Biology subjects

Qian, H.

Publications and source records attributed to Qian, H..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Depression Attenuates Caudate and Dorsolateral Prefrontal Cortex Alpha and Beta Power Response to Reward

Depression is a prevalent psychiatric condition and a common comorbidity across neurological disorders. Common symptoms include anhedonia, negative emotional biases, and cognitive dysfunction. Beta (15-30 Hz) neural oscillations have been shown to increase during reward-based learning within fronto-striatal reward networks. Corticostriatal beta oscillations have also been implicated in cognitive functions including working memory. However, the relationship between beta oscillations and depression remains unknown. Using intracranial recordings, we aimed to investigate how depression modulates the spectral power of neural oscillations in corticostriatal structures during reward feedback in a working memory task. Thirty movement disorder patients undergoing awake deep brain stimulation surgery with electrode trajectories traversing the caudate or dorsolateral prefrontal cortex (DLPFC) participated in this study. We recorded local field potential data intraoperatively as subjects completed a 2-back verbal working memory task where they identified whether a word matched the word presented two trials prior. Subjects received reward in the form of visual feedback for correct answers. Word stimuli had either a positive, negative, or neutral emotional valence. Subjects completed the Beck Depression Inventory-II preoperatively, and we used a cut-off score of 14 to identify patients with depression. We found that caudate and DLPFC power increased in the alpha (8-15 Hz) and beta range during reward feedback and that this increase was significantly greater for subjects without depression compared to depressed subjects. In non-depressed patients, positive feedback stimuli evoked significantly higher beta power in the caudate during reward compared to neutral and negative stimuli. In depressed patients, emotional valence did not affect reward-related caudate spectral power, while DLPFC alpha power was significantly higher following positive emotional stimuli in comparison to neutral but not negative stimuli. We additionally found that anti-depressant medications (ADMs) generally blunted alpha and beta reward signaling processes in the DLPFC. This blunting effect on reward-related alpha power in the DLPFC, however, was reversed in depressed patients, indicating that the effects of ADMs on reward signaling processes may depend on whether a patient is exhibiting depression symptoms. Our findings suggest that depression suppresses the alpha and beta power response to both reward and emotional stimuli during working memory, indicating power attenuation in these frequency bands may contribute to emotional and cognitive depression symptoms.

neuroscience↗

bioRxiv2023

The Rho GTPase Rac1 mediates exercise training adaptations

Exercise training elicits tremendous health benefits; however, the molecular underpinnings are poorly understood. As one of the most regulated groups of proteins following acute exercise in human muscle, Rho GTPases are unexplored candidates for mediating the beneficial effects of exercise. The Rho GTPase Rac1 was activated during multiple exercise modalities and remained elevated hours after resistance exercise in human muscle. Inducible muscle-specific Rac1 knockout (Rac1 imKO) mice, displayed attenuated muscle protein synthesis, glycogen resynthesis and p38 MAPK signaling in recovery from contractions. Exercise training upregulated Rac1 protein content in human and mouse muscle. Overexpression of hyperactive Rac1 elevated reactive oxidant species production during exercise yet did not induce a trained muscle phenotype. In Rac1 imKO mice, the improvements in running capacity and muscle mass after exercise training were diminished. Using gain- and loss-of-function mouse models and human muscle biopsies, we identify Rac1 as a regulator of exercise training adaptions. HighlightsO_LIVarious exercise modalities activate Rac1 signaling in human skeletal muscle. C_LIO_LIHSP27, MNK1, and CREB are Rac1-dependent contraction-responsive targets in muscle. C_LIO_LIPost-contraction protein synthesis requires Rac1 but not NOX2. C_LIO_LIRac1-NOX2 signaling is necessary for post-contraction glycogen resynthesis. C_LIO_LIExercise training increases Rac1 protein content in human and mouse muscles. C_LIO_LIRac1 mediates critical adaptations to exercise training. C_LI

molecular biology↗

bioRxiv2023

Single-molecule analysis unveils the phosphorylation of FLS2 regulates its spatiotemporal dynamics and immunity

The Arabidopsis thaliana FLAGELLIN-SENSITIVE2 (FLS2), a typical receptor kinase, recognizes the conserved 22 amino acid sequence in the N-terminal region of flagellin (flg22) to initiate plant defense pathways, which was intensively studied in the past decades. However, the dynamic regulation of FLS2 phosphorylation at the plasma membrane after flg22 recognition needs further elucidation. Through single-particle tracking, we demonstrated that upon flg22 treatment, the phosphorylation of Ser-938 in FLS2 impacts its spatiotemporal dynamics and lifetime. Following forster resonance energy transfer-fluorescence lifetime (FRET-FLIM) imaging microscopy and protein proximity indexes (PPI) assays revealed that flg22 treatment increased the co-localization of GFP-tagged FLS2/FLS2S938D but not FLS2S938A with AtRem1.3-mCherry, a sterol-rich lipid marker, indicating that the phosphorylation of FLS2S938 affects FLS2 sorting efficiency to AtRem1.3-associated nanodomains. Importantly, we found that the phosphorylation of Ser-938 enhanced flg22-induced FLS2 internalization and immune responses, demonstrating that the phosphorylation may activate flg22-triggered immunity through partitioning FLS2 into functional AtRem1.3-associated nanodomains, which fills the gap between the FLS2S938 phosphorylation and FLS2-mediated immunity.

cell biology↗

bioRxiv2023

Neuropathy target esterase activity predicts retinopathy among PNPLA6 disorders

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism, and hair anomalies. PNPLA6 encodes Neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a clinical meta-analysis of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 10 variants as likely pathogenic and 36 variants as pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship and the generation of a preclinical animal model pave the way for therapeutic trials, using NTE as a biomarker.

neuroscience↗

bioRxiv2023

Cell population growth as manifestation of stochastic heterogeneity of cell phenotype

Recent studies at individual cell resolution have revealed phenotypic heterogeneity in nominally clonal tumor cell populations. The heterogeneity affects cell growth behaviors, which can result in departure from the idealized exponential growth. Here we measured the stochastic time courses of growth of an ensemble of populations of HL60 leukemia cells in cultures, starting with distinct initial cell numbers to capture the departure from the exponential growth model in the initial growth phase. Despite being derived from the same cell clone, we observed significant variations in the early growth patterns of individual cultures with statistically significant differences in growth kinetics and the presence of subpopulations with different growth rates that endured for many generations. Based on the hypothesis of existence of multiple inter-converting subpopulations, we developed a branching process model that captures the experimental observations.

cancer biology↗

bioRxiv2023

Establishment of primary renal lymphoma model and the clinical relevance

Extranodal dissemination was an important feature of aggressive B-cell lymphoma. Due to the lack of available animal model, the causes of extranodal dissemination of lymphoma were largely unknown. Here, we identified a novel cell line, named MA-K, which originated from the E-Myc;Cdkn2a-/- cell line, named MA-LN in this study. Compared to MA-LN, MA-K tended to disseminate in the kidney rather than lymph nodes in lymphoma transplantation model, resembling human primary renal lymphoma. The transcriptome analysis revealed that MA-K had undergone the transcriptional evolution during the culture. Specialized transcriptional pattern analysis, we proposed in this study, identified that FOXO1-BTG1-MYD88 pattern was formed in MA-K. Further analysis found that translation pathway was the most enriched pathway in specially expressed genes (SEGs) in MA-K. Among the SEGs, 3 up-regulated genes, RPLP2, RPS16 and MRPS16, and 5 down-regulated genes, SSPN, CD52, ANKRD37, CCDC82 and VPREB3, in MA-K were identified as promising biomarkers to predict the clinical outcomes of human DLBCL. Moreover, the joint expression of the 5-gene signature could effectively predict clinical outcomes of human DLBCL in triple groups. These findings suggested that the MA-K cell line had strong clinical relevance with human aggressive B-cell lymphoma. Moreover, the MA-K primary renal lymphoma model, as a novel syngenetic mouse model, would be greatly useful for both the basic research on lymphoma dissemination and preclinical efficacy evaluation of chemotherapy and immunotherapy.

cancer biology↗

bioRxiv2023

EFNB1 level affects drug response in DLBCL cell lines

Targeted therapy was a promising therapy for aggressive B-cell lymphoma. However, drug resistance was still an unavoidable problem. Here, we explored the effect of EFNB1 on drug response. Analysis of IC50 data showed that high level of EFNB1 was associated with resistance to most targeted drugs targeting BCR in human DLBCL cell lines. Drug response assay showed that Efnb1 could enhance SRC phosphorylation and increased the sensitivity of cells to SRC inhibitors. Meanwhile, Efnb1 could sensitize cells to most cytotoxic drugs, especially DOX and VCR. Efnb1 could confer cells sensitivity to VCR by enhancing the phosphorylation of Stmn1 at serine 28. Survival analysis revealed that the expression level of genes phosphorylated in Efnb1 cells were associated with poor prognosis of human DLBC. Together, this study revealed that EFNB1 level, as a non-genetic mechanism, greatly affected drug response of targeted drugs and cytotoxic drugs through the phosphorylation network. Our findings would provide important insights into EFNB1-SRC activated B-cell lymphoma and efficacy evaluation.

pharmacology and toxicology↗

bioRxiv2022

Differences in self-reported benefits for student-artist versus faculty experiences in a virtual artist-in-residence program.

The value of science communication in engaging the public has been well established. While many new programs bridge the arts and sciences, conducting comprehensive examination of exiting art-science programs can produce more efficient training and program development guidance for improving visual communications in the sciences. Here, we recruited a variety of scientists and artists to collaborate in creating visual science communication products over three summers. Using survey data, we performed qualitative and quantitative analyses to define sources for negative and positive experiences and outcomes from the Vanderbilt Institute for Infection, Immunology, and Inflammation (VI4) Artist-in-Residence (AiR) program. Further, we analyze responses from participants, student-artists and faculty, to specify areas for improvement and areas successful in producing a positive experience and outcome in an AiR program. We found that time and virtual delivery of the program could be modified to improve the experience. Additionally, we found that student participants had more positive responses about "learning something new" from the program than faculty members. However, the most surprising aspect of our analysis suggests that for both "way of thinking" and "science communication to the public or general audience," there may be more significant beneficial gains for faculty compared to students. We conclude this analysis with suggestions to enhance the benefits and outcomes of an AiR program and ways to minimize the difficulties, such as communication and collaboration, faced by participants and program designers.

scientific communication and education↗

bioRxiv2022

Acetylation of a fungal effector that translocates host PR1 facilitates virulence

Pathogens utilize a panoply of effectors to manipulate plant defense. However, despite their importance, relatively little is actually known about regulation of these virulence factors. Here, we show that the effector FolSvp1, secreted from fungal pathogen Fusarium oxysporum f. sp. lycopersici (Fol) directly binds and translocates the tomato pathogenesis-related protein1, SlPR1, from the apoplast outside the plasma membrane to the host nucleus via its nuclear localization signal. Relocation of SlPR1 abolishes generation of the defense signaling peptide, CAPE1, from its C-terminus, and as a consequence, facilitates pathogen invasion of plants. The action of FolSvp1 requires covalent modification by acetylation for full virulence in host tomato tissues. The modification is catalyzed by the Fol FolArd1 lysine acetyltransferase prior to secretion. Addition of an acetyl group to one residue, K167, prevents ubiquitination-dependent degradation of FolSvp1 in both Fol and plant cells with different mechanisms, allowing it to function normally in fungal invasion. Either inactivation of FolSvp1 or removal of the acetyl group on K167 leads to impaired pathogenicity of Fol. These findings indicate that acetylation can regulate the stability of effectors of fungal plant pathogens with impact on virulence.

microbiology↗

bioRxiv2022

Identification of GTF2IRD1 as a novel transcription factor essential for acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive blood malignancy characterized by clonal accumulation of immature myeloid progenitors in the bone marrow and peripheral blood. Transcription factors are the most frequently mutated and dysregulated genes in AML, and they have critical roles in AML pathogenesis and progression. In this study, we performed large-scale RNA interference screens in MLL-AF9-transformed AML cells and identified GTF2IRD1 as a novel transcription factor essential for the survival of various types of myeloid leukemic cells in vitro and in vivo, but not for primary normal hematopoietic cells. Inhibition of GTF2IRD1 reduced the frequency of primary childhood and adult AML cells, including cell populations enriched for leukemia-initiating cells. In animal models for AML, inhibition of GTF2IRD1 significantly delayed the disease progression. Loss of GTF2IRD1 promoted accumulation of AML cells in the G0 phase of the cell cycle but caused minor effects in apoptosis induction. In line with this, RNA sequencing analysis revealed a significant downregulation of E2F targets as a consequence of genetic inhibition of GTF2IRD1. Taken together, we identified GTF2IRD1 as a transcription factor with a selective importance in AML, and our findings may contribute to the development of improved therapeutic inventions for the disease.

cancer biology↗

bioRxiv2022

Corticostriatal Beta Power Changes Associated with Cognitive Function in Parkinsons Disease

Cognitive impairment (CI) is the most frequent nonmotor symptom in Parkinsons Disease (PD) and is associated with deficits in executive functions such as working memory. Previous studies have demonstrated that caudate beta power is involved in learning and working memory. Decreased dopamine in motor cortico-striato-thalamo-cortical (CSTC) circuits results in increased beta power and PD motor symptoms. Analogous changes in cognitive CSTC circuits, including the caudate and dorsolateral prefrontal cortex (DLPFC), may contribute to PD CI. The objective of our study is to evaluate whether beta power changes in caudate and DLPFC contribute to cognitive impairment in PD patients. To investigate this, we used local field potential (LFP) recordings during deep brain stimulation surgery in 15 PD patients. LFP signals from DLPFC and caudate were performed at rest and during a verbal working memory task. We examined beta power changes during the working memory task and relationship of beta power to pre-operative neuropsychological testing results. Beta power decreased in both DLPFC and caudate during encoding of correct trials, whereas beta power increased in DLPFC and caudate during feedback for correct responses. Subjects with cognitive impairment showed smaller decreases in caudate and DLPFC beta power during encoding, greater increases in beta power during feedback, and lower average resting-state beta power. Additionally, reduced caudate beta power during encoding correlated with better memory scores on pre-operative neuropsychological testing, while greater DLPFC beta power during feedback correlated with worse scores in the attention domain. Our findings suggest that similar to the relationship between beta power in motor CSTC circuits and PD motor symptoms, beta power changes in parallel cognitive CSTC circuits may be correlated with cognitive symptoms in PD patients.

neuroscience↗

bioRxiv2022

CaMKII binding to GluN2B flips a β-adrenergic switch from synaptic depression to potentiation

Learning, memory and cognition are thought to require forms of synaptic plasticity such as hippocampal long-term potentiation and depression (LTP and LTD), and such plasticity can be modulated by {beta}-adrenergic stimulation with isoproterenol or norepinephrine. For instance, LTP versus LTD is induced by high-versus low-frequency stimulation (HFS versus LFS) but, stimulating {beta}-adrenergic receptors ({beta}ARs) enables LTP induction also by LFS. In contrast to HFS-LTP, such {beta}AR-LTP requires signaling by L-type voltage-gated Ca2+-channels, not NMDA-type glutamate receptors (NMDARs). Surprisingly, we found that {beta}AR-LTP still required a non-ionotropic NMDAR function: the stimulus-induced binding of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) that mediates CaMKII movement to excitatory synapses. In hippocampal neurons, {beta}-adrenergic stimulation with isoproterenol transformed LTD-type CaMKII movement to LTP-type movement, resulting in CaMKII movement to excitatory instead of inhibitory synapses. Additionally, isoproterenol enabled induction of a major cell-biological feature of LTP in response to LTD stimuli: increased SEP-GluA1 surface expression. Like for the {beta}AR-LTP in hippocampal slices, the effects of isoproterenol on CaMKII movement and SEP-GluA1 surface expression involved L-type Ca2+-channels. Taken together, these results indicate that isoproterenol transforms LTD stimuli to LTP signals by switching CaMKII movement and GluN2B binding to LTP mode. One Sentence SummaryBuonarati et al. show that {beta}-adrenergic stimulation enables LTP induction in response to LTD stimuli by switching synaptic CaMKII movement to LTP mode.

neuroscience↗

bioRxiv2022

Inhibition of Fas Receptor Endocytosis Sensitizes Cancer Cells to Fas-induced Apoptosis

The transmembrane death receptor Fas transduces apoptotic signals upon binding its ligand, FasL. Although Fas is highly expressed in cancer cells, insufficient cell surface Fas expression desensitizes cancer cells to Fas-induced apoptosis. Here, we show that the increase in Fas microaggregate formation on the plasma membrane in response to the inhibition of endocytosis sensitizes cancer cells to Fas-induced apoptosis. We used a clinically accessible Rho-kinase inhibitor, fasudil, that reduces endocytosis dynamics by increasing plasma membrane tension. In combination with exogenous soluble FasL (sFasL), fasudil promoted cancer cell apoptosis, but this collaborative effect was substantially weaker in nonmalignant cells. The combination of sFasL and fasudil prevented glioblastoma cell growth in embryonic stem cell-derived brain organoids and induced tumor regression in a xenograft mouse model. Our results demonstrate that sFasL has strong potential for apoptosis-directed cancer therapy when Fas microaggregate formation is augmented by mechano-inhibition of endocytosis.

cancer biology↗

bioRxiv2022

Highly dense and scalable protein arrays for single-molecule studies

Single-molecule proteomic studies are critically important for understanding the molecular origins of cellular phenotypes. However, no currently available technology can achieve both the single-molecule sensitivity and high dynamic range required to comprehensively analyze the complex mixtures of proteins in biological samples. One approach to achieve high sensitivity across a wide dynamic range would be to create a protein array that arranges billions of single molecules with regular spacing on a patterned surface. However, creating such a protein array has remained an unsolved challenge for the field. Here, we present a highly scalable method for fabricating dense single-molecule protein arrays using a specially designed DNA origami structure, protein click-conjugation, photolithography and surface functionalization. The origami-structure is enhanced via terminal deoxynucleotidyl transferase-extension, which generates brush-like projections, increasing the effective size of the origami from 88 nm to greater than 200 nm. These particles are large enough to enable super-Poisson deposition of individual protein molecules on a nano-patterned chip (>98% occupancy with only 1% of sites occupied with multiple protein molecules). This approach allowed for single-molecule protein display of 600 million protein molecules per microscope slide-sized chip with the potential to scale further with denser feature spacing. We hypothesize that this technology will ultimately enable the development of highly scalable proteomic analysis platforms that address the currently unmet need for protein measurements at single-molecule sensitivity across an exceptionally wide dynamic range of protein concentrations.

bioengineering↗

bioRxiv2022

FOXO dictates initiation of B cell development and myeloid restriction in common lymphoid progenitors

The development of B cells relies on an intricate network of transcription factors critical for developmental progression and lineage commitment. In the B cell developmental trajectory, a temporal switch from predominant Foxo3 to Foxo1 expression occurs at the CLP stage. Utilizing VAV-iCre mediated conditional deletion, we found that the loss of FOXO3 impaired B cell development from LMPP down to B cell precursors, while the loss of FOXO1 impaired B cell commitment and resulted in a complete developmental block at the CD25 negative proB cell stage. Strikingly, the combined loss of FOXO1 and FOXO3 resulted in the failure to restrict the myeloid potential of CLPs and the complete loss of the B cell lineage. This is underpinned by the failure to enforce the early B-lineage gene regulatory circuitry upon a predominantly pre-established open chromatin landscape. Altogether, this demonstrates that FOXO3 and FOXO1 cooperatively govern early lineage restriction and initiation of B-lineage commitment in CLPs. SUMMARYCommon lymphoid progenitors co-express the transcription factors FOXO1 and FOXO3. Removing FOXO1 and FOXO3 at this developmental stage results in regained myeloid potential, failed establishment of the early B cell gene regulatory program, and the complete loss of the B cell lineage.

immunology↗

bioRxiv2021

A model for the intrinsic limit of cancer therapy: duality of treatment-induced cell death and treatment-induced stemness

AO_SCPLOWBSTRACTC_SCPLOWIntratumor cellular heterogeneity and non-genetic cell plasticity in tumors pose a recently recognized challenge to cancer treatment. Because of the dispersion of initial cell states within a clonal tumor cell population, a perturbation imparted by a cytocidal drug only kills a fraction of cells. Due to dynamic instability of cellular states the cells not killed are pushed by the treatment into a variety of functional states, including a "stem-like state" that confers resistance to treatment and regenerative capacity. This immanent stress-induced stemness competes against cell death in response to the same perturbation and may explain the near-inevitable recurrence after any treatment. This double-edged-sword mechanism of treatment complements the selection of preexisting resistant cells in explaining post-treatment progression. Unlike selection, the induction of a resistant state has not been systematically analyzed as an immanent cause of relapse. Here, we present a generic elementary model and analytical examination of this intrinsic limitation to therapy. We show how the relative proclivity towards cell death versus transition into a stem-like state, as a function of drug dose, establishes either a window of opportunity for containing tumors or the inevitability of progression following therapy. The model considers measurable cell behaviors independent of specific molecular pathways and provides a new theoretical framework for optimizing therapy dosing and scheduling as cancer treatment paradigms move from "maximal tolerated dose," which may promote therapy induced-stemness, to repeated "minimally effective doses" (as in adaptive therapies), which contain the tumor and avoid therapy-induced progression.

cancer biology↗

bioRxiv2021

Reference genomes of 545 silkworms enable high-throughput exploring genotype-phenotype relationships

The silkworm Bombyx mori is a domestic insect for silk production and a lepidopteran model. The currently available genomes limit a full understanding of its genetic and phenotypic diversity. Here we assembled long-read genomes of 545 domestic and wild silkworms and constructed a high-resolution pan-genome dataset. We found that the silkworm population harbors extremely variable genomes containing 7,308 new gene families, 4,260 (22%) core gene families, and 3,432,266 non-redundant SVs. We deciphered a series of causal genes and variants associated with domestication, breeding, and ecological adaptation traits, and experimentally validated two of those genes using CRISPR-Cas9 or RNA interference. This unprecedented large-scale genomic resource allows for high-throughput screening of interesting traits for functional genomic research and breeding improvement of silkworms and may serve as a guideline for traits decoding in other species.

genomics↗

bioRxiv2021

Structural basis for sterol sensing by Scap and Insig

The sterol regulatory element-binding protein (SREBP) pathway senses the cellular cholesterol level through sterol regulated association between Scap and Insig. Despite the recent structural determination of the transmembrane domains of human Scap and Insig-2 bound to 25-hydroxycholesterol (25HC), the structure and regulatory mechanism of the luminal domains of Scap by cholesterol remains elusive. Here, combining cryo-EM analysis and artificial intelligence-facilitated structural prediction, we report the structure of the human Scap/Insig-2 complex in the presence of digitonin instead of 25HC. Despite the lack of sequence similarity, the structure of the luminal domain Loop 1 and a co-folded segment in Loop 7 of Scap resembles that of the luminal/extracellular domain in NPC1 and related proteins. Comparison of the sterol-loaded structures of these proteins provides clues of the regulation of Loop 1/7 interaction by cholesterol. We also show that the structure of Scap(D428A), which suppresses SREBP activation under sterol depletion, is identical to WT when complexed with Insig-2, although the gain of function may also involve a later step in protein trafficking.

biochemistry↗