Can an Intermediate Rate of Nitrogen Inversion Affect Drug Efficacy?

Nitrogen-inversion rates and diffusion coefficients were measured using 1H NMR for 14 drug-like molecules. The slow nitrogen-inversion rates interconverting the enantiomers of these molecules lay within a postulated intermediate range in terms of their ability to bind to proteins bounded by diffusion constraints, potentially affecting the availability, hence efficacy, of these compounds if they were utilized as drugs. The postulated intermediate range is based on a capture-volume concept, whereby the nitrogen inversion during the time a ligand takes to pass through a volume surrounding the protein binding site, as calculated by the diffusion rate, determines if it will influence ligand binding to the protein. In the systems examined here, the measured nitrogen-inversion rates and the times required to traverse the capture volume differed by a few orders of magnitude. Potentially more consequential are intermediate nitrogen-inversion rates in epimeric cases—since the energies of the interconverting species are unequal, a heavy bias against the eutomer might occur. The implications of an intermediate nitrogen-inversion rate are significant for in silico drug design, drug efficacy, molecular modeling of drug–protein binding, pharmacokinetics, drug enantiomer evaluation, etc. Due consideration of the process should thus be taken into account for drug development directions and in vitro evaluation.

Comparison of Monthly IMERG Precipitation Estimates with PACRAIN Atoll Observations

Satellite-based precipitation estimates provide valuable information where surface observations are not readily available, especially over the large expanses of the ocean where in-situ precipitation observations are very sparse. This study compares monthly precipitation estimates from the Integrated Multi-satellitE Retrievals for GPM (IMERG) with gauge observations from 37 low-lying atolls from the Pacific Rainfall Database for the period June 2000 – August 2020. Over the analysis period, IMERG estimates are slightly higher than the atoll observations by 0.67% with a monthly correlation of 0.68. Seasonally, DJF shows excellent agreement with a near-zero bias, while MAM shows IMERG is low by 4.6%, and JJA is high by 1.2%. SON exhibits the worst performance, with IMERG overestimating by 6.5% compared to the atolls. The seasonal correlations are well-contained in the range 0.67 – 0.72, with the exception of SON at 0.62. Furthermore, SON has the highest RMSE at 4.70 mm/day, making it the worst season for all metrics. Scatterplots of IMERG versus atolls show IMERG, on average, is generally low for light precipitation accumulations and high for intense precipitation accumulations, with best agreement at intermediate rates. Seasonal variations exist at light and intermediate rate accumulations, but IMERG consistently overestimates at intense precipitation rates. The differences between IMERG and atolls varies over time but does not exhibit any discernable trend or dependence on atoll population. The PACRAIN atoll gauges are not wind-loss corrected, so application of an appropriate adjustment would increase the precipitation amounts compared to IMERG. These results provide useful insight to users as well as valuable information for future improvements to IMERG.

A new and rapid micropropagation protocol for Eucalyptus grandis Hill ex Maiden

Aim of the study: We developed a faster micropropagation protocol specifically designed for Eucalyptus grandis. Eucalyptus breeding programs use micropropagation protocols to obtain high quality cloned seedlings, but current protocols are excessively time consuming.Area of the study: The protocol has been developed in Argentina, but it can be applied in anywhere.Materials and methods: We used nodal segments as initial explants to obtain micropropagated shoots, which were then simultaneously rooted ex vitro and acclimated in a hydroponic system. Nodal segments were cultured in a MS medium supplemented with 1 mg l-1 6-benzylaminopurine, 30 g l-1 sucrose, 1 g l-1 active charcoal and 8 g l-1 agar and incubated for four weeks at 25 ± 2°C under 16 h day photoperiod. Then, micropropagated shoots were exposed 15 seconds to 5000 ppm indol-butyric acid prior to being transferred to a hydroponic system, allowing simultaneous ex vitro rooting and acclimatization.Main results: 73 ± 9% of nodal segments grew to generate 1.73 ± 1.03 shoots per explant (length: 0.76 ± 0.44 cm). After four weeks in hydroponic system, 46 ± 4 % of micropropagated shoots developed roots, which represents an acceptable and intermediate rate of success, compared to the reported in vitro rooting rates.Research highlights: Our protocol allowed to obtain micropropagated seedlings in a total timespan of 8 weeks. Our results show that, by utilizing a hydroponic system, traditional protocols to micropropagate Eucalyptus can be substantially enhanced, allowing for improved production dynamics and potentially resulting in better organized seedling manufacturing facilities.Keywords: Woody plants; silviculture; nursery seedlings; rooting methods; hydroponics; acclimatization.

CO2 Permeability of Rat Hepatocytes and Relation of CO2 Permeability to CO2 Production

Background/Aims: It has been described that cells in culture with very low oxidative metabolism possess a low CO2 membrane permeability, PCO2, of ∼ 0.01 cm/s. On the other hand, cardiomyocytes and mitochondria with extremely high rates of O2 consumption exhibit very high CO2 membrane permeabilities of 0.1 and 0.3 cm/s, repectively. To ascertain that this represents a systematic relationship, we determine here PCO2 of hepatocytes, which exhibit an intermediate rate of O2 consumption. Methods: We isolated intact hepatocytes with vitalities of ∼ 70% from rat liver and measured their CO2 permeability by the previously published mass spectrometric 18O exchange technique. Results: We find a PCO2 of hepatocytes of 0.03 cm/s in the presence of FC5-208A and verapamil. FC5-208A was necessary to inhibt extracellular carbonic anhydrase, and verapamil was necessary to inhibit intracellular uptake of FC5-208A by the organic cation transporter OCT1 of hepatocytes. Conclusion: Rat hepatocytes with their intermediate rate of oxygen consumption also possess an intermediate CO2 permeability. From pairs of data for five types of cells/organelles, we find an excellent positive linear correlation between PCO2 and metabolic rate, suggesting an adaptation of PCO2 to the rate of O2 consumption.

Cause for pause before leaping to conclusions about stepping

Many neurons in parietal and prefrontal association cortex undergo gradual changes in firing rate during the formation of some perceptual decisions. These dynamics are often ramp-like increases or decreases depending on the sign and strength of the sensory evidence and are thus hypothesized to represent the accumulation of noisy samples of evidence, analogous to biased diffusion. This idea was challenged recently. An analysis of sequences of action potentials recorded from neurons in the lateral intraparietal cortex (area LIP) suggests that the spikes on single trials are explained by rates that undergo a discrete step from an intermediate rate to either a low or high rate at a random time during deliberation. The average of such steps, like the average of biased diffusion, is consistent with the ramp-like firing rates observed in LIP, but a Bayesian model comparison deemed stepping superior. Here we show that a shortcoming in the mathematical depiction of drift-diffusion led to a severe bias in the model comparison. We conclude that at present there is no compelling evidence that favors the stepping account.

Durable thrombosis in a rat model of arteriovenous malformation treated with radiosurgery and vascular targeting

Object Radiosurgical treatment of brain arteriovenous malformations (AVMs) has the significant shortcomings of being limited to lesions smaller than 3 cm in diameter and of a latency-to-cure time of up to 3 years. A possible method of overcoming these limitations is stimulation of thrombosis by using vascular targeting. Using an animal model of AVM, the authors examined the durability of the thrombosis induced by the vascular-targeting agents lipopolysaccharide and soluble tissue factor conjugate (LPS/sTF). Methods Stereotactic radiosurgery or sham radiation was administered to 32 male Sprague-Dawley rats serving as an animal model of AVM; 24 hours after this intervention, the rats received an intravenous injection of LPS/sTF or normal saline. The animals were killed at 1, 7, 30, or 90 days after treatment. Immediately beforehand, angiography was performed, and model AVM tissue was harvested for histological analysis to assess rates of vessel thrombosis. Results Among rats that received radiosurgery and LPS/sTF, induced thrombosis occurred in 58% of small AVM vessels; among those that received radiosurgery and saline, thrombosis occurred in 12% of small AVM vessels (diameter < 200 μm); and among those that received LPS/sTF but no radiosurgery, thrombosis occurred at an intermediate rate of 43%. No systemic toxicity or intravascular thrombosis remote from the target region was detected in any of the animals. Conclusions Vascular targeting can increase intravascular thrombosis after radiosurgery, and the vessel occlusion is durable. Further work is needed to refine this approach to AVM treatment, which shows promise as a way to overcome the limitations of radiosurgery.

Pathologic Complete Response Rates in Young Women With BRCA1-Positive Breast Cancers After Neoadjuvant Chemotherapy

Purpose To estimate the rate of pathologic complete response (pCR) to neoadjuvant chemotherapy in BRCA1 mutation carriers according to chemotherapy regimen. Patients and Methods From a registry of 6,903 patients, we identified 102 women who carried a BRCA1 founder mutation and who had been treated for breast cancer with neoadjuvant chemotherapy. Pathologic complete response was evaluated using standard criteria. Results Twenty-four (24%) of the 102 BRCA1 mutation carriers experienced a pCR. The response rate varied widely with treatment: a pCR was observed in one (7%) of 14 women treated with cyclophosphamide, methotrexate, and fluorouracil (CMF); in two (8%) of 25 women treated with doxorubicin and docetaxel (AT); in 11 (22%) of 51 women treated with doxorubicin and cyclophosphamide (AC) or fluorouracil, doxorubicin, and cyclophosphamide (FAC), and in 10 (83%) of 12 women treated with cisplatin. Conclusion A low rate of pCR was observed in women with breast cancer and a BRCA1 mutation who were treated with AT or CMF. A high rate of pCR was seen after treatment with cisplatin. An intermediate rate of PCR was associated with AC or FAC. The relative benefits of AC and platinum therapy need to be confirmed through follow-up of this and other cohorts.