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Protein lifespan is regulated by co-translational modification by several enzymes, including methionine aminopeptidases and N-alpha-aminoterminal acetyltransferases. The NatB enzymatic complex is an N-terminal acetyltransferase constituted by two subunits, NAA20 and NAA25, whose interaction is necessary to avoid NAA20 catalytic subunit degradation. We found that deletion of the first five amino acids of hNAA20 or fusion of a peptide to its amino terminal end abolishes its interaction with hNAA25. Substitution of the second residue of hNAA20 with amino acids with small, uncharged side-chains allows NatB enzymatic complex formation. However, replacement by residues with large or charged side-chains interferes with its hNAA25 interaction, limiting functional NatB complex formation. Comparison of NAA20 eukaryotic sequences showed that the residue following the initial methionine, an amino acid with a small uncharged side-chain, has been evolutionarily conserved. We have confirmed the relevance of second amino acid characteristics of NAA20 in NatB enzymatic complex formation in Drosophila melanogaster. Moreover, we have evidenced the significance of NAA20 second residue in Saccharomyces cerevisiae using different NAA20 versions to reconstitute NatB formation in a yNAA20-KO yeast strain. The requirement in humans and in fruit flies of an amino acid with a small uncharged side-chain following the initial methionine of NAA20 suggests that methionine aminopeptidase action may be necessary for the NAA20 and NAA25 interaction. We showed that inhibition of MetAP2 expression blocked hNatB enzymatic complex formation by retaining the initial methionine of NAA20. Therefore, NatB-mediated protein N-terminal acetylation is dependent on methionine aminopeptidase, providing a regulatory mechanism for protein N-terminal maturation.

Contains fulltext : 225281.pdf (Publisher’s version ) (Closed access) Contains fulltext : 225281pos.pdf (Author’s version postprint ) (Open Access) BACKGROUND & AIMS: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of multiple biliary cysts. Recently, novel PLD-causative genes, encoding for endoplasmic reticulum (ER)-resident proteins involved in protein biogenesis and transport, were identified. We hypothesized that aberrant proteostasis contributes to PLD pathogenesis, representing a potential therapeutic target. METHODS: ER stress was analysed at transcriptional (qPCR), proteomic (mass spectrometry), morphological (transmission electron microscopy, TEM) and functional (proteasome activity) levels in different PLD models. The effect of ER stress inhibitors [4-phenylbutyric acid (4-PBA)] and/or activators [tunicamycin (TM)] was tested in polycystic (PCK) rats and cystic cholangiocytes in vitro. RESULTS: The expression levels of unfolded protein response (UPR) components were upregulated in liver tissue from PLD patients and PCK rats, as well as in primary cultures of human and rat cystic cholangiocytes, compared to normal controls. Cystic cholangiocytes showed altered proteomic profiles, mainly related to proteostasis (ie synthesis, folding, trafficking and degradation of proteins), marked enlargement of the ER lumen (by TEM) and hyperactivation of the proteasome. Notably, chronic treatment of PCK rats with 4-PBA decreased liver weight, as well as both liver and cystic volumes, of animals under baseline conditions or after TM administration compared to controls. In vitro, 4-PBA downregulated the expression (mRNA) of UPR effectors, normalized proteomic profiles related to protein synthesis, folding, trafficking and degradation and reduced the proteasome hyperactivity in cystic cholangiocytes, reducing their hyperproliferation and apoptosis. CONCLUSIONS: Restoration of proteostasis in cystic cholangiocytes with 4-PBA halts hepatic cystogenesis, emerging as a novel therapeutic strategy.

Criticism of the Centers for Disease Control and Prevention (CDC) and its efforts to put forth recommendations and data based on core public health practice and principles is contrary to the realities of the work that the CDC has done on preparedness in past decades In 2001, the CDC funded a project intended to facilitate the development of an integrated national system of Academic Centers for Public Health Preparedness (CPHPs) to train frontline public health professionals who respond to bioterrorist incidents and other emerging infectious diseases Nineteen CPHPs were funded until the program was discontinued in August 2010 and replaced by 14 Preparedness and Emergency Response Learning Centers, whose funding ended in 2018 2 CPHPs worked to identify core principles for public health preparedness and response, strategies for local and state data collection, and curricula and best practices for educating the public health and first responder workforce

CONTEXT In March, 2020, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19), was spreading in the Bay Area, especially in Santa Clara County, causing increases in cases, hospitalizations, and deaths. PROGRAM The Association of Bay Area Health Officials (ABAHO) represents 13 Bay Area health jurisdictions. IMPLEMENTATION On March 15, 2020, the local health officers of 7 ABAHO members (counties of Alameda, Contra Costa, Marin, San Francisco, San Mateo, and Santa Clara and the city of Berkeley) decided to issue legal orders on March 16 for 6.7 million residents to shelter in place to prevent the spread of SARS-CoV-2, the causal agent of COVID-19. The Bay Area was the first region in the United States to shelter in place, and within days, other regions in the United States followed. EVALUATION Subsequent comparative analyses have confirmed that acting early in issuing shelter-in-place orders prevented a large number of cases, hospitalizations, and deaths in the Bay Area throughout the United States. The quality of a decision-in this case, for crisis decision making-cannot be judged by the outcome. A good decision can have a bad outcome, and a bad decision can have a good outcome. The quality of a decision depends only on the quality of the decision-making process at the time the decision was made. DISCUSSION In this Field Report, we review how we made this collective decision. With the benefit of hindsight and reflection, we recount our story through the lens of public health legal authority, meta-leadership, and decision intelligence. Our purpose is to improve the crisis decision-making skills of public health officials by improving how we make high-stakes decisions each day in our continuing fight to contain the SARS-CoV-2 pandemic, to save lives, and to eliminate COVID-19 racial/ethnic inequities.

Tight control of transgene expression is key to ensure the efficacy of a wide range of gene therapy interventions, in which the magnitude and duration of gene expression have to be adjusted to therapeutic needs, thereby limiting secondary effects. The development of upgraded strategies to link transgene expression to pathological stress episodes is an unmet need in gene therapy. Here, we propose an expression strategy that associates transgene expression to an intracellular stress coping mechanism, the unfolded protein response. Specifically, we harnessed the

Loss of protein folding homeostasis features many of the most prevalent neurodegenerative disorders. As coping mechanism to folding stress within the endoplasmic reticulum (ER), the unfolded protein response (UPR) comprises a set of signaling mechanisms that initiate a gene expression program to restore proteostasis, or when stress is chronic or overwhelming promote neuronal death. This fate-defining capacity of the UPR has been proposed to play a key role in amyotrophic lateral sclerosis (ALS). However, the several genetic or pharmacological attempts to explore the therapeutic potential of UPR modulation have produced conflicting observations. In order to establish the precise relationship between UPR signaling and neuronal death in ALS, we have developed a neuronal model where the toxicity of a familial ALS-causing allele (mutant G93A SOD1) and UPR activation can be longitudinally monitored in single neurons over the process of neurodegeneration by automated microscopy. Using fluorescent UPR reporters we established the temporal and causal relationship between UPR and neuronal death by Cox regression models. Pharmacological inhibition of discrete UPR processes allowed us to establish the contribution of PERK (PKR-like ER kinase) and IRE1 (inositol-requiring enzyme-1) mechanisms to neuronal fate. Importantly, inhibition of PERK signaling with its downstream inhibitor ISRIB, but not with the direct PERK kinase inhibitor GSK2606414, significantly enhanced the survival of G93A SOD1-expressing neurons. Characterization of the inhibitory properties of both drugs under ER stress revealed that in neurons (but not in glial cells) ISRIB overruled only part of the translational program imposed by PERK, relieving the general inhibition of translation, but maintaining the privileged translation of ATF4 (activating transcription factor 4) messenger RNA. Surprisingly, the fine-tuning of the PERK output in G93A SOD1-expressing neurons led to a reduction of IRE1-dependent signaling. Together, our findings identify ISRIB-mediated translational reprogramming as a new potential ALS therapy.

Alpha-synuclein (aSyn) protein levels are sufficient to drive Parkinson's disease (PD) and other synucleinopathies. Despite the biomedical/therapeutic potential of aSyn protein regulation, little is known about mechanisms that limit/control aSyn levels. Here, we investigate the role of a post-translational modification, N-terminal acetylation, in aSyn neurotoxicity. N-terminal acetylation occurs in all aSyn molecules and has been proposed to determine its lipid binding and aggregation capacities; however, its effect in aSyn stability/neurotoxicity has not been evaluated. We generated N-terminal mutants that alter or block physiological aSyn N-terminal acetylation in wild-type or pathological mutant E46K aSyn versions and confirmed N-terminal acetylation status by mass spectrometry. By optical pulse-labeling in living primary neurons we documented a reduced half-life and accumulation of aSyn N-terminal mutants. To analyze the effect of N-terminal acetylation mutants in neuronal toxicity we took advantage of a neuronal model where aSyn toxicity was scored by longitudinal survival analysis. Salient features of aSyn neurotoxicity were previously investigated with this approach. aSyn-dependent neuronal death was recapitulated either by higher aSyn protein levels in the case of WT aSyn, or by the combined effect of protein levels and enhanced neurotoxicity conveyed by the E46K mutation. aSyn N-terminal mutations decreased E46K aSyn-dependent neuronal death both by reducing protein levels and, importantly, by reducing the intrinsic E46K aSyn toxicity, being the D2P mutant the least toxic. Together, our results illustrate that the N-terminus determines, most likely through its acetylation, aSyn protein levels and toxicity, identifying this modification as a potential therapeutic target.

Since its discovery more than 25 years ago, great progress has been made in our understanding of the unfolded protein response (UPR), a homeostatic mechanism that adjusts endoplasmic reticulum (ER) function to satisfy the physiological demands of the cell. However, if ER homeostasis is unattainable, the UPR switches to drive cell death to remove defective cells in an effort to protect the health of the organism. This functional dichotomy places the UPR at the crossroads of the adaptation versus apoptosis decision. Here, we focus on new developments in UPR signaling mechanisms, in the interconnectivity among the signaling pathways that make up the UPR in higher eukaryotes, and in the coordination between the UPR and other fundamental cellular processes.

Background & Aims HDV infection induces the most severe form of human viral hepatitis. However, the specific reasons for the severity of the disease remain unknown. Recently, we developed an HDV replication mouse model in which, for the first time, liver damage was detected. Methods HDV and HBV replication-competent genomes and HDV antigens were delivered to mouse hepatocytes using adeno-associated vectors (AAVs). Aminotransferase elevation, liver histopathology, and hepatocyte death were evaluated and the immune infiltrate was characterized. Liver transcriptomic analysis was performed. Mice deficient for different cellular and molecular components of the immune system, as well as depletion and inhibition studies, were employed to elucidate the causes of HDV-mediated liver damage. Results AAV-mediated HBV/HDV coinfection caused hepatocyte necrosis and apoptosis. Activated T lymphocytes, natural killer cells, and proinflammatory macrophages accounted for the majority of the inflammatory infiltrate. However, depletion studies and the use of different knockout mice indicated that neither T cells, natural killer cells nor macrophages were necessary for HDV-induced liver damage. Transcriptomic analysis revealed a strong activation of type I and II interferon (IFN) and tumor necrosis factor (TNF)-α pathways in HBV/HDV-coinfected mice. While the absence of IFN signaling had no effect, the use of a TNF-α antagonist resulted in a significant reduction of HDV-associated liver injury. Furthermore, hepatic expression of HDAg resulted in the induction of severe liver damage, which was T cell- and TNF-α-independent. Conclusions Both host (TNF-α) and viral (HDV antigens) factors play a relevant role in HDV-induced liver damage. Importantly, pharmacological inhibition of TNF-α may offer an attractive strategy to aid control of HDV-induced acute liver damage. Lay summary Chronic hepatitis delta constitutes the most severe form of viral hepatitis. There is limited data on the mechanism involved in hepatitis delta virus (HDV)-induced liver pathology. Our data indicate that a cytokine (TNF-α) and HDV antigens play a relevant role in HDV-induced liver damage., Graphical abstract, Highlights • There is limited data on the mechanisms involved in HDV-induced liver pathology. • Our data indicate that both TNF-α and HDV antigens play a relevant role in HDV-induced liver damage. • Pharmacological inhibition of TNF-α may offer an attractive strategy to aid control of HDV-induced acute liver damage.

Background Endoplasmic reticulum (ER) stress results from protein misfolding imbalance and has been postulated as a therapeutic strategy. ER stress activates the unfolded protein response which leads to a complex cellular response, including the upregulation of aberrant protein degradation in the ER, with the goal of resolving that stress. O(6)-methylguanine DNA methyltransferase (MGMT), N-methylpurine DNA glycosylase (MPG), and Rad51 are DNA damage repair proteins that mediate resistance to temozolomide in glioblastoma. In this work we sought to evaluate whether ER stress-inducing drugs were able to downmodulate DNA damage repair proteins and become candidates to combine with temozolomide. Methods MTT assays were performed to evaluate the cytotoxicity of the treatments. The expression of proteins was evaluated using western blot and immunofluorescence. In vivo studies were performed using 2 orthotopic glioblastoma models in nude mice to evaluate the efficacy of the treatments. All statistical tests were 2-sided. Results Treatment of glioblastoma cells with ER stress-inducing drugs leads to downregulation of MGMT, MPG, and Rad51. Inhibition of ER stress through pharmacological treatment resulted in rescue of MGMT, MPG, and Rad51 protein levels. Moreover, treatment of glioblastoma cells with salinomycin, an ER stress-inducing drug, and temozolomide resulted in enhanced DNA damage and a synergistic antitumor effect in vitro. Of importance, treatment with salinomycin/temozolomide resulted in a significant antiglioma effect in 2 aggressive orthotopic intracranial brain tumor models. Conclusions These findings provide a strong rationale for combining temozolomide with ER stress-inducing drugs as an alternative therapeutic strategy for glioblastoma.

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH., Alcoholic hepatitis, a common cause of liver failure, lacks effective treatment. Here, the authors show altered hepatic HNF4a isoform expression and hypermethylation of its target genes in patients. HNF4a dysregulation is improved in vitro by TGFb or PPARg modulation suggesting potential therapeutic avenues.

Early life events are associated with the susceptibility to chronic diseases in adult life. Perturbations of endoplasmic reticulum (ER) homeostasis activate the unfolded protein response (UPR), which contributes to the development of metabolic alterations. Our aim was to evaluate liver UPR in an animal model of intrauterine growth restriction (IUGR). A significantly increased expression of X-box binding protein-1 spliced (XBP1s) mRNA (p

Author(s): Grumbach, Kevin; Vargas, Roberto A; Fleisher, Paula; Aragon, Tomas J; Chung, Lisa; Chawla, Colleen; Yant, Abbie; Garcia, Estela R; Santiago, Amor; Lang, Perry L; Jones, Paula; Liu, Wylie; Schmidt, Laura A | Abstract: BackgroundThe San Francisco Health Improvement Partnership (SFHIP) promotes health equity by using a novel collective impact model that blends community engagement with evidence-to-policy translational science. The model involves diverse stakeholders, including ethnic-based community health equity coalitions, the local public health department, hospitals and health systems, a health sciences university, a school district, the faith community, and others sectors.Community contextWe report on 3 SFHIP prevention initiatives: reducing consumption of sugar sweetened beverages (SSBs), regulating retail alcohol sales, and eliminating disparities in children's oral health.MethodsSFHIP is governed by a steering committee. Partnership working groups for each initiative collaborate to 1) develop and implement action plans emphasizing feasible, scalable, translational-science-informed interventions and 2) consider sustainability early in the planning process by including policy and structural interventions.OutcomeThrough SFHIP's efforts, San Francisco enacted ordinances regulating sale and advertising of SSBs and a ballot measure establishing a soda tax. Most San Francisco hospitals implemented or committed to implementing healthy-beverage policies that prohibited serving or selling SSBs. SFHIP helped prevent Starbucks and Taco Bell from receiving alcohol licenses in San Francisco and helped prevent state authorization of sale of powdered alcohol. SFHIP increased the number of primary care clinics providing fluoride varnish at routine well-child visits from 3 to 14 and acquired a state waiver to allow dental clinics to be paid for dental services delivered in schools.InterpretationThe SFHIP model of collective impact emphasizing community engagement and policy change accomplished many of its intermediate goals to create an environment promoting health and health equity.

In this article, we describe the San Francisco Department of Public Health's (SFDPH's) framework for developing evidence-based screening and vaccination recommendations. We first reviewed our local data using surveillance and syndemic data. We then compiled and compared existing federal, state, and local recommendations. Then we identified differences as compared with our local evidence; where more evidence was required to make a recommendation, we culled from additional data sources and conducted additional analyses. Lastly, we developed our guidelines by confirming existing recommendations or making new recommendations based on this process. In the end, we successfully developed evidence-based clinical screening and prevention guidelines that have been adopted by the SFDPH Health Commission. We encourage the use of this framework in other public health settings at the local level.

Acute intermittent porphyria (AIP) is a hepatic metabolic disease that results from haplo-insufficient activity of porphobilinogen deaminase (PBGD). The dominant clinical feature is acute intermittent attacks when hepatic heme synthesis is activated by endocrine or exogenous factors. Gene therapy vectors over-expressing PBGD protein in the liver offers potential as a cure for AIP. Here, we developed a helper-dependent adenovirus (HDA) encoding human PBGD (hPBGD) and assessed its therapeutic efficacy in a murine model of AIP. Intravenous or intrahepatic administration of HDA-hPBGD to AIP mice resulted in a sustained hepatic hPBGD expression in a dose-dependent manner. Intrahepatic administration conveyed full protection against induced porphyria attacks at a significantly lower viral dose than intravenous injection. Transgenic hPBGD accumulated only in the cytosol of hepatocytes as the endogenous protein. Characterization of PBGD-deficient mouse strains revealed that a strong PBGD deficiency causes the chronic disturbance of cytosolic and endoplasmic reticulum folding machineries. This disturbance was completely restored over time by the over-expression of hPBGD. HDA-hPBGD is a promising vector that protects against porphyria attacks and resolves the chronic folding stress associated with low levels of PBGD activity.

The unfolded protein response (UPR) allows cells to adjust secretory pathway capacity according to need. Ire1, the endoplasmic reticulum (ER) stress sensor and central activator of the UPR is conserved from the budding yeast Saccharomyces cerevisiae to humans. Under ER stress conditions, Ire1 clusters into foci that enable optimal UPR activation. To discover factors that affect Ire1 clustering, we performed a high-content screen using a whole-genome yeast mutant library expressing Ire1–mCherry. We imaged the strains following UPR induction and found 154 strains that displayed alterations in Ire1 clustering. The hits were enriched for iron and heme effectors and binding proteins. By performing pharmacological depletion and repletion, we confirmed that iron (Fe3+) affects UPR activation in both yeast and human cells. We suggest that Ire1 clustering propensity depends on membrane composition, which is governed by heme-dependent biosynthesis of sterols. Our findings highlight the diverse cellular functions that feed into the UPR and emphasize the cross-talk between organelles required to concertedly maintain homeostasis., Highlighted Article: To respond to folding stress in the ER, cells activate the conserved sensor Ire1. We show that iron is required for optimal Ire1 activation and suggest this is because iron is required for ergosterol biosynthesis.

Background & Aims Liver regeneration after partial hepatectomy (PH) increases the protein folding burden at the endoplasmic reticulum of remnant hepatocytes, resulting in induction of the unfolded protein response. We investigated the role of the core unfolded protein response transcription factor X-box binding protein 1 (XBP1) in liver regeneration using genome-wide chromatin immunoprecipitation analysis. Methods We performed studies with C57Bl6-J (control) and interleukin 6-knockout mice. Mice underwent PH or sham surgeries. In some mice, hepatic expression of XBP1 was knocked down by injection of adenoviral vectors encoding small hairpin RNAs against Xbp1 messenger RNA. Liver tissues were collected before surgery and at 6 and 48 hours after surgery and analyzed by chromatin immunoprecipitation followed by sequencing. We also performed functional analyses of HepG2 cells. Results Expression of XBP1 by hepatocytes increased immediately after PH (priming phase of liver regeneration) in control mice, but this effect was delayed in interleukin 6-deficient mice. In mice with knockdown of XBP1, we observed of liver tissue persistent endoplasmic reticulum stress, defects in acute-phase response, and increased hepatocellular damage, compared with control mice. Chromatin immunoprecipitation analyses of liver tissue showed that at 6 hours after PH, liver XBP1 became bound to a large set of genes implicated in proteostasis, the acute-phase response, metabolism, and the DNA damage response (DDR). At this time point, XBP1 bound the promoter of the signal transducer and activator of transcription 3 gene ( Stat3 ). Livers of XBP1-knockdown mice showed reduced expression of STAT3 and had lower levels of STAT3 phosphorylation at Ser727, a modification that promotes cell proliferation and the DDR. Regenerating livers from XBP1-knockdown mice expressed high levels of a marker of DNA double-strand breaks, phosphorylated histone 2A, member X (H2AX), compared with control mice. The inhibition of XBP1 expression caused a reduced up-regulation of DDR messenger RNAs in regenerating hepatocytes. Conclusion In livers of mice, we found that PH induces expression of XBP1, and that this activity requires interleukin 6. XBP1 expression regulates the unfolded protein response, acute-phase response, and DDR in hepatocytes. In regenerating livers, XBP1 deficiency leads to endoplasmic reticulum stress and DNA damage.

The unfolded protein response (UPR) governs homeostasis of both luminal content and membrane of the endoplasmic reticulum (ER). In Molecular Cell, Halbleib et al. identified how a twist in the juxta-membrane amphipathic helix of the UPR transducer Ire1 in yeast is essential for responding to both proteostatic and lipostatic ER stress.

Deficiencies in the protein-folding capacity of the endoplasmic reticulum (ER) in all eukaryotic cells lead to ER stress and trigger the unfolded protein response (UPR). ER stress is sensed by Ire1, a transmembrane kinase/endoribonuclease, which initiates the non-conventional splicing of the messenger RNA encoding a key transcription activator, Hac1 in yeast or XBP1 in metazoans. In the absence of ER stress, ribosomes are stalled on unspliced HAC1 mRNA. The translational control is imposed by a base-pairing interaction between the HAC1 intron and the HAC1 5' untranslated region. After excision of the intron, transfer RNA ligase joins the severed exons, lifting the translational block and allowing synthesis of Hac1 from the spliced HAC1 mRNA to ensue. Hac1 in turn drives the UPR gene expression program comprising 7-8% of the yeast genome to counteract ER stress. Here we show that, on activation, Ire1 molecules cluster in the ER membrane into discrete foci of higher-order oligomers, to which unspliced HAC1 mRNA is recruited by means of a conserved bipartite targeting element contained in the 3' untranslated region. Disruption of either Ire1 clustering or HAC1 mRNA recruitment impairs UPR signalling. The HAC1 3' untranslated region element is sufficient to target other mRNAs to Ire1 foci, as long as their translation is repressed. Translational repression afforded by the intron fulfils this requirement for HAC1 mRNA. Recruitment of mRNA to signalling centres provides a new paradigm for the control of eukaryotic gene expression.

MAJOR ARTICLE Case-Control Study of Shigellosis in San Francisco: The Role of Sexual Transmission and HIV Infection Toma´s J. Arago´n, 1,2 Duc J. Vugia, 3,4 Sue Shallow, 4 Michael C. Samuel, 4 Arthur Reingold, 2,4 Frederick J. Angulo, 5 and Williamson Z. Bradford 4 San Francisco Department of Public Health, City and County of San Francisco, San Francisco, 2 School of Public Health, University of California at Berkeley, Berkeley, 3 California Department of Health Services, Richmond, and 4 California Emerging Infections Program, Oakland, California; and 5 Centers for Disease Control and Prevention, Atlanta, Georgia (See the editorial commentary by Daskalakis and Blaser on pages 335–7) Background. Shigella species infect ∼450,000 persons annually in the United States. Person-to-person trans- mission of Shigella species, which have a low infectious dose, occurs frequently, particularly in areas with poor sanitation and hygiene. Sexual transmission of Shigella species among men who have sex with men (MSM) has been inferred from outbreaks of shigellosis among that population, and limited studies have suggested the im- portance of human immunodeficiency virus (HIV) infection as a risk factor for shigellosis. No population-based study of sporadic shigellosis has evaluated the role of sexual practices (especially among MSM) and HIV infection along with other established risk factors for shigellosis. Methods. We conducted a population-based case-control study of shigellosis in adults in San Francisco, Cal- ifornia, during the period 1998–1999. Cases of Shigella infection were identified through laboratory-based active surveillance conducted by the California Emerging Infections Program. Seventy-six case patients were matched by sex with 146 control subjects. Exposure data were collected on established risk factors, sexual practices, and HIV infection status. Bivariable and multivariable analyses were conducted. Population-attributable fractions were calculated. Results. From the multivariable analysis, for men, shigellosis was associated with MSM (odds ratio [OR], 8.24; 95% confidence interval [CI], 2.70–25.2), HIV infection (OR, 8.17; 95% CI, 2.71–24.6), direct oral-anal contact (OR, 7.50; 95% CI, 1.74–32.3), and foreign travel (OR, 20.0; 95% CI, 5.26–76.3), with population-attributable fractions of 0.72, 0.42, 0.31, and 0.18, respectively. For women, shigellosis was associated only with foreign travel (OR, 21.0; 95% CI, 2.52–899), with a population-attributable fraction of 0.37. Conclusions. Among MSM, shigellosis is predominantly a sexually transmitted disease, with direct oral-anal contact conferring the highest risk and HIV infection likely contributing to increased host susceptibility. Each year, an estimated 450,000 persons in the United States are infected with Shigella species, resulting in 6200 hospitalizations and 70 deaths [1]. Humans and other primates are the only natural reservoirs for Shi- gella species [2]. Shigella species are transmitted by the fecal-oral route, and most infections are transmitted from person to person, reflecting the low infectious dose [3]; as few as 10 viable organisms can result in clinical infection [4]. In areas in which infection is prev- Received 6 September 2006; accepted 27 September 2006; electronically published 29 December 2006. Reprints or correspondence: Dr. Toma´s J. Arago´n, School of Public Health, Div. of Epidemiology, University of California at Berkeley, 140 Warren Hall, MC-7360, Berkeley, CA 94720-7360 (aragon@berkeley.edu). Clinical Infectious Diseases 2007; 44:327–34 2006 by the Infectious Diseases Society of America. All rights reserved. alent, risk for Shigella infection increases with poor hand hygiene, ingestion of contaminated food or water, inadequate sanitation and toileting, overcrowding, and sexual contact [5–13]. Among reported culture-confirmed infections in the United States during the period 1989–2002, 72% were due to Shigella sonnei, 18% were due to Shigella flexneri, 1.6% were due to Shigella boydii, and 0.7% were due to Shigella dysenteriae [3]. Most reported cases occurred in children ! 10 years of age, followed by women 20– 39 years of age; the high rate of infection in the latter group was presumably related to caring for infected children. In the mid-1970s, shigellosis was recognized as a potentially sexually transmitted disease among men who have sex with men (MSM) [7, 14, 15]. In the late 1970s and early 1980s, the increased incidence of S. flexneri infection in men was attributed to the sexual Sexual Transmission of Shigellosis • CID 2007:44 (1 February) • 327

INFECTIOUS DISEASE/EDITORIAL Tomas J. Aragon, MD, DrPH Susan E. Fernyak, MD, MPH From the Center for Infectious Disease Preparedness, University of California–Berkeley (Aragon), Berkeley, CA; the Department of Medicine, University of California–San Francisco (Aragon, Fernyak), San Francisco, CA; and the San Francisco Department of Public Health (Aragon, Fernyak), City and County of San Francisco, CA. Editor’s note: This article was first published on Annals’ Web site (www.mosby.com/AnnEmergMed) on September 16, 2003. Articles of particular interest are published on the Web site in advance of their appearance in the print journal. In the future, an increasing percentage of our content will be published first on the Web, predat- ing the print publication as a service to our readers. Copyright © 2003 by the American College of Emergency Physicians. doi:10.1067/mem.2003.418 NOVEMBER 2003 ANNALS OF EMERGENCY MEDICINE The Risks and Benefits of Pre-event Smallpox Vaccination: Where You Stand Depends on Where You Sit See related article, p. 665, and editorial, p. 685. [Ann Emerg Med. 2003;42:681-684.] In this issue of Annals, Thorne et al 1 present a compre- hensive review of smallpox vaccination complications, as well as special issues related to smallpox vaccine programs and transmission of vaccinia. This topic is of importance to emergency physicians, who have a spe- cial role in the medical and public health response to microbial threats such as smallpox. In an outbreak, persons with smallpox are likely to seek care at emer- gency care settings even before an outbreak or release has been recognized. Like severe acute respiratory syn- drome, 2 health care workers may be infected with smallpox at higher rates unless they recognize this con- tagious threat and practice good infection control or are immune through prior successful smallpox vacci- nation. To prepare for such a scenario, the federal gov- ernment initiated the Smallpox Vaccination Program and recommended pre-event smallpox vaccination of up to 440,000 civilian public health and hospital-based personnel during the winter and spring of 2003 (Phase 1). 3 This was to be followed by Phase 2, where an addi- tional 10 million public safety and health care workers would be offered vaccine. 3 Despite federal support of this program, 37,802 civilians had been vaccinated as of June 20, 2003, 4 less than 10% of the anticipated number. Clearly, health care workers have voted with their arms on this initia

Context Extreme weather events, unpredictable and often far-reaching, constitute a persistent challenge for public health preparedness. Objective The goal of this research is to inform public health systems improvement through examination of extreme weather events, comparing across cases to identify recurring patterns in event and response characteristics. Design Structured telephone-based interviews were conducted with representatives from health departments to assess characteristics of recent extreme weather events and agencies' responses. Response activities were assessed using the Centers for Disease Control and Prevention Public Health Emergency Preparedness Capabilities framework. Challenges that are typical of this response environment are reported. Setting Forty-five local health departments in 20 US states. Results Respondents described public health system responses to 45 events involving tornadoes, flooding, wildfires, winter weather, hurricanes, and other storms. Events of similar scale were infrequent for a majority (62%) of the communities involved; disruption to critical infrastructure was universal. Public Health Emergency Preparedness Capabilities considered most essential involved environmental health investigations, mass care and sheltering, surveillance and epidemiology, information sharing, and public information and warning. Unanticipated response activities or operational constraints were common. Conclusions We characterize extreme weather events as a "quadruple threat" because (1) direct threats to population health are accompanied by damage to public health protective and community infrastructure, (2) event characteristics often impose novel and pervasive burdens on communities, (3) responses rely on critical infrastructures whose failure both creates new burdens and diminishes response capacity, and (4) their infrequency and scale further compromise response capacity. Given the challenges associated with extreme weather events, we suggest opportunities for organizational learning and preparedness improvements.

Insufficient protein-folding capacity in the endoplasmic reticulum (ER) induces the unfolded protein response (UPR). In the ER lumen, accumulation of unfolded proteins activates the transmembrane ER-stress sensor Ire1 and drives its oligomerization. In the cytosol, Ire1 recruits HAC1 mRNA, mediating its non-conventional splicing. The spliced mRNA is translated into Hac1, the key transcription activator of UPR target genes that mitigate ER-stress. In this study, we report that oligomeric assembly of the ER-lumenal domain is sufficient to drive Ire1 clustering. Clustering facilitates Ire1's cytosolic oligomeric assembly and HAC1 mRNA docking onto a positively charged motif in Ire1's cytosolic linker domain that tethers the kinase/RNase to the transmembrane domain. By the use of a synthetic bypass, we demonstrate that mRNA docking per se is a pre-requisite for initiating Ire1's RNase activity and, hence, splicing. We posit that such step-wise engagement between Ire1 and its mRNA substrate contributes to selectivity and efficiency in UPR signaling. DOI: http://dx.doi.org/10.7554/eLife.05031.001, eLife digest Proteins are built based on instructions in template molecules called messenger RNAs (or mRNAs), which are copied from the DNA of genes. As they are made, proteins must fold into a specific three-dimensional shape and some proteins pass into a compartment in the cell, called the endoplasmic reticulum, in which they fold. So-called molecular chaperone proteins assist this folding process. From the endoplasmic reticulum, most proteins travel to other destinations within or outside of the cell. If the molecular chaperones in the endoplasmic reticulum are overwhelmed by their protein folding task, unfolded proteins accumulate; a situation that can be harmful to the cell. In eukaryotic cells including yeast, a sensor protein called Ire1 detects when unfolded proteins build up in the endoplasmic reticulum. As a result, the Ire1 sensor proteins join together to form clusters and an mRNA molecule called HAC1 is specifically recruited to the Ire1 clusters. The portions of the Ire1 protein that extend out from the endoplasmic reticulum into the cell proper then bind to HAC1 mRNA and cut a piece out of it. This edited mRNA encodes the instructions to build a protein that in turn boosts the expression of various components—including the appropriate molecular chaperones—that are needed to alleviate the stress caused by an excess of unfolded proteins. Within clusters, individual Ire1 proteins interact through the portions of the protein found on the inside of the endoplasmic reticulum. Now, van Anken et al. show that these interactions are sufficient for forming and maintaining clusters. The interactions between the portions of the Ire1 proteins outside of the endoplasmic reticulum are needed for editing the HAC1 mRNA but not for forming and maintaining the clusters or for recruiting the HAC1 mRNA molecule to bind to Ire1. Instead, van Anken et al. discovered an mRNA binding site on the Ire1 clusters, which is separate from the part of the Ire1 protein that cuts the mRNA molecules. The Ire1 protein needs to first bind the HAC1 mRNA molecule at this binding site before it can cut it; van Anken et al. suggest that this two-step process helps ensure accurate and efficient editing of the HAC1 mRNA by Ire1. This process could also help to minimize the chance of other mRNA molecules being edited by mistake. It will be of interest to investigate if similar safety measures are key for endoplasmic reticulum stress signaling mechanisms in humans, and whether these newly discovered steps can be targeted by drugs to treat disease. DOI: http://dx.doi.org/10.7554/eLife.05031.002

Public health surveillance and epidemiologic investigations are critical functions for the control and prevention of infectious diseases. The activities associated with these functions, including case and contact investigations, public health surveillance, and data analysis, are conducted by trained personnel in response to a variety of infectious disease threats, including those with pandemic potential, such as novel influenza.1–3 According to the 2010 National Profile of Local Health Departments, 92% of local health departments (LHDs) in the United States conduct epidemiology and surveillance for communicable diseases, while 77% conduct these activities for environmental health issues.4 In 2005, approximately 25% of all LHDs employed one or more epidemiologists, and epidemiologic activities were conducted by individuals with a wide range of backgrounds and training.5 For many LHDs that do not employ epidemiologists, other public health professionals (e.g., health officers, public health nurses, or environmental health staff) may fulfill epidemiologic functions within the LHD. To create and maintain sustainable preparedness and response systems, the public health workforce must have the proper skills, capabilities, and adequate staffing levels to respond successfully in a public health emergency.6 In 2007, the results of a survey of LHDs in California demonstrated that not all disease investigation staff had received basic epidemiology training and not all staff that might supply surge capacity for disease investigations had received formal disease investigation training.7 In 2005, 12 of 56 (21%) LHDs reported having a formal agreement with neighboring jurisdictions to secure services of qualified epidemiologists in an emergency.8 From 2006 to 2010, cuts to bioterrorism and emergency response funding resulted in substantial decreases in epidemiology capacity among state health departments nationally.9 Despite the decrease in preparedness and response funding, public health preparedness and emergency response remains an area of critical importance for LHDs; maintaining the public health capacity to detect, investigate, and respond to infectious disease threats is an essential component of preparedness efforts.10 The purpose of this study was to describe the public health workforce involved in public health surveillance and epidemiologic activities among LHDs in California. Other studies such as the Council of State and Territorial Epidemiologists (CSTE) Epidemiology Capacity Assessments (ECAs)11–15 have attempted to enumerate and assess the epidemiology capacity among LHDs in the United States. Our goals were to describe the functional epidemiology capacity among California LHDs, understand the internal and external networks that are used to support epidemiologic and surveillance functions, and find out how health departments recruit additional epidemiologic support during infectious disease emergency events. For the purposes of this study, we have defined “functional epidemiology capacity” to mean the ability of the organization to conduct epidemiology-related tasks, regardless of the personnel performing them. An in-depth understanding of the sources of epidemiologic support during infectious disease emergencies and ensuring these individuals are trained to meet the functional needs are essential to an effective public health response.

Dispatches HIV Infection as a Risk Factor for Shigellosis 1 Jefferson T. Baer,* Duc J. Vugia,*†‡ Arthur L. Reingold ,*§ Tomas Aragon,¶ Frederick J. Angulo,# and Williamson Z. Bradford*§** *California Emerging Infections Program, San Francisco, California, USA; †California Department of Health Services, Berkeley, California, USA; ‡University of California, San Francisco, California, USA; §School of Public Health, University of California, Berkeley, California, USA; ¶San Francisco Department of Public Health, San Francisco, California, USA; #Centers for Disease Control and Prevention, Atlanta, Georgia, USA; and **IntraBiotics Pharmaceuticals, Mountain View, California, USA We investigated cases of shigellosis in San Francisco and Alameda Counties identified during 1996 by active laboratory surveillance to assess the role of HIV infection as a risk factor for shigellosis. Dramatically elevated rates of shigellosis in HIV-infected persons implicate HIV infection as an important risk factor for shigellosis in San Francisco. Shigella infections are responsible for an estimated 300,000 illnesses and 600 deaths per year in the United States and more than 600,000 deaths per year worldwide (1). Shigella species are typically transmitted by direct or indirect fecal-oral contact; as a result, shigellosis has long been associated with outbreaks in day-care centers, nursing homes, and institutionalized populations (2-4). However, several studies have demonstrated an increased frequency of shigello- sis cases in young adult men residing in urban settings who have little, if any, exposure to these traditionally recognized risk groups (5-9). These investigations also suggest that Shigella infection occurs during the practice of gay sex; however, since most of these studies occurred before the HIV epidemic, the relationship between HIV infection and gay sex and the subsequent risk for shigellosis has yet to be evaluated (5-9). HIV-infected persons are at increased risk for infection by several common enteric pathogens (10). Previous investigations have demonstrated that HIV-infected patients are at 20 times greater risk for infection with Address for correspondence: Williamson Z. Bradford, IntraBiotics Pharmaceuticals, Inc., 1255 Terra Bella Ave., Mountain View, CA 94080, USA; fax: 650-969-0663; e-mail: BBradford@intrabiotics.com. 1 Presented Salmonella species and 39 times greater risk for infection with Campylobacter species than the general population (11,12). To determine the rate of shigellosis in HIV-infected persons, we investigated all cases of shigellosis in San Francisco, a county with a high prevalence of HIV infection and a high incidence of shigellosis. Alameda, a neighboring county with lower rates of shigellosis and HIV infection, was used as a comparison area for our investigation because of its proximity and differing shigellosis and HIV epidemiology. During 1996, cases of culture-confirmed shigellosis were identified in San Francisco and Alameda Counties by active surveillance in 28 laboratories for isolates of Shigella species cultured from any anatomic site as part of the California Emerging Infections Program. The program comprises one of five sites in the Foodborne Diseases Active Surveillance Net- work (FoodNet), which is part of the Centers for Disease Control and Prevention’s Emerging Infections Program. All available medical records of patients were reviewed by a standardized data collection instrument detailing demographic and medical information. Data concerning sexual activity and orientation and foreign travel were obtained from routine telephone interviews of patients with shigellosis, conducted by the San in part at the International Conference on Emerging Infections, March 1998, Atlanta, Georgia. Emerging Infectious Diseases Vol. 5, No. 6, November–December 1999

et al., [Background & Aims]: Cardiotrophin-1 (CT-1) is a hepatoprotective cytokine that modulates fat and glucose metabolism in muscle and adipose tissue. Here we analyzed the changes in hepatic fat stores induced by recombinant CT-1 (rCT-1) and its therapeutic potential in non-alcoholic fatty liver disease (NAFLD). [Methods]: rCT-1 was administered to two murine NAFLD models: ob/ob and high fat diet-fed mice. Livers were analyzed for lipid composition and expression of genes involved in fat metabolism. We studied the effects of rCT-1 on lipogenesis and fatty acid (FA) oxidation in liver cells and the ability of dominant negative inhibitor of AMP-activated protein kinase (AMPK) to block these effects. [Results]: CT-1 was found to be upregulated in human and murine steatotic livers. In two NAFLD mouse models, treatment with rCT-1 for 10 days induced a marked decrease in liver triglyceride content with augmented proportion of poly-unsaturated FA and reduction of monounsaturated species. These changes were accompanied by attenuation of inflammation and improved insulin signaling. Chronic administration of rCT-1 caused downregulation of lipogenic genes and genes involved in FA import to hepatocytes together with amelioration of ER stress, elevation of NAD+/NADH ratio, phosphorylation of LKB1 and AMPK, increased expression and activity of sirtuin1 (SIRT1) and upregulation of genes mediating FA oxidation. rCT-1 potently inhibited de novo lipogenesis and stimulated FA oxidation in liver cells both in vitro and in vivo. In vitro studies showed that these effects are mediated by activated AMPK. [Conclusions]: rCT-1 resolves hepatic steatosis in obese mice by mechanisms involving AMPK activation. rCT-1 deserves consideration as a potential therapy for NAFLD. © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved., Work in the authors’ laboratory was supported by Fundación para la Investigación Médica Aplicada (FIMA) and by Fondo de Investigaciones Sanitarias (FIS) PI10/01516 to M.B., MICINN SAF300–45 to J.P., (BFU) 2010-18826 to J.B. and by Instituto de Salud Carlos III, CIBERehd. DC and EL have been supported by DIGNA Biotech.

Background Public health surveillance and epidemiologic investigations are critical public health functions for identifying threats to the health of a community. Very little is known about how these functions are conducted at the local level. The purpose of the Epidemiology Networks in Action (EpiNet) Study was to describe the epidemiology and surveillance response to the 2009 pandemic influenza A (H1N1) by city and county health departments in the San Francisco Bay Area in California. The study also documented lessons learned from the response in order to strengthen future public health preparedness and response planning efforts in the region. Methods In order to characterize the epidemiology and surveillance response, we conducted key informant interviews with public health professionals from twelve local health departments in the San Francisco Bay Area. In order to contextualize aspects of organizational response and performance, we recruited two types of key informants: public health professionals who were involved with the epidemiology and surveillance response for each jurisdiction, as well as the health officer or his/her designee responsible for H1N1 response activities. Information about the organization, data sources for situation awareness, decision-making, and issues related to surge capacity, continuity of operations, and sustainability were collected during the key informant interviews. Content and interpretive analyses were conducted using ATLAS.ti software. Results The study found that disease investigations were important in the first months of the pandemic, often requiring additional staff support and sometimes forcing other public health activities to be put on hold. We also found that while the Incident Command System (ICS) was used by all participating agencies to manage the response, the manner in which it was implemented and utilized varied. Each local health department (LHD) in the study collected epidemiologic data from a variety of sources, but only case reports (including hospitalized and fatal cases) and laboratory testing data were used by all organizations. While almost every LHD attempted to collect school absenteeism data, many respondents reported problems in collecting and analyzing these data. Laboratory capacity to test influenza specimens often aided an LHD’s ability to conduct disease investigations and implement control measures, but the ability to test specimens varied across the region and even well-equipped laboratories exceeded their capacity. As a whole, the health jurisdictions in the region communicated regularly about key decision-making (continued on next page) (continued from previous page) related to the response, and prior regional collaboration on pandemic influenza planning helped to prepare the region for the novel H1N1 influenza pandemic. The study did find, however, that many respondents (including the majority of epidemiologists interviewed) desired an increase in regional communication about epidemiology and surveillance issues. Conclusion The study collected information about the epidemiology and surveillance response among LHDs in the San Francisco Bay Area that has implications for public health preparedness and emergency response training, public health best practices, regional public health collaboration, and a perceived need for information sharing.

Understanding how neural cells handle proteostasis stress in the endoplasmic reticulum (ER) is important to decipher the mechanisms that underlie the cell death associated with neurodegenerative diseases and to design appropriate therapeutic tools. Here we have compared the sensitivity of a human neuroblastoma cell line (SH-SY5H) to the ER stress caused by an inhibitor of protein glycosylation with that observed in human embryonic kidney (HEK-293T) cells. In response to stress, SH-SY5H cells increase the expression of mRNA encoding downstream effectors of ER stress sensors and transcription factors related to the unfolded protein response (the spliced X-box binding protein 1, CCAAT-enhancer-binding protein homologous protein, endoplasmic reticulum-localized DnaJ homologue 4 and asparagine synthetase). Tunicamycin-induced death of SH-SY5H cells was prevented by terminal aromatic substituted butyric or valeric acids, in association with a decrease in the mRNA expression of stress-related factors, and in the accumulation of the ATF4 protein. Interestingly, this decrease in ATF4 protein occurs without modifying the phosphorylation of the translation initiation factor eIF2α. Together, these results show that when short chain phenyl acyl acids alleviate ER stress in SH-SY5H cells their survival is enhanced.

The unfolded protein response (UPR) monitors the protein folding capacity of the endoplasmic reticulum (ER). In all organisms analyzed to date, the UPR drives transcriptional programs that allow cells to cope with ER stress. The non-conventional splicing of Hac1 (yeasts) and XBP1 (metazoans) mRNA, encoding orthologous UPR transcription activators, is conserved and dependent on Ire1, an ER membrane-resident kinase/endoribonuclease. We found that the fission yeast Schizosaccharomyces pombe lacks both a Hac1/XBP1 ortholog and a UPR-dependent-transcriptional-program. Instead, Ire1 initiates the selective decay of a subset of ER-localized-mRNAs that is required to survive ER stress. We identified Bip1 mRNA, encoding a major ER-chaperone, as the sole mRNA cleaved upon Ire1 activation that escapes decay. Instead, truncation of its 3′ UTR, including loss of its polyA tail, stabilized Bip1 mRNA, resulting in increased Bip1 translation. Thus, S. pombe uses a universally conserved stress-sensing machinery in novel ways to maintain homeostasis in the ER. DOI: http://dx.doi.org/10.7554/eLife.00048.001, eLife digest Protein folding—the process by which a sequence of amino acids adopts the precise shape that is needed to perform a specific biological function—is one of the most important processes in all of biology. Any sequence of amino acids has the potential to fold into a large number of different shapes, and misfolded proteins can lead to toxicity and other problems. For example, all cells rely on signaling proteins in the membranes that enclose them to monitor their environment so that they can adapt to changing conditions and, in multicellular organisms, communicate with neighboring cells: without properly folded signaling proteins, chaos would ensue. Moreover, many diseases—including diabetes, cancer, viral infection and neurodegenerative disease—have been linked to protein folding processes. It is not surprising, therefore, that cells have evolved elaborate mechanisms to exert exquisite quality control over protein folding. One of these mechanisms, called the unfolded protein response (UPR), operates in a compartment within the cell known as the endoplasmic reticulum (ER). The ER is a labyrinthine network of tubes and sacs within all eukaryotic cells, and most proteins destined for the cell surface or outside the cell adopt their properly folded shapes within this compartment. If the ER does not have enough capacity to fold all of the proteins that are delivered there, the UPR switches on to increase the protein folding capacity, to expand the surface area and volume of the compartment, and to degrade misfolded proteins. If the UPR cannot adequately adjust the folding capacity of the ER to meet the demands of the cell, the UPR triggers a program that kills the cell to prevent putting the whole organism at risk. Researchers have identified the cellular components that monitor the protein folding conditions inside the ER. All eukaryotic cells, from unicellular yeasts to mammalian cells, contain a highly conserved protein-folding sensor called Ire1. In all species analyzed to date, Ire1 is known to activate the UPR through an messenger RNA (mRNA) splicing mechanism. This splicing event provides the switch that drives a gene expression program in which the production of ER components is increased to boost the protein folding capacity of the compartment. Kimmig, Diaz et al. now report the first instance of an organism in which the UPR does not involve mRNA splicing or the initiation of a gene expression program. Rather, the yeast Schizosaccharomyces pombe utilizes Ire1 to an entirely different end. The authors find that the activation of Ire1 in S. pombe leads to the selective decay of a specific class of mRNAs that all encode proteins entering the ER. Thus, rather than increasing the protein folding capacity of the ER when faced with an increased protein folding load, S. pombe cells correct the imbalance by decreasing the load. The authors also show that a lone mRNA—the mRNA that encodes the molecular chaperone BiP, which is one of the major protein-folding components in the ER—uniquely escapes this decay. Rather than being degraded, Ire1 truncates BiP mRNA and renders it more stable. By studying the UPR in a divergent organism, the authors shed new light on the evolution of a universally important process and illustrate how conserved machinery has been repurposed. DOI: http://dx.doi.org/10.7554/eLife.00048.002

Background In recent years, national and global mortality data have been characterized in terms of well-established risk factors. In this regard, alcohol consumption has been called the third leading "actual cause of death" (modifiable behavioral risk factor) in the United States, after tobacco use and the combination of poor diet and physical inactivity. Globally and in various regions of the world, alcohol use has been established as a leading contributor to the overall burden of disease and as a major determinant of health disparities, but, to our knowledge, no one has characterized alcohol-related harm in such broad terms at the local level. We asked how alcohol-related premature mortality in San Francisco, measured in years of life lost (YLLs), compares with other well-known causes of premature mortality, such as ischemic heart disease or HIV/AIDS. Methods We applied sex- and cause-specific population-attributable fractions (PAFs) of years of life lost (YLLs) from the Global Burden of Disease Study to 17 comparable outcomes among San Francisco males and females during 2004-2007. We did this in three ways: Method 1 assumed that all San Franciscans drink like populations in developed economies. These estimates were limited to alcohol-related harm. Method 2 modified these estimates by including several beneficial effects. Method 3 assumed that Latino and Asian San Franciscans drink alcohol like populations in the global regions related to their ethnicity. Results By any of these three methods, alcohol-related premature mortality accounts for roughly a tenth of all YLLs among males. Alcohol-related YLLs among males are comparable to YLLs for leading causes such as ischemic heart disease and HIV/AIDS, in some instances exceeding them. Latino and black males bear a disproportionate burden of harm. Among females, for whom estimates differed more by method and were smaller than those for males, alcohol-related YLLs are comparable to leading causes which rank somewhere between fifth and fourteenth. Conclusions Alcohol consumption is a major contributor to premature mortality in San Francisco, especially among males. Interventions to avert alcohol-related harm in San Francisco should be taken at the population level and deserve the same attention that is given to other major risk factors, such as smoking or obesity.

Computational modeling and experimentation in the unfolded protein response reveals a role for the ER-resident chaperone protein BiP in fine-tuning the system's response dynamics., The unfolded protein response (UPR) is an intracellular signaling pathway that counteracts variable stresses that impair protein folding in the endoplasmic reticulum (ER). As such, the UPR is thought to be a homeostat that finely tunes ER protein folding capacity and ER abundance according to need. The mechanism by which the ER stress sensor Ire1 is activated by unfolded proteins and the role that the ER chaperone protein BiP plays in Ire1 regulation have remained unclear. Here we show that the UPR matches its output to the magnitude of the stress by regulating the duration of Ire1 signaling. BiP binding to Ire1 serves to desensitize Ire1 to low levels of stress and promotes its deactivation when favorable folding conditions are restored to the ER. We propose that, mechanistically, BiP achieves these functions by sequestering inactive Ire1 molecules, thereby providing a barrier to oligomerization and activation, and a stabilizing interaction that facilitates de-oligomerization and deactivation. Thus BiP binding to or release from Ire1 is not instrumental for switching the UPR on and off as previously posed. By contrast, BiP provides a buffer for inactive Ire1 molecules that ensures an appropriate response to restore protein folding homeostasis to the ER by modulating the sensitivity and dynamics of Ire1 activity., Author Summary Secreted and membrane-spanning proteins constitute one of every three proteins produced by a eukaryotic cell. Many of these proteins initially fold and assemble in the endoplasmic reticulum (ER). A variety of physiological and environmental conditions can increase the demands on the ER, overwhelming the ER protein folding machinery. To restore homeostasis in response to ER stress, cells activate an intracellular signaling pathway called the unfolded protein response (UPR) that adjusts the folding capacity of the ER according to need. Its failure impairs cell viability and has been implicated in numerous disease states. In this study, we quantitatively interrogate the homeostatic capacity of the UPR. We arrive at a mechanistic model for how the ER stress sensor Ire1 cooperates with its binding partner BiP, a highly redundant ER chaperone, to fine-tune UPR activity. Moving between a predictive computational model and experiments, we show that BiP release from Ire1 is not the switch that activates Ire1; rather, BiP modulates Ire1 activation and deactivation dynamics. BiP binding to Ire1 and its dissociation in an ER stress-dependent manner buffers the system against mild stresses. Furthermore, BiP binding accelerates Ire1 deactivation when stress is removed. We conclude that BiP binding to Ire1 serves to fine-tune the dynamic behavior of the UPR by modulating its sensitivity and shutoff kinetics. This function of the interaction between Ire1 and BiP may be a general paradigm for other systems in which oligomer formation and disassembly must be finely regulated.

In June 2006, the Centers for Disease Control and Prevention released a request for applications to identify, improve, and evaluate the effectiveness of nonpharmaceutical interventions (NPIs)—strategies other than vaccines and antiviral medications—to mitigate the spread of pandemic influenza within communities and across international borders (RFA-CI06-010). These studies have provided major contributions to seasonal and pandemic influenza knowledge. Nonetheless, key concerns were identified related to the acceptability and protective efficacy of NPIs. Large-scale intervention studies conducted over multiple influenza epidemics, as well as smaller studies in controlled laboratory settings, are needed to address the gaps in the research on transmission and mitigation of influenza in the community setting. The current novel influenza A (H1N1) pandemic underscores the importance of influenza research.

Background A core function of local health departments is to conduct health assessments. The analysis of death certificates provides information on diseases, conditions, and injuries that are likely to cause death – an important outcome indicator of population health. The expected years of life lost (Y LL) measure is a valid, stand-alone measure for identifying and ranking the underlying causes of premature death. The purpose of this study was to rank the leading causes of premature death among San Francisco residents, and to share detailed methods so that these analyses can be used in other local health jurisdications. Methods Using death registry data and population estimates for San Francisco deaths in 2003–2004, we calculated the number of deaths, Y LL, and age-standardized Y LL rates (ASY Rs). The results were stratified by sex, ethnicity, and underlying cause of death. The Y LL values were used to rank the leading causes of premature death for men and women, and by ethnicity. Results In the years 2003–2004, 6312 men died (73,627 years of life lost), and 5726 women died (51,194 years of life lost). The ASY R for men was 65% higher compared to the ASY R for women (8971.1 vs. 5438.6 per 100,000 persons per year). The leading causes of premature deaths are those with the largest average Y LLs and are largely preventable. Among men, these were HIV/AIDS, suicide, drug overdose, homicide, and alcohol use disorder; and among women, these were lung cancer, breast cancer, hypertensive heart disease, colon cancer, and diabetes mellitus. A large health disparity exists between African Americans and other ethnic groups: African American age-adjusted overall and cause-specific Y LL rates were higher, especially for homicide among men. Except for homicide among Latino men, Latinos and Asians have comparable or lower Y LL rates among the leading causes of death compared to whites. Conclusion Local death registry data can be used to measure, rank, and monitor the leading causes of premature death, and to measure and monitor ethnic health disparities.

Background Previous smallpox ring vaccination models based on contact tracing over a network suggest that ring vaccination would be effective, but have not explicitly included response logistics and limited numbers of vaccinators. Methods We developed a continuous-time stochastic simulation of smallpox transmission, including network structure, post-exposure vaccination, vaccination of contacts of contacts, limited response capacity, heterogeneity in symptoms and infectiousness, vaccination prior to the discontinuation of routine vaccination, more rapid diagnosis due to public awareness, surveillance of asymptomatic contacts, and isolation of cases. Results We found that even in cases of very rapidly spreading smallpox, ring vaccination (when coupled with surveillance) is sufficient in most cases to eliminate smallpox quickly, assuming that 95% of household contacts are traced, 80% of workplace or social contacts are traced, and no casual contacts are traced, and that in most cases the ability to trace 1–5 individuals per day per index case is sufficient. If smallpox is assumed to be transmitted very quickly to contacts, it may at times escape containment by ring vaccination, but could be controlled in these circumstances by mass vaccination. Conclusions Small introductions of smallpox are likely to be easily contained by ring vaccination, provided contact tracing is feasible. Uncertainties in the nature of bioterrorist smallpox (infectiousness, vaccine efficacy) support continued planning for ring vaccination as well as mass vaccination. If initiated, ring vaccination should be conducted without delays in vaccination, should include contacts of contacts (whenever there is sufficient capacity) and should be accompanied by increased public awareness and surveillance.

Background The United States (US) has re-instituted smallpox vaccinations to prepare for an intentional release of the smallpox virus into the civilian population. In an outbreak, people of all ages will be vaccinated. To prepare for the impact of large-scale ring and mass vaccinations, we conducted a systematic review of the complication and mortality risks of smallpox vaccination. We summarized these risks for post-vaccinial encephalitis, vaccinia necrosum (progressive vaccinia), eczema vaccinatum, generalized vaccinia, and accidental infection (inadvertant autoinoculation). Methods Using a MEDLINE search strategy, we identified 348 articles, of which seven studies met our inclusion criteria (the number of primary vaccinations and re-vaccinations were reported, sufficient data were provided to calculate complication or case-fatality risks, and comparable case definitions were used). For each complication, we estimated of the complication, death, and case-fatality risks. Results The life-threatening complications of post-vaccinial encephalitis and vaccinia necrosum were at least 3 and 1 per million primary vaccinations, respectively. Twenty-nine percent of vaccinees with post-vaccinial encephalitis died and 15% with vaccinia necrosum died. There were no deaths among vaccinees that developed eczema vaccinatum; however, 2.3% of non-vaccinated contacts with eczema vaccinatum died. Among re-vaccinees, the risk of post-vaccinial encephalitis was reduced 26-fold, the risk of generalized vaccinia was reduced 29-fold, and the risk of eczema vaccinatum was reduced 12-fold. However, the risk reductions of accidental infection and vaccinia necrosum were modest (3.8 and 1.5 fold respectively).

Background In persons with acquired immunodeficiency syndrome (AIDS), Cryptosporidium parvum causes a prolonged, severe diarrheal illness to which there is no effective treatment, and the risk of developing cryptosporidiosis from drinking tap water in non-outbreak settings remains uncertain. To test the hypothesis that drinking tap water was associated with developing cryptosporidiosis, we conducted a matched case-control study among persons with AIDS in San Francisco. Methods Among patients reported to the San Francisco AIDS Registry from May 1996 through September 1998, we compared patients who developed cryptosporidiosis to those who did not. Cases were individually matched to controls based on age, sex, race/ethnicity, CD4+ T lymphocyte count, date of CD4+ count, and date of case diagnosis. Population attributable fractions (PAFs) were calculated. Results The study consisted of 49 cases and 99 matched controls. In the multivariable analysis with adjustments for confounders, tap water consumption inside and outside the home at the highest exposure categories was associated with the occurrence of cryptosporidiosis (inside the home: odds ratio (OR), 6.76; 95% CI 1.37–33.5, and outside the home: OR 3.16; 95% CI 1.23–8.13). The PAF was 85%; that is, the proportion of cases of cryptosporidiosis in San Francisco AIDS patients attributable to tap water consumption could have been as high as 85%. Conclusions Although the results from this observational study cannot be considered definitive, until there is more data, we recommend persons with AIDS, especially those with compromised immune systems, consider avoiding tap water.

A molecular epidemiologic investigation was performed on a cluster of severe necrotizing Clostridium infections in 5 injection drug users admitted to an urban community hospital. Interviews with survivors suggested a point source of infection. Pulsed-field gel electrophoresis of Sma I restriction digests was performed to determine the molecular relatedness of clinically obtained isolates and isolates obtained from heroin samples and the home environment. A common clonal strain was found in Clostridium sordellii isolates from 2 socially unrelated patients and from drug paraphernalia. Clonality of a Clostridium perfringens strain from another patient isolate was identical to an isolate from a syringe found in her home. Other C perfringens isolates from patients, heroin, and the environment were determined to be polyclonal. We postulate that rapid recognition and public health notification led to rapid resolution of the outbreak.

OBJECTIVES: This study determined infection risk for HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) from needle reuse at a phlebotomy center that possibly exposed 3810 patients to infection. METHODS: We used a model for the risk of infection per blood draw, supplemented by subsequent testing results from 1699 patients. RESULTS: The highest risk of transmission was for HBV infection: 1.1 x 10(-6) in the best case and 1.2 x 10(-3) in the (unlikely) worst case. Subsequent testing yielded prevalence rates of 0.12%, 0.41%, and 0.88% for HIV, HBV, and HCV, respectively, lower than National Health and Nutrition Examination Survey III prevalence estimates. CONCLUSIONS: The infection risk was very low; few, if any, transmissions are likely to have occurred.

Background China's one-child-per-couple policy, introduced in 1979, led to profound demographic changes for nearly a quarter of the world's population. Several decades later, the consequences include decreased fertility rates, population aging, decreased household sizes, changes in family structure, and imbalanced sex ratios. The epidemiology of communicable diseases may have been affected by these changes since the transmission dynamics of infectious diseases depend on demographic characteristics of the population. Of particular interest is influenza because China and Southeast Asia lie at the center of a global transmission network of influenza. Moreover, changes in household structure may affect influenza transmission. Is it possible that the pronounced demographic changes that have occurred in China have affected influenza transmission? Methods and Findings To address this question, we developed a continuous-time, stochastic, individual-based simulation model for influenza transmission. With this model, we simulated 30 years of influenza transmission and compared influenza transmission rates in populations with and without the one-child policy control. We found that the average annual attack rate is reduced by 6.08% (SD 2.21%) in the presence of the one-child policy compared to a population in which no demographic changes occurred. There was no discernible difference in the secondary attack rate, −0.15% (SD 1.85%), between the populations with and without a one-child policy. We also forecasted influenza transmission over a ten-year time period in a population with a two-child policy under a hypothesis that a two-child-per-couple policy will be carried out in 2015, and found a negligible difference in the average annual attack rate compared to the population with the one-child policy. Conclusions This study found that the average annual attack rate is slightly lowered in a population with a one-child policy, which may have resulted from a decrease in household size and the proportion of children in the population.

The authors reviewed the medical records of 194 human immunodeficiency virus (HIV)-positive patients newly diagnosed with cryptosporidiosis and all 3,564 patients with newly diagnosed acquired immunodeficiency syndrome (AIDS) at San Francisco General Hospital for the period 1986-1992. The study was designed to address three questions: 1) How do AIDS patients who present with cryptosporidiosis differ from other patients with AIDS? 2) What factors are associated with survival among AIDS patients with newly diagnosed cryptosporidiosis? 3) Does a diagnosis of cryptosporidiosis impact survival after AIDS diagnosis? A total of 194 cases of cryptosporidiosis among HIV-infected patients were identified during the study period. Of the 194 patients, 109 (56%) had no prior diagnosis of AIDS. These 109 patients represented 3.1% of the 3,564 newly diagnosed cases of AIDS in the same period. Among the 134 patients with CD4 T-lymphocyte counts performed within 3 months of Cryptosporidium diagnosis, 34 (25%) had CD4 counts greater than 209 cells/ml. In a multivariate conditional logistic regression model, the incidence of Cryptosporidium was related to ethnicity (for blacks vs. whites, matched odds ratio (OR) = 0.15, 95% confidence interval (CI) 0.03-0.73), CD4 count (for a CD4 count ofor = 53 cells/ml vs.53 cells/ml, matched OR = 12.60, 95% CI 4.01-39.61), and age (for a 10-year increase, matched OR = 0.51, 95% CI 0.27-0.98). Two factors measured at the time of Cryptosporidium diagnosis were identified as being independently associated with survival (p0.001) in the proportional hazards model: CD4 countor = 53 cells/ml versus53 cells/ml (relative hazard = 6.18, 95% CI 2.99-12.76) and hematocritor 37% versus37% (relative hazard = 2.27, 95% CI 1.22-4.22). The median durations of survival in the four subgroups of Cryptosporidium-infected patients defined by these two variables differed significantly from each other (range, 204-1,119 days). Cryptosporidiosis as an initial AIDS-defining diagnosis was associated with an elevated relative hazard of death in comparison with other AIDS-defining diagnoses (relative hazard = 2.01, 95% CI 1.38-2.93). These data identify the groups of HIV-infected individuals at risk for presentation with symptomatic Cryptosporidium infection; the distinct survival patterns among subgroups of those patients already infected with this parasite; and the survival of AIDS patients with newly diagnosed cryptosporidiosis relative to patients with other AIDS-defining conditions. Such information is necessary for the design of prospective studies, the development of prophylactic strategies, the evaluation of candidate therapies, and the provision of prognostic information to patients.

We conducted a retrospective cohort study to evaluate the occurrence of bacteremia and associated mortality among hospitalized patients who were seropositive for the human immunodeficiency virus (HIV) and who developed fever and neutropenia following antineoplastic chemotherapy or for other reasons. Review of medical records revealed 224 episodes in 142 patients. Of these episodes, 57% occurred following antineoplastic chemotherapy, and 43% occurred under other circumstances. Members of the chemotherapy group had significantly less-advanced HIV disease, a lower mean absolute-neutrophil-count nadir, and a shorter duration of hospitalization. There was no difference between the two groups in the frequency of bacteremia or mortality due to all causes when they were compared by multivariate analysis. Statistically significant univariate and multivariate predictors of bacteremia included sepsis syndrome and concurrent infection. Predictors of mortality included sepsis syndrome, concurrent infection, bacteremia, and antimicrobial therapy. This study suggests that the cause of neutropenia in HIV-seropositive patients is not a predictor of the outcome of fever and neutropenic episodes. Instead, clinical presentation and concomitant illnesses have a greater impact on outcome for a patient.

Background On Friday March 11, 2011 a 9.0 magnitude earthquake triggered a tsunami off the eastern coast of Japan, resulting in thousands of lives lost and billions of dollars in damage around the Pacific Rim. The tsunami first reached the California coast on Friday, March 11th, causing more than $70 million in damage and at least one death. While the tsunami's impact on California pales in comparison to the destruction caused in Japan and other areas of the Pacific, the event tested emergency responders' ability to rapidly communicate and coordinate a response to a potential threat. Methods To evaluate the local public health system emergency response to the tsunami threat in California, we surveyed all local public health, emergency medical services (EMS), and emergency management agencies in coastal or floodplain counties about several domains related to the tsunami threat in California, including: (1) the extent to which their community was affected by the tsunami, (2) when and how they received notification of the event, (3) which public health response activities were carried out to address the tsunami threat in their community, and (4) which organizations contributed to the response. Public health activities were characterized using the Centers for Disease Control and Prevention (CDC) Public Health Preparedness Capabilities (PHEP) framework. Findings The tsunami's impact on coastal communities in California ranged widely, both in terms of the economic consequences and the response activities. Based on estimates from the National Oceanic and Atmospheric Administration (NOAA), ten jurisdictions in California reported tsunami-related damage, which ranged from $15,000 to $35 million. Respondents first became aware of the tsunami threat in California between the hours of 10:00pm Pacific Standard Time (PST) on Thursday March 10th and 2:00pm PST on Friday March 11th, a range of 16 hours, with notification occurring through both formal and informal channels. In response to this threat, the activities most commonly reported by the local government agencies included in this study were: emergency public information and warning, emergency operations coordination, and inter-organizational information sharing, which were reported by 86%, 75%, and 65% of all respondents, respectively. When looking at the distribution of responsibility, emergency management agencies were the most likely to report assuming a lead role in these common activities as well as those related to evacuation and community recovery. While activated less frequently, public health agencies carried out emergency response functions related to surveillance and epidemiology, environmental health, and mental health/psychological support. Both local public health and EMS agencies took part in mass care and medical material management activities. A large network of organizations contributed to response activities, with emergency management, law enforcement, fire, public health, public works, EMS, and media cited by more than half of respondents. Conclusions In response to the tsunami threat in California, we found that emergency management agencies assumed a lead role in the local response efforts. While public health and medical agencies played a supporting role in the response, they uniquely contributed to a number of specific activities. If the response to the recent tsunami is any indication, these support activities can be anticipated in planning for future events with similar characteristics to the tsunami threat. Additionally, we found that many respondents first learned of the tsunami through the media, rather than through rapid notification systems, which suggests that government agencies must continue to develop and maintain the ability to rapidly aggregate and analyze information in order to provide accurate assessments and guidance to a potentially well-informed public. Citation: Hunter JC, Crawley AW, Petrie M, Yang JE, Aragon TJ. Local Public Health System Response to the Tsunami Threat in Coastal California following the Tōhoku Earthquake. PLoS Currents Disasters. 2012 Jul 16. Language: en

Agonist anti-CD137 monoclonal antibodies are employed to enhance CD8-mediated antitumor immunity both in mouse models and in clinical trials. A panel of agonist anti-human CD137 mAb was prepared recognizing three different epitopes on the CD137 surface glycoprotein. All mAb costimulated T cell activation irrespectively of interference or not with natural ligand-binding. Interestingly, CD137 perturbation with agonist mAb results in internalization towards a vesicular endosomal compartment derived from the plasma membrane. Such internalization was observed on CD137 transfectants in 293 cellsas well as on primary activated T cells from humans and mice. In vivo treatment with anti-CD137 mAb of immunodeficient mice harboring activated human or mouse T cells results in internalization of CD137 to this vesicular compartment. CD137 is known to associate with TRAF2 at the plasma membrane. TRAF-2 is an adaptor protein endowed with E3 ubiquitin ligase activity that synthesizes k63-polyubiquitin chains. K63 polyubiquitin, as opposed to K48 polyubiquitin, constitute a docking site for downtream signaling proteins that lead to NF-kB and AP-1 activation. CD137 vesicles are decorated with k63-polyubiquitin and CD137 stimulation leads to the formation of K63-polyub containing complexes. Therefore CD137 stimulation under therapy like conditions with mAbs leads to the assembly of an intracellular signaling compartment that we term as CD137 -signalsomes Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4567. doi:10.1158/1538-7445.AM2011-4567

Charles J. Vukotich, Jr., Rebecca M. Coulborn, Tomas J. Aragon, Michael G. Baker, Barri B. Burrus, Allison E. Aiello, Benjamin J. Cowling, Alasdair Duncan, Wayne Enanoria, M. Patricia Fabian, Yu-hui Ferng, Elaine L. Larson, Gabriel M. Leung, Howard Markel, Donald K. Milton, Arnold S. Monto, Stephen S. Morse, J. Alexander Navarro, Sarah Y. Park, Patricia Priest, Samuel Stebbins, Alexandra M. Stern, Monica Uddin, and Scott F. Wetterhall Author affiliations: University of Pittsburgh, Pennsylvania, USA (C.J. Vukotich, S. Stebbins); University of Michigan, Ann Arbor, Michigan, USA (R.M. Coulborn, A.E. Aiello, H. Markel, A.S. Monto, J.A. Navarro, A.M. Stern, M. Uddin); University of California, Berkeley, California, USA (T.J. Aragon, W. Enanoria); University of Otago, Dunedin, New Zealand (M.G. Baker, A. Duncan, P. Priest); RTI International, Research Triangle Park, North Carolina, USA (B.B. Burrus, S.F. Wetterhall); University of Hong Kong, Hong Kong, People's Republic of China (B.J. Cowling, G. M. Leung); University of Massachusetts, Lowell, Massachusetts, USA (M.P. Fabian); Columbia University, New York, New York, USA (Y. Ferng, E.L. Larson, S.S. Morse); University of Maryland, College Park, Maryland, USA (D.K. Milton); and Hawaii Department of Health, Honolulu, Hawaii (S.Y. Park)

Background Due to the uncommon nature of large-scale disasters and emergencies, public health practitioners often turn to simulated emergencies, known as “exercises”, for preparedness assessment and improvement. Under the right conditions, exercises can also be used to conduct original public health systems research. This paper describes the integration of a research framework into a statewide operations-based exercise program in California as a systems-based approach for studying public health emergency preparedness and response. Methods We developed a research framework based on the premise that operations-based exercises conducted by medical and public health agencies can be described using epidemiologic concepts. Using this framework, we conducted a survey of key local and regional medical and health agencies throughout California following the 2010 Statewide Medical and Health Exercise. The survey evaluated: (1) the emergency preparedness capabilities activated and functions performed in response to the emergency scenario, and (2) the major challenges to inter-organizational communications and information management. Results Thirty-five local health departments (LHDs), 24 local emergency medical services (EMS) agencies, 121 hospitals, and 5 Regional Disaster Medical and Health Coordinators/Specialists (RDMHC) responded to our survey, representing 57%, 77%, 26% and 83%, respectively, of target agencies in California. We found two sets of response capabilities were activated during the 2010 Statewide Exercise: a set of core capabilities that were common across all agencies, and a set of agency-specific capabilities that were more common among certain agency types. With respect to one response capability in particular, inter-organizational information sharing, we found that the majority of respondents’ comments were related to the complete or partial failure of communications equipment or systems. Conclusions Using the 2010 Statewide Exercise in California as an opportunity to develop our research framework, we characterized several aspects of the public health and medical system’s response to a standardized emergency scenario. From a research perspective, this study provides a potential new framework for conducting exercise-based research. From a practitioner’s perspective, our results provide a starting point for preparedness professionals’ dialogue about expected and actual organizational roles, responsibilities, and resource capacities within the public health system. Additionally, the identification of specific challenges to inter-organizational communications and information management offer specific areas for intervention.