At synapses, the release of neurotransmitter is regulated by molecular machinery that aggregates at specialized presynaptic release sites termed active zones. The complement of active zone proteins at each site is a determinant of release efficacy and can be remodeled to alter synapse function. The small GTPase Rab3 was previously identified as playing a novel role that controls the distribution of active zone proteins to individual release sites at the Drosophila neuromuscular junction. Rab3 has been extensively studied for its role in the synaptic vesicle cycle; however, the mechanism by which Rab3 controls active zone development remains unknown. To explore this mechanism, we conducted a mutational analysis to determine the molecular and structural requirements of Rab3 function at Drosophila synapses. We find that GTP-binding is required for Rab3 to traffick to synapses and distribute active zone components across release sites. Conversely, the hydrolytic activity of Rab3 is unnecessary for this function. Through a structure-function analysis we identify specific residues within the effector-binding switch regions that are required for Rab3 function and determine that membrane attachment is essential. Our findings suggest that Rab3 controls the distribution of active zone components via a vesicle docking mechanism that is consistent with standard Rab protein function.

The synthetic estrogen 17α-ethinylestradiol (EE2) is an endocrine-disrupting chemical released into aquatic environments from sewage treatment facilities. We tested the effects of two environmentally relevant concentrations of waterborne EE2, 10 and 100 ng L(-1) , on reproductive endpoints in the teleost fish Betta splendens. In the first experiment, testes were removed from males and sperm were exposed to EE2 directly through the activation water. Direct exposure to EE2 had no effect on any measure of sperm swimming performance. In the second experiment, we exposed sexually mature male B. splendens to EE2 using a semi-static exposure protocol for 4 weeks. There were no significant treatment effects in the 10 ng L(-1) treatment group, but at the 100 ng L(-1) dose we found that fish had smaller gonads and reduced sperm swimming velocity. When allowed to interact freely with female conspecifics, males exposed to 100 ng L(-1) EE2 built smaller nests and showed a nonsignificant decrease in fertilization success. To investigate further the potential mechanism underlying the decrease in sperm quality, we repeated the chronic exposure experiment and analyzed the ATP content of sperm from fish in each treatment group. We found that males exposed to 100 ng L(-1) of EE2 had fewer moles of ATP per sperm than did fish in the other two treatment groups, suggesting that a decrease in intracellular ATP caused a reduction in sperm swimming velocity. The current study adds to the growing body of literature that indicates the risks to aquatic organisms of exposure to environmentally relevant concentrations of EE2.

Patient: Female, 14-year-old Final Diagnosis: Retinal vasculitis Symptoms: Itchy eyes Medication: — Clinical Procedure: — Specialty: Rheumatology Objective: Unusual clinical course Background: Systemic lupus erythematosus (SLE) can involve any part of the eye. Keratoconjunctivitis sicca (dry eye) is the most common ocular manifestation, followed by scleritis, episcleritis, and retinitis. Retinal disease affects around 10% of patients with SLE. Mild retinopathy may be asymptomatic. However, severe cases can cause visual loss requiring urgent ophthalmic evaluation. Case Report: We present a case of bilateral retinal vasculitis as the presenting manifestation of SLE. A 14-year-old girl with a history of schizophrenia presented to the emergency department (ED) with generalized weakness. Four days before her presentation, she developed itching in her eyes and frontal headaches. In the ED, she reported blurry vision in her left eye only and diffuse arthralgia. The ophthalmic evaluation showed bilateral reduced visual acuity, worse in the left eye. Both eyes had diffuse hemorrhages, white retinal lesions, and blurred optic disc margins. She was diagnosed with panuveitis and retinal vasculitis. The patient was then found to have SLE, diagnosed by the presence of arthralgias, panuveitis, severe bilateral retinal vasculitis, positive ANA and anti-dsDNA, and normocytic anemia. The patient received intravenous methylprednisolone with subsequent oral prednisone upon discharge, hydroxychloroquine, and azathioprine. One year after her presentation, she had significant visual improvement and no other system involvement. Conclusions: Retinal vasculitis, as the presenting symptom of SLE, has been overlooked in large studies. However, the number of case reports documenting this as a presenting symptom, often with minimal or no organ involvement, suggests that upon diagnosis, patients might benefit from a skilled ophthalmic evaluation.

Patient: Male, 68-year-old Final Diagnosis: Sarcoidosis • vasculitis Symptoms: Syncope Medication:— Clinical Procedure: — Specialty: Rheumatology Objective: Rare co-existance of disease or pathology Background: Cardiac sarcoidosis and large-vessel vasculitis are both rare diseases with a variety of presenting symptoms. Both can result in high morbidity and mortality if not diagnosed early. While they are each relatively uncommon on their own, there have been a few reports suggesting they may be more related than previously thought. This case report suggests that the 2 diseases can become symptomatic concurrently, complicating diagnosis. Case Report: A 68-year-old male patient was diagnosed concurrently with cardiac sarcoidosis and vasculitis after several episodes of syncope thought to be due to arrhythmia. The patient was treated with high-dose corticosteroids, and repeat imaging showed decreased inflammatory changes in the cardiac tissue and large blood vessels. Conclusions: Prior case reports have described vasculitis and sarcoidosis in the same patient; however, these patients usually had a long history of known sarcoidosis involving several organ systems. This case suggests that physicians should be alert to more limited forms of the disease in a patient with cardiac myopathy of unknown origin with new arrythmia. More research is also needed to determine how granulomatous disease and vasculitis are related to each other.

Sperm collected from male fighting fish Betta splendens were activated in control water, water containing the ion-channel blocker gadolinium (a putative positive control), or water containing the isoflavone phytoestrogen genistein to determine the effects of acute genistein exposure on male reproductive function. Computer-assisted sperm analysis was used to quantify the proportion of sperm that were motile and the swimming velocity of those sperm. The highest concentration of gadolinium (100 μM) tested was effective at reducing sperm motility and velocity, but neither concentration of genistein tested (3.7 nM or 3.7 μM) significantly affected these sperm parameters. Our findings suggest that acute exposure to waterborne phytoestrogens during activation does not reduce the motility of fish sperm.