Colorectal cancer is a leading cause of cancer-related deaths. Mutations in the innate immune sensor AIM2 are frequently identified in patients with colorectal cancer, but how AIM2 modulates colonic ...tumorigenesis is unknown. Here, we found that Aim2-deficient mice were hypersusceptible to colonic tumor development. Production of inflammasome-associated cytokines and other inflammatory mediators was largely intact in Aim2-deficient mice; however, intestinal stem cells were prone to uncontrolled proliferation. Aberrant Wnt signaling expanded a population of tumor-initiating stem cells in the absence of AIM2. Susceptibility of Aim2-deficient mice to colorectal tumorigenesis was enhanced by a dysbiotic gut microbiota, which was reduced by reciprocal exchange of gut microbiota with healthy wild-type mice. These findings uncover a synergy between a specific host genetic factor and gut microbiota in determining the susceptibility to colorectal cancer. Therapeutic modulation of AIM2 expression and microbiota has the potential to prevent colorectal cancer.
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•AIM2 is required to mediate protection against colorectal cancer•AIM2 suppresses overt proliferation in enterocytes•AIM2 inhibits expansion of the intestinal stem cell population•Transfer of healthy microbiota dampens tumor development in Aim2-deficient mice
The cytosolic DNA sensor AIM2 regulates stem cell proliferation in the intestinal mucosa in an inflammasome-independent fashion, contributing to a decrease in the likelihood of colorectal cancer development.
The incidences of chronic inflammatory disorders have increased considerably over the past three decades. Recent shifts in dietary consumption may have contributed importantly to this surge, but how ...dietary consumption modulates inflammatory disease is poorly defined. Pstpip2(cmo) mice, which express a homozygous Leu98Pro missense mutation in the Pombe Cdc15 homology family protein PSTPIP2 (proline-serine-threonine phosphatase interacting protein 2), spontaneously develop osteomyelitis that resembles chronic recurrent multifocal osteomyelitis in humans. Recent reports demonstrated a crucial role for interleukin-1β (IL-1β) in osteomyelitis, but deletion of the inflammasome components caspase-1 and NLRP3 failed to rescue Pstpip2(cmo) mice from inflammatory bone disease. Thus, the upstream mechanisms controlling IL-1β production in Pstpip2(cmo) mice remain to be identified. In addition, the environmental factors driving IL-1β-dependent inflammatory bone erosion are unknown. Here we show that the intestinal microbiota of diseased Pstpip2(cmo) mice was characterized by an outgrowth of Prevotella. Notably, Pstpip2(cmo) mice that were fed a diet rich in fat and cholesterol maintained a normal body weight, but were markedly protected against inflammatory bone disease and bone erosion. Diet-induced protection against osteomyelitis was accompanied by marked reductions in intestinal Prevotella levels and significantly reduced pro-IL-1β expression in distant neutrophils. Furthermore, pro-IL-1β expression was also decreased in Pstpip2(cmo) mice treated with antibiotics, and in wild-type mice that were kept under germ-free conditions. We further demonstrate that combined deletion of caspases 1 and 8 was required for protection against IL-1β-dependent inflammatory bone disease, whereas the deletion of either caspase alone or of elastase or neutrophil proteinase 3 failed to prevent inflammatory disease. Collectively, this work reveals diet-associated changes in the intestinal microbiome as a crucial factor regulating inflammasome- and caspase-8-mediated maturation of IL-1β and osteomyelitis in Pstpip2(cmo) mice.
Small noncoding RNAs (sRNAs) play important roles in gene regulation in both prokaryotes and eukaryotes. Thus far, no sRNA has been assigned a definitive role in virulence in the major human pathogen ...Streptococcus pneumoniae. Based on the potential coding capacity of intergenic regions, we hypothesized that the pneumococcus produces many sRNAs and that they would play an important role in pathogenesis. We describe the application of whole-genome transcriptional sequencing to systematically identify the sRNAs of Streptococcus pneumoniae. Using this approach, we have identified 89 putative sRNAs, 56 of which are newly identified. Furthermore, using targeted genetic approaches and Tn-seq transposon screening, we demonstrate that many of the identified sRNAs have important global and niche-specific roles in virulence. These data constitute the most comprehensive analysis of pneumococcal sRNAs and provide the first evidence of the extensive roles of sRNAs in pneumococcal pathogenesis.
Understanding the molecular regulation of hematopoietic stem and progenitor cell (HSPC) engraftment is paramount to improving transplant outcomes. To discover novel regulators of HSPC repopulation, ...we transplanted >1,300 mice with shRNA-transduced HSPCs within 24 h of isolation and transduction to focus on detecting genes regulating repopulation. We identified 17 regulators of HSPC repopulation: Arhgef5, Armcx1, Cadps2, Crispld1, Emcn, Foxa3, Fstl1, Glis2, Gprasp2, Gpr56, Myct1, Nbea, P2ry14, Smarca2, Sox4, Stat4, and Zfp251. Knockdown of each of these genes yielded a loss of function, except in the cases of Armcx1 and Gprasp2, whose loss enhanced hematopoietic stem cell (HSC) repopulation. The discovery of multiple genes regulating vesicular trafficking, cell surface receptor turnover, and secretion of extracellular matrix components suggests active cross talk between HSCs and the niche and that HSCs may actively condition the niche to promote engraftment. We validated that Foxa3 is required for HSC repopulating activity, as Foxa3(-/-) HSC fails to repopulate ablated hosts efficiently, implicating for the first time Foxa genes as regulators of HSPCs. We further show that Foxa3 likely regulates the HSC response to hematologic stress. Each gene discovered here offers a window into the novel processes that regulate stable HSPC engraftment into an ablated host.
Genome-wide distribution of histone H3K18 and H3K27 acetyltransferases, CBP (CREBBP) and p300 (EP300), is used to map enhancers and promoters, but whether these elements functionally require CBP/p300 ...remains largely uncertain. Here we compared global CBP recruitment with gene expression in wild-type and CBP/p300 double-knockout (dKO) fibroblasts. ChIP-seq using CBP-null cells as a control revealed nearby CBP recruitment for 20% of constitutively-expressed genes, but surprisingly, three-quarters of these genes were unaffected or slightly activated in dKO cells. Computationally defined enhancer-promoter-units (EPUs) having a CBP peak near the enhancer-like element were more predictive, with CBP/p300 deletion attenuating expression of 40% of such constitutively-expressed genes. Examining signal-responsive (Hypoxia Inducible Factor) genes showed that 97% were within 50 kilobases of an inducible CBP peak, and 70% of these required CBP/p300 for full induction. Unexpectedly, most inducible CBP peaks occurred near signal-nonresponsive genes. Finally, single-cell expression analysis revealed additional context dependence where some signal-responsive genes were not uniformly dependent on CBP/p300 in individual cells. While CBP/p300 was needed for full induction of some genes in single-cells, for other genes CBP/p300 increased the probability of maximal expression. Thus, target gene context influences the transcriptional requirement for CBP/p300, possibly by multiple mechanisms.
Performance-enhancing drugs (PEDs) can be categorized into various classes based on the physiological mechanism of the compound, with the most popular being anabolic steroids, selective androgen ...receptor modulators, and growth hormones. Ancillary compounds, such as selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders, are commonly utilized alongside a PED to counterbalance any potential undesired side effects. With little clinically relevant data to support the use of these ancillary compounds, medical education and evidence-based approaches aimed at monitoring the potential adverse effects of PED use are sparse.This study aims to identify emerging trends in the interest of PEDs and related ancillary compounds, hypothesize the physiological effects of the continued respective behavior, and propose a proxy for use by clinicians to approximate off-label drug use and subsequently modify their practices accordingly. Several significant trends were identified for non-FDA-regulated compounds (i.e., selective androgen receptor modulators such as RAD-140) and off-label indications for FDA-regulated drugs (i.e., SERMs such as tamoxifen). A significant increase in interest regarding selective androgen receptor modulators, mirrored by anecdotal reports in clinical settings and online forums, is coupled with stagnant or decreasing interest in both post-cycle therapies and anabolic steroids. Ultimately, we propose a call to action for utilizing social data and/or prescription data as a proxy for clinicians to better understand trends in these compounds and thus refine their treatment protocols in a concordant manner.
Public Policy to Maximize Tobacco Cessation McGoldrick, Daniel E., MA; Boonn, Ann V., MPH
American journal of preventive medicine,
03/2010, Volume:
38, Issue:
3
Journal Article
Peer reviewed
Abstract Tobacco use kills more than 400,000 Americans every year. For smokers, quitting is the biggest step they can take to improve their health, but it is a difficult step. Fortunately, ...policy-based interventions can both encourage smokers to quit and help them succeed. Evidence shows that tobacco tax increases encourage smokers to quit—recent state and federal increases have created dramatic surges in calls to quitlines. Similarly, smokefree workplace laws not only protect workers and patrons from secondhand smoke but also encourage smokers to quit, help them succeed, and create a social environment less conducive to smoking. The impact of policy changes can be amplified by promoting quitting around the date they are implemented. Outreach to health practitioners can alert them to encourage their patients to quit. Earned and paid media can also be used to motivate smokers to quit when policy changes are put into effect. Although these policies and efforts regarding them can generate great demand for evidence-based cessation services such as counseling and medication, it is important to make these resources available for those wanting to quit. Public and private health insurance plans should provide coverage for cessation services, and states should invest tobacco tax and/or tobacco settlement dollars in smoking-cessation programs as recommended by the CDC. Finally, the Family Smoking Prevention and Tobacco Control Act has given the U.S. Food and Drug Administration new authority to regulate tobacco products and marketing, and to prevent tobacco companies from deceptively marketing new products that discourage smokers from quitting and keep them addicted.
Many measures have been taken since late 2019 to combat the coronavirus disease (COVID-19) pandemic. National, state, and local governments employed precautions, including mask mandates, stay-at-home ...orders, and social distancing policies, to alleviate the burden on healthcare workers and slow the spread of the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) virus until an efficacious vaccine was made widely available. By early spring of 2021, three effective and well-tolerated SARS-CoV-2 vaccines emerged and underwent broad distribution. Throughout the course of the COVID-19 vaccination campaign, several key logistical and psychological issues surfaced. Of these, access to vaccines and vaccination hesitancy are cited as two substantial hindrances towards vaccination. Noting the demand for the SARS-CoV-2 vaccine and its highly sensitive storage requirements, accurate dose allocation is critical for vaccinating the population quickly and successfully. Here, we propose the use of social data as a tool to predict vaccination participation by correlating Google searches with state-level daily vaccination. We identified a temporal and regionally-ubiquitous Google search syntax that broadly captures daily vaccination trends. By correlating trends in the search syntax with daily vaccination rates, we were able to quantify the correlation and identify optimal lag periods between Google searches and daily vaccination. This work highlights the importance of analyzing social data as a metric to effectively arrange vaccination roll-outs, identify voluntary vaccination participation, and identify inflection points in vaccination participation. In addition, social data assessments can help direct dose allocation, identify geographic areas that may seek, but lack, access to the vaccines, and actively prepare for fluctuations in vaccination demands.
Due to their biomimetic properties, electrospun nanofibers have shown great potential in many biomedical fields. However, traditionally‐produced nanofibers are typically two‐dimensional (2D) ...membranes limiting their applications. Herein, we report a large‐scale synthesis of compressible and re‐expandable three‐dimensional (3D) nanofiber matrices for potential biomedical applications. The reproducible mass production of such matrices is achieved using a multiple‐emitter electrospinning machine with a controlled environment (e.g., temperature, humidity, and air flow rate) followed by an innovative gas‐foaming expansion. The modified 20‐emitter circular array with 3D‐printed needle caps is capable of maintaining stable Taylor cones under extremely high flow rates. The introduction of such an emitter array allows for the production rate of 3D nanofiber matrices to increase by over 800 times while retaining the desired morphological, mechanical, and absorptive properties when compared to ones generated by a single‐nozzle electrospinning setup. Taken together, a feasible, optimized method has been demonstrated for scaling up production of shape‐recoverable, expansile nanofiber matrices, representing a step towards translating such materials into preclinical, large animal testing, clinical trials, and eventually clinical applications.
This work describes a method for a large‐scale production of compressible and re‐expandable three‐dimensional (3D) nanofiber matrices for potential biomedical applications.
The effect that inbreeding has on the fixation and segregation of genes has rarely been confirmed by direct observation. Here, fixation, segregation, and linkage of allozymes is investigated in the ...progeny of self-fertilized hermaphrodites of the normally outcrossing Pacific oyster Crassostrea gigas. The estimate of fixation pooled over loci, individuals, and families, F = 0.462, is significantly lower than the expected value of 0.5. Log-likelihood ratios reveal significant heterogeneity in fixation among individuals, among families, and among loci. In addition, the grand pooled segregation ratio, 127:243:54, deviates significantly from 1:2:1, with a bias against homozygotes for alleles of lesser frequency in the natural population. Segregation ratios for 11 of 14 loci are significantly heterogeneous among families, and exact tests for segregation within families reveal 16 significant results out of 51 tests. Thus, fixation and segregation of allozyme markers in inbred oyster families deviates from the expectations of neutral inbreeding theory. Di-genic disequilibria are significant for four of 74 di-locus pairs revealing two linkage groups. Strong viability selection is apparently conditional on the genotype of the hermaphrodite-founders and is largely focused on these two linkage groups. These genetic effects are explained by interaction between cis-linked factors and polymorphic regulatory backgrounds.
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