Structurally similar allosteric modulators of α7 nicotinic acetylcholine receptors exhibit five distinct pharmacological effects.

Activation of nicotinic acetylcholine receptors (nAChRs) is associated with the binding of agonists such as acetylcholine to an extracellular site that is located at the interface between two adjacent receptor subunits. More recently, there has been considerable interest in compounds, such as positive and negative allosteric modulators (PAMs and NAMs), that are able to modulate nAChR function by binding to distinct allosteric sites. Here we examined a series of compounds differing only in methyl substitution of a single aromatic ring. This series of compounds includes a previously described α7-selective allosteric agonist, cis-cis-4-p-tolyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide (4MP-TQS), together with all other possible combinations of methyl substitution at a phenyl ring (18 additional compounds). Studies conducted with this series of compounds have revealed five distinct pharmacological effects on α7 nAChRs. These five effects can be summarized as: 1) nondesensitizing activation (allosteric agonists), 2) potentiation associated with minimal effects on receptor desensitization (type I PAMs), 3) potentiation associated with reduced desensitization (type II PAMs), 4) noncompetitive antagonism (NAMs), and 5) compounds that have no effect on orthosteric agonist responses but block allosteric modulation (silent allosteric modulators (SAMs)). Several lines of experimental evidence are consistent with all of these compounds acting at a common, transmembrane allosteric site. Notably, all of these chemically similar compounds that have been classified as nondesensitizing allosteric agonists or as nondesensitizing (type II) PAMs are cis-cis-diastereoisomers, whereas all of the NAMs, SAMs, and type I PAMs are cis-trans-diastereoisomers. Our data illustrate the remarkable pharmacological diversity of allosteric modulators acting on nAChRs

Vitamin B6 Deficiency and Galactose Induced Alterations in Morphology and Osmotic Fragility of Rat Erythrocytes

Recently, red blood cells have been investigated mainly for alterations in ion transporting capacity, membrane bound enzymes or modifications in the structure of its individual constituents in clinical and experimental urolithiasis. However, the implication of such modifications on the physical state or morphology of cells has not been investigated. Scanning electron microscopic studies performed in vitamin B6 deficient and/or galactose fed rat (established hyperoxaluric models) erythrocytes, showed the presence of large number of stomatocytes, spherocytes and other variously deformed cells as compared to discocytic cells seen in normal control group. These changes in shape were in concurrence with red cell osmotic fragility, which decreased both in vitamin B6 deficient and vitamin B6 deficient + galactose fed group (19% and 33% hemolysis at 4 g/l NaCl, respectively) while it increased in galactose control group (73% hemolysis at 4 g/l NaCl) as compared to normal control group (55 % hemolysis at 4 g/l NaCl). These morphological and physical state alterations could be correlated with red blood cells\u27 membrane cholesterol and phospholipid sub-class distribution. These findings suggest that some structural membrane changes occur due to vitamin B6 deficiency and/or galactose feeding, which may be responsible for the altered membrane functions known to be associated with pathogenesis of urolithiasis

The Impact of Implementing Hypofractionation Prescription Regimens and Modernizing Delivery Technique on Treatment Resources in Breast Radiotherapy

Purpose/Objective(s): To determine the change in treatment resources due to the implementation of hypofractionated prescription regimen. Materials/Methods: All patients between January 1, 2012 and December 31, 2021 receiving curative intent breast radiotherapy at a tertiary cancer center were included. Plan and patient data were extracted from the patient database with the treatment planning system and direct database query. Treatment plan categorization was completed using data elements to include only curative intent. Treatment plans for seroma boost or supraclavicular irradiation were excluded to ensure this analysis did not double-count regional nodal irradiation contribution or confound boost with hypofractionation. Treatment delivery time is recorded in the database for each patient treatment delivered. Average patient treatment time per year was estimated by multiplying the average fractions each year by average time in the same year. The standard fractionation regimens (95% of patients) are 42.56 Gy in 16, 40 Gy in 16, 27 Gy in 5 (accelerated partial breast irradiation), and 26 Gy in 5 (FAST-Forward). In the analysis, implementation milestones are indicated for new prescription regimens and delivery technique changes including deep inspiration breath hold (DIBH) for left-sided patient treatments and daily verification imaging. Results: A total of 6505 patients were included. Table 1 details the total number of patients per year, the average number of fractions treated per patient, and the average treatment time of each patient plan. The average total fractions per treatment decreased from 17.5 in 2012 to 10.9 in 2021. The average treatment delivery time increased from 12.9 minutes to 21.4 minutes. Conclusion: In considering total treatment resources, the interplay between hypofractionation and modernization delivery techniques is complex. The impact of hypofractionation reduced the average number of fractions but total treatment resources are offset with the implementation of modern treatment delivery techniques. Hypofractionated prescription regimens reduce the time and travel commitment required of patients on an individual basis, contributing to person-centered care

Lack of seroresponse to SARS-CoV-2 booster vaccines given early post-transplant in patients primed pre-transplantation

SARS-CoV-2 vaccines are recommended pre-transplantation, however, waning immunity and evolving variants mandate booster doses. Currently there no data to inform the optimal timing of booster doses post-transplant, in patients primed pre-transplant. We investigated serial serological samples in 204 transplant recipients who received 2 or 3 SARS-CoV-2 vaccines pre-transplant. Spike protein antibody concentrations, [anti-S], were measured on the day of transplantation and following booster doses post-transplant. In infection-naïve patients, post-booster [anti-S] did not change when V3 (1st booster) was given at 116(78-150) days post-transplant, falling from 122(32-574) to 111(34-682) BAU/ml, p=0.78. Similarly, in infection-experienced patients, [anti-S] on Day-0 and post-V3 were 1090(133-3667) and 2207(650-5618) BAU/ml respectively, p=0.26. In patients remaining infection-naïve, [anti-S] increased post-V4 (as 2nd booster) when given at 226(208-295) days post-transplant, rising from 97(34-1074) to 5134(229-5680) BAU/ml, p=0.0016. Whilst in patients who had 3 vaccines pre-transplant, who received V4 (as 1st booster) at 82(49-101) days post-transplant, [anti-S] did not change, falling from 981(396-2666) to 871(242-2092) BAU/ml, p=0.62. Overall, infection pre-transplant and [anti-S] at the time of transplantation predicted post-transplant infection risk. As [Anti-S] fail to respond to SARS-CoV-2 booster vaccines given early post-transplant, passive immunity may be beneficial to protect patients during this period

Proposal for a unified nomenclature for target site mutations associated with resistance to fungicides

Evolved resistance to fungicides is a major problem limiting our ability to control agricultural, medical and veterinary pathogens and is frequently associated with substitutions in the amino acid sequence of the target protein. The convention for describing amino-acid substitutions is to cite the wild type amino acid, the codon number and the new amino acid, using the one letter amino acid code. It has frequently been observed that orthologous amino acid mutations have been selected in different species by fungicides from the same mode of action class, but the amino acids have different numbers. These differences in numbering arise from the different lengths of the proteins in each species. The purpose of the current paper is to propose a system for unifying the labelling of amino acids in fungicide target proteins. To do this we have produced alignments between fungicide target proteins of relevant species fitted to a well-studied “archetype” species. Orthologous amino acids in all species are then assigned numerical “labels” based on the position of the amino acid in the archetype protein

The evaluation of "Safe Motherhood" program on maternal care utilization in rural western China: a difference in difference approach

BACKGROUND: Maternal care is an important strategy for protection and promotion of maternal and children's health by reducing maternal mortality and improving the quality of birth. However, the status of maternal care is quite weak in the less developed rural areas in western China. It is found that the maternal mortality rates in some western areas of China were 5.8 times higher than those of their eastern costal counterparts. In order to reduce the maternal mortality rates and to improve maternal care in western rural areas of China, the Chinese Ministry of Health (MOH) and the United Nations Children's Fund (UNICEF) sponsored a program named "Safe Motherhood" in ten western provinces of China from 2001 through 2005. This study mainly aims to evaluate the effects of "Safe Motherhood" program on maternal care utilization. METHODS: 32 counties were included in both surveys conducted in 2001 and 2005, respectively. Ten counties of which implemented comprehensive community-based intervention were used as intervention groups, while 22 counties were used as control groups. Stratified 3-stage probability-proportion-to-size sampling method was used to select participating women. Two cross-sectional surveys were conducted with questionnaires about the prenatal care utilization in 2001 and 2005, respectively. Difference in difference estimation was used to assess the effect of intervention on the maternal care utilization while controlling for socio-economic characteristics of women. RESULTS: After the intervention, the proportion of pregnant women who had their first prenatal visit in the first trimester was increased from 38.9% to 76.1%. The proportion of prenatal visits increased from 82.6% to 98.3%. The proportion of women mobilized to deliver in hospitals increased from 62.7% to 94.5%. Hospital delivery was improved greatly from 31.1% to 87.3%. The maternal mortality rate was lowered by 34.9% from 91.76 to 59.74 per 100,000 live births. The community-based intervention had increased prenatal visits rate by 5.2%, first prenatal visit in first trimester rate by 12.0% and hospital delivery rate by 22.5%, respectively. No effect was found on rate of women being mobilized to hospital delivery compared with that of the control group. CONCLUSION: The intervention program seemed to have improved the prenatal care utilization in rural western China

A lineage-specific Exo70 is required for receptor kinase-mediated immunity in barley

In the evolution of land plants, the plant immune system has experienced expansion in immune receptor and signaling pathways. Lineage-specific expansions have been observed in diverse gene families that are potentially involved in immunity but lack causal association. Here, we show that Rps8-mediated resistance in barley to the pathogen Puccinia striiformis f. sp. tritici (wheat stripe rust) is conferred by a genetic module: Pur1 and Exo70FX12, which are together necessary and sufficient. Pur1 encodes a leucine-rich repeat receptor kinase and is the ortho-log of rice Xa21, and Exo70FX12 belongs to the Poales-specific Exo70FX clade. The Exo70FX clade emerged after the divergence of the Bromeliaceae and Poaceae and comprises from 2 to 75 members in sequenced grasses. These results demonstrate the requirement of a lineage-specific Exo70FX12 in Pur1-mediated immunity and sug-gest that the Exo70FX clade may have evolved a specialized role in receptor kinase signalin