Biology subjects

Teng, S.

Publications and source records attributed to Teng, S..

33 records · Page 2Linked to original sources

bioRxiv2022

A SHR-IDD-PIN regulatory network mediates minor vein differentiation in rice

C3 and C4 grasses directly and indirectly provide the vast majority of calories to the human diet, yet our understanding of the molecular mechanisms driving photosynthetic productivity in grasses is largely unexplored. Here we define a genetic circuit comprised of SHR, IDD and PIN family members that specify vascular identify and ground cell proliferation in leaves of both C3 and C4 grasses. Ectopic expression and loss-of-function mutant studies of SHORT ROOT (SHR) paralogs in C3 Oryza sativa (rice) and C4 Setaria viridis (green millet) revealed a role in both minor vein formation and ground cell differentiation. Genetic and in vitro studies further suggest that SHR regulates this process through its interaction with Indeterminate Domain (IDD) IDD 12 and 13. We further show a direct interaction of these IDD proteins with a putative regulatory element within the auxin transporter PIN5c gene. Collectively, these studies indicated that a SHR-IDD regulatory circuit mediates auxin flow through the negative regulation of PIN protein expression to modulate minor vein patterning in the grasses.

plant biology↗

bioRxiv2022

Spike-specific CXCR3+ TFH cells play a dominant functional role in supporting antibody responses in SARS-CoV-2 infection and vaccination

CD4+ T follicular helper (TFH) cells are required for high-quality antibody generation and maintenance. However, the longevity and functional role of these cells are poorly defined in COVID-19 convalescents and vaccine recipients. Here, we longitudinally investigated the dynamics and functional roles of spike-specific circulating TFH cells and their subsets in convalescents at the 2nd, 5th, 8th, 12th and 24th months after COVID-19 symptom onset and in vaccinees after two and three doses of inactivated vaccine. SARS-CoV-2 infection elicited robust spike-specific TFH cell and antibody responses, of which spike-specific CXCR3+ TFH cells but not spike-specific CXCR3- TFH cells and neutralizing antibodies were persistent for at least two years in more than 80% of convalescents who experienced symptomatic COVID-19, which was well coordinated between spike-specific TFH cell and antibody responses at the 5th month after infection. Inactivated vaccine immunization also induced spike-specific TFH cell and antibody responses; however, these responses rapidly declined after six months with a two-dose standard administration, and a third dose significantly promoted antibody maturation and potency. Functionally, spike-specific CXCR3+ TFH cells exhibited better responsiveness than spike-specific CXCR3- TFH cells upon spike protein stimulation in vitro and showed superior capacity in supporting spike-specific antibody secreting cell (ASC) differentiation and antibody production than spike-specific CXCR3- TFH cells cocultured with autologous memory B cells. In conclusion, spike-specific CXCR3+ TFH cells played a dominant functional role in antibody elicitation and maintenance in SARS-CoV-2 infection and vaccination, suggesting that induction of CXCR3-biased spike-specific TFH cell differentiation will benefit SARS-CoV-2 vaccine development aiming to induce long-term protective immune memory. HighlightsO_LISARS-CoV-2 infection elicited robust spike-specific TFH cell and antibody responses, which persisted for at least two years in the majority of symptomatic COVID-19 convalescent patients. C_LIO_LIInactivated vaccine immunization also elicited spike-specific TFH cell and antibody responses, which rapidly declined over time, and a third dose significantly promoted antibody maturation and potency. C_LIO_LISpike-specific CXCR3+ TFH cells exhibited more durable responses than spike-specific CXCR3- TFH cells, correlated with antibody responses and showed superior capacity in supporting ASC differentiation and antibody production than spike-specific CXCR3- TFH cells. C_LI

immunology↗

bioRxiv2022

Sensory regulation of absence seizures in a mouse model of Gnb1 encephalopathy

Absence seizures, a type of non-convulsive epilepsy manifested by spike-wave discharges (SWD) in the electroencephalogram (EEG), display synchronous reciprocal excitation between the neocortex and thalamus. Recent studies have revealed that inhibitory neurons in the reticular thalamic (RT) nucleus and excitatory thalamocortical (TC) neurons are two key subcortical players in generating SWD. However, the signals that drive SWD-related thalamic activity remain elusive. Here, we show that SWD predominately occurs during wakefulness in several mouse models of absence epilepsy. In more focused studies of Gnb1 mutant mice, we found that sensory input regulates SWD. Using in vivo recording, we demonstrate that TC cells are activated prior to the onset of SWD and then inhibited during SWD. On the contrary, RT cells are slightly inhibited prior to SWD, but are strongly activated during SWD. Furthermore, chemogenetic activation of TC cells leads to the enhancement of SWD in Gnb1 mice. Together, our results indicate that sensory input in the periphery can regulate SWD by activating the thalamocortical pathway.

neuroscience↗

bioRxiv2021

Computational saturation mutagenesis of SARS-CoV-1 spike glycoprotein: stability, binding affinity, and comparison with SARS-CoV-2

Severe Acute respiratory syndrome coronavirus (SARS-CoV-1) attaches to the host cell surface to initiate the interaction between the receptor-binding domain (RBD) of its spike glycoprotein (S) and the human Angiotensin-converting enzyme (hACE2) receptor. SARS-CoV-1 mutates frequently because of its RNA genome, which challenges the antiviral development. Here, we performed computational saturation mutagenesis of the S protein of SARS-CoV-1 to identify the residues crucial for its functions. We used the structure-based energy calculations to analyze the effects of the missense mutations on the SARS-CoV-1 S stability and the binding affinity with hACE2. The sequence and structure alignment showed similarities between the S proteins of SARS-CoV-1 and SARS-CoV-2. Interestingly, we found that target mutations of S protein amino acids generate similar effects on their stabilities between SARS-CoV-1 and SARS-CoV-2. For example, G839W of SARS-CoV-1 corresponds to G857W of SARS-CoV-2, which decrease the stability of their S glycoproteins. The viral mutation analysis of the two different SARS-CoV-1 isolates showed that mutations, T487S and L472P, weakened the S-hACE2 binding of the 2003-2004 SARS-CoV-1 isolate. In addition, the mutations of L472P and F360S destabilized the 2003-2004 viral isolate. We further predicted that many mutations on N-linked glycosylation sites would increase the stability of the S glycoprotein. Our results can be of therapeutic importance in the design of antivirals or vaccines against SARS-CoV-1 and SARS-CoV-2. Author SummarySevere acute respiratory syndrome coronavirus (SARS-CoV-1) is an RNA virus that undergoes frequent mutations, which may result in more virulent SARS-CoV-1 variants. To prevent another pandemic in the future, scientists must understand the mechanisms of viral mutations and predict if any variants could become a dominant. The infection of SARS-CoV-1 in cells is largely depending on the interactions of the viral Spike (S) and human angiotensin-converting enzyme 2 (hACE2). We applied a computational method to predict S missense mutations that will make SARS-CoV-1 more virulent. We are interested in the variants that can change SARS-CoV-1 spike protein stability and/or change the virus-receptor interactions. We mutated each residue of SARS-CoV-1 spike to all possible amino acids; we calculated the differences between the folding energy and binding energy of each variant and the wildtype and identified the target S mutations with significant effects on protein stability and protein-protein interaction. We found some viral mutations could destabilize S and weaken S-hACE2 binding of SARS-CoV-1 isolate. Our results show that the computational saturation mutagenesis is a reliable approach in the analysis and prediction of missense mutations.

bioinformatics↗

bioRxiv2021

Medulla glutamatergic neurons control wake-sleep transitions

Sleep is a ubiquitous behavior in animal species. Yet, brain circuits controlling sleep remain poorly understood. Previous studies have identified several brain structures that promote sleep, but whether these structures are involved in sleep initiation or sleep maintenance remains largely unknown. Here we identified a population of glutamatergic neurons in the medulla that project to the preoptic area (POA), a prominent sleep-promoting region. Chemogenetic silencing of POA-projecting medulla neurons disrupts the transitions from wakefulness to Non-Rapid Eye Movement (NREM) sleep, whereas chemogenetic activation of these neurons promotes NREM sleep. Moreover, we show that optogenetic activation of medulla glutamatergic neurons or their projections in the POA reliably initiates long-lasting NREM sleep in awake mice. Together, our findings uncover a novel excitatory brainstem-hypothalamic circuit that controls the wake-sleep transitions.

neuroscience↗

bioRxiv2020

A Systemic and Molecular Study of Subcellular Localization of SARS-CoV-2 Proteins

Coronavirus possesses the largest RNA genome among all the RNA viruses. Its genome encodes about 29 proteins. Most of the viral proteins are non-structural proteins (NSP) except envelop (E), membrane (M), nucleocapsid (N) and Spike (S) proteins that constitute the viral nucleocapsid, envelop and surface. We have recently cloned all the 29 SARS-CoV-2 genes into vectors for their expressions in mammalian cells except NSP11 that has only 14 amino acids (aa). We are able to express all the 28 cloned SARS-CoV-2 genes in human cells to characterize their subcellular distributions. The proteins of SARS-CoV-2 are mostly cytoplasmic but some are both cytoplasmic and nuclear. Those punctate staining proteins were further investigated by immunofluorescent assay (IFA) using specific antibodies or by co-transfection with an organelle marker-expressing plasmid. As a result, we found that NSP15, ORF6, M and ORF7a are related to Golgi apparatus, and that ORF7b, ORF8 and ORF10 colocalize with endoplasmic reticulum (ER). Interestingly, ORF3a distributes in cell membrane, early endosome, endosome, late endosome and lysosome, which suggests that ORF3a might help the infected virus to usurp endosome and lysosome for viral use. Furthermore, we revealed that NSP13 colocalized with SC35, a protein standing for splicing compartments in the nucleus. Our studies for the first time visualized the subcellular locations of SARS-CoV-2 proteins and might provide novel insights into the viral proteins biological functions.

microbiology↗

bioRxiv2020

Phase response analyses support a relaxation oscillator model of locomotor rhythm generation in Caenorhabditis elegans

Neural circuits coordinate with muscles and sensory feedback to generate motor behaviors appropriate to an animals environment. In C. elegans, the mechanisms by which the motor circuit generates undulations and modulates them based on the environment are largely unclear. We quantitatively analyzed C. elegans locomotion during free movement and during transient optogenetic muscle inhibition. Undulatory movements were highly asymmetrical with respect to the duration of bending and unbending during each cycle. Phase response curves induced by brief optogenetic inhibition of head muscles showed gradual increases and rapid decreases as a function of phase at which the perturbation was applied. A relaxation oscillator model based on proprioceptive thresholds that switch the active muscle moment was developed and is shown to quantitatively agree with data from free movement, phase responses, and previous results for gait adaptation to mechanical loadings. Our results suggest a neuromuscular mechanism underlying C. elegans motor pattern generation within a compact circuit.

neuroscience↗

bioRxiv2020

Spatiotemporal Dynamics of Sound Representations Reveal a Hierarchical Progression of Category Selectivity

As the human brain transforms incoming sounds, it remains unclear whether semantic meaning is assigned via distributed, domain-general architectures or specialized hierarchical streams. Here we show that the spatiotemporal progression from acoustic to semantically dominated representations is consistent with a hierarchical processing scheme. Combining magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) patterns, we found superior temporal responses beginning ~80 ms post-stimulus onset, spreading to extratemporal cortices by ~130 ms. Early acoustically-dominated representations trended systematically toward semantic category dominance over time (after ~200 ms) and space (beyond primary cortex). Semantic category representation was spatially specific: vocalizations were preferentially distinguished in temporal and frontal voice-selective regions and the fusiform face area; scene and object sounds were distinguished in parahippocampal and medial place areas. Our results are consistent with an extended auditory processing hierarchy in which acoustic representations give rise to multiple streams specialized by category, including areas typically considered visual cortex.

neuroscience↗

bioRxiv2020

Systemic Effects of Missense Mutations on SARS-CoV-2 Spike Glycoprotein Stability and Receptor Binding Affinity

The spike (S) glycoprotein of SARS-CoV-2 is responsible for the binding to the permissive cells. The receptor-binding domain (RBD) of SARS-CoV-2 S protein directly interacts with the human angiotensin-converting enzyme 2 (ACE2) on the host cell membrane. In this study, we used computational saturation mutagenesis approaches, including structure-based energy calculations and sequence-based pathogenicity predictions, to quantify the systemic effects of missense mutations on SARS-CoV-2 S protein structure and function. A total of 18,354 mutations in S protein were analyzed and we discovered that most of these mutations could destabilize the entire S protein and its RBD. Specifically, residues G431 and S514 in SARS-CoV-2 RBD are important for S protein stability. We analyzed 384 experimentally verified S missense variations and revealed that the dominant pandemic form, D614G, can stabilize the entire S protein. Moreover, many mutations in N-linked glycosylation sites can increase the stability of the S protein. In addition, we investigated 3,705 mutations in SARS-CoV-2 RBD and 11,324 mutations in human ACE2 and found that SARS-CoV-2 neighbor residues G496 and F497 and ACE2 residues D355 and Y41 are critical for the RBD-ACE2 interaction. The findings comprehensively provide potential target sites in the development of drugs and vaccines against COVID-19.

bioinformatics↗

bioRxiv2020

Visual Experience is not Necessary for the Development of Face Selectivity in the Lateral Fusiform Gyrus

Here we show robust face-selectivity in the lateral fusiform gyrus of congenitally blind participants during haptic exploration of 3D-printed stimuli, indicating that neither visual experience, nor fovea-biased input, nor visual expertise is necessary for face-selectivity to arise in its characteristic location. Similar resting fMRI correlation fingerprints in individual blind and sighted participants suggest a role for long-range connectivity in the specification of the cortical locus of face-selectivity.

neuroscience↗

bioRxiv2019

G protein-coupled potassium channels implicated in mouse and cellular models of GNB1 Encephalopathy

De novo mutations in GNB1, encoding the G{beta}1 subunit of G proteins, cause a neurodevelopmental disorder with global developmental delay and epilepsy. Mice carrying a pathogenic mutation, K78R, recapitulate aspects of the disorder, including developmental delay and frequent spike-wave discharges (SWD). Cultured mutant cortical neurons display aberrant bursting activity on multi-electrode arrays. Strikingly, the antiepileptic drug ethosuximide (ETX) restores normal neuronal network behavior in vitro and suppresses SWD in vivo. In contrast, while valproic acid suppresses SWD, it does not restore normal network behavior, suggesting that ETX has mechanistic specificity for the effects of aberrant G{beta}1 signaling. Consistent with this, we show that K78R is a gain-of-function of G protein-coupled potassium channel (GIRK) activation that is potently inhibited by ETX. This work suggests that altered G{beta}1 signaling causes disease in part through effects on GIRK channels, illustrates the utility of cultured neuronal networks in pharmacological screening, and establishes effective pre-clinical models for GNB1 Encephalopathy.

neuroscience↗

bioRxiv2017

Rice TSV3 Encoding Obg-like GTPase Protein is Essential for Chloroplast Development during the Early Leaf Stage under Cold Stress

The Spo0B-associated GTP-binding (Obg) proteins occupy a wide variety of roles in the viability of nearly all bacteria. Its detailed roles in higher plants have not yet been elucidated. A novel rice thermo-sensitive virescent mutant tsv3 was identified in this study that displayed albino phenotype at 20{degrees}C before the 3-leaf stage while being normal green at 32{degrees}C or even at 20{degrees}C after the 4-leaf stage. The mutant phenotype was aligned with altered chlorophyll (Chl) content and chloroplast development. Map-based cloning and complementation test showed that TSV3 encoded a kind of small GTP binding protein. Subcellular localization revealed that TSV3 was in chloroplast. TSV3 transcripts were highly expressed in leaves and weak or undetectable in other tissues, suggesting the tissue-specific expression. In tsv3 mutant, the transcriptional levels of certain genes associated with biogenesis of chloroplast ribosomes 50S subunit were severely decreased at the 3-leaf-stage under cold stress, but could be recovered to normal levels at a higher temperature (32{degrees}C). The observations from this study indicated that the rice nuclear-encoded TSV3 plays important roles in chloroplast development at early leaf stage under cold stress.

plant biology↗

bioRxiv2017

Distributed Rhythm Generators Underlie Caenorhabditis elegans Forward Locomotion

Coordinated rhythmic movements are ubiquitous in animal behavior. In many organisms, chains of neural oscillators underlie the generation of these rhythms. In C. elegans, locomotor wave generation has been poorly understood; in particular, it is unclear where in the circuit rhythms are generated, and whether there exists more than one such generator. We used optogenetic and ablation experiments to probe the nature of rhythm generation in the locomotor circuit. We found that multiple sections of forward locomotor circuitry are capable of independently generating rhythms. By perturbing different components of the motor circuit, we localize the source of secondary rhythms to cholinergic motor neurons in the midbody. Using rhythmic optogenetic perturbation we demonstrate bidirectional entrainment of oscillations between different body regions. These results show that, as in many other vertebrates and invertebrates, the C. elegans motor circuit contains multiple oscillators that coordinate activity to generate behavior.

neuroscience↗

bioRxiv2017

Epigenetic Reprogramming of Tissue-Specific Transcription Promotes Metastasis

Tumor metastasis is the cause of death for 90% of cancer patients, and no currently-available therapies target this multi-step process in which cancer cells spread from the local tissue of a primary tumor to distant organs where they establish secondary tumors1. Although epithelial-to-mesenchymal transition2, tumor-secreted exosomes3, epigenetic regulators as well as other genes4-8 have been implicated in metastasis, little is known about how cells adapt to and colonize new tissue environments. Here, we show that the epigenetics-mediated reprogramming of tissue-specific gene transcription in cancer cells promotes metastasis. Using colorectal cancer (CRC) as a model, we found in both clinical and cell line studies that metastatic CRC cells lose their colon-specific gene transcription program and gain a liver-specific gene transcription program as they metastasize in the liver. Further, we found this transcription reprogramming is driven by a reshaped epigenetic landscape of both typical and super-enhancers. Chemical inhibition of enhancer activity disrupts the ability of cells to execute altered transcription programs and consequently inhibits metastasis. Binding motif analysis of the enhancers in liver metastatic CRC cells identified the liver-specific transcription factor FOXA2 as a key regulator, and knocking down of FOXA2 expression prevents the colonization of metastatic CRC cells in the liver of a mice xenograft model. These results, together with additional observations of similar reprogramming in several cohorts of clinical CRC tumor samples and in multiple other forms of metastatic cancers, indicate that this reprogramming may be a common feature of metastasis in multiple cancers and suggest the targeted disruption of this epigenetic reprogramming as a strategy for the development of therapies to treat metastasis, the leading cause of cancer-related mortality.

cancer biology↗

bioRxiv2016

Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia

Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) are common psychiatric illnesses. All have been associated with lower cognitive ability, and show evidence of genetic overlap and substantial evidence of pleiotropy with cognitive function and neuroticism. Disrupted in schizophrenia 1 (DISC1) protein directly interacts with a large set of proteins (DISC1 Interactome) that are involved in brain development and signaling. Modulation of DISC1 expression alters the expression of a circumscribed set of genes (DISC1 Regulome) that are also implicated in brain biology and disorder. Here, we report targeted sequencing of 59 DISC1 Interactome genes and 154 Regulome genes in 654 psychiatric patients and 889 cognitively-phenotyped control subjects, on whom we previously reported evidence for trait association from complete sequencing of the DISC1 locus. Burden analyses of rare and singleton variants predicted to be damaging were performed for psychiatric disorders, cognitive variables and personality traits. The DISC1 Interactome and Regulome showed differential association across the phenotypes tested. After family-wise error correction across all traits (FWERacross), an increased burden of singleton disruptive variants in the Regulome was associated with SCZ (FWERacross P=0.0339). The burden of singleton disruptive variants in the DISC1 Interactome was associated with low cognitive ability at age 11 (FWERacross P=0.0043). These results suggest that variants in the DISC1 Interactome effect the risk of psychiatric illness through altered expression of schizophrenia-associated genes. The biological impact of rare variants highlighted here merit further study.

genetics↗