Using the Unfolded State as the Reference State Improves the Performance of Statistical Potentials

AbstractDistance-dependent statistical potentials are an important class of energy functions extensively used in modeling protein structures and energetics. These potentials are obtained by statistically analyzing the proximity of atoms in all combinatorial amino-acid pairs in proteins with known structures. In model evaluation, the statistical potential is usually subtracted by the value of a reference state for better selectivity. An ideal reference state should include the general chemical properties of polypeptide chains so that only the unique factors stabilizing the native structures are retained after calibrating on reference state. However, reference states available as of this writing rarely model specific chemical constraints of peptide bonds and therefore poorly reflect the behavior of polypeptide chains. In this work, we proposed a statistical potential based on unfolded state ensemble (SPOUSE), where the reference state is summarized from the unfolded state ensembles of proteins produced according to the statistical coil model. Due to its better representation of the features of polypeptides, SPOUSE outperforms three of the most widely used distance-dependent potentials not only in native conformation identification, but also in the selection of close-to-native models and correlation coefficients between energy and model error. Furthermore, SPOUSE shows promising possibility of further improvement by integration with the orientation-dependent side-chain potentials

A CFD-DEM Based Numerical Investigation of Debris Flow on Ballasted Railway Track

Debris flow occurring in mountainous areas can cause issues to railway tracks. Debris flow may cause large track deformation and even track breakage and introduce server ballast fouling afterwards. After the flash of a debris flow, the fine particles can be retained in the ballast layer and significantly reduce track drainage, leading to lower bearing capacity and a higher risk of track lateral stability problems. Moreover, these solid particles may deposit on the railway surface and endanger the train directly. Unfortunately, those debris flow introduced track issues have not been thoroughly investigated. This study presents a numerical investigation of the impact of the debris flow on the railway track. Various factors governing the debris flow are considered, including particle size and solid fraction. Besides, those factors affecting the ballast are also discussed, such as fouling condition and initial void ratio. A coupled computational fluid dynamics and discrete element method (CFD-DEM) approach is developed to capture the interactions between particles/particles, water/air, and particles/fluid. The results from this study may help the railway to improve track resilience before the debris flow and to improve maintenance strategy after the debris flow flashing

Higher-Order DCA Attacks on White-Box Implementations with Masking and Shuffling Countermeasures

On white-box implementations, it has been proven that differential computation analysis (DCA) can recover secret keys without time-costly reverse engineering. At CHES 2021, Seker et al. combined linear and non-linear masking protections (SEL masking) to prevent sensitive variables from being predicted by DCA. At Eurocrypt 2021, Biryukov and Udovenko introduced a public dummy shuffling construction (BU shuffling) to protect sensitive functions. In this paper, we extend higher-order DCA (HO-DCA) to higher-degree context for exploiting the vulnerabilities against the state-of-the-art countermeasures. The data-dependency HO-DCA (DDHO-DCA), which is proposed at CHES 2020, is improved to successfully recover the correct key of SEL masking. In specific, our improved DDHO-DCA can also enhance the attack result of #100 which is the third winning challenge in WhibOx 2019. Since the XOR phase plays the same role as linear masking, we prove that a specific BU shuffling is vulnerable to HO-DCA attacks. Furthermore, we demonstrate that the combination of SEL masking and the specific BU shuffling still cannot defeat our higher-degree HO-DCA and improved DDHO-DCA attacks

ANKRD22 enhances breast cancer cell malignancy by activating the Wnt/β-catenin pathway via modulating NuSAP1 expression

Breast cancer is one of the most prevalent malignancies in women worldwide. Although great advancements have been achieved in the diagnosis and treatment of breast cancer, the prognosis of patients with breast cancer is still poor due to distal recurrence and metastasis after surgery. This study aimed to assess the role of ankyrin repeat domain 22 (ANKRD22) in the progression of breast cancer and investigate the molecular mechanism. Using immunohistochemistry, we demonstrated that the expression level of ANKRD22 in human breast cancer tissues was significantly higher than that in normal breast tissues. ANKRD22 knockdown inhibited the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of breast cancer cells, as confirmed by BrdU, colony formation, transwell, and immunoblot assays. Immunoblot assays further indicated that ANKRD22 regulated the expression of nucleolar and spindle-associated protein 1 (NuSAP1) and then caused the activation of Wnt/β-catenin signaling pathway. Moreover, overexpression of NUSAP1 reversed the inhibitory effects of ANKRD22 knockdown on the proliferation, invasion, and EMT of breast cancer cells. In summary, this study demonstrated that ANKRD22 enhanced breast cancer cell malignancy by activating the Wnt/β-catenin pathway via modulating NuSAP1 expression, which might shed light on new therapeutic approaches for breast cancer

Evaluation of Metformin on Cognitive Improvement in Patients With Non-dementia Vascular Cognitive Impairment and Abnormal Glucose Metabolism

Objective: Recent studies have suggested that metformin can penetrate the blood–brain barrier, protecting neurons via anti-inflammatory action and improvement of brain energy metabolism. In this study, we aim to investigate the effect of metformin on cognitive function in patients with abnormal glucose metabolism and non-dementia vascular cognitive impairment (NDVCI).Methods: One hundred patients with NDVCI and abnormal glucose metabolism were randomly allocated into two groups: metformin and donepezil (n = 50) or acarbose and donepezil (n = 50). The neuropsychological status, glucose metabolism, and common carotid arteries intima–media thickness (CCA-IMT) before and after a year of treatment, were measured and compared between the groups.Results: Ninety four patients completed all the assessment and follow-up. After a year of treatment, there was a decrease in Alzheimer’s disease Assessment Scale-Cognitive Subscale scores and the duration of the Trail Making Test in the metformin-donepezil group. Furthermore, these patients showed a significant increase in World Health Organization–University of California–Los Angeles Auditory Verbal Learning Test scores after treatment (all P < 0.05). However, there was no obvious improvement in cognitive function in the acarbose-donepezil group. We also observed a significant decrease in the level of fasting insulin and insulin resistance (IR) index in the metformin-donepezil group, with a lower CCA-IMT value than that in the acarbose-donepezil group after a year of treatment (P < 0.05).Conclusion: We conclude that metformin can improve cognitive function in patients with NDVCI and abnormal glucose metabolism, especially in terms of performance function. Improved cognitive function may be related to improvement of IR and the attenuated progression of IMT.Trial Registration:ChiCTR-IPR-17011855

Final report on project SP1210: Lowland peatland systems in England and Wales – evaluating greenhouse gas fluxes and carbon balances

Lowland peatlands represent one of the most carbon-rich ecosystems in the UK. As a result of widespread habitat modification and drainage to support agriculture and peat extraction, they have been converted from natural carbon sinks into major carbon sources, and are now amongst the largest sources of greenhouse gas (GHG) emissions from the UK land-use sector. Despite this, they have previously received relatively little policy attention, and measures to reduce GHG emissions either through re-wetting and restoration or improved management of agricultural land remain at a relatively early stage. In part, this has stemmed from a lack of reliable measurements on the carbon and GHG balance of UK lowland peatlands. This project aimed to address this evidence gap via an unprecedented programme of consistent, multi year field measurements at a total of 15 lowland peatland sites in England and Wales, ranging from conservation managed ‘near-natural’ ecosystems to intensively managed agricultural and extraction sites. The use of standardised measurement and data analysis protocols allowed the magnitude of GHG emissions and removals by peatlands to be quantified across this heterogeneous data set, and for controlling factors to be identified. The network of seven flux towers established during the project is believed to be unique on peatlands globally, and has provided new insights into the processes the control GHG fluxes in lowland peatlands. The work undertaken is intended to support the future development and implementation of agricultural management and restoration measures aimed at reducing the contribution of these important ecosystems to UK GHG emissions

Population response of intestinal microbiota to acute Vibrio alginolyticus infection in half-smooth tongue sole (Cynoglossus semilaevis)

IntroductionVibriosis causes enormous economic losses of marine fish. The present study investigated the intestinal microbial response to acute infection of half-smooth tongue sole with different-dose Vibrio alginolyticus within 72 h by metagenomic sequencing.MethodsThe inoculation amount of V. alginolyticus for the control, low-dose, moderate-dose, and high-dose groups were 0, 8.5 × 101, 8.5 × 104, and 8.5 × 107 cells/g respectively, the infected fish were farmed in an automatic seawater circulation system under a relatively stable temperature, dissolved oxygen and photoperiod, and 3 ~ 6 intestinal samples per group with high-quality DNA assay were used for metagenomics analysis.ResultsThe acute infections with V. alginolyticus at high, medium, and low doses caused the change of different-type leukocytes at 24 h, whereas the joint action of monocytes and neutrophils to cope with the pathogen infection only occurred in the high-dose group at 72 h. The metagenomic results suggest that a high-dose V. alginolyticus infection can significantly alter the intestinal microbiota, decrease the microbial α-diversity, and increase the bacteria from Vibrio and Shewanella, including various potential pathogens at 24 h. High-abundance species of potential pathogens such as V. harveyii, V. parahaemolyticus, V. cholerae, V. vulnificus, and V. scophthalmi exhibited significant positive correlations with V. alginolyticus. The function analysis revealed that the high-dose inflection group could increase the genes closely related to pathogen infection, involved in cell motility, cell wall/ membrane/envelope biogenesis, material transport and metabolism, and the pathways of quorum sensing, biofilm formation, flagellar assembly, bacterial chemotaxis, virulence factors and antibiotic resistances mainly from Vibrios within 72 h.DiscussionIt indicates that the half-smooth tongue sole is highly likely to be a secondary infection with intestinal potential pathogens, especially species from Vibrio and that the disease could become even more complicated because of the accumulation and transfer of antibiotic-resistance genes in intestinal bacteria during the process of V. alginolyticus intensified infection