Evidence for tyrosine at the ligand binding center of beta-adrenergic receptors

Beta 1- and beta 2-adrenergic receptor radioligand antagonist binding activities in plasma membrane preparations from mammalian lung, as well as amphibian and avian red blood cells, have been shown to be inactivated by agents which specifically alkylate tyrosine. In membrane preparations, protection against inactivation was afforded by both agonists and antagonists. In soluble purified preparations, antagonists but not agonists protected against inactivation. These results suggest that tyrosine is located at or near the ligand binding site of both beta 1- and beta 2-adrenergic receptors.     

Toxicity of Toxaphene in the Rat and Beagle Dog

Toxicity of Toxaphene in the Rat and Beagle Dog. CHU, I., VILLENEUVE,D.C, SUN, C., SECOURS, V., PROCTER, B., ARNOLD, E., CLEGG, D.,REYNOLDS, L., AND VALLI, V.E. (1986). Fundam Appl. Toxicol.7, 406-418. Residues of the insecticidal mixture, toxaphene,have been found in Great Lakes fish. The purpose of the presentstudy was to assess the subchronic toxicity of toxaphene inthe rat and beagle dog. In the rat study, groups of 10 maleand 10 female animals were fed diets containing 0, 4, 20, 100,or 500 ppm of the test compound for 13 weeks. No clinical signsof toxicity or spontaneous deaths were observed. Toxaphene treatmentup to 500 ppm had no effects on weight gain or food consumption.The liver/body weight ratio and hepatic microsomal enzyme activities(phenobarbital type) were increased in both sexes fed 500 ppmof the test compound. Toxaphene at the highest dose also causedkidney enlargement in male but not in female rats. Dose-dependenthistological changes were seen in the kidney, thyroid, and liver.Changes in the liver and thyroid were considered to be adaptativebut the injury in the proximal tubules of the kidney was focallysevere. Groups of six male and six female beagle dogs were fedtoxaphene in gelatin capsules at 0, 0.2, 2.0, and 5.0 mg/kgbody wt/day for 13 weeks. Food consumption and growth rate werenot affected. All animals survived the entire treatment period.No clinical signs of toxicity were observed. The liver/bodyweight ratio and serum alkaline phosphatase were increased indogs of both sexes fed 5.0 mg/kg. Mild to moderate dose-dependenthistological changes were observed in the liver and thyroid.Toxaphene was accumulated in a dose-dependent manner in thefat and liver of dogs and rats. Based on the biochemical, histological,and residue data, it was concluded that the no-adverse-effectlevels of the pesticide were 4.0 ppm (0.35 mg/kg) for the ratand 0.2 mg/kg for the dog.     

Naturalistic Language Input is Associated with Resting-State Functional Connectivity in Infancy

The quantity and quality of the language input that infants receive from their caregivers affects their future language abilities; however, it is unclear how variation in this input relates to preverbal brain circuitry. The current study investigated the relation between naturalistic language input and the functional connectivity (FC) of language networks in human infancy using resting-state functional magnetic resonance imaging (rsfMRI). We recorded the naturalistic language environments of five- to eight-month-old male and female infants using the Linguistic ENvironment Analysis (LENA) system and measured the quantity and consistency of their exposure to adult words (AWs) and adult–infant conversational turns (CTs). Infants completed an rsfMRI scan during natural sleep, and we examined FC among regions of interest (ROIs) previously implicated in language comprehension, including the auditory cortex, the left inferior frontal gyrus (IFG), and the bilateral superior temporal gyrus (STG). Consistent with theory of the ontogeny of the cortical language network (Skeide and Friederici, 2016), we identified two subnetworks posited to have distinct developmental trajectories: a posterior temporal network involving connections of the auditory cortex and bilateral STG and a frontotemporal network involving connections of the left IFG. Independent of socioeconomic status (SES), the quantity of CTs was uniquely associated with FC of these networks. Infants who engaged in a larger number of CTs in daily life had lower connectivity in the posterior temporal language network. These results provide evidence for the role of vocal interactions with caregivers, compared with overheard adult speech, in the function of language networks in infancy.     

Geotemporal analysis of perinatal care changes and maternal mental health: an example from the COVID-19 pandemic

Archives of Women's Mental Health - Our primary objective was to document COVID-19 induced changes to perinatal care across the USA and examine the implication of these changes for maternal...     

A 2-gene classifier for predicting response to the farnesyltransferase inhibitor tipifarnib in acute myeloid leukemia

At present, there is no method available to predict response to farnesyltransferase inhibitors (FTIs). We analyzed gene expression profiles from the bone marrow of patients from a phase 2 study of the FTI tipifarnib in older adults with previously untreated acute myeloid leukemia (AML). The RASGRP1/APTX gene expression ratio was found to predict response to tipifarnib with the greatest accuracy using a "leave one out" cross validation (LOOCV; 96%). RASGRP1 is a guanine nucleotide exchange factor that activates RAS, while APTX (aprataxin) is involved in DNA excision repair. The utility of this classifier for predicting response to tipifarnib was validated in an independent set of 58 samples from relapsed or refractory AML, with a negative predictive value (NPV) and positive predictive value (PPV) of 92% and 28%, respectively (odds ratio of 4.4). The classifier also predicted for improved overall survival (154 vs 56 days; P < .001), which was independent of other covariates, including a previously described prognostic gene expression classifier. Therefore, these data indicate that a 2-gene expression assay may have utility in categorizing a population of patients with AML who are more likely to respond to tipifarnib.     

A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis

Ruxolitinib, a potent Janus kinase 1/2 inhibitor, resulted in rapid and durable improvements in splenomegaly and disease-related symptoms in the 2 phase III COMFORT studies. In addition, ruxolitinib was associated with prolonged survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). We present a pooled analysis of overall survival in the COMFORT studies using an intent-to-treat analysis and an analysis correcting for crossover in the control arms. Overall, 301 patients received ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 patients received placebo (n=154) or best available therapy (n=73). After a median three years of follow up, intent-to-treat analysis showed that patients who received ruxolitinib had prolonged survival compared with patients who received placebo or best available therapy [hazard ratio=0.65; 95% confidence interval (95%CI): 0.46–0.90; P=0.01]; the crossover-corrected hazard ratio was 0.29 (95%CI: 0.13–0.63). Both patients with intermediate-2– or high-risk disease showed prolonged survival, and patients with high-risk disease in the ruxolitinib group had survival similar to that of patients with intermediate-2–risk disease in the control group. The Kaplan-Meier estimate of overall survival at week 144 was 78% in the ruxolitinib arm, 61% in the intent-to-treat control arm, and 31% in the crossover-adjusted control arm. While larger spleen size at baseline was prognostic for shortened survival, reductions in spleen size with ruxolitinib treatment correlated with longer survival. These findings are consistent with previous reports and support that ruxolitinib offers a survival benefit for patients with myelofibrosis compared with conventional therapies. (clinicaltrials.gov identifiers: COMFORT-I, {"type":"clinical-trial","attrs":{"text":"NCT00952289","term_id":"NCT00952289"}}NCT00952289; COMFORT-II, {"type":"clinical-trial","attrs":{"text":"NCT00934544","term_id":"NCT00934544"}}NCT00934544)