Lower Bounds for Possibly Divergent Probabilistic Programs

We present a new proof rule for verifying lower bounds on quantities of probabilistic programs. Our proof rule is not confined to almost-surely terminating programs -- as is the case for existing rules -- and can be used to establish non-trivial lower bounds on, e.g., termination probabilities and expected values, for possibly divergent probabilistic loops, e.g., the well-known three-dimensional random walk on a lattice

Manipulation of LIPSS orientation on silicon surfaces using orthogonally polarized femtosecond laser double-pulse trains

Laser-induced periodic surface structures (LIPSS) provide an easy and costeffective means of fabricating gratings and have been widely studied in recent decades. To overcome the challenge of orientation controllability, we developed a feasible and efficient method for manipulating the orientation of LIPSS in real time. Specifically, we used orthogonally polarized and equal-energy femtosecond laser (50 fs, 800 nm) double-pulse trains with time delay about 1ps, total peak laser fluence about 1.0 J/cm2, laser repetition frequency at 100 Hz and scanning speed at 150 μm/s to manipulate the LIPSS orientation on silicon surfaces perpendicular to the scanning direction, regardless of the scanning paths. The underlying mechanism is attributed to the periodic energy deposition along the direction of surface plasmon polaritons (SPPs), which can be controlled oriented along the scanning direction in orthogonally polarized femtosecond laser double-pulse trains surface scan processing. An application of structural colors presents the functionality of our method

Manipulation of LIPSS orientation on silicon surfaces using orthogonally polarized femtosecond laser double-pulse trains

Laser-induced periodic surface structures (LIPSS) provide an easy and costeffective means of fabricating gratings and have been widely studied in recent decades. To overcome the challenge of orientation controllability, we developed a feasible and efficient method for manipulating the orientation of LIPSS in real time. Specifically, we used orthogonally polarized and equal-energy femtosecond laser (50 fs, 800 nm) double-pulse trains with time delay about 1ps, total peak laser fluence about 1.0 J/cm2, laser repetition frequency at 100 Hz and scanning speed at 150 μm/s to manipulate the LIPSS orientation on silicon surfaces perpendicular to the scanning direction, regardless of the scanning paths. The underlying mechanism is attributed to the periodic energy deposition along the direction of surface plasmon polaritons (SPPs), which can be controlled oriented along the scanning direction in orthogonally polarized femtosecond laser double-pulse trains surface scan processing. An application of structural colors presents the functionality of our method

Medicinal chemistry strategies towards the development of non-covalent SARS-CoV-2 Mpro inhibitors

The main protease (Mpro) of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle. The covalent Mpro inhibitor nirmatrelvir (in combination with ritonavir, a pharmacokinetic enhancer) and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use. Effective antiviral drugs are needed to fight the pandemic, while non-covalent Mpro inhibitors could be promising alternatives due to their high selectivity and favorable druggability. Numerous non-covalent Mpro inhibitors with desirable properties have been developed based on available crystal structures of Mpro. In this article, we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent Mpro inhibitors, followed by a general overview and critical analysis of the available information. Prospective viewpoints and insights into current strategies for the development of non-covalent Mpro inhibitors are also discussed.We gratefully acknowledge financial support from Major Basic Research Project of Shandong Provincial Natural Science Foundation (ZR2021ZD17, China), Science Foundation for Outstanding Young Scholars of Shandong Province (ZR2020JQ31, China), Foreign Cultural and Educational Experts Project (GXL20200015001, China), Guangdong Basic and Applied Basic Research Foundation (2021A1515110740, China), China Postdoctoral Science Foundation (2021M702003). This work was supported in part by the Ministry of Science and Innovation of Spain through grant PID2019-104176RB-I00/AEI/10.13039/501100011033 awarded to Luis Menéndez-Arias; An institutional grant of the Fundación Ramón Areces (Madrid, Spain) to the CBMSO is also acknowledged.Peer reviewe

Clinical significance of CD155 expression and correlation with cellular components of tumor microenvironment in gastric adenocarcinoma

IntroductionCD155 is recently emerging as a promising target in malignancies. However, the relationship between CD155 expression and tumor microenvironment (TME) cell infiltration in gastric adenocarcinoma (GAC) has rarely been clarified.MethodsWe measured CD155 expression in specimens of gastric precancerous disease and GAC by immunohistochemistry. The association of CD155 expression with GAC progression and cells infiltration in TME was evaluated through 268 GAC tissues and public dataset analysis.ResultsWe showed that the expression of CD155 was positively correlated with the pathological development of gastric precancerous disease (r = 0.521, P < 0.0001). GAC patients with high CD155 expression had a poorer overall survival (P = 0.033). Moreover, CD155 expression correlated with aggressive clinicopathological features including tumor volume, tumor stage, lymph node involvement, and cell proliferation (P <0.05). Remarkably, CD155 expression positively related to the infiltration of CD68+ macrophages in TME (P = 0.011). Meanwhile, the positive correlation was observed between CD155 and CD31 (P = 0.026). In addition, patients with high CD155 expression combined with low CD3, CD4, CD8, IL-17, IFN-γ or CD19 expression as well as those with high CD155 and α-SMA expression showed significantly worse overall survival (P < 0.05).ConclusionsCD155 may play a pivotal role in the development of GAC through both immunological and non-immunological mechanisms and be expected to become a novel target of immunotherapy in GAC patients

The interaction between the soluble programmed death ligand-1 (sPD-L1) and PD-1+ regulator B cells mediates immunosuppression in triple-negative breast cancer

Accumulating evidence suggests that regulatory B cells (Bregs) play important roles in inhibiting the immune response in tumors. Programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) are important molecules that maintain the balance of the immune response and immune tolerance. This study aims to evaluate the soluble form of PD-L1 and its function in inducing the differentiation of B lymphocytes, investigate the relationship between soluble PD-L1 (sPD-L1) and B-cell subsets, and explore the antitumor activity of T lymphocytes after PD-L1 blockade in coculture systems. In an effort to explore the role of sPD-L1 in human breast cancer etiology, we examined the levels of sPD-L1 and interleukin-10 (IL-10) in the serum of breast tumor patients and the proportions of B cells, PD-1+ B cells, Bregs, and PD-1+ Bregs in the peripheral blood of patients with breast tumors and assessed their relationship among sPD-L1, IL-10, and B-cell subsets. The levels of sPD-L1 and IL-10 in serum were found to be significantly higher in invasive breast cancer (IBCa) patients than in breast fibroadenoma (FIBma) patients. Meanwhile, the proportions and absolute numbers of Bregs and PD-1+ Bregs in the peripheral blood of IBCa patients were significantly higher than those of FIBma patients. Notably, they were the highest in triple-negative breast cancer (TNBC) among other subtypes of IBCa. Positive correlations of sPD-L1 and IL-10, IL-10 and PD-1+ Bregs, and also sPD-L1 and PD-1+ Bregs were observed in IBCa. We further demonstrated that sPD-L1 could induce Breg differentiation, IL-10 secretion, and IL-10 mRNA expression in a dose-dependent manner in vitro. Finally, the induction of regulatory T cells (Tregs) by Bregs was further shown to suppress the antitumor response and that PD-L1 blockade therapies could promote the apoptosis of tumor cells. Together, these results indicated that sPD-L1 could mediate the differentiation of Bregs, expand CD4+ Tregs and weaken the antitumor activity of CD4+ T cells. PD-L1/PD-1 blockade therapies might be a powerful therapeutic strategy for IBCa patients, particularly for TNBC patients with high level of PD-1+ Bregs