Screening Privileged Alkyl Guanidinium Motifs under Host-Mimicking Conditions Reveals a Novel Antibiotic with an Unconventional Mode of Action.

Screening large molecule libraries against pathogenic bacteria is often challenged by a low hit rate due to limited uptake, underrepresentation of antibiotic structural motifs, and assays that do not resemble the infection conditions. To address these limitations, we present a screen of a focused library of alkyl guanidinium compounds, a structural motif associated with antibiotic activity and enhanced uptake, under host-mimicking infection conditions against a panel of disease-associated bacteria. Several hit molecules were identified with activities against Gram-positive and Gram-negative bacteria, highlighting the fidelity of the general concept.

Unraveling the mechanism of small molecule induced activation of Staphylococcus aureus signal peptidase IB.

Staphylococcus aureus signal peptidase IB (SpsB) is an essential enzyme for protein secretion. While inhibition of its activity by small molecules is a well-precedented mechanism to kill bacteria, the mode of activation is however less understood. We here investigate the activation mechanism of a recently introduced activator, the antibiotic compound PK150, and demonstrate by combined experimental and Molecular Dynamics (MD) simulation studies a unique principle of enzyme stimulation.

Perturbation of periodic spot-generation balance leads to diversified pigmentation patterning of harlequin Phalaenopsis orchids: in silico prediction.

Background: A retrotransposon HORT1 in the promoter of the anthocyanin activator gene PeMYB11, microRNA858 (miR858) that targets PeMYB11, and a repressor PeMYBx have been implicated in pigmentation patterning diversity of harlequin Phalaenopsis orchids. However, the interrelationship among them remains to be elucidated.

Results: To understand how these factors interact to generate anthocyanin spots in Phalaenopsis, we successfully developed a mathematical model based on the known reaction-diffusion system to simulate their interplay and refined the conceptual biological model.

Effect of Fe and Zn co-doping on LiCoPO cathode materials for High-Voltage Lithium-Ion batteries.

Lithium cobalt phosphate (LiCoPO) has great potential to be developed as a cathode material for lithium-ion batteries (LIBs) due to its structural stability and higher voltage platform with a high theoretical energy density. However, the relatively low diffusion of lithium ions still needs to be improved. In this work, Fe and Zn co-doped LiCoPO: LiCoFeZnPO/C is utilized to enhance the battery performance of LiCoPO.

Text2Face: Text-Based Face Generation With Geometry and Appearance Control.

Recent years have witnessed the emergence of various techniques proposed for text-based human face generation and manipulation. Such methods, targeting bridging the semantic gap between text and visual contents, provide users with a deft hand to turn ideas into visuals via text interface and enable more diversified multimedia applications. However, due to the flexibility of linguistic expressiveness, the mapping from sentences to desired facial images is clearly many-to-many, causing ambiguities during text-to-face generation.

How Modulator Binding at the Amyloidβ-γ-Secretase Interface Enhances Substrate Binding and Attenuates Membrane Distortion.

Inhibition of γ-secretase, an intramembrane protease, to reduce secretion of Amyloid-β (Aβ) peptides has been considered for treating Alzheimer's disease. However, γ-secretase inhibitors suffer from severe side effects. As an alternative, γ-secretase modulators (GSM) reduce the generation of toxic peptides by enhancing the cleavage processivity without diminishing the enzyme activity.

APP substrate ectodomain defines amyloid-β peptide length by restraining γ-secretase processivity and facilitating product release.

Sequential proteolysis of the amyloid precursor protein (APP) by γ-secretases generates amyloid-β (Aβ) peptides and defines the proportion of short-to-long Aβ peptides, which is tightly connected to Alzheimer's disease (AD) pathogenesis. Here, we study the mechanism that controls substrate processing by γ-secretases and Aβ peptide length. We found that polar interactions established by the APP ectodomain (ECD), involving but not limited to its juxtamembrane region, restrain both the extent and degree of γ-secretases processive cleavage by destabilizing enzyme-substrate interactions.

LC-NeRF: Local Controllable Face Generation in Neural Radiance Field.

3D face generation has achieved high visual quality and 3D consistency thanks to the development of neural radiance fields (NeRF). However, these methods model the whole face as a neural radiance field, which limits the controllability of the local regions. In other words, previous methods struggle to independently control local regions, such as the mouth, nose, and hair.

Enzyme-substrate hybrid β-sheet controls geometry and water access to the γ-secretase active site.

γ-Secretase is an aspartyl intramembrane protease that cleaves the amyloid precursor protein (APP) involved in Alzheimer's disease pathology and other transmembrane proteins. Substrate-bound structures reveal a stable hybrid β-sheet immediately following the substrate scissile bond consisting of β1 and β2 from the enzyme and β3 from the substrate. Molecular dynamics simulations and enhanced sampling simulations demonstrate that the hybrid β-sheet stability is strongly correlated with the formation of a stable cleavage-compatible active geometry and it also controls water access to the active site.

What Makes a Good Protein-Protein Interaction Stabilizer: Analysis and Application of the Dual-Binding Mechanism.

Protein-protein interactions (PPIs) are essential for biological processes including immune reactions and diseases. Inhibition of PPIs by drug-like compounds is a common basis for therapeutic approaches. In many cases the flat interface of PP complexes prevents discovery of specific compound binding to cavities on one partner and PPI inhibition.

A Chemical Proteomic Strategy Reveals Inhibitors of Lipoate Salvage in Bacteria and Parasites.

The development of novel anti-infectives requires unprecedented strategies targeting pathways which are solely present in pathogens but absent in humans. Following this principle, we developed inhibitors of lipoic acid (LA) salvage, a crucial pathway for the survival of LA auxotrophic bacteria and parasites but non-essential in human cells. An LA-based probe was selectively transferred onto substrate proteins via lipoate protein ligase (LPL) in intact cells, and their binding sites were determined by mass spectrometry.

Keyframe Control of Music-Driven 3D Dance Generation.

For 3D animators, choreography with artificial intelligence has attracted more attention recently. However, most existing deep learning methods mainly rely on music for dance generation and lack sufficient control over generated dance motions. To address this issue, we introduce the idea of keyframe interpolation for music-driven dance generation and present a novel transition generation technique for choreography.

Identity-Aware and Shape-Aware Propagation of Face Editing in Videos.

The development of deep generative models has inspired various facial image editing methods, but many of them are difficult to be directly applied to video editing due to various challenges ranging from imposing 3D constraints, preserving identity consistency, ensuring temporal coherence, etc. To address these challenges, we propose a new framework operating on the StyleGAN2 latent space for identity-aware and shape-aware edit propagation on face videos. In order to reduce the difficulties of maintaining the identity, keeping the original 3D motion, and avoiding shape distortions, we disentangle the StyleGAN2 latent vectors of human face video frames to decouple the appearance, shape, expression, and motion from identity.

The Effectiveness of a Critical Appraisal Skills Workshop 6 Months After Nurses' Participation.

Background The aim of this study was to explore whether nursing staff retained knowledge, self-confidence, and attitudes 6 months after participating in a critical appraisal skills workshop. Method A retrospective matched case-control study was conducted to ascertain the effects of this training on the ability to appraise literature. Results Mean scores on the critical appraisal knowledge test, self-confidence, and attitudes were significantly higher in the case group compared to the control group ( < .

Population genetics and genetic variation of Ctenocephalides felis and Pulex irritans in China by analysis of nuclear and mitochondrial genes.

Background: Fleas are the most economically significant blood-feeding ectoparasites worldwide. Ctenocephalides felis and Pulex irritans can parasitize various animals closely related to humans and are of high veterinary significance.

Methods: In this study, 82 samples were collected from 7 provinces of China.

DrawingInStyles: Portrait Image Generation and Editing With Spatially Conditioned StyleGAN.

The research topic of sketch-to-portrait generation has witnessed a boost of progress with deep learning techniques. The recently proposed StyleGAN architectures achieve state-of-the-art generation ability but the original StyleGAN is not friendly for sketch-based creation due to its unconditional generation nature. To address this issue, we propose a direct conditioning strategy to better preserve the spatial information under the StyleGAN framework.

An internal docking site stabilizes substrate binding to γ-secretase: Analysis by molecular dynamics simulations.

Amyloid precursor protein (APP) is cleaved and processed sequentially by γ-secretase yielding amyloid β (Aβ) peptides of different lengths. Longer Aβ peptides are associated with the formation of neurotoxic plaques related to Alzheimer's disease. Based on the APP substrate-bound structure of γ-secretase, we investigated the enzyme-substrate interaction using molecular dynamics simulations and generated model structures that represent the sequentially cleaved intermediates during the processing reaction.

Molecular Identification and Phylogenetic Analysis of in Wild Animals.

Ascarid nematodes are the most common and harmful nematodes parasites in animals. By analyzing genetic variation, this study explores the genetic and phylogenetic relationship among ascarids from 11 different hosts. This study collected ascarid samples from the feces of nine animal species in Changsha Ecological Zoo of Hunan Province and two animal kinds in the College of Veterinary Medicine of Hunan Agricultural University.

Molecular Characterization and Phylogenetic Analysis of Tapeworms from Snakes in Hunan Province.

Sparganosis is a neglected zoonotic parasitic disease that poses huge threats to humans worldwide. Snakes play an important role in sparganosis transmission because they are the most common second intermediate hosts for parasites. However, the population genetics of isolates from snakes is currently not well studied in China.

Spatiotemporal Dynamics of Cerebral Vascular Permeability in Type 2 Diabetes-Related Cerebral Microangiopathy.

Aims: Diabetes-related cerebral microangiopathy can manifest as cerebral small vessel disease (CSVD) and exhibit cognitive decline. To find the early change of function in advance, this study examined the spatiotemporal dynamics of cerebral vascular permeability () in the progression of type 2 diabetes mellitus (T2DM).

Methods: was cross-sectionally measured in T2DM and non-diabetes groups with or without CSVD using dynamic contrast-enhanced MRI (DCE-MRI).