CD8
T cells are critical mediators of cytotoxic effector function in infection, cancer and autoimmunity. In cancer and chronic viral infection, CD8
T cells undergo a progressive loss of cytokine ...production and cytotoxicity, a state termed T cell exhaustion. In autoimmunity, autoreactive CD8
T cells retain the capacity to effectively mediate the destruction of host tissues. Although the clinical outcome differs in each context, CD8
T cells are chronically exposed to antigen in all three. These chronically stimulated CD8
T cells share some common phenotypic features, as well as transcriptional and epigenetic programming, across disease contexts. A better understanding of these CD8
T cell states may reveal novel strategies to augment clearance of chronic viral infection and cancer and to mitigate self-reactivity leading to tissue damage in autoimmunity.
Provision of safe drinking water in the United States is a great public health achievement. However, new waterborne disease challenges have emerged (e.g., aging infrastructure, chlorine-tolerant and ...biofilm-related pathogens, increased recreational water use). Comprehensive estimates of the health burden for all water exposure routes (ingestion, contact, inhalation) and sources (drinking, recreational, environmental) are needed. We estimated total illnesses, emergency department (ED) visits, hospitalizations, deaths, and direct healthcare costs for 17 waterborne infectious diseases. About 7.15 million waterborne illnesses occur annually (95% credible interval CrI 3.88 million-12.0 million), results in 601,000 ED visits (95% CrI 364,000-866,000), 118,000 hospitalizations (95% CrI 86,800-150,000), and 6,630 deaths (95% CrI 4,520-8,870) and incurring US $3.33 billion (95% CrI 1.37 billion-8.77 billion) in direct healthcare costs. Otitis externa and norovirus infection were the most common illnesses. Most hospitalizations and deaths were caused by biofilm-associated pathogens (nontuberculous mycobacteria, Pseudomonas, Legionella), costing US $2.39 billion annually.
T cell dysfunction is a hallmark of many cancers, but the basis for T cell dysfunction and the mechanisms by which antibody blockade of the inhibitory receptor PD-1 (anti-PD-1) reinvigorates T cells ...are not fully understood. Here we show that such therapy acts on a specific subpopulation of exhausted CD8
tumor-infiltrating lymphocytes (TILs). Dysfunctional CD8
TILs possess canonical epigenetic and transcriptional features of exhaustion that mirror those seen in chronic viral infection. Exhausted CD8
TILs include a subpopulation of 'progenitor exhausted' cells that retain polyfunctionality, persist long term and differentiate into 'terminally exhausted' TILs. Consequently, progenitor exhausted CD8
TILs are better able to control tumor growth than are terminally exhausted T cells. Progenitor exhausted TILs can respond to anti-PD-1 therapy, but terminally exhausted TILs cannot. Patients with melanoma who have a higher percentage of progenitor exhausted cells experience a longer duration of response to checkpoint-blockade therapy. Thus, approaches to expand the population of progenitor exhausted CD8
T cells might be an important component of improving the response to checkpoint blockade.
•Over 20% of E. coli O157 illnesses and over 5% of Salmonella illnesses are estimated to be attributable to beef consumption in the United States.•Irradiating ground beef is one possible method to ...reduce disease burden.•Simulation modeling suggests that irradiating 50% of the currently unirradiated ground beef supply could avert 3,285 E. coli O157 illnesses and 20,308 Salmonella illnesses.•Additional studies should assess whether targeted irradiation of higher-risk ground beef products could prevent similar numbers of illnesses with less total product irradiated.
Over 20% of E. coli O157 illnesses and over 5% of Salmonella illnesses are estimated to be attributable to beef consumption in the United States. Irradiating ground beef is one possible method to reduce disease burden. We simulated the effect of ground beef irradiation on illnesses, hospitalizations, deaths, and direct healthcare costs from ground beef-associated E. coli O157 and Salmonella illnesses in the United States. To estimate the fraction of illnesses, hospitalizations, deaths, and direct healthcare costs preventable by ground beef irradiation, we multiplied the disease burden attributable to ground beef; the estimated percentage of ground beef sold that is not currently irradiated; the percentage of unirradiated ground beef that would be irradiated; and the percentage reduction in risk of illness after irradiation. We multiplied this fraction by estimates of burden and direct healthcare costs to calculate the numbers or amounts averted. Model inputs were obtained from the literature and expert opinion. We used Monte Carlo simulation to incorporate uncertainty in inputs into model estimates. Simulation outcomes were summarized with means and 95% uncertainty intervals (UI). Irradiating 50% of the currently unirradiated ground beef supply would avert 3,285 (95% UI: 624–9,977) E. coli O157 illnesses, 135 (95% UI: 24–397) hospitalizations, 197 (95% UI: 34–631) hemolytic uremic syndrome cases, 2 (95% UI: 0–16) deaths, and $2,972,656 (95% UI: $254,708–$14,496,916) in direct healthcare costs annually. For Salmonella, irradiation would avert 20,308 (95% UI: 9,858–38,903) illnesses, 400 (95% UI: 158–834) hospitalizations, 6 (95% UI: 0–18) deaths, and $7,318,632 (95% UI: $1,436,141–$26,439,493) in direct healthcare costs. Increasing ground beef irradiation could reduce E. coli O157 and Salmonella burden in the United States. Additional studies should assess whether targeted irradiation of higher-risk ground beef products could prevent similar numbers of illnesses with less total product irradiated.
Naegleria fowleri is a free-living ameba that causes primary amebic meningoencephalitis (PAM), a rare but usually fatal disease. We analyzed trends in recreational water exposures associated with PAM ...cases reported during 1978-2018 in the United States. Although PAM incidence remained stable, the geographic range of exposure locations expanded northward.
Illnesses transmitted by food and water cause a major disease burden in the United States despite advancements in food safety, water treatment, and sanitation. We report estimates from a structured ...expert judgment study using 48 experts who applied Cooke's classical model of the proportion of disease attributable to 5 major transmission pathways (foodborne, waterborne, person-to-person, animal contact, and environmental) and 6 subpathways (food handler-related, under foodborne; recreational, drinking, and nonrecreational/nondrinking, under waterborne; and presumed person-to-person-associated and presumed animal contact-associated, under environmental). Estimates for 33 pathogens were elicited, including bacteria such as Salmonella enterica, Campylobacter spp., Legionella spp., and Pseudomonas spp.; protozoa such as Acanthamoeba spp., Cyclospora cayetanensis, and Naegleria fowleri; and viruses such as norovirus, rotavirus, and hepatitis A virus. The results highlight the importance of multiple pathways in the transmission of the included pathogens and can be used to guide prioritization of public health interventions.
Plants leaves develop proximodistal, dorsoventral (adaxial-abaxial), and mediolateral patterns following initiation. The Myb domain gene
PHANTASTICA (
PHAN) is required for adaxial fate in many ...plants
1, 2, but the
Arabidopsis ortholog
ASYMMETRIC LEAVES1 (
AS1) has milder effects, suggesting that alternate or redundant pathways exist
3, 4. We describe enhancers of
as1 with more elongate and dissected leaves. As well as
RDR6, an RNA-dependent RNA polymerase previously proposed to influence
as1 through microRNA
5, these enhancers disrupt
ARGONAUTE7 (
AGO7)/
ZIPPY,
SUPPRESSOR OF GENE SILENCING3 (
SGS3), and
DICER-LIKE4 (
DCL4), which instead regulate
trans-acting small interfering RNA (ta-siRNA)
6–12. Microarray analysis revealed that the
AUXIN RESPONSE FACTOR genes
ETTIN (
ETT)/
ARF3 and
ARF4 were upregulated in
ago7, whereas
FILAMENTOUS FLOWER (
FIL) was upregulated only in
as1 ago7 double mutants.
RDR6 and
SGS3 likewise repress these genes, which specify abaxial fate
13–17. We show that the
trans-acting siRNA gene
TAS3, which targets
ETT and
ARF4, is expressed in the adaxial domain, and
ett as1 ago7 triple mutants resemble
as1. Thus
FIL is downregulated redundantly by
AS1 and by
TAS3, acting through
ETT, revealing a role for ta-siRNA in leaf polarity.
RDR6 and
DCL4 are required for systemic silencing, perhaps implicating ta-siRNA as a mobile signal.
More than 7.15 million cases of domestically acquired infectious waterborne illnesses occurred in the United States in 2014, causing 120,000 hospitalizations and 6,600 deaths. We estimated disease ...incidence for 17 pathogens according to recreational, drinking, and nonrecreational nondrinking (NRND) water exposure routes by using previously published estimates. In 2014, a total of 5.61 million (95% credible interval CrI 2.97-9.00 million) illnesses were linked to recreational water, 1.13 million (95% CrI 255,000-3.54 million) to drinking water, and 407,000 (95% CrI 72,800-1.29 million) to NRND water. Recreational water exposure was responsible for 36%, drinking water for 40%, and NRND water for 24% of hospitalizations from waterborne illnesses. Most direct costs were associated with pathogens found in biofilms. Estimating disease burden by water exposure route helps direct prevention activities. For each exposure route, water management programs are needed to control biofilm-associated pathogen growth; public health programs are needed to prevent biofilm-associated diseases.
Tap water is not sterile, and its use in home medical devices can result in infections from waterborne pathogens. However, many participants in a recent survey in the United States said tap water ...could safely be used for home medical devices. These results can inform communication materials to reduce the high consequence of infections.
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