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Etymologically, the word 'sarcasm' is derived from the Greek "sarkazein," meaning "to speak bitterly or sneer", or, more literally, "to tear flesh" ("sarcasm," 2014). Sarcasm, then, is far from a benign feature of language, and there appears to be an inherent acerbity, or even a note of provocation, located within. In spite of any innate or perceived aggression, sarcasm is, in fact, quite a common feature in spoken discourse. Studies have placed the use of sarcastic language at roughly 8% of conversational turns (Gibbs, 2000, p. 5; Tannen, 1984, p. 131), so it is certainly a notable and oft-tapped linguistic resource. As technology progresses, however, computer-mediated communication is becoming increasingly common and, with the advent of social media (Twitter, Facebook, Whatsapp, etc.), increasingly conversational. In this vein, perhaps sarcasm's role as a feature of primarily spoken discourse needs to be re-evaluated. This article offs a descriptive analysis of sarcasm as produced in an exclusively digital space, as well as bring attention to a novel use of sarcasm specific to this environment: sarcasm used as a "pseudo-argument."

CONTENTS I. INTRODUCTION II. HOW DID WE GET HERE? A. The Mezzanatto Case 1. The Holding 2. The Case Itself 3. The Mezzanatto Appeal; The Mezzanatto Proviso B. Plea Bargaining [...], Plea bargaining is the dominant means of disposing of criminal charges in the United States, in both state and federal courts. This administrative mechanism has become a system that is grossly abusive of individual rights, leading to many well-known maladies of the criminal justice system, which include overcharging, overincarceration, convictions on charges that would likely fail at trial, and even conviction of "factually innocent" persons. Instrumental in the abuses of plea bargaining is the so-called Mezzanatto waiver, which takes its name from a 1995 Supreme Court decision that approved the practice of getting defendants to agree that anything they say in negotiations with prosecutors can be admitted against them if a trial ensues, despite Evidence Rule 410, which provides that such statements are inadmissible. These waivers, which are largely overlooked in the vast literature that criticizes plea bargaining, are in fact lynchpins in a system that is horrifying to contemplate. These waivers mean that the very act of negotiation almost guarantees conviction of something, imposing one-sided risks on defendants that can only benefit prosecutors. They amount to a kind of palpable unfairness that the system tolerates. They not only contribute to the maladies described above, but they produce rulings (if a trial goes forward) that admit unreliable statements. There are many reasons why these waivers should be disapproved, including policy arguments (they are unfair, produce bad results and unreliable statements) and arguments based on contract law, on Rule 410 itself, on a widely-recognized but seldom enforced "unitary" principle, and--finally--on the "Mezzanatto proviso" (a widely ignored term in the decision itself). This Article explores the origins and operation of Mezzanatto waivers, examines and expounds the reasons for disapproving them and taking a new direction, and offers a reply to standard arguments that prosecutors need them (they really do not and have other means to hold defendants to their bargains).

Pseudomonas aeruginosa is a Gram‐negative bacterium causing morbidity and mortality in immuno‐compromised humans. It produces a lectin, LecB, that is considered a major virulence factor, however, its impact on the immune system remains incompletely understood. Here we show that LecB binds to endothelial cells in human skin and mice and disrupts the transendothelial passage of leukocytes in vitro. It impairs the migration of dendritic cells into the paracortex of lymph nodes leading to a reduced antigen‐specific T cell response. Under the effect of the lectin, endothelial cells undergo profound cellular changes resulting in endocytosis and degradation of the junctional protein VE‐cadherin, formation of an actin rim, and arrested cell motility. This likely negatively impacts the capacity of endothelial cells to respond to extracellular stimuli and to generate the intercellular gaps for allowing leukocyte diapedesis. A LecB inhibitor can restore dendritic cell migration and T cell activation, underlining the importance of LecB antagonism to reactivate the immune response against P. aeruginosa infection. Synopsis: Pseudomonas aeruginosa lectin B binds to endothelial cells and inflicts junctional and cytoskeletal changes. Lectin B restricts migration of dendritic cells from tissue to lymph nodes and thereby has negative repercussion on adaptive immune responses. Pseudomonas aeruginosa lectin B binds to the lymphatics.Endothelial cells undergo cell structural changes upon LecB binding.Leukocyte diapedesis is inhibited by LecB.LecB inhibits T cell priming by impeding dendritic cell migration to the lymph node paracortex. [ABSTRACT FROM AUTHOR]

Liquid biopsies are proving to have diagnostic and prognostic value in many different cancers, and in breast cancer they have the potential to improve outcomes by providing valuable information throughout a patient's cancer journey. However, patients with triple negative breast cancer (TNBC) have received little benefit from such liquid biopsies due to underlying limitations in the discovery and utility of robust biomarkers. Here, we examine the development of DNA methylation-based liquid biopsy assays for breast cancer and how they pertain to TNBC. We conducted a systematic review of liquid biopsy assays for breast cancer and analyzed their relevance in TNBC. We show that the utility of DNA mutation-based assays is poor for TNBC due to the low mutational frequencies across the genome in this subtype. We offer a detailed review of mDETECT – a liquid biopsy specifically designed for assessing tumor burden in TNBC patients. DNA methylation are foundational and robust events that occur in cancer evolution and may differentiate almost all forms of cancer, including TNBC. Longitudinal patient monitoring using DNA methylation-based liquid biopsies offers great potential for improving the detection and management of TNBC. [ABSTRACT FROM AUTHOR]

A data-parallel, multiprocessor and clustered implementation of the dot plot algorithm is presented and challenges in developing high performance software to develop large data sets are demonstrated. The model-driven development style helped in rigorous approach towards implementation and studies the system parameters that affected it.

CD169+ macrophages reside in lymph node (LN) and spleen and play an important role in the immune defense against pathogens. As resident macrophages, they are responsive to environmental cues to shape their tissue-specific identity. We have previously shown that LN CD169+ macrophages require RANKL for formation of their niche and their differentiation. Here, we demonstrate that they are also dependent on direct lymphotoxin beta (LTβ) receptor (R) signaling. In the absence or the reduced expression of either RANK or LTβR, their differentiation is perturbed, generating myeloid cells expressing SIGN-R1 in LNs. Conditions of combined haploinsufficiencies of RANK and LTβR revealed that both receptors contribute equally to LN CD169+ macrophage differentiation. In the spleen, the Cd169-directed ablation of either receptor results in a selective loss of marginal metallophilic macrophages (MMMs). Using a RANKL reporter mouse, we identify splenic marginal zone stromal cells as a source of RANKL and demonstrate that it participates in MMM differentiation. The loss of MMMs had no effect on the splenic B cell compartments but compromised viral capture and the expansion of virus-specific CD8+ T cells. Taken together, the data provide evidence that CD169+ macrophage differentiation in LN and spleen requires dual signals from LTβR and RANK with implications for the immune response. [ABSTRACT FROM AUTHOR]

Introduction: Prior data suggest associations between hearing loss, cardiovascular (CV) risk factors, and CV disease. Whether specific hearing loss patterns, including a strial pattern associated with inner ear vascular disease, are associated with systemic endothelial dysfunction and carotid intima–media thickness (IMT) remains unclear. Methods: We evaluated participants without prevalent CVD in the Framingham Offspring Study who underwent formal audiogram testing and brachial and carotid artery ultrasounds. Audiograms were categorized as normal or as belonging to one of four abnormal patterns: cochlear-conductive, low-sloping, sensorineural, or strial. Endothelial function as measured by brachial artery flow-mediated dilation (FMDmm and FMD%). Internal and common intima–media thicknesses (icIMT and ccIMT, respectively) were compared between audiogram patterns. Results: We studied 1672 participants (mean age 59 years, 57.6% women). The prevalence of each hearing pattern was as follows: 43.7% normal; 20.3% cochlear-conductive; 20.3% sensorineural; 7.7% low-sloping; and 8.0% strial. Strial pattern hearing loss was nearly twice as prevalent (p = 0.001) in those in the highest quartile of ccIMT and nearly 50% higher in those in the highest icIMT quartile (p = 0.04). There were no statistically significant differences between the prevalence of the strial pattern comparing the lowest quartiles of FMDmm and FMD% with the upper three quartiles. Age- and sex-adjusted linear regression models did not show significant associations between the vascular measures and hearing patterns. Conclusion: Abnormal hearing patterns were not significantly associated with impaired brachial FMD and increased carotid IMT after adjusting for age and sex effects, which may reflect age and sex-related distributional differences based on hearing loss pattern. [ABSTRACT FROM AUTHOR]

In the light of the success and the expected growth of its arsenal, immuno-therapy may become the standard neoadjuvant procedure for many cancers in the near future. However, aspects such as the identity, organization and the activation status of the peri- and intra-tumoral immune cells would represent important elements to weigh in the decision for the appropriate treatment. While important progress in non-invasive imaging of immune cells has been made over the last decades, it falls yet short of entering the clinics, let alone becoming a standard procedure. Here, we provide an overview of the different intra-vital imaging approaches in the clinics and in pre-clinical settings and discuss their benefits and drawbacks for assessing the activity of the immune system, globally and on a cellular level. Stimulated by further research, the future is likely to see many technological advances both on signal detection and emission as well as image specificity and resolution to tackle current hurdles. We anticipate that the ability to precisely determine an immune stage of cancer will capture the attention of the oncologist and will create a change in paradigm for cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Immune modulation by vitamin D3 through dendritic cells (DCs) remains controversial. Human DCs exposed in vitro counteract type‐1 T‐helper (Th1) differentiation and induce regulatory T cells. However, cutaneous application on mice promotes Th2‐driven inflammation resembling atopic dermatitis and relying on thymic stromal lymphopoietin (TSLP) from keratinocytes and T‐cell orientation by TSLP‐stimulated skin DCs. We studied the effects of vitamin D3 in human skin, focusing on TSLP production and the role of skin DCs in T‐cell differentiation. Methods: Human healthy skin explants were exposed in vitro to vitamin D3 analogs. Migrating DCs were analyzed and TSLP quantified in the supernatant. Allogeneic naïve CD4+ T cells were cocultured with DCs to assess their proliferation and cytokine production. Results: Vitamin D3 induced skin DCs to differentiate Th2 cells producing IL‐4 and IL‐13. Vitamin D3 triggered TSLP release in ~30% of skin explants, correlating with IL‐13 detection in Th2 cells. In these donors, blocking TSLP receptor during skin explant cultures abrogated IL‐13 production, yet IL‐4+ Th2 cells were unaffected. Among skin DCs emerged CD14+ cells that had responded directly to vitamin D3 and differed from classical CD14+ dermal emigrants. Vitamin D3‐elicited CD14+ DCs sufficed to promote IL‐4+ Th2 cells in a TSLP‐independent manner. Conclusion: Vitamin D3, despite inducing TSLP in some donors, had a direct influence on skin DCs, affecting their phenotype and ability to drive Th2 responses independently of TSLP. Our findings pave the way toward in vitro systems that accurately model human cutaneous Th2 responses, notably involved in atopic dermatitis. [ABSTRACT FROM AUTHOR]

Abstract Background BRCA1 has recently been identified as a potential regulator of mammary stem/progenitor cell differentiation, and this function may explain the high prevalence of breast cancer in BRCA1 mutation carriers, as well as the downregulation of BRCA1 in a large proportion of sporadic breast cancers. That is, loss of BRCA1 function results in blocked differentiation with expansion of the mammary stem/progenitor cells. Because BRCA1 also maintains genomic integrity, its loss could produce a pool of genetically unstable stem/progenitor cells that are prime targets for further transforming events. Thus, elucidating the regulatory mechanisms of BRCA1 expression is important to our understanding of normal and malignant breast differentiation. Results Loss of BRCA1 expression in the ErbB2-amplified SK-BR-3 cell line was found to be the result of loss of activity of the ets transcription factor GABP, a previously characterized regulator of BRCA1 transcription. The expression of the non-DNA binding GABPβ subunit was shown to be deficient, while the DNA binding subunit, GABPα was rendered unstable by the absence of GABPβ. Deletion analysis of the GABPβ proximal promoter identified a potential NRF-1 binding site as being critical for expression. Supershift analysis, the binding of recombinant protein and chromatin immunoprecipitation confirmed the role of NRF-1 in regulating the expression of GABPβ. The siRNA knockdown of NRF-1 resulted in decreased GABPβ and BRCA1 expression in MCF-7 cells indicating that they form a transcriptional network. NRF-1 levels and activity did not differ between SK-BR-3 and MCF-7 cells, however the NRF-1 containing complex on the GABPβ promoter differed between the two lines and appears to be the result of altered coactivator binding. Conclusions Both NRF-1 and GABP have been linked to the regulation of nuclear-encoded mitochondrial proteins, and the results of this study suggest their expression is coordinated by NRF-1's activation of the GABPβ promoter. Their linkage to BRCA1, a potential breast stem cell regulator, implies a connection between the induction of mitochondrial metabolism and breast differentiation.