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Optic photoreception is a critical function for animal survival. Across the evolutionary spectrum, diverse animal models have been used to investigate visual system function and potential mechanisms under physiological or pathophysiological states. However less is known on photoreceptive behaviors and retinal processing in invertebrates, especially molluscs. This study focuses on the freshwater pond snail, Lymnaea stagnalis (L. stagnalis), to explore its visual function and underlying mechanisms. Using anatomical and histological approaches we characterized the L. stagnalis eye structure and demonstrated structural connections and retinal rhodopsin-positive sensory cells potentially critical for phototransduction. To assess the snail phototactic responses, we developed a new neurobehavioral protocol and employed DeepLabCut to track and quantify animal locomotion. We demonstrated that L. stagnalis exhibits a positive locomotory response to intense focal light and has diverse photo-locomotory responses. Further, we conducted phylogenetic and protein structure analyses and demonstrated that L. stagnalis has a unique repertoire of both vertebrate and invertebrate phototransduction genes. Further characterization of a rhodopsin-like gene identified unique characteristics compared to other mollusks and vertebrates, suggesting different mechanisms of phototransduction. Taken together, our work establishes L. stagnalis as a model organism for studying optic photoreception, offering new insights into the evolution and diversity of visual function across animal species. [ABSTRACT FROM AUTHOR]

Idiosyncratic drug reactions (IDRs) are associated with significant patient morbidity/mortality and lead to considerable drug candidate attrition in drug development. Their idiosyncratic nature makes the study of IDRs difficult. In particular, nevirapine is associated with a relatively high risk of serious skin rash and liver injury. We previously found that nevirapine causes a similar skin rash in female Brown Norway rats, but these animals do not develop significant liver injury. Programmed cell death protein-1 (PD-1) is an immune checkpoint involved in immune tolerance, and anti-PD-1 antibodies have been used to treat cancer. However, they increase the risk of liver injury caused by co-administered drugs. We found that PD-1−/− mice are more susceptible to drug-induced liver injury, but PD-1−/− mice are not a good model for all drugs. In particular, they do not develop a skin rash when treated with nevirapine, at least in part because they lack the sulfotransferase in their skin that forms the reactive metabolite responsible for the rash. Therefore, we developed a PD-1 mutant (PD-1m/m) rat, with an excision in the ligand-binding domain of PD-1, to test whether nevirapine would cause a more serious skin rash in these animals. The PD-1m/m rat was based on a Sprague Dawley background, which has a lower incidence of skin rash than Brown Norway rats. The treated PD-1m/m rats developed more severe liver injury than PD-1−/− mice, but in contrast to expectations, they did not develop a skin rash. Functional knockouts provide a unique tool to study the mechanisms of IDRs. [ABSTRACT FROM AUTHOR]

In a mouse mutagenesis screen, we isolated a mutant, Myshkin (Myk), with autosomal dominant complex partial and secondarily generalized seizures, a greatly reduced threshold for hippocampal seizures in vitro, posttetanic hyperexcitability of the CA3-CA1 hippocampal pathway, and neuronal degeneration in the hippocampus. Positional cloning and functional analysis revealed that Myk/+ mice carry a mutation (I810N) which renders the normally expressed [Na.sup.+],[K.sup.+]-ATPase [alpha]3 isoform inactive. Total [Na.sup.+],[K.sup.+]-ATPase activity was reduced by 42% in Myk/+ brain. The epilepsy in Myk/+ mice and in vitro hyperexcitability could be prevented by delivery of additional copies of wild-type [Na.sup.+],[K.sub.+]-ATPase [alpha]3 by transgenesis, which also rescued [Na.sup.+],[K.sup.+]-ATPase activity. Our findings reveal the functional significance of the [Na.sup.+],[K.sup.+]-ATPase [alpha]3 isoform in the control of epileptiform activity and seizure behavior. alpha3 [Na.sup.+],[K.sup.+] ATPase | BAC rescue | epilepsy | forward genetic screen | mouse

Research has been conducted on EphB/EphrinB receptors. Results indicate that beta-catenin and TCF control the expression of these receptors and their ligand ephrin-B1 in colorectal cancer.

The apoptosis of cells is necessary during development to establish normal organ size and architecture. The caspase cascade is an important component of the cell death machinery. Investigations of the requirement of various mammalian cells for two components of these cascade, caspase 9 (Casp9) and caspase 3 (Casp3) revealed that there are four cellular death pathways wherein the requirements for Casp9 and Casp3 differ.

Two mutations in the mouse germline were generated to address the biological functions of the Eph family member Nuk. The two mutations are a protein null allele (Nuk1) and an allele that encodes a Nuk-beta gal fusion receptor whose tyrone kinase and C-terminal domains are absent. Most axons forming the anterior commissure's posterior tract aberrantly migrate to the brain's floor in Nuk1 homozygous brains. This prevents cortical neurons from linking the two temporal lobes. Results demonstrate the role of Nuk in pathfinding specific axons in the mammalian central nervous system.

Aberrant regulation of programmed cell death (PCD) has been tied to an array of human pathologies ranging from cancers to autoimmune disorders to diverse forms of neurodegeneration. Pharmacologic modulation of PCD signalling is therefore of central interest to a number of clinical and biomedical applications. A key component of PCD signalling involves the modulation of pro‐ and anti‐apoptotic Bcl‐2 family members. Among these, Bax translocation represents a critical regulatory phase in PCD. In the present study, we have employed a high‐content high‐throughput screen to identify small molecules which inhibit the cellular process of Bax re‐distribution to the mitochondria following commitment of the cell to die. Screening of 6246 Generally Recognized As Safe compounds from four chemical libraries post‐induction of cisplatin‐mediated PCD resulted in the identification of 18 compounds which significantly reduced levels of Bax translocation. Further examination revealed protective effects via reduction of executioner caspase activity and enhanced mitochondrial function. Consistent with their effects on Bax translocation, these compounds exhibited significant rescue against in vitro and in vivo cisplatin‐induced apoptosis. Altogether, our findings identify a new set of clinically useful small molecules PCD inhibitors and highlight the role which cAMP plays in regulating Bax‐mediated PCD. [ABSTRACT FROM AUTHOR]

Therapeutic antibodies (e.g., trastuzumab, TRA) against human epidermal growth factor receptor 2 (HER2)-positive breast cancers have shown benefits in controlling primary tumors, yet are ineffective against brain metastases due to their inability to cross the blood-brain barrier (BBB). A novel hybrid nanoconstruct system is designed to deliver trastuzumab to brain metastasis of HER2-positive breast cancer via a two-step sequential targeting approach. Self-assembly of a polysorbate 80 (PS 80)-containing polymer, lipid, and polymer-conjugated TRA forms hybrid nanoconstructs (TRA-terpolymer nanoparticles (TPN)) with high encapsulation efficiency and bioactivity. The PS 80 moiety enables the first-step targeting and receptor-mediated trancytosis across BBB is demonstrated in vitro with a 3D human BBB model in healthy and brain tumor-bearing mice. The subsequent partial dissociation of the nanoconstructs exposes the encapsulated TRA for the second-step targeting to HER2-positive cancer cells in the brain. Intravenously injected TRA- TPN delivers 50-fold TRA compared to free TRA to the brain metastasis of HER2-positive breast cancer. Treatment with TRA-TPN increases tumor cell apoptosis by 4-fold, inhibits tumor growth by 43-fold, and prolongs median survival by >1.3-fold compared to free TRA, without causing noticeable organ toxicity. These findings suggest the two-step targeted nanoconstruct system is promising for shuttling therapeutic antibodies to treat central nervous system diseases. [ABSTRACT FROM AUTHOR]