This paper is a critique of the current version of Derk Pereboom’s “disappearing agent argument” against event-causal libertarianism. Special attention is paid to a notion that does a lot of work in ...his argument—that of settling which decision occurs (of the various decisions it is open to the agent to make at the time). It is argued that Pereboom’s disappearing agent argument fails to show that event-causal libertarians lack the resources to accommodate agents’ having freedom-level control over what they decide. The connection between the disappearing agent argument and the problem of present luck is explored, as is the connection between settling which decision one makes and luck. Pereboom’s disappearing agent argument also is distinguished from another argument with the same name that targets intentional action itself.
Human immunodeficiency virus type 1 (HIV-1) encodes a transactivator of transcription (Tat) protein, which has several functions that promote viral replication, pathogenesis, and disease. Amino acid ...variation within Tat has been observed to alter the functional properties of Tat and, depending on the HIV-1 subtype, may produce Tat phenotypes differing from viruses’ representative of each subtype and commonly used in in vivo and in vitro experimentation. The molecular properties of Tat allow for distinctive functional activities to be determined such as the subcellular localization and other intracellular and extracellular functional aspects of this important viral protein influenced by variation within the Tat sequence. Once Tat has been transported into the nucleus and becomes engaged in transactivation of the long terminal repeat (LTR), various Tat variants may differ in their capacity to activate viral transcription. Post-translational modification patterns based on these amino acid variations may alter interactions between Tat and host factors, which may positively or negatively affect this process. In addition, the ability of HIV-1 to utilize or not utilize the transactivation response (TAR) element within the LTR, based on genetic variation and cellular phenotype, adds a layer of complexity to the processes that govern Tat-mediated proviral DNA-driven transcription and replication. In contrast, cytoplasmic or extracellular localization of Tat may cause pathogenic effects in the form of altered cell activation, apoptosis, or neurotoxicity. Tat variants have been shown to differentially induce these processes, which may have implications for long-term HIV-1-infected patient care in the antiretroviral therapy era. Future studies concerning genetic variation of Tat with respect to function should focus on variants derived from HIV-1-infected individuals to efficiently guide Tat-targeted therapies and elucidate mechanisms of pathogenesis within the global patient population.
This article addresses two influential lines of argument for what might be termed "scientific epiphenomenalism" about conscious intentions - the thesis that neither conscious intentions nor their ...physical correlates are among the causes of bodily motions - and links this thesis to skepticism about free will and moral responsibility. One line of argument is based on Benjamin Libet's neuroscientific work on free will. The other is based on a mixed bag of findings presented by social psychologist Daniel Wegner. It is argued that both lines of argument are unsuccessful.
Interleukin (IL)-27, a member of the IL-12 family of cytokines, induces human immunodeficiency virus (HIV)-resistant monocyte-derived macrophages and T cells. This resistance is mediated via the ...downregulation of spectrin beta, non-erythrocytic 1 (SPTBN1), induction of autophagy, or suppression of the acetylation of Y-box binding protein-1 (YB-1); however, the role of IL-27 administration during the induction of immature monocyte-derived dendritic cells (iDC) is poorly investigated. In the current study, we investigated the function of IL-27-induced iDC (27DC) on HIV infection. 27DC inhibited HIV infection by 95 ± 3% without significant changes in the expression of CD4, CCR5, and SPTBN1 expression, autophagy induction and acetylation of YB-1 compared to iDC. An HIV proviral DNA copy number assay displayed that 27DC suppressed reverse transcriptase (RT) reaction without influencing the virus entry. A DNA microarray analysis was performed to identify the differentially expressed genes between 27DC and iDC. Compared to iDC, 51 genes were differentially expressed in 27DC, with more than 3-fold changes in four independent donors. Cross-reference analysis with the reported 2,214 HIV regulatory host genes identified nine genes as potential interests: Ankyrin repeat domain 22, Guanylate binding protein (GBP)-1, -2, -4, -5, Stabilin 1, Serpin family G member 1 (SERPING1), Interferon alpha inducible protein 6, and Interferon-induced protein with tetratricopeptide repeats 3. A knock-down study using si-RNA failed to determine a key factor associated with the anti-HIV activity due to the induction of robust amounts of off-target effects. Overexpression of each protein in cells had no impact on HIV infection. Thus, we could not define the mechanism of the anti-HIV effect in 27DC. However, our findings indicated that IL-27 differentiates monocytes into HIV-resistant DC, and the inhibitory mechanism differs from IL-27-induced HIV-resistant macrophages and T cells.
Despite antiretroviral therapy human immunodeficiency virus type-1 (HIV-1) infection results in neuroinflammation of the central nervous system that can cause HIV-associated neurocognitive disorders ...(HAND). The molecular mechanisms involved in the development of HAND are unclear, however, they are likely due to both direct and indirect consequences of HIV-1 infection and inflammation of the central nervous system. Additionally, opioid abuse in infected individuals has the potential to exacerbate HIV-comorbidities, such as HAND. Although restricted for productive HIV replication, astrocytes (comprising 40-70% of all brain cells) likely play a significant role in neuropathogenesis in infected individuals due to the production and response of viral proteins. The HIV-1 protein Tat is critical for viral transcription, causes neuroinflammation, and can be secreted from infected cells to affect uninfected bystander cells. The Wnt/β-catenin signaling cascade plays an integral role in restricting HIV-1 infection in part by negatively regulating HIV-1 Tat function. Conversely, Tat can overcome this negative regulation and inhibit β-catenin signaling by sequestering the critical transcription factor TCF-4 from binding to β-catenin. Here, we aimed to explore how opiate exposure affects Tat-mediated suppression of β-catenin in astrocytes and the downstream modulation of neuroinflammatory genes. We observed that morphine can potentiate Tat suppression of β-catenin activity in human astrocytes. In contrast, Tat mutants deficient in secretion, and lacking neurotoxic effects, do not affect β-catenin activity in the presence or absence of morphine. Finally, morphine treatment of astrocytes was sufficient to reduce the expression of genes involved in neuroinflammation. Examining the molecular mechanisms of how HIV-1 infection and opiate exposure exacerbate neuroinflammation may help us inform or predict disease progression prior to HAND development.
Why neuroscience does not disprove free will Brass, Marcel; Furstenberg, Ariel; Mele, Alfred R.
Neuroscience and biobehavioral reviews,
July 2019, 2019-07-00, 20190701, Letnik:
102
Journal Article
Recenzirano
Odprti dostop
•Neuroscience does not disprove our intuition of free will.•Decision models of Libet-type experiments are compatible with conscious free will.•Brain activation preceding conscious decisions reflects ...the decision process rather than a decision.•Conditional intentions configure the decision process in Libet-type experiments.
While the question whether free will exists or not has concerned philosophers for centuries, empirical research on this question is relatively young. About 35 years ago Benjamin Libet designed an experiment that challenged the common intuition of free will, namely that conscious intentions are causally efficacious. Libet demonstrated that conscious intentions are preceded by a specific pattern of brain activation, suggesting that unconscious processes determine our decisions and we are only retrospectively informed about these decisions. Libet-style experiments have ever since dominated the discourse about the existence of free will and have found their way into the public media. Here we review the most important challenges to the common interpretation of Libet-style tasks and argue that the common interpretation is questionable. Brain activity preceding conscious decisions reflects the decision process rather than its outcome. Furthermore, the decision process is configured by conditional intentions that participants form at the beginning of the experiment. We conclude that Libet-style tasks do not provide a serious challenge to our intuition of free will.
Background and aims: Cirrhotic patients frequently undergo screening endoscopy for the presence of oesophageal varices (OV). In the future, this social and medical burden will increase due to the ...greater number of patients with chronic liver disease and their improved survival. In this study, our aims were (1) to identify clinical, biochemical, and ultrasonographic parameters which might non-invasively predict the presence of OV in patients with liver cirrhosis; (2) to evaluate the reproducibility of the obtained results in a different, although related, further group of patients; and (3) to assess the predictiveness of the identified rules in patients with compensated cirrhosis. Methods: In the first part of the study we retrospectively evaluated the presence of OV in 145 cirrhotic patients, and in the second part we evaluated the reproducibility of the study results in a subsequent group of 121 patients. Finally, we evaluated these parameters in a subgroup of 145 patients with compensated disease. All 266 patients underwent a complete biochemical workup, upper digestive endoscopy, and ultrasonographic measurement of spleen bipolar diameter. Platelet count/spleen diameter ratio was calculated for all patients. Results: The prevalence rates of OV were 61% and 58% in the first and second groups of patients, respectively. In the first part of the study, we found that platelet count, spleen diameter, platelet count/spleen diameter ratio, and Child- Pugh class were significantly different among patients with or without OV, although the platelet count/spleen diameter ratio was the only parameter which was independently associated with the presence of OV in a multivariate analysis. A platelet count/spleen diameter ratio cut off value of 909 had 100% negative predictive value for a diagnosis of OV. This result was reproduced in the second group of patients as well as in patients with compensated disease. In a cost-benefit analysis, screening cirrhotic patients according to the “platelet count/spleen diameter ratio strategy” was far more cost effective compared with the “scope all strategy”. Conclusions: The platelet count/spleen diameter ratio is the only parameter which is independently associated with the presence of OV, and its negative predictive value is reproducible. Its use is of value even in the subgroup of patients with compensated disease, and it is also cost effective.
The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 gene editing system has been shown to be effective at inhibiting human immunodeficiency virus type 1 (HIV-1). Studies have ...not consistently used a trackable dual reporter system to determine what cells received the Cas9/gRNA to determine the overall knockdown of HIV. Some studies have used stably transduced cells under drug selection to accomplish this goal. Here a two-color system was used that allows tracking of viral protein expression and which cells received the CRISPR/Cas9 system. These experiments ensured that each gRNA used was a perfect match to the intended target to remove this variable. The data showed that gRNAs targeting the transactivation response element (TAR) region or other highly conserved regions of the HIV-1 genome were effective at stopping viral gene expression, with multiple assays demonstrating greater than 95 percent reduction. Conversely, gRNAs targeting conserved sites of the 5' portion of the U3 region were largely ineffective, demonstrating that the location of edits in the long terminal repeat (LTR) matter with respect to function. In addition, it was observed that a gRNA targeting Tat was effective in a T-cell model of HIV-1 latency. Taken together, these studies demonstrated gRNAs designed to highly conserved functional regions have near 100% efficacy
in cells known to have received the Cas9/gRNA pair.
On being able to intend Mele, Alfred R
Philosophical studies,
2023/1, Letnik:
180, Številka:
1
Journal Article
Recenzirano
What is it to be able to intend to do something? At the end of her ground-breaking book, Agents’ Abilities, Romy Jaster identifies this question as a topic for future research. This article tackles ...the question from within the framework Jaster assembled for understanding abilities. The discussion takes place in two different spheres: intentions formed in acts of deciding, and intentions not so formed. The gradability of abilities has an important place in Jaster’s framework, and it is explained how abilities to acquire intentions of these two kinds -- including both general and specific abilities—can come in degrees, as she conceives of degrees of ability. Although Jaster “sympathizes with the idea that having an ability to intend to A is a matter of intending to A in a sufficient proportion of the relevant possible situations in which there is an overriding reason to intend to A,” an alternative to this idea is developed.
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