Parallel Pathways Research Articles

Convolutional neural networks for vision neuroscience: significance, developments, and outstanding issues.

Convolutional Neural Networks (CNN) are a class of machine learning models predominately used in computer vision tasks and can achieve human-like performance through learning from experience. Their striking similarities to the structural and functional principles of the primate visual system allow for comparisons between these artificial networks and their biological counterparts, enabling exploration of how visual functions and neural representations may emerge in the real brain from a limited set of computational principles. After considering the basic features of CNNs, we discuss the opportunities and challenges of endorsing CNNs as in silico models of the primate visual system. Specifically, we highlight several emerging notions about the anatomical and physiological properties of the visual system that still need to be systematically integrated into current CNN models. These tenets include the implementation of parallel processing pathways from the early stages of retinal input and the reconsideration of several assumptions concerning the serial progression of information flow. We suggest design choices and architectural constraints that could facilitate a closer alignment with biology provide causal evidence of the predictive link between the artificial and biological visual systems. Adopting this principled perspective could potentially lead to new research questions and applications of CNNs beyond modeling object recognition.

Complete degradation of di-n-butyl phthalate by Glutamicibacter sp. strain 0426 with a novel pathway.

Di-n-butyl phthalate (DBP) is widely used as plasticizer that has potential carcinogenic, teratogenic, and endocrine effects. In the present study, an efficient DBP-degrading bacterial strain 0426 was isolated and identified as a Glutamicibacter sp. strain 0426. It can utilize DBP as the sole source of carbon and energy and completely degraded 300mg/L of DBP within 12h. The optimal conditions (pH 6.9 and 31.7°C) for DBP degradation were determined by response surface methodology and DBP degradation well fitted with the first-order kinetics. Bioaugmentation of contaminated soil with strain 0426 enhanced DBP (1mg/g soil) degradation, indicating the application potential of strain 0426 for environment DBP removal. Strain 0426 harbors a distinctive DBP hydrolysis mechanism with two parallel benzoate metabolic pathways, which may account for the remarkable performance of DBP degradation. Sequences alignment has shown that an alpha/beta fold hydrolase (WP_083586847.1) contained a conserved catalytic triad and pentapeptide motif (GX1SX2G), of which function is similar to phthalic acid ester (PAEs) hydrolases and lipases that can efficiently catalyze hydrolysis of water-insoluble substrates. Furthermore, phthalic acid was converted to benzoate by decarboxylation, which entered into two different pathways: one is the protocatechuic acid pathway under the role of pca cluster, and the other is the catechol pathway. This study demonstrates a novel DBP degradation pathway, which broadens our understanding of the mechanisms of PAE biodegradation.

Optogenetic control of the integrated stress response reveals proportional encoding and the stress memory landscape.

The integrated stress response (ISR) is a conserved signaling network that detects aberrations and computes cellular responses. Dissecting these computations has been difficult because physical and chemical inducers of stress activate multiple parallel pathways. To overcome this challenge, we engineered a photo-switchable control over the ISR sensor kinase PKR (opto-PKR), enabling virtual, on-target activation. Using light to control opto-PKR dynamics, we traced information flow through the transcriptome and for key downstream ISR effectors. Our analyses revealed a biphasic, proportional transcriptional response with two dynamic modes, transient and gradual, that correspond to adaptive and terminal outcomes. We then constructed an ordinary differential equation (ODE) model of the ISR, which demonstrated the dependence of future stress responses on past stress. Finally, we tested our model using high-throughput light-delivery to map the stress memory landscape. Our results demonstrate that cells encode information in stress levels, durations, and the timing between encounters. A record of this paper's transparent peer review process is included in the supplemental information.

An Efficient Path Classification Algorithm Based on Variational Autoencoder to Identify Metastable Path Channels for Complex Conformational Changes.

Conformational changes (i.e., dynamic transitions between pairs of conformational states) play important roles in many chemical and biological processes. Constructing the Markov state model (MSM) from extensive molecular dynamics (MD) simulations is an effective approach to dissect the mechanism of conformational changes. When combined with transition path theory (TPT), MSM can be applied to elucidate the ensemble of kinetic pathways connecting pairs of conformational states. However, the application of TPT to analyze complex conformational changes often results in a vast number of kinetic pathways with comparable fluxes. This obstacle is particularly pronounced in heterogeneous self-assembly and aggregation processes. The large number of kinetic pathways makes it challenging to comprehend the molecular mechanisms underlying conformational changes of interest. To address this challenge, we have developed a path classification algorithm named latent-space path clustering (LPC) that efficiently lumps parallel kinetic pathways into distinct metastable path channels, making them easier to comprehend. In our algorithm, MD conformations are first projected onto a low-dimensional space containing a small set of collective variables (CVs) by time-structure-based independent component analysis (tICA) with kinetic mapping. Then, MSM and TPT are constructed to obtain the ensemble of pathways, and a deep learning architecture named the variational autoencoder (VAE) is used to learn the spatial distributions of kinetic pathways in the continuous CV space. Based on the trained VAE model, the TPT-generated ensemble of kinetic pathways can be embedded into a latent space, where the classification becomes clear. We show that LPC can efficiently and accurately identify the metastable path channels in three systems: a 2D potential, the aggregation of two hydrophobic particles in water, and the folding of the Fip35 WW domain. Using the 2D potential, we further demonstrate that our LPC algorithm outperforms the previous path-lumping algorithms by making substantially fewer incorrect assignments of individual pathways to four path channels. We expect that LPC can be widely applied to identify the dominant kinetic pathways underlying complex conformational changes.

Central carbon flux controls growth/damage balance for Streptococcus pyogenes.

Microbial pathogens balance growth against tissue damage to achieve maximum fitness. Central carbon metabolism is connected to growth, but how it influences growth/damage balance is largely unknown. Here we examined how carbon flux through the exclusively fermentative metabolism of the pathogenic lactic acid bacterium Streptococcus pyogenes impacts patterns of growth and tissue damage. Using a murine model of soft tissue infection, we systematically examined single and pair-wise mutants that constrained carbon flux through the three major pathways that S. pyogenes employs for reduction of the glycolytic intermediate pyruvate, revealing distinct disease outcomes. Its canonical lactic acid pathway (via lactate dehydrogenase) made a minimal contribution to virulence. In contrast, its two parallel pathways for mixed-acid fermentation played important, but non-overlapping roles. Anaerobic mixed acid fermentation (via pyruvate formate lyase) was required for growth in tissue, while aerobic mixed-acid pathway (via pyruvate dehydrogenase) was not required for growth, but instead regulated levels of tissue damage. Infection of macrophages in vitro revealed that pyruvate dehydrogenase was required to prevent phagolysosomal acidification, which altered expression of the immunosuppressive cytokine IL-10. Infection of IL-10 deficient mice confirmed that the ability of aerobic metabolism to regulate levels of IL-10 plays a key role in the ability of S. pyogenes to modulate levels of tissue damage. Taken together, these results show critical non-overlapping roles for anaerobic and aerobic metabolism in soft tissue infection and provide a mechanism for how oxygen and carbon flux act coordinately to regulate growth/damage balance. Therapies targeting carbon flux could be developed to mitigate tissue damage during severe S. pyogenes infection.

Hydrodynamic Diversity of Jets Mediated by Giant and Non-Giant Axon Systems in Brief Squid.

Neural input is critical for establishing behavioral output, but understanding how neuromuscular signals give rise to behaviors remains a challenge. In squid, locomotion through jet propulsion underlies many key behaviors, and the jet is mediated by two parallel neural pathways, the giant and non-giant axon systems. Much work has been done on the impact of these two systems on jet kinematics, such as mantle muscle contraction and pressure-derived jet speed at the funnel aperture. However, little is known about any influence these neural pathways may have on the hydrodynamics of the jet after it leaves the squid and transfers momentum to the surrounding fluid for the animal to swim. To gain a more comprehensive view of squid jet propulsion, we made simultaneous measurements of neural activity, pressure inside the mantle cavity, and wake structure. By computing impulse and time-averaged forces from the wake structures of jets associated with giant or non-giant axon activity, we show that the influence of neural pathways on jet kinematics could extend to hydrodynamic impulse and force production. Specifically, the giant axon system produced jets with, on average, greater impulse magnitude than those of the non-giant system. However, non-giant impulse could exceed that of the giant system, evident by the graded range of its output in contrast to the stereotyped nature of the giant system. Our results suggest that the non-giant system offers flexibility in hydrodynamic output, while recruitment of giant axon activity can provide a reliable boost when necessary.

Learned spatiotemporal correlation priors for CEST image denoising using incorporated global-spectral convolution neural network.

To develop a deep learning-based method, dubbed Denoising CEST Network (DECENT), to fully exploit the spatiotemporal correlation prior to CEST image denoising. DECENT is composed of two parallel pathways with different convolution kernel sizes aiming to extract the global and spectral features embedded in CEST images. Each pathway consists of a modified U-Net with residual Encoder-Decoder network and 3D convolution. Fusion pathway with 1 × 1 × 1 convolution kernel is utilized to concatenate two parallel pathways, and the output of DECENT is noise-reduced CEST images. The performance of DECENT was validated in numerical simulations, egg white phantom experiments, and ischemic mouse brain and human skeletal muscle experiments in comparison with existing state-of-the-art denoising methods. Rician noise was added to CEST images to mimic a low SNR situation for numerical simulation, egg white phantom experiment, and mouse brain experiments, while human skeletal muscle experiments were of inherently low SNR. From the denoising results evaluated by peak SNR (PSNR) and structural similarity index (SSIM), the proposed deep learning-based denoising method (DECENT) can achieve better performance compared to existing CEST denoising methods such as NLmCED, MLSVD, and BM4D, avoiding complicated parameter tuning or time-consuming iterative processes. DECENT can well exploit the prior spatiotemporal correlation knowledge of CEST images and restore the noise-free images from their noisy observations, outperforming state-of-the-art denoising methods.

Hypericum perforatum L. and the Underlying Molecular Mechanisms for Its Choleretic, Cholagogue, and Regenerative Properties.

Any defects in bile formation, secretion, or flow may give rise to cholestasis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. As the pathogenesis of hepatic disorders is multifactorial, targeting parallel pathways potentially increases the outcome of therapy. Hypericum perforatum has been famed for its anti-depressive effects. However, according to traditional Persian medicine, it helps with jaundice and acts as a choleretic medication. Here, we will discuss the underlying molecular mechanisms of Hypericum for its use in hepatobiliary disorders. Differentially expressed genes retrieved from microarray data analysis upon treatment with safe doses of Hypericum extract and intersection with the genes involved in cholestasis are identified. Target genes are located mainly at the endomembrane system with integrin-binding ability. Activation of α5β1 integrins, as osmo-sensors in the liver, activates a non-receptor tyrosine kinase, c-SRC, which leads to the insertion of bile acid transporters into the canalicular membrane to trigger choleresis. Hypericum upregulates CDK6 that controls cell proliferation, compensating for the bile acid damage to hepatocytes. It induces ICAM1 to stimulate liver regeneration and regulates nischarin, a hepatoprotective receptor. The extract targets the expression of conserved oligomeric Golgi (COG) and facilitates the movement of bile acids toward the canalicular membrane via Golgi-derived vesicles. In addition, Hypericum induces SCP2, an intracellular cholesterol transporter, to maintain cholesterol homeostasis. We have also provided a comprehensive view of the target genes affected by Hypericum's main metabolites, such as hypericin, hyperforin, quercitrin, isoquercitrin, quercetin, kaempferol, rutin, and p-coumaric acid to enlighten a new scope in the management of chronic liver disorders. Altogether, standard trials using Hypericum as a neo-adjuvant or second-line therapy in ursodeoxycholic-acid-non-responder patients define the future trajectories of cholestasis treatment with this product.

Gravity and magnetic models at Rangitoto Volcano, Auckland Volcanic Field, New Zealand: Implications for basement control on magma ascent

In small-volume volcanism, pre-existing crustal structures can influence magma ascent processes. Rangitoto volcano in the Auckland Volcanic Field, New Zealand, provides a possible example of magma-structure interaction as this volcano was emplaced adjacent to an outcrop of a regional-scale basement fault, the Islington Bay Fault. In this study, we evaluated the magmatic plumbing system of Rangitoto using gravity and magnetic data acquired over the volcano and the adjacent, non-volcanic Motutapu Island. We modelled the Rangitoto internal architecture and magma plumbing using 2.5D forward and 3D inverse modelling methods. Both models are constrained by petrophysical data, while drill hole logs are only used to constrain the 2.5D model. Our model endmembers suggest that parallel magma pathways are present below the Rangitoto summit cones. In 3D magnetic models, this is evidenced by a fault-aligned pair of high-susceptibility bodies. Interpreting our models in conjunction with previously published geological and geophysical models allows us to hypothesise that the fault-parallel alignment of Rangitoto magma pathways reflects the primary influence of the Islington Bay Fault over the Rangitoto magma ascent. Magma diversion at shallow levels by other finer structures intersecting and adjacent to the fault could explain why Rangitoto erupted 3.5 km west of the Islington Bay Fault surface trace.

Characterizing the Semiconductor Nanocrystal Surface through Chemical Reactivity.

ConspectusMany desirable and undesirable properties of semiconductor nanocrystals (NCs) can be traced to the NC surface due to the large surface-to-volume ratio. Therefore, precise control of the NC surface is imperative to achieve NCs with the desired qualities. Ligand-specific reactivity and surface heterogeneity make it difficult to accurately control and tune the NC surface. Without a molecular-level appreciation of the NC surface chemistry, modulating the NC surface is impossible and the risk of introducing deleterious surface defects is imminent. To gain a more comprehensive understanding of the surface reactivity, we have utilized a variety of spectroscopic techniques and analytical methods in concert.This Account describes our use of robust characterization techniques and ligand exchange reactions in effort to establish a molecular-level understanding of NC surface reactivity. The utility of NCs in target applications such as catalysis and charge transfer hangs on precise tunability of NC ligands. Modulating the NC surface requires the necessary tools to monitor chemical reactions. One commonly utilized analytical method to achieve targeted surface compositions is 1H nuclear magnetic resonance (NMR) spectroscopy. Here we describe our use of 1H NMR spectroscopy to monitor chemical reactions at CdSe and PbS NC surfaces to identify ligand specific reactivity. However, seemingly straightforward ligand exchange reactions can vary widely depending on the NC materials and anchoring group. Some non-native X-type ligands will irreversibly displace native ligands. Other ligands exist in equilibrium with native ligands. Depending on the application, it is important to understand the nature of exchange reactions. This level of understanding can be obtained by extracting exchange ratios, exchange equilibrium, and reaction mechanism information from 1H NMR spectroscopy to establish precise NC reactivity.Reactivity that occurs through multiple, parallel ligand exchange mechanisms can involve both the liberation of metal-based Z-type ligands in addition to reactivity of X-type ligands. In these reactions, 1H NMR spectroscopy fails to discern between an X-type oleate or a Z-type Pb(oleate)2 because only the alkene resonance of the organic constituent is probed by this method. Multiple, parallel reaction pathways occur when thiol ligands are introduced to oleate-capped PbS NCs. This necessitated the use of synergistic characterization methods including 1H NMR spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, and inductively coupled plasma mass spectrometry (ICP-MS) to characterize both surface-bound and liberated ligands.Similar analytical methods have been employed to probe the NC topology, which is an important, but often overlooked, component to NC reactivity given the facet-specific reactivity of PbS NCs. Through the tandem use of NMR spectroscopy and ICP-MS, we have monitored the liberation of Pb(oleate)2 as an L-type ligand is titrated to the NC to determine the quantity and equilibrium of Z-type ligands. By studying a variety of NC sizes, we correlated the number of liberated ligands with the size-dependent topology of PbS NCs.Lastly, we incorporate redox-active chemical probes into our toolbox to study NC surface defects. We describe how the site-specific reactivity and relative energetics of redox-active surface-based defects are elucidated using redox probes and show that this reactivity is highly dependent on the surface composition. This Account is designed to encourage readers to consider the necessary characterization techniques needed establish a molecular-level understanding of NC surfaces in their own work.

SNARE Protein Snc1 Is Essential for Vesicle Trafficking, Membrane Fusion and Protein Secretion in Fungi.

Fungi are an important group of microorganisms that play crucial roles in a variety of ecological and biotechnological processes. Fungi depend on intracellular protein trafficking, which involves moving proteins from their site of synthesis to the final destination within or outside the cell. The soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) proteins are vital components of vesicle trafficking and membrane fusion, ultimately leading to the release of cargos to the target destination. The v-SNARE (vesicle-associated SNARE) Snc1 is responsible for anterograde and retrograde vesicle trafficking between the plasma membrane (PM) and Golgi. It allows for the fusion of exocytic vesicles to the PM and the subsequent recycling of Golgi-localized proteins back to the Golgi via three distinct and parallel recycling pathways. This recycling process requires several components, including a phospholipid flippase (Drs2-Cdc50), an F-box protein (Rcy1), a sorting nexin (Snx4-Atg20), a retromer submit, and the COPI coat complex. Snc1 interacts with exocytic SNAREs (Sso1/2, Sec9) and the exocytic complex to complete the process of exocytosis. It also interacts with endocytic SNAREs (Tlg1 and Tlg2) during endocytic trafficking. Snc1 has been extensively investigated in fungi and has been found to play crucial roles in various aspects of intracellular protein trafficking. When Snc1 is overexpressed alone or in combination with some key secretory components, it results in enhanced protein production. This article will cover the role of Snc1 in the anterograde and retrograde trafficking of fungi and its interactions with other proteins for efficient cellular transportation.

Identification of a damage-associated molecular pattern (DAMP) receptor and its cognate peptide ligand in sweet potato (Ipomoea batatas).

Sweet potato (Ipomoea batatas) is an important tuber crop, but also target of numerous insect pests. Intriguingly, the abundant storage protein in tubers, sporamin, has intrinsic trypsin protease inhibitory activity. In leaves, sporamin is induced by wounding or a volatile homoterpene and enhances insect resistance. While the signalling pathway leading to sporamin synthesis is partially established, the initial event, perception of a stress-related signal is still unknown. Here, we identified an IbLRR-RK1 that is induced upon wounding and herbivory, and related to peptide-elicitor receptors (PEPRs) from tomato and Arabidopsis. We also identified a gene encoding a precursor protein comprising a peptide ligand (IbPep1) for IbLRR-RK1. IbPep1 represents a distinct signal in sweet potato, which might work in a complementary and/or parallel pathway to the previously described hydroxyproline-rich systemin (HypSys) peptides to strengthen insect resistance. Notably, an interfamily compatibility in the Pep/PEPR system from Convolvulaceae and Solanaceae was identified.

The Diels–Alder Reaction between Euparin and Dimethyl Acetylenedicarboxylate; a Joint Experimental and Density Functional Theory Study

In this project, we have investigated the Diels–Alder (DA) reaction between euparin (as a natural furan derivative) and dimethyl acetylenedicarboxylate (DMAD) as an electrophilic acetylene. The experimental observations during the reaction in different conditions showed that the yield and the rate of the process would increase with increasing the polarity of the solvent. Such observation suspected us that like several recent reports, the mechanism of this DA reaction takes place through a stepwise route containing a zwitterionic intermediate or at least through a relatively polar transition state (TS). Next, during the density functional theory (DFT) studies and the potential energy surface (PES) investigations, we have detected a stepwise reaction pathway in parallel with the one-step route. The results of this work are in agreement with the recent reports about the competition between the one-step and multisteps routes in the DA reactions.

Social distance of bystanders affects people’s embarrassment via changing fear of negative evaluation and feelings of attachment security

BackgroundEmbarrassment is a self-conscious emotion with important social functions, but it is not well understood. The perception of bystanders is considered a precondition for embarrassment, which makes it unique from other self-conscious emotions. Studies have shown that socially close bystanders can reduce individuals’ embarrassment. However, whether and how the embarrassment of individuals varies with the changes in social distance between them and their bystanders remained unclear, which indicates the key characteristics of embarrassment.MethodsThe current research consists of two studies. Study 1 tested whether participants’ embarrassment systematically varied with social distance by setting up three levels of social distance: close friends (i.e., short), casual friends (i.e., medium), and strangers (i.e., long), based on 159 participants. With two full mediation models, study 2 investigated whether and how the fear of negative evaluation and state attachment security mediated the influence of social distance on embarrassment based on 155 participants.ConclusionsThe current findings revealed that the social distance between bystanders and protagonists systematically influenced the embarrassment of protagonists and this effect occurred via two parallel pathways, i.e., by increasing the fear of negative evaluation and by reducing state attachment security. The findings not only showed the unique role of bystander characteristics on embarrassment, but also two cognitive processes behind this unique self-conscious emotion: fearing negative evaluation and seeking attachment for security.

Construction of C–X (X = S, O, Se) Bonds via Lewis Acid-Promoted Functionalization of Trifluoromethylarenes

The conversion of easily available trifluoromethylarenes through C–F bond activation provides an attractive pathway for rapid access to difluorobenzylic substructures in producing pharmaceuticals and agrochemicals. However, recent advances in this area have been confined to C–C(H) bond construction, thus limiting the diversity of the accessible motifs. In contrast, the selective formation of a carbon–heteroatom bond via C–F bond functionalization, which enable fast and convenient access to diverse fluorine-containing motifs with high chemical diversity, remains a formidable synthetic challenge. Herein, we disclosed a Lewis acid promoted photoredox-catalyzed strategy for the construction of C–X (X = S, O or Se) bonds by single C(sp3)–F bond activation of trifluoromethylarenes, which enable the direct synthesis of medicinally interesting aryldifluoromethyl ether [ArCF2X– (X = S, O, or Se)] scaffolds. This method relies on readily available reagents and can tolerate a range of thiol, phenol, and selenol nucleophiles. Its utility was exemplified in the late-stage modifications of several pharmaceutical ingredients. Preliminary studies suggest two parallel pathways: a photocatalytic single electron-transfer (SET), and an electron donor–acceptor (EDA) process.

Phosphorus-Induced Dual-Sites and High-Index PtCu (3 1 1) crystal planes for modifying oxygen reduction pathway

The oxygen reduction reaction (ORR) on Pt-based catalysts is largely retarded by the stronger adsorption of the intermediates on Pt (111) than ideal catalysts. Synergistic catalysis offers a promising approach to reshape the electronic structure of the designed catalyst for optimizing the adsorption energy of the intermediates on its surface. Herein, we certificate that the intermediates adsorption on the C-supported PtCu alloy catalyst can be modulated synergistically by distorted PtCu (111) crystal planes and P-C sites caused by P-doping, leading to a substantial increase in ORR. In situ spectral evidence of two *OOH intermediates on the above dual sites identifies the role of introduced metalloid P elements in promoting the ORR association pathway. Notably, the high-index PtCu (311) crystal planes of the P-doped catalysts have shown a distinct enhancement with abundant terraces and step densities, which contributes to the highest ORR activity of PtCu/PC-3 with the mass activity (MA) of 0.82 A mgPt-1 (0.8 V). Analysis of the *OH real-time adsorption behaviors on this crystal plane suggests that another parallel dissociation pathway is also in operation. Benefiting from the increased active site species and the enhanced intrinsic activity, the optimal PtCu/PC-3 also exhibits the impressive performance in methanol oxidation reaction (MOR).

Abstract B033: Wild-type RAS signaling is an essential therapeutic target in RAS-mutated cancers

Abstract Single-agent targeting of RAS-mutated cancers using RAF/MEK/ERK or PI3K/AKT pathway inhibitors is ineffective; blocking one pathway relieves negative feedback control of RTK signaling and hyperactivates parallel effector pathways. While combined MEK and PI3K inhibition is effective in preclinical models, toxicity of this combination prevents its clinical use. Alternative strategies for treating RAS-mutated cancers are essential. Therapeutics directly targeting mutated RAS proteins have the potential to spare normal cellular function thereby lessening overall toxicity. Unfortunately, direct RAS inhibition as a monotherapy does not fully block RAS effector signaling. RAS proteins show differential activation of RAF and PI3K pathways: KRAS potently activates RAF but poorly activates PI3K, whereas HRAS effectively activates PI3K but poorly activates RAF. Further, mutant RAS inhibition relieves negative feedback controls leading to rapid hyperactivation of RTK−WT RAS signaling. A more comprehensive understanding of the interplay between mutant RAS and RTK−WT RAS signaling is essential to developing rational therapeutic approaches to treat RAS-mutated cancers. We found that WT RAS enhanced mutant RAS-driven transformation by activating RAS effectors poorly engaged by mutated RAS. Further, inhibition of RAS effectors activated poorly by mutant RAS synergized with and limited resistance to mutant HRAS and KRAS inhibitors. The mutant HRAS inhibitor tipifarnib blocked PI3K signaling and synergized with MEK inhibitors in HRAS-mutated cancer cell lines; covalent KRASG12C inhibitors blocked MEK signaling and synergized with PI3K inhibitors in KRASG12C-mutated cell lines. Synergy between inhibitors of mutant RAS and RAS effectors was dependent on intact RTK/WT RAS signaling and was lost in both RASless or SOSless MEFs. These results should inform the design of clinical trials for patients with RAS-mutated cancers. Citation Format: Nancy Sealover, Bridget Finniff, Robert Kortum. Wild-type RAS signaling is an essential therapeutic target in RAS-mutated cancers [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr B033.

Cr(VI)-bioremediation mechanism of a novel strain Bacillus paramycoides Cr6 with the powerful ability to remove Cr(VI) from contaminated water

This research provided an excellent novel hexavalent chromium (Cr(VI))-removal bacterium, Bacillus paramycoides Cr6, and investigated its removal mechanism from the perspective of molecular biology. Cr6 could resist up to 2500 mg/L Cr(VI), and the removal rate of 2000 mg/L Cr(VI) reached 67.3% under the optimal culture conditions of 220 r/min, pH 8 and 31 ℃. When the initial concentration of Cr(VI) was 200 mg/L, Cr6 had a removal rate of 100% within 18 h. The differential transcriptome analysis identified two key structural genes named bcr005 and bcb765 of Cr6, which were upregulated by Cr(VI). Their functions were predicted and further confirmed by bioinformatic analyses and in vitro experiments. bcr005 encodes Cr(VI)-reductase BCR005, and bcb765 encodes Cr(VI)-binding protein BCB765. Real-time fluorescent quantitative PCRs were performed, and the data illustrated a parallel pathway (one is Cr(VI) reduction, and the other is Cr(VI) immobilisation) of Cr6 to remove Cr(VI), which relies on the synergistic expression of the genes bcr005 and bcb765 induced by different concentrations of Cr(VI). In summary, a deeper molecular mechanism of Cr(VI) microorganism removal was elaborated; Bacillus paramycoides Cr6 was an exceptional novel Cr(VI)-removed bacterial resource, while BCR005 and BCB765 were two new-found efficient enzymes that have potential practical applications for sustainable microbial remediation of Cr-contaminated water.

A Subset of Circadian Neurons Expressing dTRPA1 Enables Appropriate Phasing of Activity Rhythms in Drosophila melanogaster Under Warm Temperatures.

Under conditions of prolonged durations of warmth, flies counter potential temperature stress by shifting their locomotor activity from day into night when the conditions are likely to be less harsh. Modulation of a rhythmic behavior such as this in response to the environment would require interaction between at least 2 neuronal systems: (1) a sensory system to receive input from the environment, and (2) the internal clock to correctly time rhythmic activity in response to this thermosensory input. Our previous studies found that a thermosensory mutant of the ion channel Drosophila Transient Receptor Potential-A1 (dTRPA1) failed to shift activity into the dark like control flies do and also identified the role of a specific cluster of the dTRPA1-expressing neurons, the dTRPA1sh+neurons necessary for this. In this study, we extended our previous findings and characterized the identity of these dTRPA1sh+ neurons based on their overlap with circadian neurons. Utilizing various genetic manipulations, we asked whether the overlapping neurons could be potential points of intersection between the 2 circuits that modulate behavior under warm temperature, meaning whether they function as both-sensory and clock neurons. We found that the molecular clock within the dTRPA1sh+ cluster was not necessary, but the expression of dTRPA1 in a subset of circadian neurons, the small ventrolateral neurons (sLNvs), was necessary in modulating phasing of behavior under warm temperature. Furthermore, attempting to identify the neuronal circuit, we were able to uncover the potential roles of serotonin and acetylcholine in modulating this temperature-dependent behavior. Finally, we also discuss possible parallel neuronal pathways that may exist to give rise to this modulation of behavior under warm temperature, thereby supporting and expanding the knowledge of the field about circuits that control temperature-mediated behavioral outcomes.

Bioinspired figure-ground discrimination via visual motion smoothing

Flies detect and track moving targets among visual clutter, and this process mainly relies on visual motion. Visual motion is analyzed or computed with the pathway from the retina to T4/T5 cells. The computation of local directional motion was formulated as an elementary movement detector (EMD) model more than half a century ago. Solving target detection or figure-ground discrimination problems can be equivalent to extracting boundaries between a target and the background based on the motion discontinuities in the output of a retinotopic array of EMDs. Individual EMDs cannot measure true velocities, however, due to their sensitivity to pattern properties such as luminance contrast and spatial frequency content. It remains unclear how local directional motion signals are further integrated to enable figure-ground discrimination. Here, we present a computational model inspired by fly motion vision. Simulations suggest that the heavily fluctuating output of an EMD array is naturally surmounted by a lobula network, which is hypothesized to be downstream of the local motion detectors and have parallel pathways with distinct directional selectivity. The lobula network carries out a spatiotemporal smoothing operation for visual motion, especially across time, enabling the segmentation of moving figures from the background. The model qualitatively reproduces experimental observations in the visually evoked response characteristics of one type of lobula columnar (LC) cell. The model is further shown to be robust to natural scene variability. Our results suggest that the lobula is involved in local motion-based target detection.