Biology subjects

Wen, T.

Publications and source records attributed to Wen, T..

33 records · Page 2Linked to original sources

bioRxiv2022

Pancreatic Tumor Eradication via Selective PIN1 Inhibition in Cancer Associated Fibroblasts and T Lymphocytes Engagement

Cancer associated fibroblasts (CAFs) support tumors via multiple mechanisms, including maintaining the immunosuppressive tumor microenvironment and limiting infiltration of immune cells. The prolyl isomerase PIN1, whose overexpression in CAFs hasnt been fully profiled yet, plays critical roles in tumor initiation and progression. To decipher effects of selective PIN1 inhibition in CAFs on pancreatic cancer, we formulate DNA-barcoded micellular systems (DMS) encapsulating PIN1 inhibitor. DMS functionalized with CAFs-targeting antibodies (antiCAFs-DMS) can selectively inhibit PIN1 in CAFs of the tumor, leading to efficacious but temporal tumor inhibitions. We further integrate DNA aptamers (AptT), which can engage CD8+ T lymphocytes, to antiCAFs-DMS and thus prepare the bispecific antiCAFs-DMS-AptT system. AntiCAFs-DMS-AptT shows its potent capacity to eradicate pre-established subcutaneous and orthotopic pancreatic cancer on mice.

bioengineering↗

bioRxiv2022

Retrieval context determines whether event boundaries impair or enhance temporal order memory

Meaningful changes in context create "event boundaries", segmenting continuous experience into distinct episodes in memory. A foundational finding in this literature is that event boundaries impair memory for the temporal order of stimuli spanning a boundary compared to equally spaced stimuli within an event. This seems surprising in light of intuitions about memory in everyday life, where the order of within-event experiences (did I have coffee before the first bite of bagel?) often seems more difficult to recall than the order of events per se (did I have breakfast or do the dishes first?). Here, we aimed to resolve this discrepancy by manipulating whether stimuli carried information about their encoding context during retrieval, as they often do in everyday life (e.g., bagel-breakfast). In Experiments 1 and 2, we show that stimuli inherently associated with a unique encoding context produce a "flipped" order memory effect, whereby temporal memory was superior for cross-boundary than within-event item pairs. In Experiments 3 and 4, we added context information at retrieval to a standard laboratory event memory protocol where stimuli were encoded in the presence of arbitrary context cues (colored frames). We found that whether temporal order memory for cross-boundary stimuli was enhanced or impaired relative to within-event items depended on whether the context was present or absent during the memory test. Taken together, we demonstrate that the effect of event boundaries on temporal memory is malleable, and determined by the availability of context information at retrieval.

neuroscience↗

bioRxiv2021

Targeting of Cdc42 GTPase in regulatory T cells unleashes anti-tumor T cell immunity

Regulatory T (Treg) cells play an important role in maintaining immune tolerance through inhibiting effector T cell function. In the tumor microenvironment, Treg cells are utilized by tumor cells to counteract effector T cell-mediated tumor killing. Targeting Treg cells may thus unleash the anti-tumor activity of effector T cells. While systemic depletion of Treg cells can cause excessive effector T cell responses and subsequent autoimmune diseases, controlled targeting of Treg cells may benefit cancer patients. Here we show that Treg cell-specific heterozygous deletion or pharmacological targeting of Cdc42 GTPase does not affect Treg cell numbers but induces Treg cell plasticity, leading to anti-tumor T cell immunity without detectable autoimmune reactions. Cdc42 targeting potentiates an immune checkpoint blocker anti-PD-1 antibody-mediated T cell response against mouse and human tumors. Mechanistically, Cdc42 targeting induces Treg cell plasticity and unleashes antitumor T cell immunity through carbonic anhydrase I-mediated pH changes. Thus, rational targeting of Cdc42 in Treg cells holds therapeutic promises in cancer immunotherapy. SignificanceEffector T lymphocytes promote autoimmune diseases but have potential to kill tumor cells. However, cancer cells can evade T cell-mediated killing in part by utilizing regulatory T (Treg) cells to inhibit effector T cell function. Here we show that Treg cell-specific heterozygous deletion of Cdc42 gene that encodes Cdc42 GTPase dampens Treg cell fitness through carbonic anhydrase I-mediated pH changes, leading to anti-tumor T cell immunity. Pharmacological targeting of Cdc42 mimics genetic deletion of Cdc42 in impairing Treg cell fitness and evoking anti-tumor T cell immunity. Importantly, Cdc42 targeting does not appear to cause systemic autoimmunity. Given that current cancer immunotherapies only demonstrate limited clinical efficacies, our findings may open a new avenue for cancer immunotherapy.

immunology↗

bioRxiv2021

A p53-Phosphoinositide Signalosome Regulates Nuclear Akt Activation

The tumor suppressor p53 and the phosphoinositide 3-kinase (PI3K)-Akt pathway have fundamental roles in regulating cell growth, apoptosis and are frequently mutated in cancer. Here, we show that genotoxic stress induces nuclear Akt activation by a p53-dependent mechanism that is independent from the canonical membrane-localized PI3K-Akt pathway. Upon genotoxic stress a nuclear p53-PI3,4,5P3 complex is generated in regions devoid of membranes by a nuclear PI3K, and this complex recruits all the kinases required to activate Akt and phosphorylate FOXOs, inhibiting DNA damage-induced apoptosis. Wild-type p53 activates nuclear Akt in an on/off fashion upon stress, whereas mutant p53 stimulates high basal Akt activity, indicating a fundamental difference. The nuclear p53-phosphoinositide signalosome is distinct from the canonical membrane-localized pathway and insensitive to PI3K inhibitors currently in the clinic, underscoring its therapeutic relevance. In briefp53 assembles a PI3K-Akt pathway that regulates nuclear Akt activation independent of the canonical pathway on membranes.

cell biology↗

bioRxiv2021

Dynamic assembly of the calcium hemostasis modulator 1 channel gates ATP permeation

Calcium hemostasis modulator 1 (CALHM1) is a voltage- and Ca2+-gated ATP channel that plays an important role in neuronal signaling. The currently reported CALHM structures are all in an ATP-conducting state, and the gating mechanism of ATP permeation remains elusive. Here, we report three cryo-EM reconstructions of Danio rerio heptameric CALHM1s with ordered or flexible long C-terminal helices as well as Danio rerio octameric CALHM1 with flexible long C-terminal helices at resolutions of 3.2 [A], 2.9 [A], and 3.5 [A]. Structural analysis revealed that the heptameric CALHM1s are in an ATP nonconducting state in which the pore diameter in the middle is approximately 6.6 [A]. Compared with those inside the octameric CALHM1s, the N- helices inside heptameric CALHM1s are in the "down" position to avoid steric clash with neighboring TM1 helices. Molecular dynamic simulation shows that the pore size is significantly increased for ATP molecule permeation during the movement of the N- helix from the "down" position to the "up" position. Therefore, we proposed a mechanism in which the "piston-like" motion of the N-helix drives the dynamic assembly of the CALHM1 channel for ATP molecule permeation. Our results provide insights into the ATP permeation mechanism of the CALHM1 channel.

biochemistry↗

bioRxiv2021

Cryo-EM structure of the human TACAN channel in a closed state

TACAN is an ion channel involved in sensing mechanical pain. It has recently been shown to represent a novel and evolutionarily conserved class of mechanosensitive channels. Here, we present the cryoelectron microscopic structure of human TACAN (hTACAN). hTACAN forms a dimer in which each protomer consists of a transmembrane globular domain (TMD) that is formed of six helices and an intracellular domain (ICD) that is formed of two helices. Molecular dynamic simulations suggest that a putative ion conduction pathway is located inside each protomer. Single point mutation of the key residue Met207 significantly increased the surface tension activated currents. Moreover, cholesterols were identified at the flank of each subunit. Our data show the molecular assembly of hTACAN and suggest that the wild type hTACAN is in a closed state, providing a basis for further understanding the activation mechanism of the hTACAN channel.

biochemistry↗

bioRxiv2021

Transfer of learned cognitive flexibility to novel stimuli and task sets

Adaptive behavior requires learning about the structure of ones environment to derive optimal action policies, and previous studies have documented transfer of such structural knowledge to bias choices in new environments. Here, we asked whether people could also acquire and transfer more abstract knowledge across different task environments, specifically expectations about cognitive control demands. Over three experiments, participants performed a probabilistic card-sorting task in environments of either a low or high volatility of task rule changes (requiring low or high cognitive flexibility respectively) before transitioning to a medium-volatility environment. Using reinforcement learning modeling, we consistently found that previous exposure to high task rule volatilities led to faster adaptation to rule changes in the subsequent transfer phase. These transfers of expectations about cognitive flexibility demands were both task- (Experiment 2) and stimulus- (Experiment 3) independent, thus demonstrating the formation and generalization of environmental structure knowledge to guide cognitive control. Statement of RelevanceWe investigated whether structural knowledge of one task environment can be transferred to guide cognitive control strategies in new environments. Past research has found that while learning generally improves subsequent performance, it does so only for the learned task ("near transfer") and has little or no generalizability to novel task rules and stimuli ("far transfer"). However, recent studies suggest that learning more abstract, structural task features (e.g., cognitive maps) allows for that knowledge to be applied to new environments. Here, we took a critical additional step and showed that people can acquire and transfer expectations about cognitive control demands (specifically cognitive flexibility) across different task environments. To our knowledge, this is the first demonstration of peoples ability to extract and re-use cognitive control learning parameters that transcend specific stimuli and tasks. This transfer of learned cognitive flexibility is particularly noteworthy because such flexibility is impaired in several common psychiatric conditions.

neuroscience↗

bioRxiv2021

Alternating lysis and lysogeny is a winning strategy in bacteriophages due to Parrondo's Paradox

Temperate bacteriophages lyse or lysogenize the host cells depending on various parameters of infection, a key one being the host population density. However, the effect of different propensities of phages for lysis and lysogeny on phage fitness is an open problem. We explore a nonlinear dynamic evolution model of competition between two phages, one of which is disadvantaged in both the lytic and lysogenic phases. We show that the disadvantaged phage can win the competition by alternating between the lytic and lysogenic phases, each of which individually is a "loser". This counter-intuitive result recapitulates Parrondos paradox in game theory, whereby individually losing strategies can combine to produce a winning outcome. The results suggest that evolution of phages optimizes the ratio between the lysis and lysogeny propensities rather than the phage reproduction rate in any individual phase. These findings are expected to broadly apply to the evolution of host-parasite interactions.

bioinformatics↗

bioRxiv2020

Lack of dcf1 leads to neuronal migration delay, axonal swollen and autism-related deficits

Perturbed neuronal migration and abnormal axonogenesis have been shown to be implicated in the pathogenesis of autism spectrum disorder (ASD). However, the molecular mechanism remains unknown. Here we demonstrate that dendritic cell factor 1(DCF1) is involved in neuronal migration and axonogenesis. The deletion of dcf1 in mice delays the localization of callosal projection neurons, while dcf1 overexpression restores normal migration. Delayed neurons appear as axon swelling and axonal boutons loss, resulting in a permanent deficit in the callosal projections. Western blot analysis indicates that absence of dcf1 leads to the abnormal activation of ERK signal. Differential protein expression assay shows that PEBP1, a negative regulator of the ERK signal, is significant downregulation in dcf1 KO mice. Direct interaction between DCF1 and PEBP1 is confirmed by Co-immunoprecipitation test, thus indicating that DCF1 regulates the ERK signal in a PEBP1-dependent pattern. As a result of the neurodevelopmental migration disorder, dcf1 deletion results in ASD-like behaviors in mice. This finding identifies a link between abnormal activated ERK signaling, delayed neuronal migration and autistic-like behaviors in humans.

neuroscience↗

bioRxiv2019

The functional convergence and heterogeneity of social, episodic, and self-referential thought in the default mode network

The default mode network (DMN) is engaged in a variety of cognitive settings, including social, semantic, temporal, spatial, and self-related tasks. Andrews-Hanna et al. (2010, 2012) proposed that the DMN consists of three distinct functional-anatomical subsystems - a dorsal medial prefrontal cortex (dMPFC) subsystem that supports social processing and introspection about mental states; a medial temporal lobe (MTL) subsystem that contributes to memory retrieval and construction of mental scenes; and a set of midline core hubs that are involved in processing self-referential information. We examined activity in the DMN subsystems during six different tasks: (1) theory of mind and (2) moral dilemmas (for social cognition), (3) autobiographical memory and (4) spatial navigation (for memory-based construction/simulation), (5) self/other adjective judgement (for self-related cognition), and finally, (6) a rest condition compared to a working memory task. At a broad level, we observed similar whole-brain activity maps for the six contrasts, and some response to every contrast in each of the three subsystems. In more detail, both univariate analysis and multivariate activity patterns showed partial functional separation, much of it in close accord with the proposals of separate dMPFC and MTL subsystems, though with less support for common activity across anterior and posterior regions of a midline core. Integrating social, spatial, self-related, and other aspects of a cognitive situation or episode, multiple components of the DMN may work closely together to provide the broad context for current mental activity.\n\nSignificance StatementActivity in the default mode network (DMN) can been found across a wide range of high-level tasks that involve social, semantic, episodic, or self-referential cognition. Given this diversity, an important proposal is that the DMN can be parcellated into subsystems with different cognitive functions. The current experiment employed a wide range of experimental tasks to directly test for functional convergence and heterogeneity between DMN regions. The results support both partial differentiation and integration; working together, distributed DMN regions may assemble the multiple contextual components of a cognitive situation or episode.

neuroscience↗

bioRxiv2019

Representation of task episodes in human cortical networks

Task episodes consist of sequences of steps that are performed to achieve a goal. We used fMRI to examine neural representation of task identity, component items, and sequential position, focusing on two major cortical systems - the multiple-demand (MD) and default mode networks (DMN). Human participants (20 male, 22 female) learned six tasks each consisting of four steps. Inside the scanner, participants were cued which task to perform and then sequentially identified the target item of each step in the correct order. Univariate time-course analyses indicated that intra-episode progress was tracked by a tonically increasing global response, plus an increasing phasic step response specific to MD regions. Inter-episode boundaries evoked a widespread response at episode onset, plus a marked offset response specific to DMN regions. Representational similarity analysis was used to examine encoding of task identity and component steps. Both networks represented the content and position of individual steps, but the DMN preferentially represented task identity while the MD network preferentially represented step-level information. Thus, although both DMN and MD networks are sensitive to step-level and episode-level information in the context of hierarchical task performance, they exhibit dissociable profiles in terms of both temporal dynamics and representational content. The results suggest collaboration of multiple brain regions in control of multi-step behavior, with MD regions particularly involved in processing the detail of individual steps, and DMN adding representation of broad task context. Significance StatementAchieving ones goals requires knowing what to do and when. Tasks are typically hierarchical, with smaller steps nested within overarching goals. For effective, flexible behavior, the brain must represent both levels. We contrast response time-courses and information content of two major cortical systems - the multiple-demand (MD) and default mode networks (DMN) - during multi-step task episodes. Both networks are sensitive to step-level and episode-level information, but with dissociable profiles. Intra-episode progress is tracked by tonically increasing global responses, plus MD-specific increasing phasic step responses. Inter-episode boundaries evoke widespread responses at episode onset, plus DMN-specific offset responses. Both networks encode content and position of individual steps, but the DMN and MD networks favor task identity and step-level information respectively.

neuroscience↗

bioRxiv2019

The time-course of component processes of selective attention

Attentional selection shapes human perception, enhancing relevant information, according to behavioral goals. While many studies have investigated individual neural signatures of attention, here we used multivariate decoding of electrophysiological brain responses (MEG/EEG) to track and compare multiple component processes of selective attention. Auditory cues instructed participants to select a particular visual target, embedded within a subsequent stream of displays. Combining single and multi-item displays with different types of distractors allowed multiple aspects of information content to be decoded, distinguishing distinct components of attention, as the selection process evolved. Although the task required comparison of items to an attentional \"template\" held in memory, signals consistent with such a template were largely undetectable throughout the preparatory period but re-emerged after presentation of a non-target choice display. Choice displays evoked strong neural representation of multiple target features, evolving over different timescales. We quantified five distinct processing operations with different time-courses. First, visual properties of the stimulus were strongly represented. Second, the candidate target was rapidly identified and localized in multi-item displays, providing the earliest evidence of modulation by behavioral relevance. Third, the identity of the target continued to be enhanced, relative to distractors. Fourth, only later was the behavioral significance of the target explicitly represented in single-item displays. Finally, if the target was not identified and search was to be resumed, then an attentional template was weakly reactivated. The observation that an items behavioral relevance directs attention in multi-item displays prior to explicit representation of target/non-target status in single-item displays is consistent with two-stage models of attention.

neuroscience↗

bioRxiv2018

Connectivity Patterns in Cognitive Control Networks Predict Naturalistic Multitasking Ability

Multitasking is a fundamental aspect of everyday life activities. To achieve a complex, multi-component goal, the tasks must be subdivided into sub-tasks and component steps, a critical function of prefrontal networks. The prefrontal cortex is considered to be organized in a cascade of executive processes from the sensorimotor to anterior prefrontal cortex, which includes execution of specific goal-directed action, to encoding and maintaining task rules, and finally monitoring distal goals. In the current study, we used a virtual multitasking paradigm to tap into real-world performance and relate it to each individuals resting-state functional connectivity in fMRI. While did not find any correlation between global connectivity of any of the major networks with multitasking ability, global connectivity of the lateral prefrontal cortex (LPFC) was predictive of EVET score. Further analysis showed that multivariate connectivity patterns within the sensorimotor network (SMN), and between-network connectivity of the frontopartietal network (FPN) and dorsal attention network (DAN), predicted individual multitasking ability and could be generalized to novel individuals. Together, these results support previous research that prefrontal networks underlie multitasking abilities and show that connectivity patterns in the cascade of prefrontal networks may explain individual differences in performance.

neuroscience↗

bioRxiv2018

Response of the multiple-demand network during simple stimulus discriminations

The multiple-demand (MD) network is sensitive to many aspects of task difficulty, including such factors as rule complexity, memory load, attentional switching and inhibition. Many accounts link MD activity to top-down task control, raising the question of response when performance is limited by the quality of sensory input, and indeed, some prior results suggest little effect of sensory manipulations. Here we examined judgments of motion direction, manipulating difficulty by either motion coherence or salience of irrelevant dots. We manipulated each difficulty type across six levels, from very easy to very hard, and additionally manipulated whether difficulty level was blocked, and thus known in advance, or randomized. Despite the very large manipulations employed, difficulty had little effect on MD activity, especially for the coherence manipulation. Contrasting with these small or absent effects, we observed the usual increase of MD activity with increased rule complexity. We suggest that, for simple sensory discriminations, it may be impossible to compensate for reduced stimulus information by increased top-down control.

neuroscience↗

bioRxiv2018

The Specificity of IQGAP1 Toward the PI3K-Akt Pathway is Dependent on the IQ3 motif

Epidermal growth factor receptor (EGFR) and its downstream phosphatidylinositol 3-kinase (PI3K) pathway are commonly deregulated in many cancers including head and neck cancer (HNC). Recently, we have shown that the IQ motif-containing GTPase-activating protein 1 (IQGAP1) provides a molecular platform to scaffold all the components from the PI3K-Akt pathway and results in the sequential generation of phosphatidylinositol-3,4,5-triphosphate (PI3,4,5P3). This makes the IQGAP1-PI3K scaffold a promising therapeutic target. In addition to the PI3K-Akt pathway, IQGAP1 also scaffolds the Ras-ERK pathway. To identify an IQGAP1 mutant that specifically loses IQGAP1-PI3K signaling but not other functions, we have focused on the IQ3 motif since this region binds with both the PIPK1 and PI3K enzymes and a short peptide derived from this sequence blocks binding and PI3K signaling. An IQ3 deletion mutant ({Delta}IQ3) in IQGAP1 was functionally compared with wild-type (WT) IQGAP1. We found that the IQ3 domain specifically mediates the PI3K-Akt pathway but does not regulate the Ras-ERK pathway. The IQ3 deletion mutant lost interactions with PI3K-Akt components but retained its binding of ERK pathway components and cell surface receptors, EGFR and integrins. In addition, the IQ3 deletion mutant lost regulation of cell migration. Consistently, the IQ3 motif derived peptide blocked Akt activation and led to the blockage of invasion mediated by EGFR organized into an integrin complex by syndecan-4. Taken together, this work has defined the IQGAP1 IQ3 motif as a specific target sequence for the scaffolding of the PI3K-AKT pathway.

cell biology↗