Notes on the coexistence of limit notions

We summarize the current knowledge on the three limit notions: ultrafilter-limits, closed-ultrafilter-limits and FAM-limits. Also, we consider the possibility to perform an iteration which has all the three limits and clarify the problem we face.Comment: 19 pages, 2 figures. To appear in RIMS K\^oky\^uroku, Kyoto University. arXiv admin note: substantial text overlap with arXiv:2401.1460

Cicho\'n's maximum with evasion number

We show that the evasion number $\mathfrak{e}$ can be added to Cicho\'n's maximum with a distinct value. More specifically, it is consistent that $\aleph_1<\mathrm{add}(\mathcal{N})<\mathrm{cov}(\mathcal{N})<\mathfrak{b}<\mathfrak{e}<\mathrm{non}(\mathcal{M})<\mathrm{cov}(\mathcal{M})<\mathfrak{d}<\mathrm{non}(\mathcal{N})<\mathrm{cof}(\mathcal{N})<2^{\aleph_0}$ holds.Comment: 32pages,11figure

MCL1 inhibition is effective against a subset of small-cell lung cancer with high MCL1 and low BCL-XL expression

There have been few advances in the treatment of small-cell lung cancer (SCLC) because of the lack of targets. MCL1, a member of the anti-apoptotic BCL-2 family, may be a treatment target in several cancers, including SCLC. However, whether the expression profile of the anti-apoptotic BCL-2 family affects MCL1 inhibition strategy is unknown. A tissue microarray (TMA) was created from consecutive patients who were diagnosed with SCLC and had previously undergone surgery at Kyoto University Hospital (Kyoto, Japan) between 2001 and 2017. We used S63845, a MCL1 inhibitor, to assess the cytotoxic capacity in SCLC cell lines including a patient-derived cell line in vitro and in vivo. The combination of S63845 with navitoclax, a double BCL-XL/BCL-2 inhibitor, was also employed to examine the comprehensive inhibition of the anti-apoptotic BCL-2 family. Immunohistochemistry of a TMA from patients with surgically resected SCLC demonstrated high MCL1 expression with low BCL-XL and BCL-2 to be the most common expression profile. S63845 was effective in high MCL1- and low BCL-XL-expressing SCLC cell lines. S63845 induced BAK-dependent apoptosis in vitro, and the anti-tumor efficacy was confirmed in an in vivo model. Although knockdown of BCL-XL and BCL-2 improved the cytotoxic activity of S63845 and its combination with navitoclax increased the anti-tumor cytotoxicity, the therapeutic range of S63845 with navitoclax was narrow in in vivo studies. Our study suggests MCL1 inhibition therapy be applied for high MCL1- and low BCL-XL-expressing SCLC patients

Molecular basis for SMC rod formation and its dissolution upon DNA binding.

SMC condensin complexes are central modulators of chromosome superstructure in all branches of life. Their SMC subunits form a long intramolecular coiled coil, which connects a constitutive "hinge" dimerization domain with an ATP-regulated "head" dimerization module. Here, we address the structural arrangement of the long coiled coils in SMC complexes. We unequivocally show that prokaryotic Smc-ScpAB, eukaryotic condensin, and possibly also cohesin form rod-like structures, with their coiled coils being closely juxtaposed and accurately anchored to the hinge. Upon ATP-induced binding of DNA to the hinge, however, Smc switches to a more open configuration. Our data suggest that a long-distance structural transition is transmitted from the Smc head domains to regulate Smc-ScpAB's association with DNA. These findings uncover a conserved architectural theme in SMC complexes, provide a mechanistic basis for Smc's dynamic engagement with chromosomes, and offer a molecular explanation for defects in Cornelia de Lange syndrome

Pneumonia Caused by Severe Acute Respiratory Syndrome Coronavirus 2 and Influenza Virus: A Multicenter Comparative Study

Background: Detailed differences in clinical information between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia (CP), which is the main phenotype of SARS-CoV-2 disease, and influenza pneumonia (IP) are still unclear. Methods: A prospective, multicenter cohort study was conducted by including patients with CP who were hospitalized between January and June 2020 and a retrospective cohort of patients with IP hospitalized from 2009 to 2020. We compared the clinical presentations and studied the prognostic factors of CP and IP. Results: Compared with the IP group (n = 66), in the multivariate analysis, the CP group (n = 362) had a lower percentage of patients with underlying asthma or chronic obstructive pulmonary disease (P < .01), lower neutrophil-to-lymphocyte ratio (P < .01), lower systolic blood pressure (P < .01), higher diastolic blood pressure (P < .01), lower aspartate aminotransferase level (P < .05), higher serum sodium level (P < .05), and more frequent multilobar infiltrates (P < .05). The diagnostic scoring system based on these findings showed excellent differentiation between CP and IP (area under the receiver operating characteristic curve, 0.889). Moreover, the prognostic predictors were different between CP and IP. Conclusions: Comprehensive differences between CP and IP were revealed, highlighting the need for early differentiation between these 2 pneumonias in clinical settings

Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity.

BACKGROUND: Antivirals are needed to combat the COVID-19 pandemic, which is caused by SARS-CoV-2. The clinically-proven protease inhibitor Camostat mesylate inhibits SARS-CoV-2 infection by blocking the virus-activating host cell protease TMPRSS2. However, antiviral activity of Camostat mesylate metabolites and potential viral resistance have not been analyzed. Moreover, antiviral activity of Camostat mesylate in human lung tissue remains to be demonstrated. METHODS: We used recombinant TMPRSS2, reporter particles bearing the spike protein of SARS-CoV-2 or authentic SARS-CoV-2 to assess inhibition of TMPRSS2 and viral entry, respectively, by Camostat mesylate and its metabolite GBPA. FINDINGS: We show that several TMPRSS2-related proteases activate SARS-CoV-2 and that two, TMPRSS11D and TMPRSS13, are robustly expressed in the upper respiratory tract. However, entry mediated by these proteases was blocked by Camostat mesylate. The Camostat metabolite GBPA inhibited recombinant TMPRSS2 with reduced efficiency as compared to Camostat mesylate. In contrast, both inhibitors exhibited similar antiviral activity and this correlated with the rapid conversion of Camostat mesylate into GBPA in the presence of serum. Finally, Camostat mesylate and GBPA blocked SARS-CoV-2 spread in human lung tissue ex vivo and the related protease inhibitor Nafamostat mesylate exerted augmented antiviral activity. INTERPRETATION: Our results suggest that SARS-CoV-2 can use TMPRSS2 and closely related proteases for spread in the upper respiratory tract and that spread in the human lung can be blocked by Camostat mesylate and its metabolite GBPA. FUNDING: NIH, Damon Runyon Foundation, ACS, NYCT, DFG, EU, Berlin Mathematics center MATH+, BMBF, Lower Saxony, Lundbeck Foundation, Novo Nordisk Foundation

Effects of Highlighting Text on the Reading Ability of Children with Developmental Dyslexia: A Pilot Study

Digital texts can be made accessible to children with developmental dyslexia by presenting them in a simplified layout, using suitable fonts, or using text highlighting that is synchronized with audio. However, the impact of this last method on readability (as measured by eye movement) for children with developmental dyslexia remains unknown; it is unclear whether the color and length of text highlighting influences readability. We examined these issues in two experiments with seven children with developmental dyslexia (aged 7–14 years). In the first experiment, we clarified the relation between readability and text highlighting with synchronous audio by measuring the eye movements of children with developmental dyslexia. Readability was determined using the frequency of eye fixations. In the second experiment, we determined which styles of text highlighting best supported digital text reading among children with developmental dyslexia. Digital texts were created using different text highlighting colors and band lengths, and then were read using Apple iBooks on a 9.7-inch Apple iPad Air. We observed that children with developmental dyslexia found it easier to read along when audio was synchronized with text highlighting, particularly for the highlighting style that used a blue band for whole sentences. The second experiment showed that children with developmental dyslexia found it particularly easy to read digital texts that were highlighted with blue or yellow bands, both for single sentences and for single words. The method of presenting visual information for reading might help children with developmental dyslexia read more easily