Dissection and integration of bursty transcriptional dynamics for complex systems.

RNA velocity estimation is a potentially powerful tool to reveal the directionality of transcriptional changes in single-cell RNA-sequencing data, but it lacks accuracy, absent advanced metabolic labeling techniques. We developed an approach, TopicVelo, that disentangles simultaneous, yet distinct, dynamics by using a probabilistic topic model, a highly interpretable form of latent space factorization, to infer cells and genes associated with individual processes, thereby capturing cellular pluripotency or multifaceted functionality. Focusing on process-associated cells and genes enables accurate estimation of process-specific velocities via a master equation for a transcriptional burst model accounting for intrinsic stochasticity. The method obtains a global transition matrix by leveraging cell topic weights to integrate process-specific signals. In challenging systems, this method accurately recovers complex transitions and terminal states, while our use of first-passage time analysis provides insights into transient transitions. These results expand the limits of RNA velocity, empowering future studies of cell fate and functional responses.

Neural Functions Enabled by a Polarity-Switchable Nanofluidic Memristor.

Reproducing neural functions with artificial nanofluidic systems has long been an aspirational goal for neuromorphic computing. In this study, neural functions, such as neural activation and synaptic plasticity, are successfully accomplished with a polarity-switchable nanofluidic memristor (PSNM), which is based on the anodized aluminum oxide (AAO) nanochannel array. The PSNM has unipolar memristive behavior at high electrolyte concentrations and bipolar memristive behavior at low electrolyte concentrations, which can emulate neural activation and synaptic plasticity, respectively. The mechanisms for the unipolar and bipolar memristive behaviors are related to the polyelectrolytic Wien (PEW) effect and ion accumulation/depletion effect, respectively. These findings are beneficial to the advancement of neuromorphic computing on nanofluidic platforms.

Chemoproteomics of Marine Natural Product Naamidine J Unveils CSE1L as a Therapeutic Target in Acute Lung Injury.

Acute lung injury is a devastating illness characterized by severe inflammation mediated by aberrant activation of macrophages, resulting in significant morbidity and mortality, highlighting the urgent need for novel pharmacological targets and drug candidates. In this study, we identified a novel target for regulating inflammation in macrophages and acute lung injury via chemical proteomics and genetics based on a marine alkaloid, naamidine J (NJ). The structures of NJ-related naamidine alkaloids were first confirmed or revised by a combination of quantum chemical calculations and X-ray diffraction analysis. NJ was found as a potential anti-inflammatory agent by screening our compound library, and CSE1L was identified by chemoproteomics as a main cellular target of NJ to inhibit inflammation in macrophages and protect against acute lung injury. Mechanistically, we demonstrated that NJ directly interacted with CSE1L on the sites of His745 and Phe903 and then inhibited the nuclear translocation and transcriptional activity of transcription factor SP1, thereby suppressing inflammation in macrophages and ameliorating acute lung injury. Taken together, these findings have uncovered a novel pharmacological target for the treatment of acute lung injury and have also provided a potential druggable pocket of CSE1L and a lead compound or an available chemical tool from marine sources for investigating CSE1L function and developing novel drug candidates against acute lung injury.

Devastating the Supply Wagons: Multifaceted Liposomes Capable of Exhausting Tumor to Death via Triple Energy Depletion.

The anabolism of tumor cells can not only support their proliferation, but also endow them with a steady influx of exogenous nutrients. Therefore, consuming metabolic substrates or limiting access to energy supply can be an effective strategy to impede tumor growth. Herein, a novel treatment paradigm of starving-like therapy-triple energy-depleting therapy-is illustrated by glucose oxidase (GOx)/dc-IR825/sorafenib liposomes (termed GISLs), and such a triple energy-depleting therapy exhibits a more effective tumor-killing effect than conventional starvation therapy that only cuts off one of the energy supplies. Specifically, GOx can continuously consume glucose and generate toxic H2O2 in the tumor microenvironment (including tumor cells). After endocytosis, dc-IR825 (a near-infrared cyanine dye) can precisely target mitochondria and exert photodynamic and photothermal activities upon laser irradiation to destroy mitochondria. The anti-angiogenesis effect of sorafenib can further block energy and nutrition supply from blood. This work exemplifies a facile and safe method to exhaust the energy in a tumor from three aspects and starve the tumor to death and also highlights the importance of energy depletion in tumor treatment. It is hoped that this work will inspire the development of more advanced platforms that can combine multiple energy depletion therapies to realize more effective tumor treatment.

IAR4 mutation enhances cadmium toxicity by disturbing auxin homeostasis in Arabidopsis thaliana.

Cadmium (Cd) is highly toxic to plants, but the targets and modes of toxicity remain unclear. We isolated a Cd-hypersensitive mutant of Arabidopsis thaliana, Cd-induced short root 2 (cdsr2), in the background of the phytochelatin synthase-defective mutant cad1-3. Both cdsr2 and cdsr2 cad1-3 displayed shorter roots and were more sensitive to Cd than their respective wild type. Using genomic resequencing and complementation, IAR4 was identified as the causal gene, which encodes a putative mitochondrial pyruvate dehydrogenase E1α subunit. cdsr2 showed decreased pyruvate dehydrogenase activity and NADH content, but markedly increased concentrations of pyruvate and alanine in roots. Both Cd stress and IAR4 mutation decreased auxin level in the root tips, and the effect was additive. A higher growth temperature rescued the phenotypes in cdsr2. Exogenous alanine inhibited root growth and decreased auxin level in the wild type. Cadmium stress suppressed the expression of genes involved in auxin biosynthesis, hydrolysis of auxin-conjugates and auxin polar transport. Our results suggest that auxin homeostasis is a key target of Cd toxicity, which is aggravated by IAR4 mutation due to decreased pyruvate dehydrogenase activity. Decreased auxin level in cdsr2 is likely caused by increased auxin-alanine conjugation and decreased energy status in roots.

Synthesis of Silver(I) Complexes through In Situ Reactions of dppeda with dmp in the Presence of Silver Halides for Photocatalysis.

Due to the unique photosensitivity of silver compounds, they exhibit good photocatalytic activity as photocatalysts in the degradation of water pollutants. However, silver compounds have poor cycling stability and are prone to decomposition and reaction under light to form metallic silver, which greatly limits their practical application. Herein, a (2-(2-(diphenylphosphaneyl)ethyl)-9-methyl-1.10-phenanthroline (PSNNP)) pincer ligand was designed for stabilizing the central metal. The in situ-formed PSNNP ligand could be readily generated in one pot with the participation of silver halides. The reaction of silver halides with dppeda (N,N,N',N'-tetra(diphenylphosphanylmethyl)ethylene diamine) in the presence of dmp (2,9-dimethyl-1,10-phenanthroline) in acetonitrile afforded complexes Ag2X2 (PSNNP)2 (complexes 1, 2) (X = Cl, Br). Single-crystal X-ray diffraction shows that the tridentate coordination of the pincer ligand provides strong binding with metal centers and leads to high stability of the pincer metal unit. The removal rate of rhodamine B (RhB) by complexes 1 and 2 can reach up to 100%, demonstrating an excellent photocatalytic degradation performance for organic dyes. The important effect of PSNNP ligands on photocatalytic properties after coordination with central metals was studied through experiments and discrete Fourier transform (DFT) calculations. The photocatalytic reaction mechanism of complexes 1 and 2 was also studied. This result provides an effective pathway for the first synthesis of PSNNP and interesting insights into photocatalytic degradation chemistry.

Understanding Nanoscale Interactions between Minerals and Microbes: Opportunities for Green Remediation of Contaminated Sites.

In situ contaminant degradation and detoxification mediated by microbes and minerals is an important element of green remediation. Improved understanding of microbe-mineral interactions on the nanoscale offers promising opportunities to further minimize the environmental and energy footprints of site remediation. In this Perspective, we describe new methodologies that take advantage of an array of multidisciplinary tools─including multiomics-based analysis, bioinformatics, machine learning, gene editing, real-time spectroscopic and microscopic analysis, and computational simulations─to identify the key microbial drivers in the real environments, and to characterize in situ the dynamic interplay between minerals and microbes with high spatiotemporal resolutions. We then reflect on how the knowledge gained can be exploited to modulate the binding, electron transfer, and metabolic activities at the microbe-mineral interfaces, to develop new in situ contaminant degradation and detoxication technologies with combined merits of high efficacy, material longevity, and low environmental impacts. Two main strategies are proposed to maximize the synergy between minerals and microbes, including using mineral nanoparticles to enhance the versatility of microorganisms (e.g., tolerance to environmental stresses, growth and metabolism, directed migration, selectivity, and electron transfer), and using microbes to synthesize and regenerate highly dispersed nanostructures with desired structural/surface properties and reactivity.

Carneusones A-F, Benzophenone Derivatives from Sponge-Derived Fungus Aspergillus carneus GXIMD00543.

Six benzophenone derivatives, carneusones A-F (1-6), along with seven known compounds (7-13) were isolated from a strain of sponge-derived marine fungus Aspergillus carneus GXIMD00543. Their chemical structures were elucidated by detailed spectroscopic data and quantum chemical calculations. Compounds 5, 6, and 8 exhibited moderate anti-inflammatory activity on NO secretion using lipopolysaccharide (LPS)-induced RAW 264.7 cells with EC50 values of 34.6 ± 0.9, 20.2 ± 1.8, and 26.8 ± 1.7 µM, while 11 showed potent effect with an EC50 value of 2.9 ± 0.1 µM.

Design and Synthesis of Marine Polybrominated Diphenyl Ether Derivatives as Potential Anti-Inflammatory Agents.

Natural polybrominated diphenyl ethers are generally isolated from sponges and possess a broad range of biological activities. Through screening of our marine natural product library, we discovered that polybrominated diphenyl ethers 5 and 6 exhibit considerable anti-inflammatory activity. In order to expand our repertoire of derivatives for further biological activity studies, we designed and synthesized a series of 5-related polybrominated diphenyl ethers. Importantly, compound 5a showed comparable anti-inflammatory activity while much lower cytotoxicity on lipopolysaccharide (LPS)-induced RAW264.7 cells. Additionally, western blotting analysis showed that 5a reduced the expression of phosphorylated extracellular signal-regulated kinase (p-ERK). Besides, molecular docking experiments were conducted to predict and elucidate the potential mechanisms underlying the varying anti-inflammatory activities exhibited by compounds 5a, 5, and 6.

Secofumitremorgins C and D, a pair of atropisomers from saltern-derived fungus Aspergillus fumigatus GXIMD00544.

A pair of atropisomers secofumitremorgins C (1a) and D (1b), together with fifteen known alkaloids (2-16), were isolated from a saltern-derived fungus Aspergillus fumigatus GXIMD00544. The structures of atropisomers 1a and 1b were elucidated by the detailed spectroscopic data, chemical reaction and quantum chemical calculations. Compounds 1 and 8 displayed antifungal spore germination effects against plant pathogenic fungus associated with sugarcane Fusarium sp. with inhibitory rates of 53% and 77% at the concentration of 100 µM, repectively. Atropisomers 1 also exhibited antifouling potential against Balanus amphitrite larval settlement with an inhibitory rate of 96% at the concentration of 100 µM.

Cytoplasm Hydrogelation-Mediated Cardiomyocyte Sponge Alleviated Coxsackievirus B3 Infection.

Viral myocarditis (VMC), commonly caused by coxsackievirus B3 (CVB3) infection, lacks specific treatments and leads to serious heart conditions. Current treatments, such as IFNα and ribavirin, show limited effectiveness. Herein, rather than inhibiting virus replication, this study introduces a novel cardiomyocyte sponge, intracellular gelated cardiomyocytes (GCs), to trap and neutralize CVB3 via a receptor-ligand interaction, such as CAR and CD55. By maintaining cellular morphology, GCs serve as sponges for CVB3, inhibiting infection. In vitro results revealed that GCs could inhibit CVB3 infection on HeLa cells. In vivo, GCs exhibited a strong immune escape ability and effectively inhibited CVB3-induced viral myocarditis with a high safety profile. The most significant implication of this study is to develop a universal antivirus infection strategy via intracellular gelation of the host cell, which can be employed not only for treating defined pathogenic viruses but also for a rapid response to infection outbreaks caused by mutable and unknown viruses.

Incorporating seasonality, predictability, and modularity into the optimization of biodiversity conservation for ecological networks.

Improving the connectivity of ecological networks (ENs) is a proven strategy for biological conservation. However, without a clear understanding of animal movement, research on ENs may not provide a sufficient reference for maintaining biodiversity. To address this gap, we embraced central concepts of movement ecology and conducted a study in the Qilian Mountains. The predictability and seasonality of environmental conditions were combined to identify ecological sources with rich temporal niches and improve the informed preference character of resistance surface. Then, we constructed ENs with six dispersal thresholds. Further, integrating modularity and circuit theory, we pinpointed priority areas for restoration within the ENs. Our findings indicated that the eastern part of the Qilian Mountains showed higher biodiversity suitability, with terrain being the primary factor limiting dispersal. Additionally, comparative analyses demonstrate that the new method for measuring biodiversity from the perspective of temporal niche is reliable and better aligns with the needs of biodiversity conservation. In light of emerging challenges within the study area, where apex predators seriously suppress the populations of some smaller predators, we propose a novel conservation idea that emphasizes the strategic retention and removal of barriers to maintain biological balance. This study enriches methodologies for biodiversity measurement, provides forward-looking conservation strategies, and offers practical contributions toward mitigating biodiversity loss.

Myricetin Acts as an Inhibitor of Type II NADH Dehydrogenase from Staphylococcus aureus.

BACKGROUND: Staphylococcus aureus is a common pathogenic microorganism in humans and animals. Type II NADH oxidoreductase (NDH-2) is the only NADH:quinone oxidoreductase present in this organism and represents a promising target for the development of anti-staphylococcal drugs. Recently, myricetin, a natural flavonoid from vegetables and fruits, was found to be a potential inhibitor of NDH-2 of S. aureus. The objective of this study was to evaluate the inhibitory properties of myricetin against NDH-2 and its impact on the growth and expression of virulence factors in S. aureus. RESULTS: A screening method was established to identify effective inhibitors of NDH-2, based on heterologously expressed S. aureus NDH-2. Myricetin was found to be an effective inhibitor of NDH-2 with a half maximal inhibitory concentration (IC50) of 2 µM. In silico predictions and enzyme inhibition kinetics further characterized myricetin as a competitive inhibitor of NDH-2 with respect to the substrate menadione (MK). The minimum inhibitory concentrations (MICs) of myricetin against S. aureus strains ranged from 64 to 128 µg/mL. Time-kill assays showed that myricetin was a bactericidal agent against S. aureus. In line with being a competitive inhibitor of the NDH-2 substrate MK, the anti-staphylococcal activity of myricetin was antagonized by MK-4. In addition, myricetin was found to inhibit the gene expression of enterotoxin SeA and reduce the hemolytic activity induced by S. aureus culture on rabbit erythrocytes in a dose-dependent manner. CONCLUSIONS: Myricetin was newly discovered to be a competitive inhibitor of S. aureus NDH-2 in relation to the substrate MK. This discovery offers a fresh perspective on the anti-staphylococcal activity of myricetin.

Hyperbaric oxygen therapy promotes the browning of white fat and contributes to the healing of diabetic wounds.

Non-healing wounds are one of the chronic complications of diabetes and have remained a worldwide challenge as one of the major health problems. Hyperbaric oxygen (HBO) therapy is proven to be very successful for diabetic wound treatment, for which the molecular basis is not understood. Adipocytes regulate multiple aspects of repair and may be therapeutic for inflammatory diseases and defective wound healing associated with aging and diabetes. Endothelial cell-derived extracellular vesicles could promote wound healing in diabetes. To study the mechanism by which HBO promotes wound healing in diabetes, we investigated the effect of HBO on fat cells in diabetic mice. A diabetic wound mouse model was established and treated with HBO. Haematoxylin and eosin (H&E) staining and immunofluorescence were used for the analysis of wound healing. To further explore the mechanism, we performed whole-genome sequencing on extracellular vesicles (EVs). Furthermore, we conducted in vitro experiments. Specifically, exosomes were collected from human umbilical vein endothelial cell (HUVEC) cells after HBO treatment, and then these exosomes were co-incubated with adipose tissue. The wound healing rate in diabetic mice treated with HBO was significantly higher. HBO therapy promotes the proliferation of adipose precursor cells. HUVEC-derived exosomes treated with HBO significantly promoted fat cell browning. These data clarify that HBO therapy may promote vascular endothelial cell proliferation and migration, and promote browning of fat cells through vascular endothelial cells derived exosomes, thereby promoting diabetic wound healing. This provides new ideas for the application of HBO therapy in the treatment of diabetic trauma.

Triple reassortment increases compatibility among viral ribonucleoprotein genes of contemporary avian and human influenza A viruses.

Compatibility among the influenza A virus (IAV) ribonucleoprotein (RNP) genes affects viral replication efficiency and can limit the emergence of novel reassortants, including those with potential pandemic risks. In this study, we determined the polymerase activities of 2,451 RNP reassortants among three seasonal and eight enzootic IAVs by using a minigenome assay. Results showed that the 2009 H1N1 RNP are more compatible with the tested enzootic RNP than seasonal H3N2 RNP and that triple reassortment increased such compatibility. The RNP reassortants among 2009 H1N1, canine H3N8, and avian H4N6 IAVs had the highest polymerase activities. Residues in the RNA binding motifs and the contact regions among RNP proteins affected polymerase activities. Our data indicates that compatibility among seasonal and enzootic RNPs are selective, and enzoosis of multiple strains in the animal-human interface can facilitate emergence of an RNP with increased replication efficiency in mammals, including humans.

Successional adaptive strategies revealed by correlating arbuscular mycorrhizal fungal abundance with host plant gene expression.

The shifts in adaptive strategies revealed by ecological succession and the mechanisms that facilitate these shifts are fundamental to ecology. These adaptive strategies could be particularly important in communities of arbuscular mycorrhizal fungi (AMF) mutualistic with sorghum, where strong AMF succession replaces initially ruderal species with competitive ones and where the strongest plant response to drought is to manage these AMF. Although most studies of agriculturally important fungi focus on parasites, the mutualistic symbionts, AMF, constitute a research system of human-associated fungi whose relative simplicity and synchrony are conducive to experimental ecology. First, we hypothesize that, when irrigation is stopped to mimic drought, competitive AMF species should be replaced by AMF species tolerant to drought stress. We then, for the first time, correlate AMF abundance and host plant transcription to test two novel hypotheses about the mechanisms behind the shift from ruderal to competitive AMF. Surprisingly, despite imposing drought stress, we found no stress-tolerant AMF, probably due to our agricultural system having been irrigated for nearly six decades. Remarkably, we found strong and differential correlation between the successional shift from ruderal to competitive AMF and sorghum genes whose products (i) produce and release strigolactone signals, (ii) perceive mycorrhizal-lipochitinoligosaccharide (Myc-LCO) signals, (iii) provide plant lipid and sugar to AMF, and (iv) import minerals and water provided by AMF. These novel insights frame new hypotheses about AMF adaptive evolution and suggest a rationale for selecting AMF to reduce inputs and maximize yields in commercial agriculture.

Domain and range of the CIECAM16 forward transformation.

The domain and range of the CIECAM16 forward transformation was numerically determined and visualized for CIE standard illuminants, using a linear programming approach that provides the gamuts and colour solids for optimum colours. The effect of the surround, adapting luminance, and luminance of the background on the range of the CIECAM16 forward transformation were individually analyzed, showing that their ranges increased when the surround changed from dark to dim or average, the adapting luminance increased, or the luminance of the background decreased. The proposed methodology for the determination and visualization of the domain and range of the CIECAM16 forward transformation can be used for any illuminant, as well as for CIECAM02, CAM16, CAM02-UCS and CAM16-UCS. The findings of this paper not only solve the long-term unresolved domain and range problems of the CIE colour appearance models, but also find applications in cross-media colour reproduction. Furthermore, it was also found that some non-CIE colours are inside the International Color Consortium Profile Connection Space (ICC PCS), and some CIE colours are not included in that space.

TRPC6 promotes daunorubicin-induced mitochondrial fission and cell death in rat cardiomyocytes with the involvement of ERK1/2-DRP1 activation.

Daunorubicin (DNR-) induced cardiotoxicity seriously restricts its clinical application. Transient receptor potential cation channel subfamily C member 6 (TRPC6) is involved in multiple cardiovascular physiological and pathophysiological processes. However, the role of TRPC6 anthracycline-induced cardiotoxicity (AIC) remains unclear. Mitochondrial fragmentation greatly promotes AIC. TRPC6-mediated ERK1/2 activation has been shown to favor mitochondrial fission in dentate granule cells. The aim of the present study was to elucidate the effects of TRPC6 on daunorubicin- induced cardiotoxicity and identify the mechanisms associated with mitochondrial dynamics. The sparkling results showed that TRPC6 was upregulated in models in vitro and in vivo. TRPC6 knockdown protected cardiomyocytes from DNR-induced cell apoptosis and death. DNR largely facilitated mitochondrial fission, boosted mitochondrial membrane potential collapse and damaged debilitated mitochondrial respiratory function in H9c2 cells，these effects were accompanied by TRPC6 upregulation. siTRPC6 effectively inhibited these mitochondrial adverse aspects showing a positive unexposed effect on mitochondrial morphology and function. Concomitantly, ERK1/2-DRP1 which is related to mitochondrial fission was significantly activated with amplified phosphorylated forms in DNR-treated H9c2 cells. siTRPC6 effectively suppressed ERK1/2-DPR1 over activation, hinting at a potential correlation between TRPC6 and ERK1/2-DRP1 by which mitochondrial dynamics are possibly modulated in AIC. TRPC6 knockdown also raised the Bcl-2/Bax ratio, which may help to block mitochondrial fragmentation-related functional impairment and apoptotic signaling. These findings suggested an essential role of TRPC6 in AIC by intensifying mitochondrial fission and cell death via ERK1/2-DPR1, which could be a potential therapeutic target for AIC.

Peptide aptamer-based time-resolved fluoroimmunoassay for CHIKV diagnosis.

BACKGROUND: Chikungunya virus (CHIKV) and Dengue virus (DENV) have similar clinical symptoms, which often induce misdiagnoses. Therefore, an antigen detection diagnostic system that can clearly identify these two viruses is desirable. METHODS: In this study, we developed a novel peptide with high affinity and specificity to CHIKV, and further constructed peptide aptamer-based TRFIA assay to efficiently detect CHIKV. Peptide aptamer B2 (ITPQSSTTEAEL) and B3 (DTQGSNWI) were obtained through computer-aided design and selected as CHIKV-specific peptide aptamers based on their high binding affinity, strong hydrogen bonding, and RMSD of molecular docking. Then, a sandwich-Time-Resolved Fluoroimmunoassay (TRFIA) was successfully constructed for the detection of the interaction between peptide aptamers and viruses. RESULTS: When using B2 as the detection element, highly specific detection of CHIKV E2 was achieved with detection limits of 8.5 ng/ml in PBS solution. Variation coefficient between inter-assay showed the disturbances received from the detection of clinical fluid specimens (including serum and urine), were also within acceptable limits. The detection limits for 10-fold dilution serum and urine were 57.8 ng/mL and 147.3 ng/mL, respectively. The fluorescent signal intensity exhibited a good linear correlation with E2 protein concentration in the range of 0-1000 ng/mL, indicating the potential for quantitative detection of E2 protein. CONCLUSIONS: These results demonstrate that the construction of peptide aptamers with high affinity and specificity provides an excellent method for rapid diagnostic element screening, and the developed peptide aptamer B2 contributed to better detection of CHIKV viral particles compared to traditional antibodies.

Higher Variability in Fungi Compared to Bacteria in the Foraging Honey Bee Gut.

Along with bacteria, fungi can represent a significant component of animal- and plant-associated microbial communities. However, we have only begun to describe these fungi, much less examine their effects on most animals and plants. Bacteria associated with the honey bee, Apis mellifera, have been well characterized across different regions of the gut. The mid- and hindgut of foraging bees house a deterministic set of core species that affect host health, whereas the crop, or the honey stomach, harbors a more diverse set of bacteria that is highly variable in composition among individual bees. Whether this contrast between the two regions of the gut also applies to fungi remains unclear despite their potential influence on host health. In honey bees caught foraging at four sites across the San Francisco Peninsula of California, we found that fungi were less distinct in species composition between the crop and the mid- and hindgut than bacteria. Unlike bacteria, fungi varied substantially in species composition throughout the honey bee gut, and much of this variation could be predicted by the location where we collected the bees. These observations suggest that fungi may be transient passengers and unimportant as gut symbionts. However, our findings also indicate that honey bees could be vectors of infectious plant diseases as many of the fungi we found in the honey bee gut are recognized as plant pathogens.