A dynamic programming approach for generalized nearly isotonic optimization

Shape restricted statistical estimation problems have been extensively studied, with many important practical applications in signal processing, bioinformatics, and machine learning. In this paper, we propose and study a generalized nearly isotonic optimization (GNIO) model, which recovers, as special cases, many classic problems in shape constrained statistical regression, such as isotonic regression, nearly isotonic regression and unimodal regression problems. We develop an efficient and easy-to-implement dynamic programming algorithm for solving the proposed model whose recursion nature is carefully uncovered and exploited. For special $\ell_2$-GNIO problems, implementation details and the optimal ${\cal O}(n)$ running time analysis of our algorithm are discussed. Numerical experiments, including the comparison between our approach and the powerful commercial solver Gurobi for solving $\ell_1$-GNIO and $\ell_2$-GNIO problems, on both simulated and real data sets are presented to demonstrate the high efficiency and robustness of our proposed algorithm in solving large scale GNIO problems

Establishment of OPG Transgenic Mice and the Effect of OPG on Bone Microarchitecture

Osteoprotegerin (OPG) plays a determinant role in regulating bone metabolism, but the effect of OPG on bone microarchitecture needs to be further elucidated. We attempted to construct pCI-hOPGp-mOPG vector containing human OPG promoter and FLAG tag and to microinject vector into fertilized zygotes from C57BL/6J × CBA mice to prepare transgenic mice. The OPG transgenic positive mice were identified by PCR and western blotting. Twelve-week-old OPG transgenic mice (OPG-Tg mice) and wild-type mice (WT mice) were utilized in the study of bone microarchitecture. Microcomputed tomography (micro-CT) data showed that compared with WT mice, the tibia of OPG-Tg mice showed an increased volumetric BMD (vBMD), tissue BMD (tBMD), trabecular thickness (Tb.Th), and trabecular number (Tb.N), and a decreased trabecular separation (Th.Sp) (P<0.05) . The cortical bone microarchitecture parameters, such as cortical area (Ct.Ar), cortical thickness (Ct.Th), cortical BMD (Ct.BMD), cortical BMC (Ct.BMC), BMD, and BMC of femur, were increased, and the inner perimeter (In.Pm) was decreased, in OPG-Tg mice, compared to those in WT mice (P<0.05). The established OPG transgenic mouse model could be valuable for further studying the biological significance and gene regulation of OPG in vivo

SP1 enhances Zbtb7A gene expression via direct binding to GC box in HePG2 cells

<p>Abstract</p> <p>Background</p> <p>Zbtb7A is a proto-oncogenic transcriptional regulator that plays an important role in adipogenesis, osteogenesis and oncogenesis, but little is known about the regulation of Zbtb7A gene expression which is of importance in the function uncovering of this gene.</p> <p>Finding</p> <p>Here, a 5'-flanking region of the human Zbtb7A gene was cloned and characterized. It was found that the GC box within Zbtb7A promoter is necessary for the promoter activity. Furthermore, we identified that Sp1 acts as an activator in the regulation of Zbtb7A promoter activity and the physical interaction between Sp1 and GC box is responsible for the activation of Zbtb7A gene promoter.</p> <p>Conclusion</p> <p>Our results confirmed that Sp1 upregulates Zbtb7A gene expression via direct binding to GC box within the promoter.</p

Preventing Discriminatory Decision-making in Evolving Data Streams

Bias in machine learning has rightly received significant attention over the last decade. However, most fair machine learning (fair-ML) work to address bias in decision-making systems has focused solely on the offline setting. Despite the wide prevalence of online systems in the real world, work on identifying and correcting bias in the online setting is severely lacking. The unique challenges of the online environment make addressing bias more difficult than in the offline setting. First, Streaming Machine Learning (SML) algorithms must deal with the constantly evolving real-time data stream. Second, they need to adapt to changing data distributions (concept drift) to make accurate predictions on new incoming data. Adding fairness constraints to this already complicated task is not straightforward. In this work, we focus on the challenges of achieving fairness in biased data streams while accounting for the presence of concept drift, accessing one sample at a time. We present Fair Sampling over Stream ($FS^2$), a novel fair rebalancing approach capable of being integrated with SML classification algorithms. Furthermore, we devise the first unified performance-fairness metric, Fairness Bonded Utility (FBU), to evaluate and compare the trade-off between performance and fairness of different bias mitigation methods efficiently. FBU simplifies the comparison of fairness-performance trade-offs of multiple techniques through one unified and intuitive evaluation, allowing model designers to easily choose a technique. Overall, extensive evaluations show our measures surpass those of other fair online techniques previously reported in the literature

Mitochondrial stress response and myogenic differentiation

Regeneration and repair are prerequisites for maintaining effective function of skeletal muscle under high energy demands, and myogenic differentiation is one of the key steps in the regeneration and repair process. A striking feature of the process of myogenic differentiation is the alteration of mitochondria in number and function. Mitochondrial dysfunction can activate a number of transcriptional, translational and post-translational programmes and pathways to maintain cellular homeostasis under different types and degrees of stress, either through its own signaling or through constant signaling interactions with the nucleus and cytoplasm, a process known as the mitochondrial stress responses (MSRs). It is now believed that mitochondrial dysfunction is closely associated with a variety of muscle diseases caused by reduced levels of myogenic differentiation, suggesting the possibility that MSRs are involved in messaging during myogenic differentiation. Also, MSRs may be involved in myogenesis by promoting bioenergetic remodeling and assisting myoblast survival during myogenic differentiation. In this review, we will take MSRs as an entry point to explore its concrete regulatory mechanisms during myogenic differentiation, with a perspective to provide a theoretical basis for the treatment and repair of related muscle diseases

Second generation androgen receptor antagonist, TQB3720 abrogates prostate cancer growth via AR/GPX4 axis activated ferroptosis

Purpose: Prostate cancer (PCa) poses a great threat to humans. The study aimed to evaluate the potential of TQB3720 in promoting ferroptosis to suppress prostate cancer, providing a theoretical basis for PCa therapy.Methods: PCa cells and nude mice models were divided into TQB3720, enzalutamide (ENZ), and control groups. Sulforhodamine B assay, colony formation assessment, organoids culture system, and the CCK8 assay were used for detecting proliferation. Western blot assay was processed to detect the expression of androgen receptor (AR), ferroptosis, and apoptosis-related genes. Flow cytometry was applied to measure the intracellular ROS levels. ELISA was performed to determine the cellular oxidized glutathione (GSSG) and malondialdehyde (MDA) levels. RT-qPCR was conducted to detect the mRNA expression of genes in AR signaling. BODIPYTM™ 581/591 was processed for detection of intracellular lipid peroxidation levels. The interaction of AR with other translational factor complex proteins was explored using Co-immunoprecipitation (Co-IP), and the chromatin immunoprecipitation (ChIP) assay was performed to detect the binding of AR-involved translational complex to downstream genes promoter. Luciferase reporter assay was conducted to examine the translation activity of GPX4 promoter, and immunohistochemistry (IHC) was conducted to analyze the levels of c-MYC, Ki-67 and AR in TQB3720-treated cancer tissues.Results: Here, we found TQB3720 inhibits the growth of prostate cancer in vitro and in vivo. TQB3720 treatment induced intracellular levels of GSSG and MDA significantly, by which hints AR antagonist caused ferroptosis-related cell death. Moreover, molecular evidence shown TQB3720 regulates downstream of AR signaling by binding AR resulting in inhibition of AR entry into the nucleus. Additional, we also proved that TQB3720 abrogates the interaction between AR and SP1 and leads to decrease GPX4 transcription.Conclusion: TQB3720 promotes ferroptosis in prostate cancer cells by reducing the AR/SP1 transcriptional complex binding to GPX4 promoter. As a result, it is suggested to be a potential drug for clinic prostate cancer treatment

Beauvericin counteracted multi-drug resistant Candida albicans by blocking ABC transporters

AbstractMulti-drug resistance of pathogenic microorganisms is becoming a serious threat, particularly to immunocompromised populations. The high mortality of systematic fungal infections necessitates novel antifungal drugs and therapies. Unfortunately, with traditional drug discovery approaches, only echinocandins was approved by FDA as a new class of antifungals in the past two decades. Drug efflux is one of the major contributors to multi-drug resistance, the modulator of drug efflux pumps is considered as one of the keys to conquer multi-drug resistance. In this study, we combined structure-based virtual screening and whole-cell based mechanism study, identified a natural product, beauvericin (BEA) as a drug efflux pump modulator, which can reverse the multi-drug resistant phenotype of Candida albicans by specifically blocking the ATP-binding cassette (ABC) transporters; meantime, BEA alone has fungicidal activity in vitro by elevating intracellular calcium and reactive oxygen species (ROS). It was further demonstrated by histopathological study that BEA synergizes with a sub-therapeutic dose of ketoconazole (KTC) and could cure the murine model of disseminated candidiasis. Toxicity evaluation of BEA, including acute toxicity test, Ames test, and hERG (human ether-à-go-go-related gene) test promised that BEA can be harnessed for treatment of candidiasis, especially the candidiasis caused by ABC overexpressed multi-drug resistant C. albicans

Electrochemical Lithium Extraction with Gas Flushing of Porous Electrodes

Electrochemical extraction of lithium from seawater/brine is receiving more and more attention because of its environment-friendly and energy-saving features. In this work, an electrochemical lithium extraction system with gas flushing of porous electrodes is proposed. We verified that the operation of multiple gas washes can significantly reduce the consumption of ultrapure water during the solution exchange and save the time required for the continuous running of the system. The water consumption of multiple gas flush operations is only 1/60 of that of a normal single flush to obtain a purity close to 100% in the recovery solution. By comparing the ion concentration distribution on the electrode surface in flow-through and flow-by-flow modes, we demonstrate that the flow-through mode performs better. We also verified the lithium extraction performance of the whole system, achieving a purity close to 100% and average energy consumption of 0.732 kWh∙kg−1 in each cycle from the source solution of the simulated Atacama salt lake water. These results provide a feasible approach for the large-scale operation of electrochemical lithium extraction from seawater/brine

Salient difference of sea surface temperature over the North Atlantic in the spring following three super El Niño events

International audienceDespite similar evolution of Niño3.4 index for three strong El Niño events in the tropical Pacific in 1982–1983, 1997–1998 and 2015–2016, divergent sea surface temperature anomalies (SSTAs) were observed in the North Atlantic (NA) in spring following El Niño peak. Strong teleconnection occurred for the first two events in 1982–1983 and 1997–1998, leading to a negative phase of a North Atlantic Oscillation-like circulation over the extratropical NA, and thus a positive tripolar SSTA pattern in the NA. But the teleconnection was weak for the case of 2015–2016 El Niño, the SSTA in spring 2016 in NA being mainly created and maintained by the preconditioning of the NA basin and local atmosphere-ocean interactions. The salient difference among the three events resides in their ways to operate the teleconnection linking the central-eastern equatorial Pacific and the subtropical eastern North Pacific to the extratropical NA, which would be a key to explain the different impacts of the three exceptional El Niño events. It is furthermore shown that the reduced anomalous westerlies over Central America along 30° N around the peak time of 2015–2016 El Niño play a role of inhibition for an efficient Rossby wave energy propagation from the tropics, eastward into the Gulf of Mexico and northward into midlatitudes in the western NA