Pharmacological activation of FOXO3 suppresses triple-negative breast cancer in vitro and in vivo

Triple-negative breast cancer (TNBC) is the most lethal form of breast cancer. Lacking effective therapeutic options hinders treatment of TNBC. Here, we show that bepridil (BPD) and trifluoperazine (TFP), which are FDA-approved drugs for treatment of schizophrenia and angina respectively, inhibit Akt-pS473 phosphorylation and promote FOXO3 nuclear localization and activation in TNBC cells. BPD and TFP inhibit survival and proliferation in TNBC cells and suppress the growth of TNBC tumors, whereas silencing FOXO3 reduces the BPD- and TFP-mediated suppression of survival in TNBC cells. While BPD and TFP decrease the expression of oncogenic c-Myc, KLF5, and dopamine receptor DRD2 in TNBC cells, silencing FOXO3 diminishes BPD- and TFP-mediated repression of the expression of these proteins in TNBC cells. Since c-Myc, KLF5, and DRD2 have been suggested to increase cancer stem cell-like populations in various tumors, reducing these proteins in response to BPD and TFP suggests a novel FOXO3-dependent mechanism underlying BPD- and TFP-induced apoptosis in TNBC cells

Australian English Back Vowel Perception by Korean and Japanese Learners of English

This paper deals with perception of Australian English back vowels by Korean and Japanese learners of English. The results of the experiment revealed that although language-specific factors played a main role, language-universal factors, in particular with regard to the Australian vowel /ɒ/, also influenced the perception of L2 learners. Three models, the CAH, Flege's model and Best's model, did not provide a perfect prediction on the perception of Australian English back vowels by Korean and Japanese listeners

AN OVERVIEW OF THE KOREAN LANGUAGE AND KOREAN LANGUAGE EDUCATION

Little authentic documentation is available on the origin of the Korean language. Thus, inferences to the genetic affiliation of the language have been made on the basis of various degrees of linguistic resemblances, often supported by archaeological or ethnological findings. Also, earlier forms of the language are not readily accessible because written historical data for internal reconstruction or comparative work are scarce and cannot be traced far back. Some old language fragments are available only in the literature dating from the eleventh century, such as Gyun-yeo jeon (Life of the Great Master Gyun-yeo, 1075) by Hyeklyen Ceng, Gyerim Yusa (Things on Korea, 1103-4) by Chinese Sung Dynasty scholar Sun Mu, Samguk Sagi (Historical Record of the Three Kingdoms, 1145) by Kim Busik, and Samguk Yusa (Memorabilia of the Three Kingdoms, 1285) by Monk Il.yen, all of which are written in Chinese characters. Moreover, much of the earlier vocabulary has been either irretrievably lost or obscured by succeeding waves of linguistic contacts, including a massive influx of Chinese loan words. Lacking solid evidence in establishing the genealogy of Korean, innumerable attempts has been made to relate the language to diverse language families such as the Indo-European, the TibetoBurman, the Dravidian, the Atlantic, the Austronesian, and the Paleosiberian. While there are many ingenious studies based upon the widely accepted principles of comparative method and internal reconstruction, there are also numerous amateurish attempts based merely on accidental lexical resemblances, linguistic borrowings, shared typological features, or anthropological similarities. For instance, Koppelmann (1933) and Eckardt (1966) attempt to relate Korean to Indo-European, observing certain accidental lexical and anthropological resemblances. Hulbert (1905) maintains that Korean is related to the Dravidian languages in India in view of such shared syntactic features as word order and the lack of a gender system. Rahder’s (1956-61) etymological dictionary of Chinese, Japanese, Korean, and Ainu lists, for each of his lexical entries, forms from a vast variety of the world’s languages not compared in accordance with the established principles of comparative linguistics. This evidential opacity leads some linguists to treat Korean, together with Japanese, as a separate language family along with other major language families such as IndoEuropean, Afro-Asiatic, Uralic, Altaic, Sino-Tibetan, Dravidian, Austronesian, and Amerind (Pei, 1954: 31)

Setting research priorities for global pandemic preparedness: An international consensus and comparison with ChatGPT’s output

Background In this priority-setting exercise, we sought to identify leading research priorities needed for strengthening future pandemic preparedness and response across countries. Methods The International Society of Global Health (ISoGH) used the Child Health and Nutrition Research Initiative (CHNRI) method to identify research priorities for future pandemic preparedness. Eighty experts in global health, translational and clinical research identified 163 research ideas, of which 42 experts then scored based on five pre-defined criteria. We calculated intermediate criterion-specific scores and overall research priority scores from the mean of individual scores for each research idea. We used a bootstrap (n = 1000) to compute the 95% confidence intervals. Results Key priorities included strengthening health systems, rapid vaccine and treatment production, improving international cooperation, and enhancing surveillance efficiency. Other priorities included learning from the coronavirus disease 2019 (COVID-19) pandemic, managing supply chains, identifying planning gaps, and promoting equitable interventions. We compared this CHNRI-based outcome with the 14 research priorities generated and ranked by ChatGPT, encountering both striking similarities and clear differences. Conclusions Priority setting processes based on human crowdsourcing – such as the CHNRI method – and the output provided by ChatGPT are both valuable, as they complement and strengthen each other. The priorities identified by ChatGPT were more grounded in theory, while those identified by CHNRI were guided by recent practical experiences. Addressing these priorities, along with improvements in health planning, equitable community-based interventions, and the capacity of primary health care, is vital for better pandemic preparedness and response in many settings

Attenuation of PTEN increases p21 stability and cytosolic localization in kidney cancer cells: a potential mechanism of apoptosis resistance

BACKGROUND: The PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten) tumor suppressor gene is frequently mutated or deleted in a wide variety of solid tumors, and these cancers are generally more aggressive and difficult to treat than those possessing wild type PTEN. While PTEN lies upstream of the phosphoinositide-3 kinase signaling pathway, the mechanisms that mediate its effects on tumor survival remain incompletely understood. Renal cell carcinoma (RCC) is associated with frequent treatment failures (~90% in metastatic cases), and these tumors frequently contain PTEN abnormalities. RESULTS: Using the ACHN cell line containing wild type PTEN, we generated a stable PTEN knockdown RCC cell line using RNA interference. We then used this PTEN knockdown cell line to show that PTEN attenuation increases resistance to cisplatin-induced apoptosis, a finding associated with increased levels of the cyclin kinase inhibitor p21. Elevated levels of p21 result from stabilization of the protein, and they are dependent on the activities of phosphoinositide-3 kinase and Akt. More specifically, the accumulation of p21 occurs preferentially in the cytosolic compartment, which likely contributes to both cell cycle progression and resistance to apoptosis. CONCLUSION: Since p21 regulates a decision point between repair and apoptosis after DNA damage, our data suggest that p21 plays a key role in mechanisms used by PTEN-deficient tumors to escape chemotherapy. This in turn raises the possibility to use p21 attenuators as chemotherapy sensitizers, an area under active continuing investigation in our laboratories

Stabilization of single-electron pumps by high magnetic fields

We study the effect of perpendicular magnetic fields on a single-electron system with a strongly time-dependent electrostatic potential. Continuous improvements to the current quantization in these electron pumps are revealed by high-resolution measurements. Simulations show that the sensitivity of tunnel rates to the barrier potential is enhanced, stabilizing particular charge states. Nonadiabatic excitations are also suppressed due to a reduced sensitivity of the Fock-Darwin states to electrostatic potential. The combination of these effects leads to significantly more accurate current quantization

Covariant description of the black hole entropy in 3D gravity

We study the entropy of the black hole with torsion using the covariant form of the partition function. The regularization of infinities appearing in the semiclassical calculation is shown to be consistent with the grand canonical boundary conditions. The correct value for the black hole entropy is obtained provided the black hole manifold has two boundaries, one at infinity and one at the horizon. However, one can construct special coordinate systems, in which the entropy is effectively associated with only one of these boundaries.Comment: 12 pages, LaTeX, v2: new material in section IV clarifies the effects pertaining to the use of different coordinate system

A comment on pp-branes of (p+3p+3)d\rm{d} string theory

We argue that in ($p+3$)d string theory the existence of NS-NS type $p$-brane with negative tension is essential to obtain background geometry $R_2$ or $R_2 / Z_n$ on the transverse dimensions, and the usual codimension-2 brane solutions with these background geometries already contain the negative tension NS-brane implicity in their ansatz. Such an argument leads us, in the context of brane world scenarios, to a conjecture that true background $p$-brane immanent in our spacetime may perhaps be NS-NS type brane, rather than D-brane.Comment: 16 pages. Version to appear in JHE

Mixed Wino Dark Matter: Consequences for Direct, Indirect and Collider Detection

In supersymmetric models with gravity-mediated SUSY breaking and gaugino mass unification, the predicted relic abundance of neutralinos usually exceeds the strict limits imposed by the WMAP collaboration. One way to obtain the correct relic abundance is to abandon gaugino mass universality and allow a mixed wino-bino lightest SUSY particle (LSP). The enhanced annihilation and scattering cross sections of mixed wino dark matter (MWDM) compared to bino dark matter lead to enhanced rates for direct dark matter detection, as well as for indirect detection at neutrino telescopes and for detection of dark matter annihilation products in the galactic halo. For collider experiments, MWDM leads to a reduced but significant mass gap between the lightest neutralinos so that chi_2^0 two-body decay modes are usually closed. This means that dilepton mass edges-- the starting point for cascade decay reconstruction at the CERN LHC-- should be accessible over almost all of parameter space. Measurement of the m_{\tz_2}-m_{\tz_1} mass gap at LHC plus various sparticle masses and cross sections as a function of beam polarization at the International Linear Collider (ILC) would pinpoint MWDM as the dominant component of dark matter in the universe.Comment: 29 pages including 19 eps figure