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•Quantitative MRI maps dynamic brain development in rhesus monkey (2–10 years).•R2* plateauing at ≈5 years reveals a key developmental index.•A multimodal approach offers insights into microstructural maturation.•Our framework serves as a foundation for cross-species neurodevelopmental research. Despite advancements in understanding macroscopic and functional brain changes in developing nonhuman primates, a comprehensive in vivo understanding of underlying quantitative microstructural and compositional tissue changes remains elusive. To address this knowledge gap, we applied a quantitative multimodal magnetic resonance imaging (MRI) approach, integrating T1 relaxation time, R2* relaxation rate, and voxel-based morphometry, alongside hematology and serum chemistry analyses, in 94 rhesus monkeys of varying ages (62 males, 32 females; mean age = 5.66±2.08 yr; age range = 1.96–10.3 yr). Our in vivo multimodal analyses revealed distinct age-dependent brain patterns: R2* sharply increased before the age of 5 in deep gray matter (globus pallidus, striatum, thalamus), indicating rapid early iron accumulation in the brain, and then plateaued, strongly supporting a 5-yr developmental age threshold. T1 increased with age in the brainstem and cerebellum, suggesting unique microstructural changes. Voxel-based morphometry revealed a significant volume increase in the deep gray matter, including the thalamus and striatum, and white matter. This study highlights advanced quantitative MRI as a precise, noninvasive developmental index for tracking age-dependent brain tissue properties and microstructural organization in rhesus monkeys during critical developmental ages. These findings provide a robust methodological framework for future research on nonhuman primates, advancing the understanding of neurodevelopment.

Nipah virus (NiV), a highly pathogenic zoonotic paramyxovirus, causes severe respiratory and neurological disease in humans, with a case-fatality rate around 60%. Descriptions of cases in the clinical setting suggest that the two primary lineages of NiV cause disease with different presentations and outcomes. To define strain-specific differences in disease progression and host responses, African green monkeys were exposed to either the Malaysia (NiV-M) or Bangladesh (NiV-B) strain using a large-particle aerosol exposure. NiV-M infection resulted in a fatality rate of 27%, while NiV-B infection led to a 75% fatality rate characterized by rapid respiratory decline and systemic viral dissemination. Among survivors, NiV-M–infected animals mounted robust immunoglobulin M, immunoglobulin G, and neutralizing antibody responses, whereas NiV-B survivors exhibited weaker and delayed humoral responses. Non-survivors of both strains showed elevated pro-inflammatory cytokines, thrombocytopenia, and multi-organ dysfunction. Imaging showed that NiV-M infection was associated with neuroinflammation and systemic vasculitis, while NiV-B infection caused progressive pulmonary pathology. Histopathological analysis confirmed widespread vasculitis and encephalitis in animals with NiV-M infection and diffuse pulmonary hemorrhage and fibrin thrombi, consistent with vascular injury and coagulopathy, in animals with NiV-B infection. Cytokine profiling and flow cytometry showed a more intense and dysregulated immune response to NiV-B infection. Fatal outcomes in both groups were associated with thrombocytopenia, elevated pro-inflammatory cytokines, and multi-organ dysfunction. This study highlights fundamental differences in virulence, immune evasion, and pathogenesis between NiV strains and underscores the value of the African green monkey aerosol model for evaluating medical countermeasures under conditions that closely mimic natural human exposure.

Nipah virus (NiV) infection can lead to severe respiratory or neurological disease in humans. Transmission of NiV has been shown to occur through contact with virus contaminated fomites or consumption of contaminated food. Previous results using the African green monkey (AGM) model of NiV infection identified aspects of infection that, while similar to humans, don't fully recapitulate disease. Previous studies also demonstrate near uniform lethality that is not consistent with human NiV infection. In these studies, aerosol exposure using an intermediate particle size (7μm) was used to mimic potential human exposure by facilitating virus deposition in the upper respiratory tract. Computed tomography evaluation found some animals developed pulmonary parenchymal disease including consolidations, ground-glass opacities, and reactive adenopathy. Despite the lack of neurological signs, magnetic resonance imaging identified distinct brain lesions in three animals, similar to those previously reported in NiV-infected patients. Immunological characterization of tissues collected at necropsy suggested a local pulmonary inflammatory response with increased levels of macrophages in the lung, but a limited neurologic response. These data provide the first clear evidence of neurological involvement in the AGM that recapitulates human disease. With the development of a disease model that is more representative of human disease, these data suggest that NiV infection in the AGM may be appropriate for evaluating therapeutic countermeasures directed at virus-induced neuropathogenesis.

The dysregulated production of reactive oxygen species (ROS) during viral infections may lead to immune cell death and ineffective host responses. ROS dynamics have been under-investigated in severe Ebola virus disease (EVD), a condition in which hyperinflammation and excessive immune cell death are well described but poorly understood. Through ex vivo immunohistochemistry and in vivo ROS-sensitive magnetic resonance imaging (MRI) we demonstrate significant ROS-related oxidative changes in the spleens of domestic ferrets exposed to Ebola virus (EBOV). By immunohistochemistry or MRI, detection of splenic ROS was inversely correlated with the number of CD4 + /CD8 + T lymphocytes and apoptotic CD8 + lymphocytes, but detection was positively correlated with the frequency of apoptotic CD4 + cells and the number and frequency of apoptotic B lymphocytes. These results suggest that ROS-induced apoptosis may contribute to the loss of splenic CD4 + T lymphocytes in EBOV-exposed ferrets and warrant further investigation of the role of ROS in severe EVD.

A major goal of research in organic chemistry is the development of new theories which, when applied to transition states, have the same predictive power for transition states as classical organic structural theory has had for ground states. We are specifically interested in knowing how the energy of the transition state of biological group transfer reactions is influenced by changes in its structure. Described here are the attempted synthetic approaches to target molecules 34, 35 and 40. Routes based on the catalyzed Castro coupling (34, 35) and the classic Castro coupling (35) all failed to produce detectable quantities of product. Attempts to produce 40 via reactions such as the McMurry reaction, the Wittig and Stevens rearrangement, all failed. The catalyzed Castro coupling was successfully applied to the synthesis of 85 and 89. The structure of 85 in the solid state was shown by single crystal X-ray analysis to be essentially planar. Protonation of 89 gave 90. Based on NMR studies and computer simulations, a rate constant of ca. 50,000/s was estimated for the intramolecular proton transfer in acetonitrile solvent at 300 K. The measured $\\rm\\Delta pK\\sb{pyrH+}$ for the diacid of 89 was 0.69. Methylation of 89 gave 91. Based on simulations, the transition from slow to fast intramolecular methyl transfer will occur when the rate constant lies between 10/s and 30/s. Attempts to obtain more accurate estimates by dynamic NMR experiments were not successful. The rate of methyl transfer in CDCl$\\sb3$ appears to be higher than the rate in CD$\\sb3$CN.

The use of low density reinforced Reaction Injection Molded (RIM) substrates for covered interior automotive articles continues to increase globally. Reduced party mass, consolidation of manufacturing steps (labor), and the use of aluminum tooling, instead of steel, are cited advantages that LD-RIM offers when compared to traditional wood based and thermoplastic materials. Two RIM processes are successfully being used to produce covered interior door panels. Low density structural RIM (LD-SRIM), utilizing conventional RIM equipment, involves the placement of a pre-cut fiberglass mat in the tool cavity prior to open-pour injection of the 2-stream liquid urethane components. Low density reinforced RIM (LDRRIM), utilizing lance cylinder RIM equipment, incorporates reinforcing fibers, such as milled fiberglass or wollastonite, in the liquid resin component. The liquid resin containing reinforcing filler is injected with the isocyanate component into a closed mold. Both LD-SRIM and LD-RRIM covered door panels meet OEM performance specifications. Little difference exists between LD-SRIM and LDRRIM substrates, aside from tool design considerations and processing with either glass mat or reinforcing filler. In-mold polymer cure times and pressure/temperature profiles are essentially the same for both processes, and are dependent on the polyurethane components (i.e. polyol, catalysts etc.) employed, polyurethane wall thickness, and polyurethane density (1). Aluminum production tools are preferred because: 1) the polyurethane substrates are \"class B surfaces\" and do not have the distinctness of image requirements which \"class A\" parts obtain from steel surfaces, 2) the low level of reinforcement (<20 percent by weight of the substrate) is non-abrasive to the tool surface, and 3) the low tonnage (<100 ton) RIM clamps which are used. Advancements have been made in LD-RIM substrates to reduce weight further, to proliferate the LDRIM substrate to other automotive applications, to demonstrate the recyclability of both PVC covered LD-SRIM and LD-RRIM substrates, and to impart \"self-release\" properties of the LD-RIM substrate from aluminum production tools.

Non-breeding surplus in a territorial passerine was investigated by selectively removing territorial adult male Red-winged Blackbrids from several small marshes during several nesting seasons. A large number of the population, both within the removal marshes and in the surrounding marshes, were individually marked by color-banding, and included both sexes and all age classes. Observation of replacement of removed males and of the individually marked birds yielded data on density, survivorship, age specific production, nestling sex ratio, breeding sex ratio, male age class ratios, and dispersion. The data are discussed and formulated into a proposed hypothesis for the populationstructure of this species during nesting as follows: 1) Males select a breeding home range during the subadult year, possibly earlier, to which they return as adults and within which they seek territory. 2) Subadult males are for the most part behaviorally incapable of breeding regard- less of availability of habitat. 3) All yearling females probably do breed, but may lay fewer eggs on the average.4) During breeding season approximately 1/2 of the adult males are territorial and breeding and 1/2 are non-breeding.5) Subadult males occur in numbers approximating 1/2 - 2/3 the total adult male population. 6) At nesting the total of females, all of which nest, equals the total of males, which includes the breeding males, the excluded adult males and the subadult males, thus accounting for the degree of polygyny in the nesting population. The study suggests but does not directly document the inferences that 1) the non-breeding males, including subadults, are organized within the territorial structure of the nesting population, and that 2) the exclusion of potentially breeding males is probably not a major factor in regulating the population size of this species.

Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. In this open-label trial, patients (aged 1–30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2–5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test. Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death—a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30·0 (IQR 11·0–96·0) at baseline and 15·8 (5·6–57·6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36·5% (IQR 0–64·7). Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound. GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.

Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of fenfluramine in patients with Dravet syndrome. In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, fenfluramine 0·2 mg/kg per day, or fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863. Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either fenfluramine 0·2 mg/kg per day (39), fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7–72·8, p<0·0001); fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2–52·3, p=0·0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension. In Dravet syndrome, fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. Zogenix.