Internal Contrastive Learning for Generalized Out-of-distribution Fault Diagnosis (GOOFD) Framework

Fault diagnosis is essential in industrial processes for monitoring the conditions of important machines. With the ever-increasing complexity of working conditions and demand for safety during production and operation, different diagnosis methods are required, and more importantly, an integrated fault diagnosis system that can cope with multiple tasks is highly desired. However, the diagnosis subtasks are often studied separately, and the currently available methods still need improvement for such a generalized system. To address this issue, we propose the Generalized Out-of-distribution Fault Diagnosis (GOOFD) framework to integrate diagnosis subtasks, such as fault detection, fault classification, and novel fault diagnosis. Additionally, a unified fault diagnosis method based on internal contrastive learning is put forward to underpin the proposed generalized framework. The method extracts features utilizing the internal contrastive learning technique and then recognizes the outliers based on the Mahalanobis distance. Experiments are conducted on a simulated benchmark dataset as well as two practical process datasets to evaluate the proposed framework. As demonstrated in the experiments, the proposed method achieves better performance compared with several existing techniques and thus verifies the effectiveness of the proposed framework

Microglia Prevent Beta-Amyloid Plaque Formation in the Early Stage of an Alzheimer\u27s Disease Mouse Model with Suppression of Glymphatic Clearance

BACKGROUND: Soluble beta-amyloid (Aβ) can be cleared from the brain through various mechanisms including enzymatic degradation, glial cell phagocytosis, transport across the blood-brain barrier, and glymphatic clearance. However, the relative contribution of each clearance system and their compensatory effects in delaying the pathological process of Alzheimer\u27s disease (AD) are currently unknown. METHODS: Fluorescent trace, immunofluorescence, and Western blot analyses were performed to compare glymphatic clearance ability and Aβ accumulation among 3-month-old APP695/PS1-dE9 transgenic (APP/PS1) mice, wild-type mice, aquaporin 4 knock out (AQP4−/−) mice, and AQP4−/−/APP/PS1 mice. The consequence of selectively eliminating microglial cells, or downregulating apolipoprotein E (apoE) expression, on Aβ burden, was also investigated in the frontal cortex of AQP4−/−/APP/PS1 mice and APP/PS1 mice. RESULTS: AQP4 deletion in APP/PS1 mice significantly exaggerated glymphatic clearance dysfunction, and intraneuronal accumulation of Aβ and apoE, although it did not lead to Aβ plaque deposition. Notably, microglia, but not astrocytes, increased activation and phagocytosis of Aβ in the cerebral cortex of AQP4−/−/APP/PS1 mice, compared with APP/PS1 mice. Selectively eliminating microglia in the frontal cortex via local injection of clodronate liposomes resulted in deposition of Aβ plaques in AQP4−/−/APP/PS1 mice, but not APP/PS1 mice. Moreover, knockdown of apoE reduced intraneuronal Aβ levels in both APP/PS1 mice and AQP4−/−/APP/PS1 mice, indicating an inhibitory effect of apoE on Aβ clearance. CONCLUSION: The above results suggest that the glymphatic system mediated Aβ and apoE clearance and microglia mediated Aβ degradation synergistically prevent Aβ plague formation in the early stages of the AD mouse model. Protecting one or both of them might be beneficial to delaying the onset of AD

Xiaoqinglong granules as add-on therapy for asthma: latent class analysis of symptom predictors of response.

Xiaoqinglong granules (XQLG) has been shown to be an effective therapy in asthma animal models. We reviewed the literature and conducted this study to assess the impact of XQLG as an add-on therapy to treatment with fluticasone/salmeterol (seretide) in adult patients with mild-to-moderate, persistent asthma. A total of 178 patients were randomly assigned to receive XQLG and seretide or seretide plus placebo for 90 days. Asthma control was assessed by asthma control test (ACT), symptoms scores, FEV(1), and PEF. Baseline patient-reported Chinese medicine (CM)-specific symptoms were analyzed to determine whether the symptoms may be possible indicators of treatment response by conducting latent class analysis (LCA). There was no statistically significant difference in ACT score between two groups. In the subset of 70 patients with symptoms defined by CM criteria, XQLG add-on therapy was found to significantly increase the levels of asthma control according to global initiative for asthma (GINA) guidelines (P = 0.0329). There was no significant difference in another subset of 100 patients with relatively low levels of the above-mentioned symptoms (P = 0.1291). Results of LCA suggest that patients with the six typical symptoms defined in CM may benefit from XQLG

Acquired Resistance to KRAS (G12C) Inhibition in Cancer

BACKGROUND: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRAS(G12C)). The mechanisms of acquired resistance to these therapies are currently unknown. METHODS: Among patients with KRAS(G12C) -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRAS(G12C) inhibitors. RESULTS: A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRAS(G12C) allele. Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of KRAS mutations that confer resistance to KRAS(G12C) inhibitors. CONCLUSIONS: Diverse genomic and histologic mechanisms impart resistance to covalent KRAS(G12C) inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.)

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Seismic prediction of sweet spots in the Da'anzhai shale play, Yuanba area, the Sichuan Basin

Burial depth, thickness, total organic carbon (TOC) content, brittleness and fracture development of shale reservoirs are the main geologic indexes in the evaluation of sweet spots in shale gas plays. Taking the 2nd interval of Da'anzhai shale of the Lower Jurassic as the study object, a set of techniques in seismic prediction of sweet spots were developed based on special processing of seismic data and comprehensive analysis of various data based on these geologic indexes. First, logging and seismic responses of high quality shales were found out through fine calibration of shale reservoir location with seismogram, which was combined with seismic facies analysis to define the macroscopic distribution of the shale. Then, seismic impedance inversion and GR inversion were used to identify shale from limestone and sandstone. Based on statistical analysis of sensitive parameters such as TOC, the uranium log inversion technique was used to quantitatively predict TOC of a shale reservoir and the thickness of a high quality shale reservoir. After that, fracture prediction technique was employed to predict play fairways. Finally, the pre-stack joint P-wave and S-wave impedance inversion technique was adopted to identify shales with high brittleness suitable for hydraulic fracturing. These seismic prediction techniques have been applied in sorting out sweet spots in the 2nd interval of the Da'anzhai shale play of the Yuanba area, and the results provided a sound basis for the optimization of horizontal well placement and hydraulic fracturing

Preservation conditions for marine shale gas at the southeastern margin of the Sichuan Basin and their controlling factors

Complex tectonic movements and high thermal maturity of marine shale dominate South China, where preservation conditions are critical for shale gas enrichment and productivity. Based on the exploration practices of the Silurian shale gas at the southeastern margin of the Sichuan Basin in recent years, conventional gas and shale gas were compared in terms of their preservation conditions. The results revealed that superior roof and floor conditions are indispensable to shale gas preservation. Moreover, the self-sealing ability and the huge gap of up to 2–8 times between vertical and lateral permeability of shale gas reservoirs determine the lateral diffusion as the basic pattern of shale gas migration. The unconformity at the bottom of Lower Cambrian leads to worse preservation conditions in the system, and cutting by faults may accelerate the diffusion of shale gas. Major controlling factors for shale gas preservation and their criteria of discrimination were also investigated. It is suggested that: (1) the strength of tectonic modification is the major factor controlling shale gas preservation. Broad and gentle structures with continuous seals and an anticlinal setting are more favorable for the enrichment of shale gas, and a closed evolutionary environment with late uplifting is more favorable for the preservation of shale gas; (2) shale gas can be preserved well in downdip areas without faults or effectively closed or shielded by faults and areas far away from outcrops or zones with stratigraphic hiatus; (3) pressure coefficient is a comprehensive indicator for discriminating preservation conditions. In the study area, the pressure coefficient is in positive correlation with shale gas production and the high or super-high pressure of reservoir is a signal of good preservation condition for shale gas; and (4) in the areas within the southeastern Sichuan Basin, other than those close to erosion zones or hiatus, the Wufeng Fm. of Upper Ordovician and the Longmaxi Fm. of Lower Silurian present high pressure coefficient (up to 2.25) generally, demonstrating good preservation conditions for shale gas, while the pressure coefficient reduces progressively toward or outside the margin of the basin, corresponding to downgrading preservation conditions

Functional Characterization of Transporters for L-Aspartate in <i>Bacillus licheniformis</i>

Amino acid efflux and influx transport systems play vital roles in industrial microorganisms’ cell growth and metabolism. However, although biochemically characterized, most of them remain unknown at the molecular level in Bacillus licheniformis. In this study, three proteins, namely, YdgF, YvbW, and YveA, were predicted to be involved in the active transport of L-aspartate (L-Asp). This was verified by manipulating their encoding genes. When growing in the minimal medium with L-Asp as the only carbon and nitrogen source, the growth of strains lacking proteins YdgF, YvbW, and YveA was significantly inhibited compared with the wild-type strains, while supplementing the expression of the corresponding proteins in the single-gene knockout strains could alleviate the inhibition. Upon overexpression, the recombinant proteins mediated the accumulation of L-aspartate to varying degrees. Compared with the wild-type strains, the single knockout strains of the three protein genes exhibited reduced absorption of L-aspartate. In addition, this study focused on the effects of these three proteins on the absorption of β-alanine, L-glutamate, D-serine, D-alanine, and glycine

Efficient Genome Editing in Bacillus licheniformis Mediated by a Conditional CRISPR/Cas9 System

Bacillus licheniformis is widely used to produce multiple enzymes and chemicals in industrial fermentation. It is also an organism that is hard to genetically manipulate, which is mainly attributed to its extremely low transformation efficiency. The lack of genetic modification technology severely limits its further application. In this study, an all-in-one conditional clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 plasmid was developed for B. licheniformis with the cas9 gene under the control of a xylose-inducible promoter. By means of this design, the expression of the cas9 gene could be repressed without xylose, which significantly improved the transformation ratio from less than 0.1 cfu/&mu;g to 2.42 cfu/&mu;g DNA. Compared with this conditional system, a constitutive overexpression system led to significant growth retardation in bacterial cells. Both the biomass and specific growth rate decreased greatly. After transformation, successful genome editing could be triggered by 0.5% xylose. When the &alpha;-amylase gene amyL was used as a genomic target, the efficiencies of its disruption using three different protospacer-adjacent motif (PAM) sequences were 64.3%, 70.9%, and 47.1%, respectively. Moreover, temperature plays a pivotal role in the function of the constructed CRISPR system. The maximum success rate reached 97% at 20 &deg;C, while higher temperatures negatively impacted the function of the system. These results suggested that the design with a cas9 gene under the strict control of a xylose-inducible promoter significantly improved the success rate of genome editing in this host. This work contributes to the development of genetic manipulation and furthers the use of B. licheniformis as an efficient industrial workhorse