Unveiling a new strategy for PDIA1 inhibition: Integration of activity-based probes profiling and targeted degradation.

The overexpression of PDIA1 in cancer has spurred the quest for effective inhibitors. However, existing inhibitors often bind to only one active site, limiting their efficacy. In our study, we developed a PROTAC-mimetic probe dPA by combining PACMA31 (PA) analogs with cereblon-directed pomalidomide. Through protein profiling and analysis, we confirmed dPA's specific interaction with PDIA1's active site cysteines. We further synthesized PROTAC variants with a thiophene ring and various linkers to enhance degradation efficiency. Notably, H4, featuring a PEG linker, induced significant PDIA1 degradation and inhibited cancer cell proliferation similarly to PA. The biosafety profile of H4 is comparable to that of PA, highlighting its potential for further development in cancer therapy. Our findings highlight a novel strategy for PDIA1 inhibition via targeted degradation, offering promising prospects in cancer therapeutics. This approach may overcome limitations of conventional inhibitors, presenting new avenues for advancing anti-cancer interventions.

Recent advances in the development of EGFR degraders: PROTACs and LYTACs.

Epidermal Growth Factor Receptor (EGFR), a transmembrane tyrosine kinase receptor, belongs to the ErbB receptor family, also known as HER1 or ErbB1. Its abnormal expression and activation contribute to tumor development, especially in non-small cell lung cancer (NCSCL). The first-to fourth-generation inhibitors of EGFR were developed to solve mutations at different sites, but the problem of resistance has not been fundamentally addressed. Targeted protein degradation (TPD) technologies, including PROteolysis Targeting Chimeras (PROTACs) and LYsosome Targeting Chimeras (LYTACs), take advantages of protein destruction mechanism in cells, which make up for shortcomings of traditional small molecular occupancy-driven inhibitors. PROTACs based heterobifunctional EGFR degraders were recently developed by making use of wild-type (WT) and mutated EGFR inhibitors. These degraders compared with EGFR inhibitors showed better efficiency in their cellular potency, inhibition and toxicity profiles. In this review, we first introduce the structural properties of EGFR, the inhibitors that have been developed against WT/mutated EGFR, and then mainly focuses on the recent advances of EGFR-targeting degraders along with its limitations and unlimited prospects.

De novo genome assembly of Bradysia cellarum (Diptera: Sciaridae), a notorious pest in traditional special vegetables in China.

Bradysia cellarum (Diptera: Sciaridae) is a destructive vegetable insect pest infesting more than 30 species of host plants from seven families in Asia and Europe. B. cellarum causes grave problems in Chinese chive, which originated in China and is cultivated widely in East Asia. The B. cellarum infestation results in economic losses and subsequent severe food safety problems in farm productions, insecticide resistance and environmental pollution. The genomic and molecular information of B. cellarum to delineate the biological features, insecticide resistance, evolution remains poorly understood. Herein, we decode the whole genome of B. cellarum to delineate the underlying molecular mechanisms causing insecticide resistance. We constructed a highly reliable genome for B. cellarum using PacBio, Illumina and 10X Genomics sequencing platforms. The genome size of B. cellarum was 375.91 Mb with a contig N50 of 1.57 Mb. A total of 16,231 genes were identified, among which 93.8% were functionally annotated, and 42.06% were repeat sequences. According to phylogenetic analysis, B. cellarum diverged from the common ancestor of Drosophila melanogaster and Musca domestica ~139.3-191.0 million years ago. Moreover, some important genes responsible for significant insecticide resistance, such as cytochrome P450s, ABC transporters and those involved in glutathione metabolism, were expanded in B. cellarum. We assembled a high-quality B. cellarum genome to provide valuable insights into their life history strategies, insecticide resistance and biological behaviours. It also lays the foundation for exploring gene structure and functional evolution, as well as comparative genomics of B. cellarum and other model insect species.

Cell-penetrating poly(disulfide)-based nanoquenchers (qCPDs) for self-monitoring of intracellular gene delivery.

Monitoring gene delivery has significant benefits in gene therapy. Herein, we report a nanoquencher system by doping a FRET pair during nucleic acid-assisted cell penetrating poly(disulfide) (CPD) formation. Our results show that this strategy not only produces an efficient gene delivery polymer with minimal endolysosomal trapping, but also enables monitoring the release of the gene from the vehicle in live cells. This study further expanded the application of CPDs as promising tools in gene delivery.

Relationship between volatile compounds of Picea likiangensis var. linzhiensis cone and host selection of Dioryctria abietella.

This study aimed to determine the relationship between volatile compounds of Picea likiangensis var. linzhiensis cone and host selection of Dioryctria abietella. During the infestation of P. likiangensis var. linzhiensis by D. abietella, their cones and branches emitted volatile compounds, which were extracted using CH2 Cl2 extraction and XAD2 adsorption methods, and were analyzed using gas chromatography-mass spectrometry. Before and after overwintering, D. abietella larva preferred annually infested cones and their extracts, and adult D. abietella preferred to lay eggs on annually infested cones and healthy cones of the year, and the oviposition rate of adult D. abietella was 72% on branches with healthy cones of the year, and no egg was laid on branches with annually healthy cones or branches without cones. The volatile compounds after infestation, α- and ß-pinene, were significantly higher in cones than those in other tissues; however, myrcene in cones was significantly lower than those in other tissues. The annually infested cones produced ß-caryophyllene and (1S)-(-)-ß-pinene, while the annually healthy cones and branches produced myrcene and 3-carene. The annually infested cones and their extracts attracted D. abietella larvae, while that of healthy cones and annually infested cones attracted the adults, indicating that the terpene compounds: α-pinene, ß-pinene, (1S)-(-)-ß-pinene, limonene, and ß-caryophyllene are attractive to D. abietella, and the terpene compounds-myrcene and 3-carene-from the branch tissues may be repulsive to D. abietella.

Dynamics of high frequency brain activity.

Evidence suggests that electroencephalographic (EEG) activity extends far beyond the traditional frequency range. Much of the prior study of >120 Hz EEG is in epileptic brains. In the current work, we measured EEG activity in the range of 200 to 2000 Hz, in the brains of healthy, spontaneously behaving rats. Both arrhythmic (1/f-type) and rhythmic (band) activities were identified and their properties shown to depend on EEG-defined stage of sleep/wakefulness. The inverse power law exponent of 1/f-type noise is shown to decrease from 3.08 in REM and 2.58 in NonREM to a value of 1.99 in the Waking state. Such a trend represents a transition from long- to short-term memory processes when examined in terms of the corresponding Hurst index. In addition, treating the 1/f-type activity as baseline noise reveals the presence of two, newly identified, high frequency EEG bands. The first band (ψ) is centered between 260-280 Hz; the second, and stronger, band is a broad peak in the 400-500 Hz range (termed ω). Both of these peaks display lognormal distributions. The functional significance of these frequency bands is supported by the variation in the strength of the peaks with EEG-defined sleep/wakefulness.

A stochastic mechanism for signal propagation in the brain: Force of rapid random fluctuations in membrane potentials of individual neurons.

There are two functionally important factors in signal propagation in a brain structural network: the very first synaptic delay-a time delay about 1ms-from the moment when signals originate to the moment when observation on the signal propagation can begin; and rapid random fluctuations in membrane potentials of every individual neuron in the network at a timescale of microseconds. We provide a stochastic analysis of signal propagation in a general setting. The analysis shows that the two factors together result in a stochastic mechanism for the signal propagation as described below. A brain structural network is not a rigid circuit rather a very flexible framework that guides signals to propagate but does not guarantee success of the signal propagation. In such a framework, with the very first synaptic delay, rapid random fluctuations in every individual neuron in the network cause an "alter-and-concentrate effect" that almost surely forces signals to successfully propagate. By the stochastic mechanism we provide analytic evidence for the existence of a force behind signal propagation in a brain structural network caused by rapid random fluctuations in every individual neuron in the network at a timescale of microseconds with a time delay of 1ms.

Signal propagation in small-world biological networks with weak noise.

An emerging notion in systems biology is that biological networks have evolved to function well while their components behave stochastically. Thus, the dynamics in a biological network consist of two parts, deterministic and stochastic. A fundamental question is to find a quantitative relation between the two parts. We term such a relation as a deterministic-stochastic principle (DSP) and propose a model for a DSP with regard to signal propagation in biological networks. In this model, (i) the dynamics in a biological network is supposed to be captured by a stochastic differential equation which has been a standard approach in modeling systems with internal noise; (ii) the internal noise of a biological network is weak as is apparent in experimental observations; and (iii) a biological network is organized as small-world as suggested by recent studies. We introduce the concept of a signaling sample path. Using this concept we relate the structure of a biological network to its dynamics. The network structure characterizes the deterministic part of the dynamics, which in turn ensures a probability for a signal to propagate. The weakness of the internal noise characterizes the stochastic part of the dynamics. Analysis of the proposed model yields a quantitative description as follows: In a small-world biological network with weak internal noise, the signaling pathways (induced by the network structure) for a signal may ensure a probability near 0 for the signal propagation. Despite such a small probability, a correct response to the signal will still occur with a probability close to 1 provided that this signal propagation can take a certain amount of time. Computer simulations are performed to illustrate this result. We also discuss how a recent study on the reconstruction of a transcription network in Saccharomyces cerevisiae has tested the proposed model against real data.

Extracellular noise-induced stochastic synchronization in heterogeneous quorum sensing network.

Quorum sensing is a bacterial mechanism used to synchronize the coordinated response of a microbial population. Because quorum sensing in Gram-negative bacteria depends on release and detection of a diffusible signaling molecule (autoinducer) among a multicellular group, it is considered a simple form of cell-cell communication for the purposes of mathematical analysis. Stochastic equation systems have provided a common approach to model biochemical or biophysical processes. Recently, the effect of noise to synchronize a specific homogeneous quorum sensing network was successfully modeled using a stochastic equation system with fixed parameters. The question remains of how to model quorum sensing networks in a general setting. To address this question, we first set a stochastic equation system as a general model for a heterogeneous quorum sensing network. Then, using two relevant biophysical characteristics of Gram-negative bacteria (the permeability of the cell membrane to the autoinducer and the symmetry of autoinducer diffusion) we construct the solution of the stochastic equation system at an abstract level. The solution indicates that stable synchronization of a quorum sensing network is robustly induced by an environment with a heterogenous distribution of extracellular and intracellular noise. The synchronization is independent of the initial state of the system and is solely the result of the connectivity of the cell network established through the effects of extracellular noise.

The mechanism for stochastic resonance enhancement of mammalian auditory information processing.

BACKGROUND: In a mammalian auditory system, when intrinsic noise is added to a subthreshold signal, not only can the resulting noisy signal be detected, but also the information carried by the signal can be completely recovered. Such a phenomenon is called stochastic resonance (SR). Current analysis of SR commonly employs the energies of the subthreshold signal and intrinsic noise. However, it is difficult to explain SR when the energy addition of the signal and noise is not enough to lift the subthreshold signal over the threshold. Therefore, information modulation has been hypothesized to play a role in some forms of SR in sensory systems. Information modulation, however, seems an unlikely mechanism for mammalian audition, since it requires significant a priori knowledge of the characteristics of the signal. RESULTS: We propose that the analysis of SR cannot rely solely on the energies of a subthreshold signal and intrinsic noise or on information modulation. We note that a mammalian auditory system expends energy in the processing of a noisy signal. A part of the expended energy may therefore deposit into the recovered signal, lifting it over threshold. We propose a model that in a rigorous mathematical manner expresses this new theoretical viewpoint on SR in the mammalian auditory system and provide a physiological rationale for the model. CONCLUSION: Our result indicates that the mammalian auditory system may be more active than previously described in the literature. As previously recognized, when intrinsic noise is used to generate a noisy signal, the energy carried by the noise is added to the original subthreshold signal. Furthermore, our model predicts that the system itself should deposit additional energy into the recovered signal. The additional energy is used in the processing of the noisy signal to recover the original subthreshold signal.