Constrained Bayesian Optimization with Adaptive Active Learning of Unknown Constraints

Optimizing objectives under constraints, where both the objectives and constraints are black box functions, is a common scenario in real-world applications such as scientific experimental design, design of medical therapies, and industrial process optimization. One popular approach to handling these complex scenarios is Bayesian Optimization (BO). In terms of theoretical behavior, BO is relatively well understood in the unconstrained setting, where its principles have been well explored and validated. However, when it comes to constrained Bayesian optimization (CBO), the existing framework often relies on heuristics or approximations without the same level of theoretical guarantees. In this paper, we delve into the theoretical and practical aspects of constrained Bayesian optimization, where the objective and constraints can be independently evaluated and are subject to noise. By recognizing that both the objective and constraints can help identify high-confidence regions of interest (ROI), we propose an efficient CBO framework that intersects the ROIs identified from each aspect to determine the general ROI. The ROI, coupled with a novel acquisition function that adaptively balances the optimization of the objective and the identification of feasible regions, enables us to derive rigorous theoretical justifications for its performance. We showcase the efficiency and robustness of our proposed CBO framework through empirical evidence and discuss the fundamental challenge of deriving practical regret bounds for CBO algorithms

Functional characterization of human hMRE11 and hMRE11-hMLH1 interplay in DNA mismatch repair

DNA mismatch repair (MMR) is a critical pathway which can maintain genetic stability by correcting mismatched nucleotides that occur during DNA replication and recombination. Cells that are deficient in MMR display microsatellite instability (MSI) and germline mutations in various MMR genes can lead to hereditary nonpolyposis colorectal cancer (HNPCC) in humans. Our study for the first time showed that hMRE11 deficiency in HeLa cells can lead to defective 3' MMR in an in vitro MMR assay. Through both GFP-based MSI reporter assay and endogenous MSI marker assay, these cells were also found to display increased levels of MSI, which is comparable to that of the hMLH1 deficient cells. Together with our previous finding that hMRE11 directly interacts with hMLH1, we raised the possibility that hMRE11 might be involved in MMR through physical interaction with hMLH1, and this interaction is critical for functional MMR. Our analysis with 7 hMLH1 HNPCC mutations located within the hMRE11-interacting domain showed that 4 of them almost completely disrupt the MRE11-MLH1 interaction. We increased our study to 64 MLH1 HNPCC mutations, which contain 38 missense mutations, and the result showed that 63% (24 out of 38) of the hMLH1 missense mutations can disrupt their interactions with hMRE11. These findings indicate that hMRE11 represents a functional protein factor in MMR pathway and disruption of hMRE11-hMLH1 could be an alternative molecular mechanism underlying the pathogenic effects of hMLH1 HNPCC mutations. To directly study the functional impact of hMRE11-hMLH1 interplay in MMR, we blocked their interaction in vivo by an hMRE11 dominant negative mutant which represents the hMLH1-interacting domain. In vitro MMR and excision assays indicate that these cells showed dramatically decreased 3' MMR activity and 3' excision activity, suggesting that the hMRE11-hMLH1 interplay is critical for functional MMR, presumably by recruiting hMRE11 for the excision step of MMR

Ischemic postconditioning protects against acute kidney injury after limb ischemia reperfusion by regulating HMGB1 release and autophagy

AbstractIschemic postconditioning (I-PostC) has a protective effect against acute kidney injury (AKI) induced by limb ischemia–reperfusion (LIR); however, the exact mechanism remains to be elucidated. Our study aims to investigate the potential involvement of high-mobility group box 1 protein (HMGB1) and autophagy in renoprotection generated by I-PostC. A rat model of LIR-induced AKI was established and rats were randomly assigned to five groups: (i) sham-operated control, (ii) I/R, (iii) I/R + I-PostC, (iv) I/R + I-PostC + rapamycin (autophagy activator), and (v) I/R + I-PostC + 3-methyladenine (autophagy inhibitor). Morphological changes in the kidneys were assessed by histology, and ultrastructural changes in renal tubular epithelial cells and glomerular podocytes were observed by transmission electron microscopy. The levels of kidney function parameters, serum inflammatory factors, and autophagy markers were detected. The results showed that the levels of HMGB1, Beclin1, LC3-II/LC3-I, and inflammatory cytokines (TNF-α and IL-6) were significantly higher in the I/R group compared to the sham control in serum and in renal tissues. I-PostC significantly reduced the levels of HMGB1, Beclin1, LC3-II/LC3-I, and inflammatory cytokines in renal tissues and improved renal function. Renal histopathology and ultrastructural observations indicated that I-PostC alleviated renal tissue injury. In addition, rapamycin (autophagy activator) treatment increased the levels of inflammatory cytokine expression levels and decreased renal function, reversed the protective effect of I-PostC against LIR-induced AKI. In conclusion, I-PostC could play a protective role against AKI by regulating the release of HMGB1 and inhibiting autophagy activation

A comprehensive analysis of immune features and construction of an immune gene diagnostic model for sepsis

Abstract Sepsis is a life-threatening syndrome resulting from immune system dysfunction that is caused by infection. It is of great importance to analyze the immune characteristics of sepsis, identify the key immune system related genes, and construct diagnostic models for sepsis. In this study, the sepsis transcriptome and expression profiling data were merged into an integrated dataset containing 277 sepsis samples and 117 non-sepsis control samples. Single-sample gene set enrichment analysis (ssGSEA) was used to assess the immune cell infiltration. Two sepsis immune subtypes were identified based on the 22 differential immune cells between the sepsis and the healthy control groups. Weighted gene co-expression network analysis (WCGNA) was used to identify the key module genes. Then, 36 differentially expressed immune-related genes were identified, based on which a robust diagnostic model was constructed with 11 diagnostic genes. The expression of 11 diagnostic genes was finally assessed in the training and validation datasets respectively. In this study, we provide comprehensive insight into the immune features of sepsis and establish a robust diagnostic model for sepsis. These findings may provide new strategies for the early diagnosis of sepsis in the future

The interplay between hMLH1 and hMRE11: Role in MMR and the effect of hMLH1 mutations

Our previous studies indicate that hMRE11 plays a role in MMR, and this function of hMRE11 is most likely mediated by the hMLH1–hMRE11 interaction. Here, we explored the functional implications of the hMLH1–hMRE11 interaction in MMR and the effects of hMLH1 mutations on their interaction. Our in vitro MMR assay demonstrated that the dominant-negative hMRE11452–634 mutant peptide (i.e., harboring only the hMLH1-interacting domain) imparted a significant reduction in both 3′ excision and 3′-directed MMR activities. Furthermore, the expression of hMRE11452–634, and to a lesser extent hMRE111–634 (ATLD1), impaired G2/M checkpoint control in response to MNU and cisplatin treatments, rendering cells resistant to killings by these two anticancer drugs. Analysis of 38 hMLH1 missense mutations showed that the majority of mutations caused significant (>50%) reductions in their interaction with hMRE11, suggesting a potential link between aberrant protein interaction and the pathogenic effects of hMLH1 variants

Physical and functional interaction between hMSH5 and c-Abl

Despite being a member of the mismatch repair family of proteins, the biological functions of hMSH5 in human cells are presently elusive. Here, we report a novel physical and functional interaction between hMSH5 and c-Abl; the latter is a critical non-receptor tyrosine kinase involved in many critical cellular functions including DNA damage response, in which the kinase activity is normally suppressed in the absence of biological challenges. Our data indicate that hMSH5 associates with c-Abl in vivo, which is mediated by a direct physical interaction between the NH2 terminus (residues 1-109) of hMSH5 and the c-Abl SH3 domain. This physical interaction facilitates the activation of c-Abl tyrosine kinase and the phosphorylation of hMSH5 in response to ionizing radiation. Our data also indicate that the hMSH5 P29S variant overactivates the c-Abl tyrosine kinase activity. Furthermore, it seems that the tyrosine phosphorylation of hMSH5 promotes the dissociation of hMSH4-hMSH5 heterocomplex. Together, the revealed physical and functional interaction of hMSH5 with c-Abl implies that the interplay between hMSH5 and c-Abl could manipulate cellular responses to ionizing radiation-induced DNA damages

A Displacement Sensor with Centimeter Dynamic Range and Submicrometer Resolution Based on an Optical Interferometer

We report a low cost and extrinsic Fabry-Perot interferometer-based optical fiber displacement sensor with a wide dynamic range, up to 2.0 cm, and 0.270 µm resolution. The fundamental design principle includes an inclined mirror, mounted on a translational stage, that combines with the end face of a single mode fiber to form a Fabry-Perot cavity. The user-configurable triangle geometry-based displacement transfer mechanism makes the sensor capable of measuring a wide displacement range. A fiber ceramic ferrule is used to support and orient the optical fiber, and a metal shell is used to package and protect the principal sensor elements. The novel sensor was employed to monitor shrinkage during the drying/curing stage of a square brick of mortar. The robust and easy-to-manufacture sensor can be easily commercialized and has great potential for applications in the chemical-oil industry, construction industry, and other industries with harsh environments

Characteristics and Risk Factors of Myocardial Injury after Traumatic Hemorrhagic Shock

Myocardial injury increases major adverse cardiovascular events and mortality in patients with traumatic hemorrhagic shock, but its prevalence and risk factors remain unclear. This study aimed to assess the prevalence and risk factors of myocardial injury after traumatic hemorrhagic shock. This was an observational, retrospective cohort study of patients with traumatic hemorrhagic shock at a tertiary university hospital from November 2012 to July 2021. Patient characteristics and clinical variables were recorded in 314 patients. The outcome was the occurrence of myocardial injury after traumatic hemorrhagic shock. Risk factors for myocardial injury were identified using logistic regression. The incidence of myocardial injury after the traumatic hemorrhagic shock was 42.4%, and 95.5% of myocardial injuries occurred within the first three days after trauma. In the multivariate analysis, the independent risk factors for myocardial injury after traumatic hemorrhagic shock included heart rate of >100 beats/min (OR [odds ratio], 3.33; 95% confidence interval [CI], 1.56–7.09; p = 0.002), hemoglobin level of p = 0.027), prothrombin time of >15 s (OR, 2.39; 95% CI, 1.12–5.10; p = 0.024), acute kidney injury (OR, 2.75; 95% CI, 1.27–5.93; p = 0.01), and a higher APACHE II score (OR, 1.08; 95% CI, 1.01–1.15; p = 0.018). The area under the receiver operating characteristic curve for the prediction of myocardial injury after a traumatic hemorrhagic shock was 0.67 (95% CI, 0.68–0.79) for a heart rate of >100 beats/min, 0.67 (95% CI, 0.61–0.73) for hemoglobin level of 15 s, 0.70 (95% CI, 0.64–0.76) for acute kidney injury, and 0.78 (95% CI, 0.73–0.83) for APACHE II scores. The incidence rate of myocardial injury in traumatic hemorrhagic shock is high, and heart rates of >100 beats/min, hemoglobin levels of 15 s, AKI and higher APACHE II scores are independent risk factors for myocardial injury after traumatic hemorrhagic shock. These findings may help clinicians to identify myocardial injury after traumatic hemorrhagic shock early and initiate appropriate treatment