Meox2 Haploinsufficiency Accelerates Axonal Degeneration in DBA/2J Glaucoma.

Purpose: Glaucoma is a complex disease with major risk factors including advancing age and increased intraocular pressure (IOP). Dissecting these earliest events will likely identify new avenues for therapeutics. Previously, we performed transcriptional profiling in DBA/2J (D2) mice, a widely used mouse model relevant to glaucoma.

Human DNA Virus Exploitation of the MAPK-ERK Cascade.

The extracellular signal-regulated kinases (ERKs) comprise a particular branch of the mitogen-activated protein kinase cascades (MAPK) that transmits extracellular signals into the intracellular environment to trigger cellular growth responses. Similar to other MAPK cascades, the MAPK-ERK pathway signals through three core kinases-Raf, MAPK/ERK kinase (MEK), and ERK-which drive the signaling mechanisms responsible for the induction of cellular responses from extracellular stimuli including differentiation, proliferation, and cellular survival. However, pathogens like DNA viruses alter MAPK-ERK signaling in order to access DNA replication machineries, induce a proliferative state in the cell, or even prevent cell death mechanisms in response to pathogen recognition.

Genetic mapping in Diversity Outbred mice identifies a Trpa1 variant influencing late-phase formalin response.

Identification of genetic variants that influence susceptibility to pain is key to identifying molecular mechanisms and targets for effective and safe therapeutic alternatives to opioids. To identify genes and variants associated with persistent pain, we measured late-phase response to formalin injection in 275 male and female Diversity Outbred mice genotyped for over 70,000 single nucleotide polymorphisms. One quantitative trait locus reached genome-wide significance on chromosome 1 with a support interval of 3.

New insights into regulation and function of planar polarity in the inner ear.

Acquisition of cell polarity generates signaling and cytoskeletal asymmetry and thus underpins polarized cell behaviors during tissue morphogenesis. In epithelial tissues, both apical-basal polarity and planar polarity, which refers to cell polarization along an axis orthogonal to the apical-basal axis, are essential for epithelial morphogenesis and function. A prime example of epithelial planar polarity can be found in the auditory sensory epithelium (or organ of Corti, OC).

Vascular Inflammation Risk Factors in Retinal Disease.

Inflammation of the blood vessels that serve the central nervous system has been increasingly identified as an early and possibly initiating event among neurodegenerative conditions such as Alzheimer's disease and related dementias. However, the causal relevance of vascular inflammation to major retinal degenerative diseases is unresolved. Here, we describe how genetics, aging-associated changes, and environmental factors contribute to vascular inflammation in age-related macular degeneration, diabetic retinopathy, and glaucoma.

Functional rescue in a mouse model of congenital muscular dystrophy with megaconial myopathy.

Congenital muscular dystrophy with megaconial myopathy (MDCMC) is an autosomal recessive disorder characterized by progressive muscle weakness and wasting. The observation of megamitochondria in skeletal muscle biopsies is exclusive to this type of MD. The disease is caused by loss of function mutations in the choline kinase beta (CHKB) gene which results in dysfunction of the Kennedy pathway for the synthesis of phosphatidylcholine.

Suppression of voluntary ethanol intake in mice under constant light and constant darkness.

Seasonal variations in photoperiod are associated with alterations in human mood and behavior. Similarly, manipulation of the environmental lighting regimen can exert pronounced effects on affective behavior in experimental animals. These observations may be due, in part, to light-induced alterations in circadian rhythms, but it seems likely that other, non-circadian factors also contribute.

Development of medical-grade, discrete, multi-walled carbon nanotubes as drug delivery molecules to enhance the treatment of hematological malignancies.

Carbon nanotubes (CNTs) hold great potential as drug delivery transporters given their large drug-binding surface area. Herein, we designed novel, multi-walled, discrete CNTs (dMWCNTs), PEGylated dMWCNTs (PEG-dMWCNTs), and bone-targeting (BT), alendronate-conjugated PEG-dMWCNTs (BT-PEG-dMWCNTs). Using zeta potential, thermogravimetric analysis, TEM, SEM, and FTIR, dMWCNTs were characterized as individual, uniform, and stable.

Enhancing face validity of mouse models of Alzheimer's disease with natural genetic variation.

Classical laboratory strains show limited genetic diversity and do not harness natural genetic variation. Mouse models relevant to Alzheimer's disease (AD) have largely been developed using these classical laboratory strains, such as C57BL/6J (B6), and this has likely contributed to the failure of translation of findings from mice to the clinic. Therefore, here we test the potential for natural genetic variation to enhance the translatability of AD mouse models.

Candidalysin activates innate epithelial immune responses via epidermal growth factor receptor.

Candida albicans is a fungal pathobiont, able to cause epithelial cell damage and immune activation. These functions have been attributed to its secreted toxin, candidalysin, though the molecular mechanisms are poorly understood. Here, we identify epidermal growth factor receptor (EGFR) as a critical component of candidalysin-triggered immune responses.

Sialyltransferase inhibition leads to inhibition of tumor cell interactions with E-selectin, VCAM1, and MADCAM1, and improves survival in a human multiple myeloma mouse model.

Aberrant glycosylation resulting from altered expression of sialyltransferases, such as ST3 β-galactoside α2-3-sialyltransferase 6, plays an important role in disease progression in multiple myeloma (MM). Hypersialylation can lead to increased immune evasion, drug resistance, tumor invasiveness, and disseminated disease. In this study, we explore the and effects of global sialyltransferase inhibition on myeloma cells using the pan-sialyltransferase inhibitor 3F-Neu5Ac delivered as a per-acetylated methyl ester pro-drug.

Intravital Imaging Reveals Divergent Cytokine and Cellular Immune Responses to Candida albicans and Candida parapsilosis.

yeasts are common commensals that can cause mucosal disease and life-threatening systemic infections. While many of the components required for defense against infection are well established, questions remain about how various host cells at mucosal sites assess threats and coordinate defenses to prevent normally commensal organisms from becoming pathogenic. Using two species, and , which differ in their abilities to damage epithelial tissues, we used traditional methods (pathogen CFU, host survival, and host cytokine expression) combined with high-resolution intravital imaging of transparent zebrafish larvae to illuminate host-pathogen interactions at the cellular level in the complex environment of a mucosal infection.

The Expectations and Challenges of Wildlife Disease Research in the Era of Genomics: Forecasting with a Horizon Scan-like Exercise.

The outbreak and transmission of disease-causing pathogens are contributing to the unprecedented rate of biodiversity decline. Recent advances in genomics have coalesced into powerful tools to monitor, detect, and reconstruct the role of pathogens impacting wildlife populations. Wildlife researchers are thus uniquely positioned to merge ecological and evolutionary studies with genomic technologies to exploit unprecedented "Big Data" tools in disease research; however, many researchers lack the training and expertise required to use these computationally intensive methodologies.

High-Throughput Characterization of Viral and Cellular Protein Expression Patterns During JC Polyomavirus Infection.

JC polyomavirus (JCPyV) is a ubiquitous human pathogen and the causative agent of a fatal demyelinating disease in severely immunocompromised individuals. Due to the lack of successful pharmacological interventions, the study of JCPyV infection strategies in a rapid and highly sensitive manner is critical for the characterization of potential antiviral therapeutics. Conventional methodologies for studying viral infectivity often utilize the detection of viral proteins through immunofluorescence microscopy-based techniques.

Affective Behavior in Withdrawal Seizure-Prone and Withdrawal Seizure-Resistant Mice during Long-Term Alcohol Abstinence.

Background: While the acute alcohol withdrawal syndrome has been well characterized both in human clinical studies and in experimental animals, much less is known regarding long-term affective disturbances that can sometimes persist during protracted abstinence. Nevertheless, since relapse often occurs long after acute detoxification and may be predicted by persistent affective disruption, a better understanding of the long-term behavioral consequences of prior alcohol dependence may lead to improved strategies for relapse prevention.

Methods: Male and female Withdrawal Seizure-Prone and Withdrawal Seizure-Resistant mice from the second selection replicate (WSP-2, WSR-2) were exposed to a 10-day chronic-intermittent ethanol vapor protocol (CIE) or plain air and then tested repeatedly on the sucrose preference test (SPT), marble burying test (MBT), and the light-dark box test (LDT) over 7 weeks of (forced) abstinence.

Modulation of TNFα Activity by the microRNA Let-7 Coordinates Zebrafish Heart Regeneration.

The adult zebrafish is capable of regenerating heart muscle, resolving collagen tissue, and fully restoring heart function throughout its life. In this study, we show that the highly upregulated, epicardium-enriched microRNA let-7i functions in wound closure and cardiomyocyte proliferation. RNA sequencing experiments identified upregulated expression of members of the tumor necrosis factor (TNF) signaling pathway in the absence of let-7.

HSP90 Inhibitor, NVP-AUY922, Improves Myelination in Vitro and Supports the Maintenance of Myelinated Axons in Neuropathic Mice.

Hereditary demyelinating neuropathies linked to peripheral myelin protein 22 (PMP22) involve the disruption of normal protein trafficking and are therefore relevant targets for chaperone therapy. Using a small molecule HSP90 inhibitor, EC137, in cell culture models, we previously validated the chaperone pathway as a viable target for therapy development. Here, we tested five commercially available inhibitors of HSP90 and identified BIIB021 and AUY922 to support Schwann cell viability and enhance chaperone expression.

Intrinsic planar polarity mechanisms influence the position-dependent regulation of synapse properties in inner hair cells.

Encoding the wide range of audible sounds in the mammalian cochlea is collectively achieved by functionally diverse type I spiral ganglion neurons (SGNs) at each tonotopic position. The firing of each SGN is thought to be driven by an individual active zone (AZ) of a given inner hair cell (IHC). These AZs present distinct properties according to their position within the IHC, to some extent forming a gradient between the modiolar and the pillar IHC side.

Dry eye sensitizes cool cells to capsaicin-induced changes in activity via TRPV1.

Corneal cool cells are sensitive to the ocular fluid status of the corneal surface and may be responsible for the regulation of basal tear production. Previously, we have shown that dry eye, induced by lacrimal gland excision (LGE) in rats, sensitized corneal cool cells to the transient receptor potential melastatin 8 (TRPM8) agonist menthol and to cool stimulation. In the present study, we examined the effect of dry eye on the sensitivity of cool cells to the transient receptor potential vanilloid 1 (TRPV1) agonist capsaicin.

Inverse correlation between trabecular bone volume and bone marrow adipose tissue in rats treated with osteoanabolic agents.

There is currently an unmet clinical need for improved treatments for skeletal diseases such as osteoporosis and cancer-induced bone disease. This is due in part to a paucity of novel targets and an incomplete understanding of the mechanisms of action for established therapies. We defined the effects of anabolic treatments on bone and the bone marrow adipocyte (BMA).

Factors that influence response classifications in chemotherapy treated patient-derived xenografts (PDX).

In this study, we investigated the impact of initial tumor volume, rate of tumor growth, cohort size, study duration, and data analysis method on chemotherapy treatment response classifications in patient-derived xenografts (PDXs). The analyses were conducted on cisplatin treatment response data for 70 PDX models representing ten cancer types with up to 28-day study duration and cohort sizes of 3-10 tumor-bearing mice. The results demonstrated that a 21-day dosing study using a cohort size of eight was necessary to reliably detect responsive models (i.

Multiple Myeloma and Fatty Acid Metabolism.

Multiple myeloma (MM) accounts for 13% to 15% of all blood cancers1 and is characterized by the proliferation of malignant cells within the bone marrow (BM). Despite important advances in treatment, most patients become refractory and relapse with the disease. As MM tumors grow in the BM, they disrupt hematopoiesis, create monoclonal protein spikes in the blood, initiate systemic organ and immune system shutdown,2 and induce painful osteolytic lesions caused by overactive osteoclasts and inhibited osteoblasts.

Studies Into β-Glucan Recognition in Fish Suggests a Key Role for the C-Type Lectin Pathway.

Immune-modulatory effects of β-glucans are generally considered beneficial to fish health. Despite the frequent application of β-glucans in aquaculture practice, the exact receptors and downstream signalling remains to be described for fish. In mammals, Dectin-1 is a member of the C-type lectin receptor (CLR) family and the best-described receptor for β-glucans.