In this essay, I propose that DNA‐binding anti‐cancer drugs work more via chromatin disruption than DNA damage. Success of long‐awaited drugs targeting cancer‐specific drivers is limited by the heterogeneity of tumors. Therefore, chemotherapy acting via universal targets (e.g., DNA) is still the mainstream treatment for cancer. Nevertheless, the problem with targeting DNA is insufficient efficacy due to high toxicity. I propose that this problem stems from the presumption that DNA damage is critical for the anti‐cancer activity of these drugs. DNA (...) in cells exists as chromatin, and many DNA‐targeting drugs alter chromatin structure by destabilizing nucleosomes and inducing histone eviction from chromatin. This effect has been largely ignored because DNA damage is seen as the major reason for anti‐cancer activity. I discuss how DNA‐binding molecules destabilize chromatin, why this effect is more toxic to tumoral than normal cells, and why cells die as a result of chromatin destabilization. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Grieving the Loss of What Medicine Was Supposed to BeKaterina V. LiongI attended a conference this year. The timing was less than ideal because it was held the weekend before the Internal Medicine clerkship exam. But as with all things, especially during medical school, there is never a "right time" to be doing anything. It was fortunate that I attended the conference anyway because I met an incredible doctor (...) there. She had given a talk called "The Myth of Physician Wellness," and somewhere in our lengthy discussion, she asked me this:"Have you ever considered that since entering medical school, you've never been able to stop and really grieve the loss of what you thought medicine would be?"I am writing this in the downtime during my surgery rotation, regretting that I didn't wait until I got home to fully feel the feelings of writing this because I cannot cry here in front of others. At the same time, I feel guilty spending time writing at all; I should instead be doing UWorld practice questions for my upcoming exam. I can feel it in my body, the feeling of being plugged up—I have allowed tears to leak out too many times this year.The first time was in Internal Medicine, after seeing an elderly patient with a terminal rectal cancer that was so far along you could see it grossly. The bulging mass was so obvious during the patient's digital rectal exam that the senior resident was able to take off his still-clean gloves mere seconds after putting them on. The patient had come in for abdominal pain and difficulty defacating; the [End Page E20] only management he'd been able to receive for his known cancer was multiple hospitalizations in the last few months for emergency blood transfusions when his Hemoglobin level, indicating blood loss from the cancer, got too low. As I was taught to do, I gave a summary statement: "So you're here because you had a primary care appointment for a regular checkup, but they wouldn't see you because they didn't take your insurance? And they sent you to the county hospital, but even though they take uninsured patients, you are technically insured, just under a terrible plan … so they transferred you here. Is that right?" Unfortunately, the man's sí of affirmation was enough to make me lose composure, and I had to step out to let the resident finish the interview.After that, all it takes recently for the tears to well up is for an attending to pull me aside for feedback and ask, "How is third year going for you?" or even "What do you feel you've done well?"I almost wonder if holding in tears is like constipation. In medical school, we learn that sometimes what we think is diarrhea in patients is actually constipation—the stool is so impacted that the only thing that can leak past the plug is liquid. We see the leakage and first interpret that as diarrhea. I have to wonder if people interpret the same about me—emotional lability? Or is my inability to prevent the tears from leaking out simply a product of all the plugging up I have been doing all along? My inability to properly grieve the loss of what medicine was going to be? Maybe the first step in processing that loss is identifying it:I thought medicine meant caring for patients. Why am I going through 7+ years of training if insurance companies are allowed to undermine us so easily?I thought medicine meant connecting with patients. Why am I spending 30 minutes seeing my patients and 2 hours writing notes?I thought medicine meant leadership. Why are others bypassing two-thirds of my time in training and ending up with almost the same job … but the only "leadership" left is that their liability falls on physicians?I thought one must be well to take care of others. Why are students working all day and studying all night, residents too overworked to take a lunch break, and attendings made to work while visibly sick and diaphoretic?I thought... (shrink)

Phenotypic plasticity is a crucial feature of aggressive cancer, providing the means for cancer progression. Stochastic changes in tumor cell transcriptional programs increase the chances of survival under any condition. I hypothesize that unstable chromatin permits stochastic transitions between transcriptional programs in aggressive cancers and supports non‐genetic heterogeneity of tumor cells as a basis for their adaptability. I present a mechanistic model for unstable chromatin which includes destabilized nucleosomes, mobile chromatin fibers and random enhancer‐promoter contacts, resulting in stochastic transcription. I (...) suggest potential markers for “unsettled” chromatin in tumors associated with poor prognosis. Although many of the characteristics of unstable chromatin have been described, they were mostly used to explain changes in the transcription of individual genes. I discuss approaches to evaluate the role of unstable chromatin in non‐genetic tumor cell heterogeneity and suggest using the degree of chromatin instability and transcriptional noise in tumor cells to predict cancer aggressiveness. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Full Collection of Personal NarrativesJake Beery, Neethi Pinto, Marcia King, Laura Wachsmuth, Alisha, Katie L. Gholson, T.S. Moran, Calvin R. Gross, Joanne Alfred, Cindy Bitter, Jenna Bennett, Nadia Khan, Clarice Douille, Kristen Carey Rock, Adrienne Feller Novick, Andrea Eisenberg, Japmehr Sandhu, Katherine Bakke, Heer Hendry, Karan K. Mirpuri, and Katerina V. Liong• Being the Difference• Grieving One More Time• Echoes of Grief: Tales from an Emergency Medicine and (...) Critical Care Nurse• Searching for Peace in Death• “I’d Love to go Off the Grid and Never Come Back”• “A Mother’s Love”• Tiny Person, Big Impact• Night Shift• Cracked Armor• Who Tells the Story• Navigating Hard Situations that Medical School Cannot Prepare You For• The Wish• Break• Five More Minutes• I Saw My Reflection• The Aftermath• Where the Journey Begins• Lessons Learned in Room 208• Joint and Grief Aches• My First Loss: Carrying His Legacy• Grieving the Loss of What Medicine Was Supposed to BeCopyright © 2024 Johns Hopkins University Press... (shrink)

We are drowning in information, while starving for wisdom.Are the smartest people also the wisest? Not necessarily. While traditional intellectual reasoning and procedural knowledge have helped build the communities we live in, there is a growing scientific understanding that we need emotionally balanced and better-fitting prosocial frameworks for coping with the uncertainties and complexities of life and addressing new challenges of the modern world. We are now poised on the edge of a new science of wisdom.The concept of wisdom, long (...) considered the “pinnacle of insight into the human condition”, has been that of an intangible, subjective, culturally specific entity—an unscientific... (shrink)

In the annotated Czech translation of Leibniz’s dialogue Pacidius Philalethi, which was published in 2019, but also in an earlier essay by the same translator on Leibniz’s dialogic way of writing as well as in other interpretations, there is little discussion of the practical implications of his dialogic method. Leibniz’s dialogical argumentation strategy, as he later applied it in his correspondence with Samuel Clarke, is therefore either completely neglected or is referred to as being typical of the time, or alternatively (...) is confused with Zeno’s dialectical method. Thus, the aim of this study is to clarify the practical implications of Leibniz’s application of the dialogic method in his final correspondence with Clarke. (shrink)

This study deals with a controversy between Leibniz and Clarke concerning the relativity of space. Although substantivalism, i.e. an approach treating space as a substance, is to be indicated as the main target of Leibniz’s attack, it has usually been replaced by Newtonian absolutism instead, as a proper opposition to Leibniz’s relationalism. However, such absolutism has not been defined ontologically, but dynamically, as if the difference between their conceptions consisted of a different approach to the inertiallity of motion. However, this (...) would mean that while Leibniz intended to reduce all motion to an inertial one, Newton reduced it to a noninertial one instead, or that only one of them acknowledged the existence of noninertial motion at all. Nevertheless, none of them actually denied the existence of noninertial motion, and although all motion indeed seemed noninertial to Newton, Leibniz never responded to such a challenge in the course of their correspondence. (shrink)

V tomto článku analyzuji virální video Přemluv bábu, které mělo ambice zasáhnout do voleb do Poslanecké sněmovny Parlamentu České republiky v roce 2010. Ke klipu přistupuji z pozice kritické diskurzivní analýzy (CDA), pracuji především s předpoklady, koncepty a analytickými nástroji Normana Fairclougha, který pomáhal CDA rozvíjet a v akademickém poli prosadit. Tvrdím, že klip Přemluv bábu těží z pružnosti, respektive uhýbavosti postmoderního diskurzu, což mohlo smysl jeho výpovědi i její naléhavost spíše oslabit a znečitelnit než podepřít. Demonstruji na příkladech a (...) snažím se identifikovaným ambivalencím porozumět s ohledem na kontext intertextový, interdiskurzivní, situační a socio-politický. (shrink)

V rámci tohoto příspěvku se pokusím zpochybnit dosavadní mainstreamovou interpretaci Leibnizovy metafyziky prostoru, jak ji představil v dopisech anglickému učenci Samuelu Clarkovi. Přestože bývá Leibnizova metafyzika prostoru právě na základě jeho korespondence s Clarkem obvykle považována za ostrý protipól metafyziky Clarkovy, respektive Newtonovy, v rámci tohoto příspěvku poukážu na to, že při zvážení Leibnizovy geometrie zvané „analysis situs“ se taková interpretace stává neudržitelnou. Leibnize nelze považovat za zastánce typicky relačního pojetí prostoru.

Studie se věnuje otázce po ontologickém statusu ideálního, potažmo fenomenálního prostoru v pojetí Gottfrieda Wilhelma Leibnize. Nejprve bude ujasněno, v jakém smyslu lze podle Leibnize za prostor v pravém slova smyslu považovat primárně pouze prostor ideální, sekundárně však rovněž prostor fenomenální. Posléze se vymezím zejména vůči takovým interpretacím leibnizovského ideálního prostoru, které v něm spatřují předzvěst prostoru kantovského. Leibnizův ideální, matematický prostor zde totiž bude přirovnán spíše k prostoru suárezovskému, případně hobbesovskému, nikoli však kantovskému.

gl. 1. Geopoliticheskai︠a︡ determinat︠s︡ii︠a︡ kulʹtury i ėkonomiki. Rolʹ geograficheskikh faktorov v razvitii obshchestva ; Geopoliticheskie osobennosti sot︠s︡iokulʹturnoĭ istorii Rossii -- gl. 2. Kulʹturnai︠a︡ sostavli︠a︡i︠u︡shchai︠a︡ geopolitiki. Kulʹtura kak instrument geopolitiki ; Dialog kulʹtur v sovremennom mire: opasnai︠a︡ illi︠u︡zii︠a︡, otchai︠a︡nnai︠a︡ vera ili velenie vremeni?

This study offers a critical analysis of Husserl's theory of meaning. The author commences by delineating the position and function of Husserl's meaning theory in the sum total of his phenomenological philosophy. He goes on to demonstrate that this theory was conceived as an integral component of Husserl's theory of knowledge. (edited).

We define proof nets for cyclic multiplicative linear logic as edge bi-coloured graphs. Our characterization is purely graph theoretical and works without further complication for proof nets with cuts, which are usually harder to handle in the non-commutative case. This also provides a new characterization of the proof nets for the Lambek calculus (with the empty sequence) which simply are a restriction on the formulas to be considered (which are asked to be intuitionistic).

This work is devoted to the relations between Lambek’s Syntactic Calculus and noncommutative variants of Girard’s Linear Logic; in particular the paper will consider: the geometrical representation of the laws of LC by means of proof-nets; the discovery - due to such a geometrical representation - of some laws of LC not yet considered; the discussion of possible linguistic uses of these new laws.

Hilbert's conference lectures during the year 1922, Neuebegründung der Mathematik. Erste Mitteilung and Die logischen Grundlagen der Mathematik (both are published in (Hilbert [1935] 1965) pp. 157-195), contain his first public presentation of an axiom system for propositional logic, or at least for a fragment of propositional logic, which is largely influenced by the study on logical woks of Frege and Russell during the previous years.The year 1922 is at the beginning of Hilbert's foundational program in its definitive form. The (...) final public presentation by Hilbert of an axiom system for propositional logic is contained in the 1934 book Grundlagen der Mathematik, I (Hilbert and Bernays [1934] 1968). Sequent .. (shrink)