Positron Emission Tomography Quantitative Assessment of Off-Target Whole-Body Biodistribution of I-124-Labeled Adeno-Associated Virus Capsids Administered to Cerebral Spinal Fluid.

Based on studies in experimental animals demonstrating that administration of adeno-associated virus (AAV) vectors to the cerebrospinal fluid (CSF) is an effective route to transfer genes to the nervous system, there are increasing number of clinical trials using the CSF route to treat nervous system disorders. With the knowledge that the CSF turns over four to five times daily, and evidence in experimental animals that at least some of CSF administered AAV vectors are distributed to systemic organs, we asked: with AAV administration to the CSF, what fraction of the total dose remains in the nervous system and what fraction goes off target and is delivered systemically? To quantify the biodistribution of AAV capsids immediately after administration, we covalently labeled AAV capsids with iodine 124 (I-124), a cyclotron generated positron emitter, enabling quantitative positron emission tomography scanning of capsid distribution for up to 96 h after AAV vector administration. We assessed the biodistribution to nonhuman primates of I-124-labeled capsids from different AAV clades, including 9 (clade F), rh.

Application of recombinant TGF-β1 inhibitory peptide to alleviate isoproterenol-induced cardiac fibrosis.

Cardiac fibrosis is a remodeling process of the cardiac interstitium, characterized by abnormal metabolism of the extracellular matrix, excessive accumulation of collagen fibers, and scar tissue hyperplasia. Persistent activation and transdifferentiation into myofibroblasts of cardiac fibroblasts promote the progression of fibrosis. Transforming growth factor-β1 (TGF-β1) is a pivotal factor in cardiac fibrosis.

The impact of vaccine-linked chemotherapy on liver health in a mouse model of chronic infection.

Background: Chagas disease, chronic infection with , mainly manifests as cardiac disease. However, the liver is important for both controlling parasite burdens and metabolizing drugs. Notably, high doses of anti-parasitic drug benznidazole (BNZ) causes liver damage.

HCK induces macrophage activation to promote renal inflammation and fibrosis via suppression of autophagy.

Renal inflammation and fibrosis are the common pathways leading to progressive chronic kidney disease (CKD). We previously identified hematopoietic cell kinase (HCK) as upregulated in human chronic allograft injury promoting kidney fibrosis; however, the cellular source and molecular mechanisms are unclear. Here, using immunostaining and single cell sequencing data, we show that HCK expression is highly enriched in pro-inflammatory macrophages in diseased kidneys.

Reciprocity and beyond: Explaining meat transfers in savanna-dwelling chimpanzees at Fongoli, Senegal.

Objectives: To understand the function of food sharing among our early hominin ancestors, we can turn to our nonhuman primate relatives for insight. Here, we examined the function of meat sharing by Fongoli chimpanzees, a community of western chimpanzees (Pan troglodytes verus) in southeastern Sénégal.

Materials And Methods: We tested three non-mutually exclusive hypotheses that have been used to explain patterns of food sharing: kin selection, generalized reciprocity, and meat-for-mating opportunities.

Heterogeneity of variance and genetic parameters for milk production in cattle, using Bayesian inference.

The goal of this study was to verify the effect of heterogeneity of variance (HV) on milk production in up to 305 days of lactation (L305) of daughters of Girolando, Gir and Holstein sires, as well as in the genetic evaluation of these sires and their progenies. in Brazil. The model included contemporary groups (consisting of herd, year and calving season) as a fixed effect, cow age at calving (linear and quadratic effects) and heterozygosity (linear effect) as covariates, in addition to the random effects of direct additive genetic and environmental, permanent and residual.

Spatial analysis of nanoparticle distribution in human breast xenografts reveals nanoparticles targeted to cancer cells localized with tumor-associated stromal cells.

The biological influence of physicochemical parameters of "targeted" nanoparticles on their delivery to cancer tumors remains poorly understood. A comparative analysis of nanoparticle distributions in tumors following systemic delivery across several models can provide valuable insights. Bionized nanoferrite nanoparticles (iron oxide core coated with starch), either conjugated with a targeted anti-HER2 antibody (BH), or unconjugated (BP), were intravenously injected into athymic nude or NOD-scid gamma (NSG) female mice bearing one of five human breast cancer tumor xenografts growing in a mammary fat pad.

Long-acting refillable nanofluidic implant confers protection against SHIV infection in nonhuman primates.

The impact of pre-exposure prophylaxis (PrEP) on slowing the global HIV epidemic hinges on effective drugs and delivery platforms. Oral drug regimens are the pillar of HIV PrEP, but variable adherence has spurred development of long-acting delivery systems with the aim of increasing PrEP access, uptake, and persistence. We have developed a long-acting subcutaneous nanofluidic implant that can be refilled transcutaneously for sustained release of the HIV drug islatravir, a nucleoside reverse transcriptase translocation inhibitor that is used for HIV PrEP.

Nerve sheath tumor in the forearm of a common marmoset (Callithrix jacchus).

Tumors of the skin and subcutaneous tissues are uncommon in marmosets. In this report, we describe the gross, histopathology, and immunohistochemical findings of a nerve sheath tumor that arose in the left forearm of an adult female marmoset (Callthrix jacchus).

Long non-coding RNA lncMGC mediates the expression of TGF-β-induced genes in renal cells via nucleosome remodelers.

MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) play key roles in diabetic kidney disease (DKD). The miR-379 megacluster of miRNAs and its host transcript lnc-megacluster (lncMGC) are regulated by transforming growth factor-β (TGF-β), increased in the glomeruli of diabetic mice, and promote features of early DKD. However, biochemical functions of lncMGC are unknown.

Longitudinal analysis of a dietary mouse model of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

Non-alcoholic fatty liver disease (NAFLD), and resultant non-alcoholic steatohepatitis (NASH), incidence and prevalence are rising globally due to increasing rates of obesity and diabetes. Currently, there are no approved pharmacological treatments for NAFLD, highlighting a need for additional mechanistic studies to develop prevention and/or therapeutic strategies. Diet-induced preclinical models of NAFLD can be used to examine the dynamic changes that occur during NAFLD development and progression throughout the lifespan.

Exclusion of Horizontal and Vertical Transmission as Major Sources of Infections in a Breeding Colony of Rhesus Macaques ().

The vector-borne protozoal parasite causes Chagas disease in humans and animals. This parasite is endemic to the southern United States where outdoor-housed NHP at biomedical facilities are at risk of infection. In addi- tion to the direct morbidity caused by , infected animals are of limited biomedical research use because infections can produce confounding pathophysiologic changes even in animals with no clinical disease.

A global catalog of whole-genome diversity from 233 primate species.

The rich diversity of morphology and behavior displayed across primate species provides an informative context in which to study the impact of genomic diversity on fundamental biological processes. Analysis of that diversity provides insight into long-standing questions in evolutionary and conservation biology and is urgent given severe threats these species are facing. Here, we present high-coverage whole-genome data from 233 primate species representing 86% of genera and all 16 families.

The landscape of tolerated genetic variation in humans and primates.

Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans.

Toxoplasmosis in ring-tailed lemurs (Lemur catta) and a peahen (Pavo cristatus) in a zoological collection caused by the common toxoplasma genotype in wild animals in the US.

Toxoplasmosis is caused by the ubiquitous Apicomplexan protozoan Toxoplasma gondii. This pathogen affects domestic and wildlife species, but prosimians including ring-tailed lemurs (Lemur catta) are highly susceptible to infection with high mortality rates. Avian species are considered resistant to infection and are often used in surveillance efforts to determine genotypes of T.

The landscape of tolerated genetic variation in humans and primates.

Unlabelled: Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole genome sequencing data for 809 individuals from 233 primate species, and identified 4.3 million common protein-altering variants with orthologs in human.

Identification of Safe and Effective Intravenous Dose of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich's Ataxia.

Friedreich's ataxia (FA) is a life-threatening autosomal recessive disorder characterized by neurological and cardiac dysfunction. Arrhythmias and heart failure are the main cause of premature death. From prior studies in murine models of FA, adeno-associated virus encoding the normal human frataxin gene (AAVrh.

Heterozygous midnolin knockout attenuates severity of nonalcoholic fatty liver disease in mice fed a Western-style diet high in fat, cholesterol, and fructose.

Although midnolin has been studied for over 20 years, its biological roles in vivo remain largely unknown, especially due to the lack of a functional animal model. Indeed, given our recent discovery that the knockdown of midnolin suppresses liver cancer cell tumorigenicity and that this antitumorigenic effect is associated with modulation of lipid metabolism, we hypothesized that knockout of midnolin in vivo could potentially protect from nonalcoholic fatty liver disease (NAFLD) which has become the most common cause of chronic liver disease in the Western world. Accordingly, in the present study, we have developed and now report on the first functional global midnolin knockout mouse model.

Behavioral and biologic characteristics of cancer-related cognitive impairment biotypes.

Psychiatric diagnosis is moving away from symptom-based classification and towards multi-dimensional, biologically-based characterization, or biotyping. We previously identified three biotypes of chemotherapy-related cognitive impairment based on functional brain connectivity. In this follow-up study of 80 chemotherapy-treated breast cancer survivors and 80 non-cancer controls, we evaluated additional factors to help explain biotype expression: neurofunctional stability, brain age, apolipoprotein (APOE) genotype, and psychoneurologic symptoms.

Changes in local tissue microenvironment in response to subcutaneous long-acting delivery of tenofovir alafenamide in rats and non-human primates.

Several implantable long-acting (LA) delivery systems have been developed for sustained subcutaneous administration of tenofovir alafenamide (TAF), a potent and effective nucleotide reverse transcriptase inhibitor used for HIV pre-exposure prophylaxis (PrEP). LA platforms aim to address the lack of adherence to oral regimens, which has impaired PrEP efficacy. Despite extensive investigations in this field, tissue response to sustained subcutaneous TAF delivery remains to be elucidated as contrasting preclinical results have been reported in the literature.

The Effects of Oral Lavender Therapy on Wounding in Chimpanzees ().

Lavender administration in humans has been shown to promote calmness without the side effects often observed with benzodiazepines. Studies in both humans and rodents have found that ingestion of oral lavender capsules resulted in significantly decreased anxiety. Additionally, mice developed an anti-conflict effect and humans increased socially inclusive behaviors.

Pathologic copulatory lock in a genetically engineered laboratory mouse breeding pair.

A breeding pair of genetically engineered laboratory mice () presented in apparent copulatory lock (coital tie). After anesthetizing the animals, gentle traction was used to separate the pair at which point a vaginal prolapse was detected and the penis was covered with black, firm, dry crusts and noted to have a solid pale, tan, firm cylindrical mass adhering to its glans. The vaginal prolapse was reduced and the female was returned to its cage.

Frequency Variation and Dose Modification of Benznidazole Administration for the Treatment of Trypanosoma cruzi Infection in Mice, Dogs, and Nonhuman Primates.

Trypanosoma cruzi naturally infects a broad range of mammalian species and frequently results in the pathology that has been most extensively characterized in human Chagas disease. Currently employed treatment regimens fail to achieve parasitological cure of T. cruzi infection in the majority of cases.