Facile metabolic reprogramming distinguishes mycobacterial adaptation to hypoxia and starvation: ketosis drives starvation-induced persistence in M. bovis BCG.

Mycobacteria adapt to infection stresses by entering a reversible non-replicating persistence (NRP) with slow or no cell growth and broad antimicrobial tolerance. Hypoxia and nutrient deprivation are two well-studied stresses commonly used to model the NRP, yet little is known about the molecular differences in mycobacterial adaptation to these distinct stresses that lead to a comparable NRP phenotype. Here we performed a multisystem interrogation of the Mycobacterium bovis BCG (BCG) starvation response, which revealed a coordinated metabolic shift away from the glycolysis of nutrient-replete growth to depletion of lipid stores, lipolysis, and fatty acid ß-oxidation in NRP. This contrasts with BCG's NRP hypoxia response involving a shift to cholesterol metabolism and triglyceride storage. Our analysis reveals cryptic metabolic vulnerabilities of the starvation-induced NRP state, such as their newfound hypersensitivity to H2O2. These observations pave the way for developing precision therapeutics against these otherwise drug refractory pathogens.

Cycle contrastive adversarial learning with structural consistency for unsupervised high-quality image deraining transformer.

In overcoming the challenges faced in adapting to paired real-world data, recent unsupervised single image deraining (SID) methods have proven capable of accomplishing notably acceptable deraining performance. However, the previous methods usually fail to produce a high quality rain-free image due to neglecting sufficient attention to semantic representation and the image content, which results in the inability to completely separate the content from the rain layer. In this paper, we develop a novel cycle contrastive adversarial framework for unsupervised SID, which mainly consists of cycle contrastive learning (CCL) and location contrastive learning (LCL). Specifically, CCL achieves high-quality image reconstruction and rain-layer stripping by pulling similar features together while pushing dissimilar features further in both semantic and discriminant latent spaces. Meanwhile, LCL implicitly constrains the mutual information of the same location of different exemplars to maintain the content information. In addition, recently inspired by the powerful Segment Anything Model (SAM) that can effectively extract widely applicable semantic structural details, we formulate a structural-consistency regularization to fine-tune our network using SAM. Apart from this, we attempt to introduce vision transformer (VIT) into our network architecture to further improve the performance. In our designed transformer-based GAN, to obtain a stronger representation, we propose a multi-layer channel compression attention module (MCCAM) to extract a richer feature. Equipped with the above techniques, our proposed unsupervised SID algorithm, called CCLformer, can show advantageous image deraining performance. Extensive experiments demonstrate both the superiority of our method and the effectiveness of each module in CCLformer. The code is available at https://github.com/zhihefang/CCLGAN.

Effects of biochar on shear strength of completely decomposed granite.

Biochar has a great potential to sustainably improve the performance of bio-engineered slope due to its ability to retain water and to supply nutrients. Existing studies mainly focus on hydrological properties of biochar-amended soil. However, the effects of biochar on shear strength of soil are not well studied. This study aims to assess the shearing behaviour of biochar-amended completely decomposed granite (CDG). Soil specimens were prepared by mixing CDG with two types of biochar at a mass ratio of 5% and compacted at 95% of the maximum dry density. Although the peak shear strength of biochar-amended CDG is reduced by up to 20% because of lower initial dry density of the soil and crushing of biochar particles during shearing, both types of biochar have negligible effects on the ultimate shear strength, which is governed by friction between soil particles. This highlights that the ultimate friction angle can be adopted for designing bio-engineered slopes using biochar-amended soils.

Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification.

Regulation of cellular iron homeostasis is crucial as both iron excess and deficiency cause hematological and neurodegenerative diseases. Here we show that mice lacking iron-regulatory protein 2 (Irp2), a regulator of cellular iron homeostasis, develop diabetes. Irp2 post-transcriptionally regulates the iron-uptake protein transferrin receptor 1 (TfR1) and the iron-storage protein ferritin, and dysregulation of these proteins due to Irp2 loss causes functional iron deficiency in ß cells. This impairs Fe-S cluster biosynthesis, reducing the function of Cdkal1, an Fe-S cluster enzyme that catalyzes methylthiolation of t6A37 in tRNALysUUU to ms2t6A37. As a consequence, lysine codons in proinsulin are misread and proinsulin processing is impaired, reducing insulin content and secretion. Iron normalizes ms2t6A37 and proinsulin lysine incorporation, restoring insulin content and secretion in Irp2-/- ß cells. These studies reveal a previously unidentified link between insulin processing and cellular iron deficiency that may have relevance to type 2 diabetes in humans.

Quantifying the RNA cap epitranscriptome reveals novel caps in cellular and viral RNA.

Chemical modification of transcripts with 5' caps occurs in all organisms. Here, we report a systems-level mass spectrometry-based technique, CapQuant, for quantitative analysis of an organism's cap epitranscriptome. The method was piloted with 21 canonical caps-m7GpppN, m7GpppNm, GpppN, GpppNm, and m2,2,7GpppG-and 5 'metabolite' caps-NAD, FAD, UDP-Glc, UDP-GlcNAc, and dpCoA. Applying CapQuant to RNA from purified dengue virus, Escherichia coli, yeast, mouse tissues, and human cells, we discovered new cap structures in humans and mice (FAD, UDP-Glc, UDP-GlcNAc, and m7Gpppm6A), cell- and tissue-specific variations in cap methylation, and high proportions of caps lacking 2'-O-methylation (m7Gpppm6A in mammals, m7GpppA in dengue virus). While substantial Dimroth-induced loss of m1A and m1Am arose with specific RNA processing conditions, human lymphoblast cells showed no detectable m1A or m1Am in caps. CapQuant accurately captured the preference for purine nucleotides at eukaryotic transcription start sites and the correlation between metabolite levels and metabolite caps.

Uncoupling Coriolis Force and Rotating Buoyancy Effects on Full-Field Heat Transfer Properties of a Rotating Channel.

An experimental method for exploring the heat transfer characteristics of an axially rotating channel is proposed. The governing flow parameters that characterize the transport phenomena in a rotating channel are identified via the parametric analysis of the momentum and energy equations referring to a rotating frame of reference. Based on these dimensionless flow equations, an experimental strategy that links the design of the test module, the experimental program and the data analysis is formulated with the attempt to reveal the isolated Coriolis-force and buoyancy effects on heat transfer performances. The effects of Coriolis force and rotating buoyancy are illustrated using the selective results measured from rotating channels with various geometries. While the Coriolis-force and rotating-buoyancy impacts share several common features among the various rotating channels, the unique heat transfer signatures are found in association with the flow direction, the channel shape and the arrangement of heat transfer enhancement devices. Regardless of the flow configurations of the rotating channels, the presented experimental method enables the development of physically consistent heat transfer correlations that permit the evaluation of isolated and interdependent Coriolis-force and rotating-buoyancy effects on the heat transfer properties of rotating channels.

N(6)-Methyladenosine RNA Modification Regulates Shoot Stem Cell Fate in Arabidopsis.

N(6)-Methyladenosine (m(6)A) represents the most prevalent internal modification on mRNA and requires a multicomponent m(6)A methyltransferase complex in mammals. How their plant counterparts determine the global m(6)A modification landscape and its molecular link to plant development remain unknown. Here we show that FKBP12 INTERACTING PROTEIN 37 KD (FIP37) is a core component of the m(6)A methyltransferase complex, which underlies control of shoot stem cell fate in Arabidopsis. The mutants lacking FIP37 exhibit massive overproliferation of shoot meristems and a transcriptome-wide loss of m(6)A RNA modifications. We further demonstrate that FIP37 mediates m(6)A RNA modification on key shoot meristem genes inversely correlated with their mRNA stability, thus confining their transcript levels to prevent shoot meristem overproliferation. Our results suggest an indispensable role of FIP37 in mediating m(6)A mRNA modification, which is required for maintaining the shoot meristem as a renewable source for continuously producing all aerial organs in plants.

A Platform for Discovery and Quantification of Modified Ribonucleosides in RNA: Application to Stress-Induced Reprogramming of tRNA Modifications.

Here we describe an analytical platform for systems-level quantitative analysis of modified ribonucleosides in any RNA species, with a focus on stress-induced reprogramming of tRNA as part of a system of translational control of cell stress response. This chapter emphasizes strategies and caveats for each of the seven steps of the platform workflow: (1) RNA isolation, (2) RNA purification, (3) RNA hydrolysis to individual ribonucleosides, (4) chromatographic resolution of ribonucleosides, (5) identification of the full set of modified ribonucleosides, (6) mass spectrometric quantification of ribonucleosides, (6) interrogation of ribonucleoside datasets, and (7) mapping the location of stress-sensitive modifications in individual tRNA molecules. We have focused on the critical determinants of analytical sensitivity, specificity, precision, and accuracy in an effort to ensure the most biologically meaningful data on mechanisms of translational control of cell stress response. The methods described here should find wide use in virtually any analysis involving RNA modifications.

The relationship between worry tendency and sleep quality in Chinese adolescents and young adults: the mediating role of state-trait anxiety.

To investigate the relationship between worry tendency and sleep quality and the mediating effect of state-trait anxiety, 1072 adolescents and young adults from Jiangxi and Fujian Provinces in China were administered questionnaires pertaining to worry tendency, sleep quality, and state-trait anxiety. The results showed significant grade differences for worry tendency, sleep quality, and state-trait anxiety. Worry tendency was negatively associated with sleep quality, which was mediated by state anxiety and trait anxiety. There is a need for interventions that aim to reduce the level of worry tendency to ensure good sleep quality and the progression from worry tendency to anxiety and to poor sleep quality.

A multiobjective simultaneous learning framework for clustering and classification.

Traditional pattern recognition involves two tasks: clustering learning and classification learning. Clustering result can enhance the generalization ability of classification learning, while the class information can improve the accuracy of clustering learning. Hence, both learning methods can complement each other. To fuse the advantages of both learning methods together, many existing algorithms have been developed in a sequential fusing way by first optimizing the clustering criterion and then the classification criterion associated with the obtained clustering results. However, such kind of algorithms naturally fails to achieve the simultaneous optimality for two criteria, and thus has to sacrifice either the clustering performance or the classification performance. To overcome that problem, in this paper, we present a multiobjective simultaneous learning framework (MSCC) for both clustering and classification learning. MSCC utilizes multiple objective functions to formulate the clustering and classification problems, respectively, and more importantly, it employs the Bayesian theory to make these functions all only dependent on a set of the same parameters, i.e., clustering centers which play a role of the bridge connecting the clustering and classification learning. By simultaneously optimizing the clustering centers embedded in these functions, not only the effective clustering performance but also the promising classification performance can be simultaneously attained. Furthermore, from the multiple Pareto-optimality solutions obtained in MSCC, we can get an interesting observation that there is complementarity to great extent between clustering and classification learning processes. Empirical results on both synthetic and real data sets demonstrate the effectiveness and potential of MSCC.

Theoretical and experimental design of atypical kinase inhibitors: application to p38 MAP kinase.

Mimics of the benzimidazolone nucleus found in inhibitors of p38 kinase are proposed, and their theoretical potential as bioisosteres is described. A set of calculated descriptors relevant to the anticipated binding interaction for the fragments 1-methyl-1H-benzotriazole 5, 3-methyl-benzo[d]isoxazole 3, and 3-methyl-[1,2,4]triazolo[4,3-a]pyridine 4, pyridine 1, and 1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one 2 are reported. The design considerations and synthesis of p38 inhibitors based on these H-bond acceptor fragments is detailed. Comparative evaluation of the pyridine-, benzimidazolone-, benzotriazole-, and triazolopyridine-based inhibitors shows the triazoles 20 and 25 to be significantly more potent experimentally than the benzimidazolone after which they were modeled. An X-ray crystal structure of 25 bound to the active site shows that the triazole group serves as the H-bond acceptor but unexpectedly as a dual acceptor, inducing movement of the crossover connection of p38alpha. The computed descriptors for the hydrophobic and pi-pi interaction capacities were the most useful in ranking potency.

Palladium-catalyzed synthesis of N-aryloxazolidinones from aryl chlorides.

An efficient method for intermolecular N-arylation of oxazolidinones using Pd(2)dba(3) and various phosphine ligands in the presence of a weak base is reported. The conditions allow the use of cheaper aryl chlorides containing functionalities such as enolizable ketones, amides, etc., which would be incompatible with other coupling methods. The coupling reaction can be used to prepare enantiopure N-aryl beta-amino alcohols. Depending on the stereoelectronic nature of the aryl chloride, careful choice of ligand was necessary for the success of these reactions. [reaction: see text]

Chemistry of 4,6-O-Benzylidene-D-glycopyranosyl Triflates: Contrasting Behavior between the Gluco and Manno Series.

Activation of either anomer of S-phenyl 2,3-di-O-benzyl-4,6-O-benzylidene-1-deoxy-1-thia-D-glucopyranoside with triflic anhydride in dichloromethane at -78 degrees C in the presence of 2,6-di-tert-butyl-4-methylpyridine affords a highly active glycosylating species which, on addition of alcohols, provides alpha-glucosides with high selectivity. This selectivity stands in stark contrast to the analogous mannopyranoside series, which affords the beta-mannosides with excellent selectivity under the same conditions. Low-temperature NMR experiments support the notion that a glucosyl triflate is formed in the initial activation step. Possible reasons for the diverging stereoselectivity in the gluco and manno series are discussed.