Flux regulation through glycolysis and respiration is balanced by inositol pyrophosphates in yeast.

Although many prokaryotes have glycolysis alternatives, it's considered as the only energy-generating glucose catabolic pathway in eukaryotes. Here, we managed to create a hybrid-glycolysis yeast. Subsequently, we identified an inositol pyrophosphatase encoded by OCA5 that could regulate glycolysis and respiration by adjusting 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-InsP7) levels. 5-InsP7 levels could regulate the expression of genes involved in glycolysis and respiration, representing a global mechanism that could sense ATP levels and regulate central carbon metabolism. The hybrid-glycolysis yeast did not produce ethanol during growth under excess glucose and could produce 2.68 g/L free fatty acids, which is the highest reported production in shake flask of Saccharomyces cerevisiae. This study demonstrated the significance of hybrid-glycolysis yeast and determined Oca5 as an inositol pyrophosphatase controlling the balance between glycolysis and respiration, which may shed light on the role of inositol pyrophosphates in regulating eukaryotic metabolism.

The evolution and diversification of oakleaf butterflies.

Oakleaf butterflies in the genus Kallima have a polymorphic wing phenotype, enabling these insects to masquerade as dead leaves. This iconic example of protective resemblance provides an interesting evolutionary paradigm that can be employed to study biodiversity. We integrated multi-omic data analyses and functional validation to infer the evolutionary history of Kallima species and investigate the genetic basis of their variable leaf wing patterns. We find that Kallima butterflies diversified in the eastern Himalayas and dispersed to East and Southeast Asia. Moreover, we find that leaf wing polymorphism is controlled by the wing patterning gene cortex, which has been maintained in Kallima by long-term balancing selection. Our results provide macroevolutionary and microevolutionary insights into a model species originating from a mountain ecosystem.

Reactivation of Dormant Relay Pathways in Injured Spinal Cord by KCC2 Manipulations.

Many human spinal cord injuries are anatomically incomplete but exhibit complete paralysis. It is unknown why spared axons fail to mediate functional recovery in these cases. To investigate this, we undertook a small-molecule screen in mice with staggered bilateral hemisections in which the lumbar spinal cord is deprived of all direct brain-derived innervation, but dormant relay circuits remain. We discovered that a KCC2 agonist restored stepping ability, which could be mimicked by selective expression of KCC2, or hyperpolarizing DREADDs, in the inhibitory interneurons between and around the staggered spinal lesions. Mechanistically, these treatments transformed this injury-induced dysfunctional spinal circuit to a functional state, facilitating the relay of brain-derived commands toward the lumbar spinal cord. Thus, our results identify spinal inhibitory interneurons as a roadblock limiting the integration of descending inputs into relay circuits after injury and suggest KCC2 agonists as promising treatments for promoting functional recovery after spinal cord injury.

Deconstruction of Corticospinal Circuits for Goal-Directed Motor Skills.

Corticospinal neurons (CSNs) represent the direct cortical outputs to the spinal cord and play important roles in motor control across different species. However, their organizational principle remains unclear. By using a retrograde labeling system, we defined the requirement of CSNs in the execution of a skilled forelimb food-pellet retrieval task in mice. In vivo imaging of CSN activity during performance revealed the sequential activation of topographically ordered functional ensembles with moderate local mixing. Region-specific manipulations indicate that CSNs from caudal or rostral forelimb area control reaching or grasping, respectively, and both are required in the transitional pronation step. These region-specific CSNs terminate in different spinal levels and locations, therefore preferentially connecting with the premotor neurons of muscles engaged in different steps of the task. Together, our findings suggest that spatially defined groups of CSNs encode different movement modules, providing a logic for parallel-ordered corticospinal circuits to orchestrate multistep motor skills.

A transcriptomic taxonomy of mouse brain-wide spinal projecting neurons.

The brain controls nearly all bodily functions via spinal projecting neurons (SPNs) that carry command signals from the brain to the spinal cord. However, a comprehensive molecular characterization of brain-wide SPNs is still lacking. Here we transcriptionally profiled a total of 65,002 SPNs, identified 76 region-specific SPN types, and mapped these types into a companion atlas of the whole mouse brain1. This taxonomy reveals a three-component organization of SPNs: (1) molecularly homogeneous excitatory SPNs from the cortex, red nucleus and cerebellum with somatotopic spinal terminations suitable for point-to-point communication; (2) heterogeneous populations in the reticular formation with broad spinal termination patterns, suitable for relaying commands related to the activities of the entire spinal cord; and (3) modulatory neurons expressing slow-acting neurotransmitters and/or neuropeptides in the hypothalamus, midbrain and reticular formation for 'gain setting' of brain-spinal signals. In addition, this atlas revealed a LIM homeobox transcription factor code that parcellates the reticulospinal neurons into five molecularly distinct and spatially segregated populations. Finally, we found transcriptional signatures of a subset of SPNs with large soma size and correlated these with fast-firing electrophysiological properties. Together, this study establishes a comprehensive taxonomy of brain-wide SPNs and provides insight into the functional organization of SPNs in mediating brain control of bodily functions.

Measuring the knot of non-Hermitian degeneracies and non-commuting braids.

Any system of coupled oscillators may be characterized by its spectrum of resonance frequencies (or eigenfrequencies), which can be tuned by varying the system's parameters. The relationship between control parameters and the eigenfrequency spectrum is central to a range of applications1-3. However, fundamental aspects of this relationship remain poorly understood. For example, if the controls are varied along a path that returns to its starting point (that is, around a 'loop'), the system's spectrum must return to itself. In systems that are Hermitian (that is, lossless and reciprocal), this process is trivial and each resonance frequency returns to its original value. However, in non-Hermitian systems, where the eigenfrequencies are complex, the spectrum may return to itself in a topologically non-trivial manner, a phenomenon known as spectral flow. The spectral flow is determined by how the control loop encircles degeneracies, and this relationship is well understood for [Formula: see text] (where [Formula: see text] is the number of oscillators in the system)4,5. Here we extend this description to arbitrary [Formula: see text]. We show that control loops generically produce braids of eigenfrequencies, and for [Formula: see text] these braids form a non-Abelian group that reflects the non-trivial geometry of the space of degeneracies. We demonstrate these features experimentally for [Formula: see text] using a cavity optomechanical system.

A general approach for inferring the ancestry of recent ancestors of an admixed individual.

The genome of an individual from an admixed population consists of segments originated from different ancestral populations. Most existing ancestry inference approaches focus on calling these segments for the extant individual. In this paper, we present a general ancestry inference approach for inferring recent ancestors from an extant genome. Given the genome of an individual from a recently admixed population, our method can estimate the proportions of the genomes of the recent ancestors of this individual that originated from some ancestral populations. The key step of our method is the inference of ancestors (called founders) right after the formation of an admixed population. The inferred founders can then be used to infer the ancestry of recent ancestors of an extant individual. Our method is implemented in a computer program called PedMix2. To the best of our knowledge, there is no existing method that can practically infer ancestors beyond grandparents from an extant individual's genome. Results on both simulated and real data show that PedMix2 performs well in ancestry inference.

Themis: advancing precision oncology through comprehensive molecular subtyping and optimization.

Recent advances in tumor molecular subtyping have revolutionized precision oncology, offering novel avenues for patient-specific treatment strategies. However, a comprehensive and independent comparison of these subtyping methodologies remains unexplored. This study introduces 'Themis' (Tumor HEterogeneity analysis on Molecular subtypIng System), an evaluation platform that encapsulates a few representative tumor molecular subtyping methods, including Stemness, Anoikis, Metabolism, and pathway-based classifications, utilizing 38 test datasets curated from The Cancer Genome Atlas (TCGA) and significant studies. Our self-designed quantitative analysis uncovers the relative strengths, limitations, and applicability of each method in different clinical contexts. Crucially, Themis serves as a vital tool in identifying the most appropriate subtyping methods for specific clinical scenarios. It also guides fine-tuning existing subtyping methods to achieve more accurate phenotype-associated results. To demonstrate the practical utility, we apply Themis to a breast cancer dataset, showcasing its efficacy in selecting the most suitable subtyping methods for personalized medicine in various clinical scenarios. This study bridges a crucial gap in cancer research and lays a foundation for future advancements in individualized cancer therapy and patient management.

Chemically Modified Platforms for Better RNA Therapeutics.

RNA-based therapies have catalyzed a revolutionary transformation in the biomedical landscape, offering unprecedented potential in disease prevention and treatment. However, despite their remarkable achievements, these therapies encounter substantial challenges including low stability, susceptibility to degradation by nucleases, and a prominent negative charge, thereby hindering further development. Chemically modified platforms have emerged as a strategic innovation, focusing on precise alterations either on the RNA moieties or their associated delivery vectors. This comprehensive review delves into these platforms, underscoring their significance in augmenting the performance and translational prospects of RNA-based therapeutics. It encompasses an in-depth analysis of various chemically modified delivery platforms that have been instrumental in propelling RNA therapeutics toward clinical utility. Moreover, the review scrutinizes the rationale behind diverse chemical modification techniques aiming at optimizing the therapeutic efficacy of RNA molecules, thereby facilitating robust disease management. Recent empirical studies corroborating the efficacy enhancement of RNA therapeutics through chemical modifications are highlighted. Conclusively, we offer profound insights into the transformative impact of chemical modifications on RNA drugs and delineates prospective trajectories for their future development and clinical integration.

Reactivating Hippo by drug compounds to suppress gastric cancer and enhance chemotherapy sensitivity.

The Hippo signaling pathway plays an essential role in organ size control and tumorigenesis. Loss of Hippo signal and hyper-activation of the downstream oncogenic YAP signaling are commonly observed in various types of cancers. We previously identified STRN3-containing PP2A phosphatase as a negative regulator of MST1/2 kinases (i.e., Hippo) in gastric cancer (GC), opening the possibility of selectively targeting the PP2Aa-STRN3-MST1/2 axis to recover Hippo signaling against cancer. Here, we further discovered 1) disulfiram (DSF), an FDA-approved drug, which can similarly block the binding of STRN3 to PP2A core enzyme and 2) CX-6258 (CX), a chemical inhibitor, that can disrupt the interaction between STRN3 and MST1/2, both allowing reactivation of Hippo activity to inhibit GC. More importantly, we found these two compounds, via an MST1/2 kinase-dependent manner, inhibit DNA repair to sensitize GC towards chemotherapy. In addition, we identified thiram, a structural analog of DSF, can function similarly to inhibit cancer cell proliferation or enhance chemotherapy sensitivity. Interestingly, inclusion of copper ion enhanced such effects of DSF and thiram on GC treatment. Overall, this work demonstrated that pharmacological targeting of the PP2Aa-STRN3-MST1/2 axis by drug compounds can potently recover Hippo signal for tumor treatment.

Comprehensive profiling of lipid metabolic reprogramming expands precision medicine for HCC.

BACKGROUND AND AIMS: Liver HCC is the second leading cause of cancer-related deaths worldwide. The heterogeneity of this malignancy is driven by a wide range of genetic alterations, leading to a lack of effective therapeutic options. In this study, we conducted a systematic multi-omics characterization of HCC to uncover its metabolic reprogramming signature. APPROACH AND RESULTS: Through a comprehensive analysis incorporating transcriptomic, metabolomic, and lipidomic investigations, we identified significant changes in metabolic pathways related to glucose flux, lipid oxidation and degradation, and de novo lipogenesis in HCC. The lipidomic analysis revealed abnormal alterations in glycerol-lipids, phosphatidylcholine, and sphingolipid derivatives. Machine-learning techniques identified a panel of genes associated with lipid metabolism as common biomarkers for HCC across different etiologies. Our findings suggest that targeting phosphatidylcholine with saturated fatty acids and long-chain sphingolipid biosynthesis pathways, particularly by inhibiting lysophosphatidylcholine acyltransferase 1 ( LPCAT1 ) and ceramide synthase 5 ( CERS5 ) as potential therapeutic strategies for HCC in vivo and in vitro. Notably, our data revealed an oncogenic role of CERS5 in promoting tumor progression through lipophagy. CONCLUSIONS: In conclusion, our study elucidates the metabolic reprogramming nature of lipid metabolism in HCC, identifies prognostic markers and therapeutic targets, and highlights potential metabolism-related targets for therapeutic intervention in HCC.

High geomagnetic field intensity recorded by anorthosite xenoliths requires a strongly powered late Mesoproterozoic geodynamo.

Obtaining estimates of Earth's magnetic field strength in deep time is complicated by nonideal rock magnetic behavior in many igneous rocks. In this study, we target anorthosite xenoliths that cooled and acquired their magnetization within ca. 1,092 Ma shallowly emplaced diabase intrusions of the North American Midcontinent Rift. In contrast to the diabase which fails to provide reliable paleointensity estimates, the anorthosite xenoliths are unusually high-fidelity recorders yielding high-quality, single-slope paleointensity results that are consistent at specimen and site levels. An average value of ∼83 ZAm2 for the virtual dipole moment from the anorthosite xenoliths, with the highest site-level values up to ∼129 ZAm2, is higher than that of the dipole component of Earth's magnetic field today and rivals the highest values in the paleointensity database. Such high intensities recorded by the anorthosite xenoliths require the existence of a strongly powered geodynamo at the time. Together with previous paleointensity data from other Midcontinent Rift rocks, these results indicate that a dynamo with strong power sources persisted for more than 14 My ca. 1.1 Ga. These data are inconsistent with there being a progressive monotonic decay of Earth's dynamo strength through the Proterozoic Eon and could challenge the hypothesis of a young inner core. The multiple observed paleointensity transitions from weak to strong in the Paleozoic and the Proterozoic present challenges in identifying the onset of inner core nucleation based on paleointensity records alone.

Exceptional Rate Performances of Li-Rich Mn-Based Cathodes Enabled by Boron-Based Additives-Driven Self-Optimized Interface.

Li-rich Mn-based cathode material (LRM), as a promising cathode for high energy density lithium batteries, suffers from severe side reactions in conventional lithium hexafluorophosphate (LiPF6)-based carbonate electrolytes, leading to unstable interfaces and poor rate performances. Herein, a boron-based additives-driven self-optimized interface strategy is presented to dissolve low ionic conductivity LiF nanoparticles at the outer cathode electrolyte interface, leading to the optimized interfacial components, as well as the enhanced Li ion migration rate in electrolytes. Being attributed to these superiorities, the LRM||Li battery delivers a high-capacity retention of 92.19% at 1C after 200 cycles and a low voltage decay of 1.08 mV/cycle. This work provides a new perspective on the rational selection of functional additives with an interfacial self-optimized characteristic to achieve a long lifespan LRM with exceptional rate performances.

The tetraspanin transmembrane protein CD53 mediates dyslipidemia and integrates inflammatory and metabolic signaling in hepatocytes.

Tetraspanins are transmembrane signaling and proinflammatory proteins. Prior work demonstrates that the tetraspanin, CD53/TSPAN25/MOX44, mediates B-cell development and lymphocyte migration to lymph nodes and is implicated in various inflammatory diseases. However, CD53 is also expressed in highly metabolic tissues, including adipose and liver; yet its function outside the lymphoid compartment is not defined. Here, we show that CD53 demarcates the nutritional and inflammatory status of hepatocytes. High-fat exposure and inflammatory stimuli induced CD53 in vivo in liver and isolated primary hepatocytes. In contrast, restricting hepatocyte glucose flux through hepatocyte glucose transporter 8 deletion or through trehalose treatment blocked CD53 induction in fat- and fructose-exposed contexts. Furthermore, germline CD53 deletion in vivo blocked Western diet-induced dyslipidemia and hepatic inflammatory transcriptomic activation. Surprisingly, metabolic protection in CD53 KO mice was more pronounced in the presence of an inciting inflammatory event. CD53 deletion attenuated tumor necrosis factor alpha-induced and fatty acid + lipopolysaccharide-induced cytokine gene expression and hepatocyte triglyceride accumulation in isolated murine hepatocytes. In vivo, CD53 deletion in nonalcoholic steatohepatitis diet-fed mice blocked peripheral adipose accumulation and adipose inflammation, insulin tolerance, and liver lipid accumulation. We then defined a stabilized and trehalase-resistant trehalose polymer that blocks hepatocyte CD53 expression in basal and over-fed contexts. The data suggest that CD53 integrates inflammatory and metabolic signals in response to hepatocyte nutritional status and that CD53 blockade may provide a means by which to attenuate pathophysiology in diseases that integrate overnutrition and inflammation, such as nonalcoholic steatohepatitis and type 2 diabetes.

Proteomics Identifies LUC7L3 as a Prognostic Biomarker for Hepatocellular Carcinoma.

Alternative splicing has been shown to participate in tumor progression, including hepatocellular carcinoma. The poor prognosis of patients with HCC calls for molecular classification and biomarker identification to facilitate precision medicine. We performed ssGSEA analysis to quantify the pathway activity of RNA splicing in three HCC cohorts. Kaplan-Meier and Cox methods were used for survival analysis. GO and GSEA were performed to analyze pathway enrichment. We confirmed that RNA splicing is significantly correlated with prognosis, and identified an alternative splicing-associated protein LUC7L3 as a potential HCC prognostic biomarker. Further bioinformatics analysis revealed that high LUC7L3 expression indicated a more progressive HCC subtype and worse clinical features. Cell proliferation-related pathways were enriched in HCC patients with high LUC7L3 expression. Consistently, we proved that LUC7L3 knockdown could significantly inhibit cell proliferation and suppress the activation of associated signaling pathways in vitro. In this research, the relevance between RNA splicing and HCC patient prognosis was outlined. Our newly identified biomarker LUC7L3 could provide stratification for patient survival and recurrence risk, facilitating early medical intervention before recurrence or disease progression.

The influence of a modified p53 C-terminal peptide by using a tumor-targeting sequence on cellular apoptosis and tumor treatment.

The restoration of the function of p53 in tumors is a therapeutic strategy for the highly frequent mutation of the TP53 tumor suppressor gene. P460 is a wild-type peptide derived from the p53 C-terminus and has been proven to be capable of restoring the tumor suppressor function of p53. The poor accumulation of drugs in tumors is a serious hindrance to tumor treatment. For enhancing the activity of P460, the tumor-targeting sequence Arg-Gly-Asp-Arg (RGDR, C-end rule peptide) was introduced into the C-terminus of P460 to generate the new peptide P462. P462 presented better activity than P460 in inhibiting the proliferation of cancer cells and increasing the number of tumor cells undergoing apoptosis. Cell adhesion analysis and tumor imaging results revealed that P462 showed more specific and extensive binding with tumor cells and greater accumulation in tumors than the wild-type peptide. Importantly, treatment with P462 was more efficacious than that with P460 in vivo and was associated with considerably improved tumor-homing activity. This study highlights the importance of the roles of the tumor-homing sequence RGDR in the enhancement in cell attachment and tumor accumulation. The results of this work indicate that P462 could be a novel drug candidate for tumor treatment.

High Safety Electrolyte Design for Enabling High Energy-Density System of LiNi0.8Co0.1Mn0.1O2//Phosphorus by Simultaneously Adjusting Dual Electrode/Electrolyte Interfaces.

The demand for state-of-the-art high-energy-density lithium-ion batteries is increasing. However, the low specific capacity of electrode materials in conventional full-cell systems cannot meet the requirements. Ni-rich layered oxide cathodes such as Li(Ni0.8Co0.1Mn0.1)O2 (NCM811) have a high theoretical specific capacity of 200 mAh g-1, but it is always accompanied by side reactions on the electrode/electrolyte interface. Phosphorus anode possesses a high theoretical specific capacity of 2596 mAh g-1, but it has a huge volume expansion (≈300%). Herein, a highly compatible and secure electrolyte is reported via introducing an additive with a narrow electrochemical window, Lithium difluoro(oxalato)borate (LiDFOB), into 1 m LiPF6 EC/DMC with tris (2,2,2-trifluoroethyl) phosphate (TFEP) as a cosolvent. LiDFOB participates in the formation of organic/inorganic hybrid electrode/electrolyte interface layers at both the cathode and anode sides. The side reactions on the surface of the NCM811 cathode and the volume expansion of the phosphorus anode are effectively alleviated. The NCM811//RP full cell in this electrolyte shows high capacity retention of 82% after 150 cycles at a 0.5C rate. Meanwhile, the electrolyte shows non-flammability. This work highlights the importance of manipulating the electrode/electrolyte interface layers for the design of lithium-ion batteries with high energy density.

Coupling MoSe2 with Non-Stoichiometry Ni0.85 Se in Carbon Hollow Nanoflowers for Efficient Electrocatalytic Synergistic Effect on Li-O2 Batteries.

Li-O2 batteries could deliver ultra-high theoretical energy density compared to current Li-ion batteries counterpart. The slow cathode reaction kinetics in Li-O2 batteries, however, limits their electrocatalytic performance. To this end, MoSe2 and Ni0.85 Se nanoflakes were decorated in carbon hollow nanoflowers, which were served as the cathode catalysts for Li-O2 batteries. The hexagonal Ni0.85 Se and MoSe2 show good structural compatibility with the same space group, resulting in a stable heterogeneous structure. The synergistic interaction of the unsaturated atoms and the built-in electric fields on the heterogeneous structure exposes abundant catalytically active sites, accelerating ion and charge transport and imparting superior electrochemical activity, including high specific capacities and stable cycling performance. More importantly, the lattice distances of the Ni0.85 Se (101) plane and MoSe2 (100) plane at the heterogeneous interfaces are highly matched to that of Li2 O2 (100) plane, facilitating epitaxial growth of Li2 O2 , as well as the formation and decomposition of discharge products during the cycles. This strategy of employing nonstoichiometric compounds to build heterojunctions and improve Li-O2 battery performance is expected to be applied to other energy storage or conversion systems.

PAX6/CXCL14 regulatory axis promotes the repair of corneal injury by enhancing corneal epithelial cell proliferation.

BACKGROUND: Corneal injuries, often leading to severe vision loss or blindness, have traditionally been treated with the belief that limbal stem cells (LSCs) are essential for repair and homeostasis, while central corneal epithelial cells (CCECs) were thought incapable of such repair. However, our research reveals that CCECs can fully heal and maintain the homeostasis of injured corneas in rats, even without LSCs. We discovered that CXCL14, under PAX6's influence, significantly boosts the stemness, proliferation, and migration of CCECs, facilitating corneal wound healing and homeostasis. This finding introduces CXCL14 as a promising new drug target for corneal injury treatment. METHODS: To investigate the PAX6/CXCL14 regulatory axis's role in CCECs wound healing, we cultured human corneal epithelial cell lines with either increased or decreased expression of PAX6 and CXCL14 using adenovirus transfection in vitro. Techniques such as coimmunoprecipitation, chromatin immunoprecipitation, immunofluorescence staining, western blot, real-time PCR, cell colony formation, and cell cycle analysis were employed to validate the axis's function. In vivo, a rat corneal epithelial injury model was developed to further confirm the PAX6/CXCL14 axis's mechanism in repairing corneal damage and maintaining corneal homeostasis, as well as to assess the potential of CXCL14 protein as a therapeutic agent for corneal injuries. RESULTS: Our study reveals that CCECs naturally express high levels of CXCL14, which is significantly upregulated by PAX6 following corneal damage. We identified SDC1 as CXCL14's receptor, whose engagement activates the NF-κB pathway to stimulate corneal repair by enhancing the stemness, proliferative, and migratory capacities of CCECs. Moreover, our research underscores CXCL14's therapeutic promise for corneal injuries, showing that recombinant CXCL14 effectively accelerates corneal healing in rat models. CONCLUSION: CCECs play a critical and independent role in the repair of corneal injuries and the maintenance of corneal homeostasis, distinct from that of LSCs. The PAX6/CXCL14 regulatory axis is pivotal in this process. Additionally, our research demonstrates that the important function of CXCL14 in corneal repair endows it with the potential to be developed into a novel therapeutic agent for treating corneal injuries.