Surveillance for Anthrax Cases Associated with Contaminated Letters, New Jersey, Delaware, and Pennsylvania, 2001

In October 2001, two inhalational anthrax and four cutaneous anthrax cases, resulting from the processing of Bacillus anthracis–containing envelopes at a New Jersey mail facility, were identified. Subsequently, we initiated stimulated passive hospital-based and enhanced passive surveillance for anthrax-compatible syndromes. From October 24 to December 17, 2001, hospitals reported 240,160 visits and 7,109 intensive-care unit admissions in the surveillance area (population 6.7 million persons). Following a change to reporting criteria on November 8, the average of possible inhalational anthrax reports decreased 83% from 18 to 3 per day; the proportion of reports requiring follow-up increased from 37% (105/286) to 41% (47/116). Clinical follow-up was conducted on 214 of 464 possible inhalational anthrax patients and 98 possible cutaneous anthrax patients; 49 had additional laboratory testing. No additional cases were identified. To verify the limited scope of the outbreak, surveillance was essential, though labor-intensive. The flexibility of the system allowed interim evaluation, thus improving surveillance efficiency

Role of the Small GTPase Rho3 in Golgi/Endosome Trafficking through Functional Interaction with Adaptin in Fission Yeast

BACKGROUND: We had previously identified the mutant allele of apm1(+) that encodes a homolog of the mammalian µ1A subunit of the clathrin-associated adaptor protein-1 (AP-1) complex, and we demonstrated the role of Apm1 in Golgi/endosome trafficking, secretion, and vacuole fusion in fission yeast. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we isolated rho3(+), which encodes a Rho-family small GTPase, an important regulator of exocystosis, as a multicopy-suppressor of the temperature-sensitive growth of the apm1-1 mutant cells. Overexpression of Rho3 suppressed the Cl(-) sensitivity and immunosuppressant sensitivity of the apm1-1 mutant cells. Overexpression of Rho3 also suppressed the fragmentation of vacuoles, and the accumulation of v-SNARE Syb1 in Golgi/endosomes and partially suppressed the defective secretion associated with apm1-deletion cells. Notably, electron microscopic observation of the rho3-deletion cells revealed the accumulation of abnormal Golgi-like structures, vacuole fragmentation, and accumulation of secretory vesicles; these phenotypes were very similar to those of the apm1-deletion cells. Furthermore, the rho3-deletion cells and apm1-deletion cells showed very similar phenotypic characteristics, including the sensitivity to the immunosuppressant FK506, the cell wall-damaging agent micafungin, Cl(-), and valproic acid. Green fluorescent protein (GFP)-Rho3 was localized at Golgi/endosomes as well as the plasma membrane and division site. Finally, Rho3 was shown to form a complex with Apm1 as well as with other subunits of the clathrin-associated AP-1 complex in a GTP- and effector domain-dependent manner. CONCLUSIONS/SIGNIFICANCE: Taken together, our findings reveal a novel role of Rho3 in the regulation of Golgi/endosome trafficking and suggest that clathrin-associated adaptor protein-1 and Rho3 co-ordinate in intracellular transport in fission yeast. To the best of our knowledge, this study provides the first evidence of a direct link between the small GTPase Rho and the clathrin-associated adaptor protein-1 in membrane trafficking

Environmental Coordination in Health and Disease

Life has evolved within a dynamic environment. In order to anticipate and prepare for recurrent environmental changes, organisms have internalized biological solutions to challenges imposed through sensory stimuli. Circadian rhythms have evolved to provide synchrony with the predictable daily oscillators of environmental cues, and interactions among circadian oscillators throughout the brain and the body influence the adaptive coordination of the organism as a whole. To abstract relevant information, organisms must constantly sample not only rhythmic features from the environment— such as light— but also more transient stimuli— such as olfactory cues. Olfaction allows for active sampling of crucial survival information including predator identification, social recognition, and sourcing of food. Importantly, odor stimuli exert powerful control over learning and memory networks through the unique anatomical structure of olfactory pathways, which in turn predispose the olfactory system to be more vulnerable to neurodegenerative diseases. This research examines how desynchrony between internal biology and external cues can impact overall organismal health, and in turn how neurodegenerative disease alters perception of environmental stimuli. First, I examine how internal desynchrony within the molecular machinery of the circadian clock affects behavior in the face of environmental challenge by testing the hypothesis that a core circadian clock gene, per2, is responsible for circadian clock responses to light. Lack of functional per2 prevents the normal circadian period lengthening and compression of active period in response to light by increasing the magnitude of phase advance in response to late evening/early morning light and decreasing the magnitude of phase delay in response to early evening light (Chapter 3). In this way, destabilization of the internal biological clock machinery through the functional mutation of the per2 gene can affect the behavioral response to environmental stimuli. Experiments in Chapter 4 disrupted circadian rhythms by manipulating exogenous stimuli: the timing of light and food, to examine whether circadian disruption exacerbated symptoms of neurodegenerative disease. In the APP/PS1-21 mouse model of Alzheimer’s Disease (AD), mice were fed either only at night or only during the day, the latter of which induced internal circadian desynchrony. Circadian desynchrony itself idiosyncratically altered performance in some behavioral cognitive and emotional tests, but it did not clearly exacerbate AD behavioral pathology. Finally, in Chapter 5, I aimed to characterize how neurodegenerative disease alters perception of environmental cues, by characterizing olfactory dysfunction in this same model of AD during the initial stage of disease. An objective of this study was to identify behavioral markers for diagnosis of AD early in development (Chapter 5). APP/PS1-21 mice at the initial stages of pathology show reduced discrimination between odorants in a non-rewarded paradigm. However, discrimination was recovered under conditions of reward, indicating that mice may be able to recruit other neural systems to compensate for impaired olfaction, when sufficiently motivated by appetitive stimuli. This presents olfactory discrimination as a potential site for behavioral diagnosis of early-stage AD. Together, these experiments identify novel interactions among sensory features of the environment and their influence on brain function, behavior, and symptoms of disease