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Biology subjects

Yang, K.

Publications and source records attributed to Yang, K..

At least 73 records · Page 4Linked to original sources

Stable White Matter Structure in the First Three Years after Psychosis Onset

BackgroundWhite matter alterations observed using diffusion weighted imaging have become a hallmark of chronic schizophrenia, but it is unclear when these changes arise over the course of the disease. Nearly all studies thus far have been cross-sectional, so despite their large sample sizes, they cannot determine if changes accumulate as a degenerative process, or if patients with pre-existing white matter damage are predisposed to more chronic forms of schizophrenia. MethodsWe examined 160 scans comprising two years of annual follow-up data from n=42 controls and n=28 schizophrenia patients recruited in the first two years since their diagnosis, totalling two to three scans per subject. We additionally examined six-month follow-up data obtained from an ultra-high field (7 Tesla) scanner (n=68 scans; n=19 first-episode schizophrenia patients; n=15 controls) as a validation dataset. A longitudinal model was used to compare the trajectory of diffusion tenor parameters between patients and controls. Positive and negative symptom scores were correlated with diffusion parameters using ROI- and clustering-based approaches. ResultsWe failed to observe any longitudinal differences in any diffusion tensor imaging parameters between patients and controls in either dataset. We did, however, observe consistent associations between white matter alterations and negative symptoms in both datasets. ConclusionsWhite matter does not appear susceptible to schizophrenia-linked degeneration in the early stages of disease, but pre-existing pathology may be linked to disease severity.

neuroscience↗

Cyclin A/B RxL Macrocyclic Inhibitors to Treat Cancers with High E2F Activity

Cancer cell proliferation requires precise control of E2F1 activity; excess activity promotes apoptosis. Here, we developed cell-permeable and bioavailable macrocycles that selectively kill small cell lung cancer (SCLC) cells with inherent high E2F1 activity by blocking RxL-mediated interactions of cyclin A and cyclin B with select substrates. Genome-wide CRISPR/Cas9 knockout and random mutagenesis screens found that cyclin A/B RxL macrocyclic inhibitors (cyclin A/Bi) induced apoptosis paradoxically by cyclin B- and Cdk2-dependent spindle assembly checkpoint activation (SAC). Mechanistically, cyclin A/Bi hyperactivate E2F1 and cyclin B by blocking their RxL-interactions with cyclin A and Myt1, respectively, ultimately leading to SAC activation and mitotic cell death. Base editor screens identified cyclin B variants that confer cyclin A/Bi resistance including several variants that disrupted cyclin B:Cdk interactions. Unexpectedly but consistent with our base editor and knockout screens, cyclin A/Bi induced the formation of neo-morphic Cdk2-cyclin B complexes that promote SAC activation and apoptosis. Finally, orally-bioavailable cyclin A/Bi robustly inhibited tumor growth in chemotherapy-resistant patient-derived xenograft models of SCLC. This work uncovers gain-of-function mechanisms by which cyclin A/Bi induce apoptosis in cancers with high E2F activity, and suggests cyclin A/Bi as a therapeutic strategy for SCLC and other cancers driven by high E2F activity.

cancer biology↗

A Drug-Elicitable Alternative-Splicing Module (DreAM) for Tunable AAV Expression and Controlled Myocardial Regeneration

Adeno-associated virus (AAV) is a major vector for gene therapy. A technique to fine-tune the time and level of AAV expression is lacking, which greatly restricts indication choice, therapeutic efficacy and safety. To solve this problem, here we developed a drug-elicitable alternative-splicing module (DreAM) responsive to risdiplam, an FDA-approved alternative splicing modulator. Risdiplam activates DreAM-regulated AAV expression in a dose-dependent manner with an over 2000-fold inducible change depending on the inducer dosage and the organ of interests. With a temporally resolution of a couple of days, DreAM could repeatedly activate AAV expression, determined by the frequency and duration of risdiplam administration. As an example of DreAM-realized gene therapy, this technique was used to control AAV-based cardiac delivery of YAP5SA, a potent cardiomyocyte regeneration factor. DreAM transiently activated AAV-YAP5SA, establishing the dedifferentiation-proliferation-redifferentiation cycle in cardiomyocytes. Consequently, DreAM fulfilled the regenerative capacity of AAV-YAP5SA in myocardial infarction while circumventing toxicity associated with prolonged AAV-YAP5SA expression. Together, these data demonstrated a tremendous potential of DreAM to enhance the efficacy, safety and applicable scope of gene therapy.

bioengineering↗

Koina: Democratizing machine learning for proteomics research

Recent developments in machine-learning (ML) and deep-learning (DL) have immense potential for applications in proteomics, such as generating spectral libraries, improving peptide identification, and optimizing targeted acquisition modes. Although new ML/DL models for various applications and peptide properties are frequently published, the rate at which these models are adopted by the community is slow, which is mostly due to technical challenges. We believe that, for the community to make better use of state-of-the-art models, more attention should be spent on making models easy to use and accessible by the community. To facilitate this, we developed Koina, an open-source containerized, decentralized and online-accessible high-performance prediction service that enables ML/DL model usage in any pipeline. Using the widely used FragPipe computational platform as example, we show how Koina can be easily integrated with existing proteomics software tools and how these integrations improve data analysis.

bioinformatics↗

Pro-inflammatory macrophage activation does not require inhibition of mitochondrial respiration

Pro-inflammatory macrophage activation is a hallmark example of how mitochondria serve as signaling organelles. Upon classical macrophage activation, oxidative phosphorylation sharply decreases and mitochondria are repurposed to accumulate signals that amplify effector function. However, evidence is conflicting as to whether this collapse in respiration is essential or largely dispensable. Here we systematically examine this question and show that reduced oxidative phosphorylation is not required for pro-inflammatory macrophage activation. Only stimuli that engage both MyD88- and TRIF-linked pathways decrease mitochondrial respiration, and different pro-inflammatory stimuli have varying effects on other bioenergetic parameters. Additionally, pharmacologic and genetic models of electron transport chain inhibition show no direct link between respiration and pro-inflammatory activation. Studies in mouse and human macrophages also reveal accumulation of the signaling metabolites succinate and itaconate can occur independently of characteristic breaks in the TCA cycle. Finally, in vivo activation of peritoneal macrophages further demonstrates that a pro-inflammatory response can be elicited without reductions to oxidative phosphorylation. Taken together, the results suggest the conventional model of mitochondrial reprogramming upon macrophage activation is incomplete.

immunology↗

Extracellular vesicles-based point-of-care testing for the diagnosis and monitoring of Alzheimer's disease

Alzheimers disease (AD) is a debilitating condition that affects millions of people worldwide. One promising strategy for detecting and monitoring AD early on is using extracellular vesicles (EVs)-based point-of-care testing; however, diagnosing AD using EVs poses a challenge due to the low abundance of EV-biomarkers. Here, we present a fully integrated organic electrochemical transistor (OECT) that enables high accuracy, speed, and convenience in the detection of EVs from AD patients. We incorporated self-aligned acoustoelectric enhancement of EVs on a chip that rapidly propels, enriches, and specifically binds EVs to the OECT detection area. With our enhancement of pre-concentration, we increased the sensitivity to a limit of detection of 500 EV particles/L and reduced the required detection time to just two minutes. We also tested the sensor on an AD mouse model to monitor AD progression, examined mouse A{beta} EVs at different time courses, and compared them with intraneuronal A{beta} cumulation using MRI. This innovative technology has the potential to diagnose Alzheimers and other neurodegenerative diseases accurately and quickly, enabling monitoring of disease progression and treatment response.

bioengineering↗

ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration

Epigenetic mechanisms, including histone acetylation, are pivotal for learning and memory, with a role in neuronal function in Alzheimers disease and Related Dementia (ADRD). Acetyl-CoA synthetase 2 (ACSS2), an enzyme that generates acetyl-CoA, is central to histone acetylation and gene regulation, particularly in neurons, due to their unique metabolic demands and postmitotic state. ACSS2 can be recruited to the nucleus and chromatin, locally supplying acetyl-CoA to directly fuel histone acetyltransferase enzymes and key neuronal gene expression. This regulatory mechanism may be a promising target for therapeutic intervention in neurodegenerative diseases. Previously we showed that systemic ACSS2 deletion in mice, although largely normal in physiology, is greatly impaired in memory. Here we investigated whether increasing ACSS2 levels could protect neurons against disease and age-associated cognitive decline. Given the role of tau in ADRD, we used primary hippocampal neurons that mimic the sporadic development of tau pathology and the P301S transgenic mouse model for tau-induced memory decline. Our results show that ACSS2 upregulation mitigates tau-induced transcriptional alterations, enhances neuronal resilience against tau pathology, improves long-term potentiation, and ameliorates memory deficits. Expanding upon these findings, we reveal that increasing histone acetylation through ACSS2 upregulation improves age-associated memory decline. These findings indicate that increasing ACSS2 is highly effective in countering age- and tau-induced transcriptome changes, preserving elevated levels of synaptic genes, and safeguarding synaptic integrity. We thus highlight ACSS2 as a key player in the epigenetic regulation of cognitive aging and ADRD, providing a foundation for targeted therapeutics to enhance brain resilience and function. SummaryACSS2 upregulation protects neurons from disease and age-related decline by enhancing synaptic and longevity gene expression.

neuroscience↗

Mispacking of the F87 sidechain drives aggregation-promoting conformational fluctuations in the subunit interfaces of the transthyretin tetramer

Aberrant formation and deposition of human transthyretin (TTR) aggregates causes transthyretin amyloidosis. To initialize aggregation, transthyretin tetramers must first dissociate into monomers that partially unfold to promote entry into the aggregation pathway. The native TTR tetramer (T) is stabilized by docking of the F87 sidechain into an interfacial cavity enclosed by several hydrophobic residues including A120. We have previously shown that an alternative tetramer (T*) with mispacked F87 sidechains is more prone to dissociation and aggregation than the native T state. However, the molecular basis for the reduced stability in T* remains unclear. Here we report characterization of the A120L mutant, where steric hindrance is introduced into the F87 binding site. The X-ray structure of A120L shows that the F87 sidechain is displaced from its docking site across the subunit interface. In A120S, a naturally occurring pathogenic mutant that is less aggregation-prone than A120L, the F87 sidechain is correctly docked, as in the native TTR tetramer. Nevertheless, 19F-NMR aggregation assays show an elevated population of a monomeric aggregation intermediate in A120S relative to a control containing the native A120, due to accelerated tetramer dissociation and slowed monomer tetramerization. The mispacking of the F87 sidechain is associated with enhanced exchange dynamics for interfacial residues. At 298 K, the T* populations of various naturally occurring mutants fall between 4-7% ({Delta}G [~] 1.5- 1.9 kcal/mol), consistent with the free energy change expected for undocking and solvent exposure of one of the four F87 sidechains in the tetramer ({Delta}G [~] 1.6 kcal/mol). Our data provide a molecular-level picture of the likely universal F87 sidechain mispacking in tetrameric TTR that promotes interfacial conformational dynamics and increases aggregation propensity.

biophysics↗

p24-Tango1 interactions ensure ER-Golgi interface stability and efficient transport

The eukaryotic p24 family, consisting of -, {beta}-, {gamma}- and {delta}-p24 subfamilies, has long been known to be involved in regulating secretion. Despite increasing interest in these proteins, fundamental questions remain about their role. Here, we systematically investigated Drosophila p24 proteins. We discovered that members of all four p24 subfamilies are required for general secretion, and that their localizations between ER exit site (ERES) and Golgi are interdependent in an [->]{beta}{delta}[->]{gamma} sequence. We also found that localization of p24 proteins and ERES determinant Tango1 requires interaction through their respective GOLD and SH3 lumenal domains, with Tango1 loss sending p24 proteins to the plasma membrane and vice versa. Finally, we show that p24 loss expands the COPII zone at ERES and increases the number of ER-Golgi vesicles, supporting a restrictive role of p24 proteins on vesicle budding for efficient transport. Our results reveal Tango1-p24 interplay as central to the generation of a stable ER-Golgi interface. SummaryYang et al. systematically analyze in Drosophila the function of the four p24 protein subfamilies and discover that interaction with Tango1 is essential for their concentration between ER and Golgi and for efficiency of COPII-mediated general secretory transport.

cell biology↗

Nephrectomy and high-salt diet inducing pulmonary hypertension and kidney damage by increasing Ang II concentration in rats

BackgroundPulmonary hypertension (PH) is a common complication in patients with chronic kidney disease (CKD), affecting prognosis. However, the pathogenesis is not clear, and the lack of a stable animal model is a significant factor. MethodsIn this study, a rat model of chronic kidney disease with pulmonary hypertension (CKD-PH) was developed through 5/6 nephrectomy combined with a high-salt diet. The models hemodynamics and pathological changes in multiple organs were dynamically assessed. Lung tissues and serum were collected from the model rats to measure the expression of ACE2, the expression levels of vascular active components related to the renin-angiotensin-aldosterone system (RAAS), and changes in the serum metabolic profile of the model. ResultsAfter 14 weeks post-surgery, the CKD-PH rat model exhibited significant changes in hemodynamic parameters indicative of pulmonary arterial hypertension, along with alterations such as right ventricular hypertrophy. However, no evidence of pulmonary vascular remodeling was observed. An imbalance in the renin-angiotensin-aldosterone system was identified in the CKD-PH rat models. Downregulation of ACE2 expression was observed in pulmonary tissues. The serum metabolic profile of the CKD-PH rat models showed distinct differences compared to the sham surgery group. ConclusionsThe development of pulmonary arterial hypertension in CKD-PH rats may be primarily attributed to the disruption of the renin-angiotensin-aldosterone system (RAAS), coupled with a decrease in ACE2 expression in pulmonary vascular endothelial tissues and metabolic disturbances.

pathology↗

Genomic features of NF1-associated peripheral nerve sheath tumors: a cohort analysis from the Johns Hopkins NF1 biospecimen repository

Neurofibromatosis type 1 (NF1) is an inherited neurocutaneous condition that predisposes to the development of peripheral nerve sheath tumors (PNST) including cutaneous neurofibromas (CNF), plexiform neurofibromas (PNF), atypical neurofibromatous neoplasms with unknown biological potential (ANNUBP), and malignant peripheral nerve sheath tumors (MPNST). The successful advancement of therapeutic development for NF1-associated PNST necessitates the systematic acquisition and analysis of human tumor specimens and their corresponding model systems. RNA sequencing (RNAseq) and whole exome sequencing (WES) data were generated from 73 and 114 primary human tumor samples, respectively. These pre-processed data, standardized for immediate computational analysis, are accessible through the NF Data Portal, allowing immediate interrogation. This analysis combines new and previously released samples, offering a comprehensive view of the entire cohort sequenced. As a dedicated effort to systematically bank tumor samples from people with NF1, in collaboration with molecular geneticists and computational biologists to advance understanding of NF1 biology, the Johns Hopkins NF1 biospecimen repository offers access to samples and genomic data to promote advancement of NF1-related therapies.

bioinformatics↗

The Arabidopsis PPR protein EMB1006 interacts with both EMB1270 and CFM2 to facilitate plastid clpP1 intron2 splicing

Plastid intron splicing is an essential step for gene expression. Although many nucleus-encoded splicing factors have been identified for plastid intron splicing, how these proteins coordinately regulate intron splicing is unclear. Here we found that EMB1006, an Arabidopsis P-type PPR protein, is required for splicing several plastid introns including clpP1 intron 2 by analyzing the level of intron retention in its knockdown lines and RIP-qPCR (RNA immunoprecipitation and quantitative PCR) assay. In addition, RNA electrophoretic mobility shift assay (REMSA) showed that EMB1006 specifically binds to the sequence UUACCAAACGU close to the 3 end of clpP1 exon 2 in vitro. Furthermore, yeast two hybrid (Y2H), split luciferase complementation (Split-LUC) and semi-in vivo pull-down assays showed that EMB1006 interacts with both EMB1270 and CFM2, which also interact each other. Taken together, our data indicate that EMB1006 forms a complex with EMB1270 and CFM2 to facilitate clpP1 intron 2 splicing in chloroplasts.

plant biology↗

Integration of multi-source gene interaction networks and omics data with graph attention networks to identify novel disease genes

The pathogenesis of diseases is closely associated with genes, and the discovery of disease genes holds significant importance for understanding disease mechanisms and designing targeted therapeutics. However, biological validation of all genes for diseases is expensive and challenging. In this study, we propose DGP-AMIO, a computational method based on graph attention networks, to rank all unknown genes and identify potential novel disease genes by integrating multi-omics and gene interaction networks from multiple data sources. DGP-AMIO outperforms other methods significantly on 20 disease datasets, with an average AUROC and AUPR exceeding 0.9. The superior performance of DGP-AMIO is attributed to the integration of multiomics and gene interaction networks from multiple databases, as well as triGAT, a proposed GAT-based method that enables precise identification of disease genes in directed gene networks. Enrichment analysis conducted on the top 100 genes predicted by DGP-AMIO and literature research revealed that a majority of enriched GO terms, KEGG pathways and top genes were associated with diseases supported by relevant studies. We believe that our method can serve as an effective tool for identifying disease genes and guiding subsequent experimental validation efforts.

bioinformatics↗

Cross-modal Generation of Hit-like Molecules via Foundation Model Encoding of Gene Expression Signatures

Designing de novo molecules with specific biological activity is an essential task since it holds the potential to bypass the exploration of target genes, which is an initial step in the modern drug discovery paradigm. However, traditional methods mainly screen molecules by comparing the desired molecular effects within the documented experimental results. The data set limits this process, and it is hard to conduct direct cross-modal comparisons. Therefore, we propose a solution based on cross-modal generation called GexMolGen (Gene Expression-based Molecule Generator), which generates hit-like molecules using gene expression signatures alone. These signatures are calculated by inputting control and desired gene expression states. Our model GexMolGen adopts a "first-align-then-generate" strategy, aligning the gene expression signatures and molecules within a mapping space, ensuring a smooth cross-modal transition. The transformed molecular embeddings are then decoded into molecular graphs. In addition, we employ an advanced single-cell large language model for input flexibility and pre-train a scaffold-based molecular model to ensure that all generated molecules are 100% valid. Empirical results show that our model can produce molecules highly similar to known references, whether feeding in- or out-of-domain transcriptome data. Furthermore, it can also serve as a reliable tool for cross-modal screening.

bioinformatics↗

Sucrose taste receptors differ in larval and adult stages of a moth

Almost all herbivorous insects feed on plants and use sucrose as a feeding stimulant, but the molecular basis of their sucrose reception remains unclear. Helicoverpa armigera as a notorious crop pest worldwide mainly feeds on reproductive organs of many plant species in the larval stage, and its adult draws nectar. In this study, we determined that the sucrose sensory neurons located in the contact chemosensilla of larval maxillary galeae were 100-1000 times more sensitive to sucrose than those of adult antennae, tarsi and proboscis. Using the Xenopus expression system, we discovered that Gr10 highly expressed in the larval sensilla was specifically tuned to sucrose, while Gr6 highly expressed in the adult sensilla responded to fucose, sucrose and fructose. Moreover, using CRISPR/Cas9, we revealed that Gr10 was mainly used by larvae to detect lower sucrose, while Gr6 was primarily used by adults to detect higher sucrose and other saccharides, which results in differences in selectivity and sensitivity between larval and adult sugar sensory neurons. Our results demonstrate the sugar receptors in this moth are evolved to adapt towards the larval and adult foods with different types and amounts of sugar, and fill in a gap in sweet taste of animals.

ecology↗

Oligodendroglia generate vascular mural cells and neurons in the adult mouse brain

BACKGROUNDOligodendroglia encompass oligodendrocyte precursor cells (OPCs) and oligodendrocytes (OLs). In the grey matter of the cortex, nearly all OPCs divide slowly, yet they dont differentiate solely into mature OLs, leaving the exact role of these OPCs in the grey matter enigmatic. METHODSOligodendroglia, including OPCs, were traced using the Sox10 Cre-ERT2 reporter mice. We compared the effect of tamoxifen dissolved in different solvents on the fate of Sox10 cells. We also compared the effect of tamoxifen dosage on the fate of Sox10 cells. The differentiation of labeled red fluorescent protein (RFP) cells was analyzed using immunofluorescence staining. RESULTSTwo groups of RFP cells, type A Sox10 (Sox10-A) cells, and type B Sox10 (Sox10-B) cells, were identified in the cortex, striatum, hippocampus, thalamus, and hypothalamus. Sox10-A cells differentiate into platelet-derived growth factor receptor-{beta} (PDGFR{beta})+, CD13+ pericytes, and smooth muscle myosin heavy chain 11 (MYH11) + smooth muscle cells when the mice received ethanol or high-dose tamoxifen. Sox10-B cells transform into glutamatergic neurons when the mice received high-dose tamoxifen. Sox10-B cells include perineurona OPCs and OLs. CONCLUSIONSThis investigation provides evidence that a substantial proportion of oligodendroglia in the grey matter serve as mural cell precursors and neuronal precursors. These two phenomena may contribute to our understanding of neurodegenerative diseases. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/549127v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@1b7bef9org.highwire.dtl.DTLVardef@5af54borg.highwire.dtl.DTLVardef@19e3d45org.highwire.dtl.DTLVardef@1c881f1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

Frequency modulation increases the specificity of time-resolved connectivity: A resting-state fMRI study

The human brain is a highly dynamic system, and the methods we use to analyze the data gathered from this organ should account for this dynamism. One such family of methods that has attracted a lot of attention in the past decades is based on networks. The most well-known method for estimating the connection among these networks uses the sliding window Pearson correlation (SWPC) estimator. Although quite a useful tool, there are some important limitations. One such limitation is that SWPC applies a high pass filter to the activity time series. If we select a small window size (which is desirable to estimate rapid changes in functional connectivity), we will filter out important low-frequency activity information. In this work, we propose an approach based on single sideband modulation (SSB) in communication theory, which aims to solve this issue, allowing us to select smaller window sizes and capture rapid changes in the time-resolved functional connectivity. We use both simulation and real data to demonstrate the superior performance of the proposed method, SSB+SWPC, compared to classical SWPC. In addition, we compare the temporal recurring functional connectivity patterns between individuals with the first episode of psychosis (FEP) and typical controls (TC) and show that FEP stays more in FNC states that show weaker connectivity across the whole brain. A result exclusive to SSB+SWPC is that TC stays more in a state with negative connectivity between sub-cortical and cortical regions. All in all, based on both simulated data and real data, we argue that the proposed method, SSB+SWPC, is more sensitive for capturing temporal variation in functional connectivity.

neuroscience↗

An Azapeptide Platform in Conjunction with Covalent Warheads to Uncover High-Potency Inhibitors for SARS-CoV-2 Main Protease

Main protease (MPro) of SARS-CoV-2, the viral pathogen of COVID-19, is a crucial nonstructural protein that plays a vital role in the replication and pathogenesis of the virus. Its protease function relies on three active site pockets to recognize P1, P2, and P4 amino acid residues in a substrate and a catalytic cysteine residue for catalysis. By converting the P1 C atom in an MPro substrate to nitrogen, we showed that a large variety of azapeptide inhibitors with covalent warheads targeting the MPro catalytic cysteine could be easily synthesized. Through the characterization of these inhibitors, we identified several highly potent MPro inhibitors. Specifically, one inhibitor, MPI89 that contained an aza-2,2-dichloroacetyl warhead, displayed a 10 nM EC50 value in inhibiting SARS-CoV-2 from infecting ACE2+ A549 cells and a selectivity index of 875. The crystallography analyses of MPro bound with 6 inhibitors, including MPI89, revealed that inhibitors used their covalent warheads to covalently engage the catalytic cysteine and the aza-amide carbonyl oxygen to bind to the oxyanion hole. MPI89 represents one of the most potent MPro inhibitors developed so far, suggesting that further exploration of the azapeptide platform and the aza-2,2-dichloroacetyl warhead is needed for the development of potent inhibitors for the SARS-CoV-2 MPro as therapeutics for COVID-19.

biochemistry↗