Existence and nonexistence of solutions to a critical biharmonic equation with logarithmic perturbation

In this paper, the following critical biharmonic elliptic problem \begin{eqnarray*} \begin{cases} \Delta^2u= \lambda u+\mu u\ln u^2+|u|^{2^{**}-2}u, &x\in\Omega,\\ u=\dfrac{\partial u}{\partial \nu}=0, &x\in\partial\Omega \end{cases} \end{eqnarray*} is considered, where $\Omega\subset \mathbb{R}^{N}$ is a bounded smooth domain with $N\geq5$. Some interesting phenomenon occurs due to the uncertainty of the sign of the logarithmic term. It is shown, mainly by using Mountain Pass Lemma, that the problem admits at lest one nontrivial weak solution under some appropriate assumptions of $\lambda$ and $\mu$. Moreover, a nonexistence result is also obtained. Comparing the results in this paper with the known ones, one sees that some new phenomena occur when the logarithmic perturbation is introduced

Existence of solutions to a perturbed critical biharmonic equation with Hardy potential

\ In this paper, the following biharmonic elliptic problem \begin{eqnarray*} \begin{cases} \Delta^2u-\lambda\frac{|u|^{q-2}u}{|x|^s}=|u|^{2^{**}-2}u+ f(x,u), &x\in\Omega,\\ u=\dfrac{\partial u}{\partial n}=0, &x\in\partial\Omega \end{cases} \end{eqnarray*} is considered. The main feature of the equation is that it involves a Hardy term and a nonlinearity with critical Sobolev exponent. By combining a careful analysis of the fibering maps of the energy functional associated with the problem with the Mountain Pass Lemma, it is shown, for some positive parameter $\lambda$ depending on $s$ and $q$, that the problem admits at least one mountain pass type solution under appropriate growth conditions on the nonlinearity $f(x,u)$.Comment: arXiv admin note: text overlap with arXiv:2211.1065

A luminescence-based method to assess antigen presentation and antigen-specific T cell responses for in vitro screening of immunomodulatory checkpoints and therapeutics

Investigations into the strength of antigen-specific responses in vitro is becoming increasingly relevant for decision making in early-phase research of novel immunotherapeutic approaches, including adoptive cell but also immune checkpoint inhibitor (ICI)-based therapies. In the latter, antigen-specific rapid and high throughput tools to investigate MHC/antigen-specific T cell receptor (TCR) activation haven't been implemented yet. Here, we present a simple and rapid luminescence-based approach using the human papillomavirus 16 (HPV16) E7 11-20 peptide as model antigen and E7-TCR transgenic Jurkat.NFAT- luciferase reporter cells. Upon E7 peptide pulsing of HLA-A2 + cell lines and macrophages, an effector to target ratio dependent increase in luminescence compared to non-pulsed cells was observed after co-incubation with E7-TCR expressing Jurkat, but not with parental cells. Analogous experiments with cells expressing full-length HPV16 identified that E7-specific activation of Jurkat cells enabled detection of endogenous antigen processing and MHC-I presentation. As proof of concept, overexpression of established checkpoints/inhibitory molecules (e.g., PD-L1 or HLA-G) significantly reduced the E7-specific TCR-induced luminescence, an effect that could be restored after treatment with corresponding targeting antagonistic antibodies. Altogether, the luminescence-based method described here represents an alternative approach for the rapid evaluation of MHC-dependent antigen-specific T cell responses in vitro. It can be used as a rapid tool to evaluate the impact of the immunosuppressive tumor microenvironment or novel ICI in triggering effective T cell responses, as well as speeding up the development of novel therapeutics within the immune-oncology field. </p

Notch1 promotes resistance to cisplatin by up-regulating Ecto-5'-nucleotidase (CD73) in triple-negative breast cancer cells

Triple-negative breast cancer (TNBC) is an aggressive molecular subtype that due to lack of druggable targets is treated with chemotherapy as standard of care. However, TNBC is prone to chemoresistance and associates with poor survival. The aim of this study was to explore the molecular mechanisms of chemoresistance in TNBC. Firstly, we found that the mRNA expression of Notch1 and CD73 in cisplatin-treated patient material associated with poor clinical outcome. Further, both were upregulated at the protein level in cisplatin-resistant TNBC cell lines. Overexpression of Notch1 intracellular domain (termed N1ICD) increased expression of CD73, whereas knockdown of Notch1 decreased CD73 expression. Using chromatin immunoprecipitation and Dual-Luciferase assay it was identified that N1ICD directly bound the CD73 promoter and activated transcription. Taken together, these findings suggest CD73 as a direct downstream target of Notch1, providing an additional layer to the mechanisms underlying Notch1-mediated cisplatin resistance in TNBC.</p

Frequency-dependent alterations in functional connectivity in patients with Alzheimer’s Disease spectrum disorders

BackgroundIn the spectrum of Alzheimer’s Disease (AD) and related disorders, the resting-state functional magnetic resonance imaging (rs-fMRI) signals within the cerebral cortex may exhibit distinct characteristics across various frequency ranges. Nevertheless, this hypothesis has not yet been substantiated within the broader context of whole-brain functional connectivity. This study aims to explore potential modifications in degree centrality (DC) and voxel-mirrored homotopic connectivity (VMHC) among individuals with amnestic mild cognitive impairment (aMCI) and AD, while assessing whether these alterations differ across distinct frequency bands.MethodsThis investigation encompassed a total of 53 AD patients, 40 aMCI patients, and 40 healthy controls (HCs). DC and VMHC values were computed within three distinct frequency bands: classical (0.01–0.08 Hz), slow-4 (0.027–0.073 Hz), and slow-5 (0.01–0.027 Hz) for the three respective groups. To discern differences among these groups, ANOVA and subsequent post hoc two-sample t-tests were employed. Cognitive function assessment utilized the mini-mental state examination (MMSE) and Montreal Cognitive Assessment (MoCA). Pearson correlation analysis was applied to investigate the associations between MMSE and MoCA scores with DC and VMHC.ResultsSignificant variations in degree centrality (DC) were observed among different groups across diverse frequency bands. The most notable differences were identified in the bilateral caudate nucleus (CN), bilateral medial superior frontal gyrus (mSFG), bilateral Lobule VIII of the cerebellar hemisphere (Lobule VIII), left precuneus (PCu), right Lobule VI of the cerebellar hemisphere (Lobule VI), and right Lobule IV and V of the cerebellar hemisphere (Lobule IV, V). Likewise, disparities in voxel-mirrored homotopic connectivity (VMHC) among groups were predominantly localized to the posterior cingulate gyrus (PCG) and Crus II of the cerebellar hemisphere (Crus II). Across the three frequency bands, the brain regions exhibiting significant differences in various parameters were most abundant in the slow-5 frequency band.ConclusionThis study enhances our understanding of the pathological and physiological mechanisms associated with AD continuum. Moreover, it underscores the importance of researchers considering various frequency bands in their investigations of brain function

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Development of Questionnaire on the Sense of Workplace Involution for Newly Recruited Employees and Its Relationship with Turnover Intention

The term &ldquo;involution&rdquo; has become a buzzword in people&rsquo;s daily communication and online discussion in recent years, and it has been used in many different contexts. However, the concept and structure of workplace involution are still unclear, and there is a lack of valid measurement tools. Objective: To explore the connotation and psychological structure of newly recruited employees&rsquo; sense of workplace involution, compile the Questionnaire on the Sense of Workplace Involution for Newly Recruited Employees, and examine its relationship with turnover intention. Methods: Through in-depth interviews with 30 newly recruited employees and based on qualitative research of the data collected by web crawler technology, the entries were compiled, 282 newly recruited employees were initially tested, and 571 newly recruited employees were given a formal questionnaire survey. The findings were analyzed using SPSS 22.0 and AMOS 24.0 for item analysis, exploratory factor analysis, and confirmatory factor analysis. Results: The newly recruited employees&rsquo; sense of workplace involution and its dimensions were significantly and positively correlated with turnover intention. Newly recruited employees&rsquo; sense of workplace involution was a significant and positive predictor of turnover intention. Conclusions: The reliability and validity of the Questionnaire on the Sense of Workplace Involution for Newly Recruited Employees met the needs of psychometric criteria, and the sense of workplace involution of newly recruited employees had a significant positive predictive effect on turnover intention