone or in combination at 5, 10 and 15 min following treatment. However, rats treated with cocaine and lidocaine in combination had significantly greater locomotor activity initially than animals treated with cocaine alone. The results suggest that cocaine and lidocaine interact on a pharmacodynamic basis without a change in the drug level of each agent.

Decreased cocaine- and lidocaine-induced seizure response by dextromethorphan and DNQX in rat.

The present study investigated the effect of dextromethorphan and 6,7-dinitroquinoxaline-2,3-dione (DNQX) pre-treatment on the development of cocaine- and lidocaine-induced seizures. The dopaminergic action of cocaine was also studied. The NMDA antagonist dextromethorphan and the non-NMDA (AMPA/kainate) antagonist DNQX both significantly decreased the intensity of the seizure response to intravenous convulsant doses of cocaine and lidocaine individually (20 mg/kg) and in combination (5 mg/kg each). The incidence of seizures in rats receiving cocaine or lidocaine individually was significantly reduced by pre-treatment with dextromethorphan but not DNQX. Haloperidol did not have an effect on the incidence or intensity of seizures induced by cocaine or lidocaine, alone or in combination. The results suggest that local anesthetic-induced convulsive seizures are mediated by excitatory glutamate transmission through both NMDA and non-NMDA receptor systems.

Cocaine and lidocaine in combination are synergistic convulsants.

The abuse of cocaine has dramatically increased in the recent decade. Cocaine obtained on the illegal market is rarely found in pure form. Most often it is adulterated with various substances, especially other local anesthetics. Lidocaine is one of the most common local anesthetics employed for adulteration of illicit cocaine. Toxicity due to the simultaneous ingestion of cocaine and lidocaine has been reported. Acute toxicity to cocaine and other local anesthetics is manifested in central nervous system aberrations, such as seizures and convulsions. This study investigated the convulsant potency of cocaine and lidocaine alone and in combination. Rats were administered intravenous injections of 5 mg/kg or 20 mg/kg of cocaine or lidocaine alone and in combination in equal proportion. Seizure activity and intensity were evaluated. The plasma concentration and brain content of each agent was also determined at the time of toxicity. The administration of 5 mg/kg of each drug alone did not yield seizure activity. However, the concomitant administration of 5 mg/kg of both cocaine and lidocaine produced a seizure response nearly equal to that produced after administration of 20 mg/kg of cocaine alone. Diazepam pre-treatment successfully antagonized the seizures induced by cocaine and lidocaine and raised the seizure threshold dose for the combination treatment by approximately four fold. The results suggest that cocaine and lidocaine interact synergistically to increase seizure activity and that the nature of this response occurs in part through a depression of inhibitory neuronal transmission.