Feed-forward Activation Research Articles

Induction of filopodia formation by α-Actinin-2 via RelA with a feedforward activation loop promoting overt bone marrow metastasis of gastric cancer

BackgroundBone marrow metastasis (BMM) is underestimated in gastric cancer (GC). GC with BMM frequently complicate critical hematological abnormalities like diffused intravascular coagulation and microangiopathic hemolytic anemia, which constitute a highly aggressive GC (HAGC) subtype. HAGC present a very poor prognosis with peculiar clinical and pathological features when compared with not otherwise specified advanced GC (NAGC). But the molecular mechanisms underlying BMM from GC remain rudimentary.MethodsThe transcriptomic difference between HAGC and NAGC were analyzed. Genes that were specifically upregulated in HAGC were identified, and their effect on cell migration and invasion was studied. The function of ACTN2 gene were confirmed by GC cell lines, bone-metastatic animal model and patients’ tissues. Furthermore, the molecular mechanism of ACTN2 derived-BMM was explored by multiple immunofluorescence staining, western blot, chromatin immunoprecipitation, and luciferase reporter assays.ResultsWe elucidated the key mechanisms of BMM depending on the transcriptomic difference between HAGC and NAGC. Five genes specifically upregulated in HAGC were assessed their effect on cell migration and invasion. The ACTN2 gene encoding protein α-Actinin-2 was detected enhanced the metastatic capability and induced BMM of GC cells in mouse models. Mechanically, α-Actinin-2 was involved in filopodia formation where it promoted the Actin filament cross-linking by replacing α-Actinin-1 to form α-Actinin-2:α-Actinin-4 complexes in GC cells. Moreover, NF-κB subunit RelA and α-Actinin-2 formed heterotrimers in the nuclei of GC cells. As a direct target of RelA:α-Actinin-2 heterotrimers, the ACTN2 gene was a positive auto-regulatory loop for α-Actinin-2 expression.ConclusionsWe demonstrated a link between filopodia, BMM and ACTN2 activation, where a feedforward activation loop between ACTN2 and RelA is established via actin in response to distant metastasis. Given the novel filopodia formation function and the new mechanism of BMM in GC, we propose ACTN2 as a druggable molecular vulnerability that may provide potential therapeutic benefit against BMM of GC.

Oncostatin-M and OSM-Receptor Feed-Forward Activation of MAPK Induces Separable Stem-like and Mesenchymal Programs.

Small-molecule MAPK inhibitors may effectively target the OSM/OSMR-axis that leads to EMT and tumor initiating properties that promote aggressive PDAC.

Recurrent Circuits Amplify Corticofugal Signals and Drive Feedforward Inhibition in the Inferior Colliculus.

The inferior colliculus (IC) is a midbrain hub critical for perceiving complex sounds, such as speech. In addition to processing ascending inputs from most auditory brainstem nuclei, the IC receives descending inputs from auditory cortex that control IC neuron feature selectivity, plasticity, and certain forms of perceptual learning. Although corticofugal synapses primarily release the excitatory transmitter glutamate, many physiology studies show that auditory cortical activity has a net inhibitory effect on IC neuron spiking. Perplexingly, anatomy studies imply that corticofugal axons primarily target glutamatergic IC neurons while only sparsely innervating IC GABA neurons. Corticofugal inhibition of the IC may thus occur largely independently of feedforward activation of local GABA neurons. We shed light on this paradox using in vitro electrophysiology in acute IC slices from fluorescent reporter mice of either sex. Using optogenetic stimulation of corticofugal axons, we find that excitation evoked with single light flashes is indeed stronger in presumptive glutamatergic neurons compared with GABAergic neurons. However, many IC GABA neurons fire tonically at rest, such that sparse and weak excitation suffices to significantly increase their spike rates. Furthermore, a subset of glutamatergic IC neurons fire spikes during repetitive corticofugal activity, leading to polysynaptic excitation in IC GABA neurons owing to a dense intracollicular connectivity. Consequently, recurrent excitation amplifies corticofugal activity, drives spikes in IC GABA neurons, and generates substantial local inhibition in the IC. Thus, descending signals engage intracollicular inhibitory circuits despite apparent constraints of monosynaptic connectivity between auditory cortex and IC GABA neurons.SIGNIFICANCE STATEMENT Descending "corticofugal" projections are ubiquitous across mammalian sensory systems, and enable the neocortex to control subcortical activity in a predictive or feedback manner. Although corticofugal neurons are glutamatergic, neocortical activity often inhibits subcortical neuron spiking. How does an excitatory pathway generate inhibition? Here we study the corticofugal pathway from auditory cortex to inferior colliculus (IC), a midbrain hub important for complex sound perception. Surprisingly, cortico-collicular transmission was stronger onto IC glutamatergic compared with GABAergic neurons. However, corticofugal activity triggered spikes in IC glutamate neurons with local axons, thereby generating strong polysynaptic excitation and feedforward spiking of GABAergic neurons. Our results thus reveal a novel mechanism that recruits local inhibition despite limited monosynaptic convergence onto inhibitory networks.

Individual alpha frequency appears unrelated to the latency of early visual responses.

A large body of work has linked neural oscillations in the alpha-band (8-13 Hz) to visual perceptual outcomes. In particular, studies have found that alpha phase prior to stimulus onset predicts stimulus detection, and sensory responses and that the frequency of alpha can predict temporal properties of perception. These findings have bolstered the idea that alpha-band oscillations reflect rhythmic sampling of visual information, however the mechanisms of this are unclear. Recently two contrasting hypotheses have been proposed. According to the rhythmic perception account, alpha oscillations impose phasic inhibition on perceptual processing and primarily modulate the amplitude or strength of visual responses and thus the likelihood of stimulus detection. On the other hand, the discrete perception account proposes that alpha activity discretizes perceptual inputs thereby reorganizing the timing (not only the strength) of perceptual and neural processes. In this paper, we sought neural evidence for the discrete perception account by assessing the correlation between individual alpha frequencies (IAF) and the latency of early visual evoked event-related potential (ERP) components. If alpha cycles were responsible for shifting neural events in time, then we may expect higher alpha frequencies to be associated with earlier afferent visual ERPs. Participants viewed large checkerboard stimuli presented to either the upper or lower visual field that were designed to elicit a large C1 ERP response (thought to index feedforward primary visual cortex activation). We found no reliable correlation between IAF and the C1 latency, or subsequent ERP component latencies, suggesting that the timing of these visual-evoked potentials was not modulated by alpha frequency. Our results thus fail to find evidence for discrete perception at the level of early visual responses but leave open the possibility of rhythmic perception.

Abstract 5150: Improvement of hematopoiesis in primary low risk MDS with the TGFBR1 investigational inhibitor TP-6379

Abstract Background: The inflammaging modulator, S100A9, mediates immunosuppression and plays a key role in the pathogenesis of low-risk myelodysplastic syndrome (MDS). Specifically, S100A9’s feedforward activation in the bone marrow (BM) induces pyroptotic cell death of hematopoietic stem and progenitor cells (HSPC) and the activation and accumulation of myeloid-derived suppressor cells (MDSC). This process creates a suppressive microenvironment including the secretion of transforming growth factor β (TGFβ) that signals through the TGFβ receptor 1 (TGFBR1) to induce inhibitory processes that contribute to this phenotype. We hypothesize that targeting with an investigational TGFBR1 inhibitor, TP-6379, reduces immune suppression and restores hematopoiesis in MDS. Methods: Primary low risk MDS BM mononuclear cells (BMMNC) were obtained from the Moffitt Total Cancer Care Protocol and cultured in vitro with TP-6379. Healthy BMMNC were purchased, treated with or without recombinant S100A9 and TP-6379. Results: Treatment of primary MDS BMMNC (n=15) and S100A9-treated healthy BMMNC (n=5) with TP-6379 for 48 hours was observed to significantly improve proliferation of hematopoietic progenitor cells as measured by colony forming capacity. Total colonies, and BFU-E specific colonies, showed significant increase. This expansion of progenitors with treatment was validated by flow cytometric analysis of Lineage−HLA-DR−CD34+ HSPC and showed a reduction in genomic instability, measured by γH2AX. In addition, TP-6379 was observed to reduce the numbers of suppressive mediators; MDSC, T regs and senescent lymphocytes and increase the number of cytotoxic cells, including NK cells. Our analysis revealed that BMMNC with spliceosomal mutations, including SF3B1, have elevated sensitivity to TP-6379 treatment. Therefore, we tested wild type and SF3B1 K700E CRISPR knock-in K562 cells in the presence of TP-6379 for 48 hours. K562 is a well-established cell line model for study of MDS. The SF3B1 mutant expressing cells have significantly reduced BFU-E colony forming capacity, compared to wild type cells, concordant with higher pyroptosis activation and consistent with the BMMNC results. Hence, we measured phospho-SMAD activity, as a direct measure of TGFBR1 inhibition. SF3B1 mutant expressing cells were shown to be highly sensitive to TP-6379, with a significant loss of SMAD activation. Expression analysis of primary MDS, S100A9-treated healthy BMMNC cells and K562 SF3B1 mutant cells revealed elevated expression of SERPINE1 which was rescued by TP-6379 treatment. Conclusions: TP-6379 restores healthy hematopoiesis in low-risk MDS, which may translate into a strong therapeutic option in a disease with few clinical options. Importantly, our work also suggests a specific role for spliceosome dysfunction in bone marrow failure and a novel role for SERPINE1 in MDS and S100A9-induced suppression. Citation Format: Erika A. Eksioglu, Gabriela M. Wright, Jason M. Foulks, Matthew Lalonde, Steven L. Warner, Kenneth L. Wright. Improvement of hematopoiesis in primary low risk MDS with the TGFBR1 investigational inhibitor TP-6379. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5150.

Improved sensitivity and microvascular weighting of 3T laminar fMRI with GE-BOLD using NORDIC and phase regression

IntroductionFunctional MRI with spatial resolution in the submillimeter domain enables measurements of activation across cortical layers in humans. This is valuable as different types of cortical computations, e.g., feedforward versus feedback related activity, take place in different cortical layers. Laminar fMRI studies have almost exclusively employed 7T scanners to overcome the reduced signal stability associated with small voxels. However, such systems are relatively rare and only a subset of those are clinically approved. In the present study, we examined if the feasibility of laminar fMRI at 3T could be improved by use of NORDIC denoising and phase regression. Methods5 healthy subjects were scanned on a Siemens MAGNETOM Prisma 3T scanner. To assess across-session reliability, each subject was scanned in 3–8 sessions on 3–4 consecutive days. A 3D gradient echo EPI (GE-EPI) sequence was used for BOLD acquisitions (voxel size 0.82 mm isotopic, TR = 2.2 s) using a block design finger tapping paradigm. NORDIC denoising was applied to the magnitude and phase time series to overcome limitations in temporal signal-to-noise ratio (tSNR) and the denoised phase time series were subsequently used to correct for large vein contamination through phase regression. Results and conclusionNORDIC denoising resulted in tSNR values comparable to or higher than commonly observed at 7T. Layer-dependent activation profiles could thus be extracted robustly, within and across sessions, from regions of interest located in the hand knob of the primary motor cortex (M1). Phase regression led to substantially reduced superficial bias in obtained layer profiles, although residual macrovascular contribution remained. We believe the present results support an improved feasibility of laminar fMRI at 3T.

Structural basis for lipid and copper regulation of the ABC transporter MsbA

A critical step in lipopolysaccharide (LPS) biogenesis involves flipping lipooligosaccharide, an LPS precursor, from the cytoplasmic to the periplasmic leaflet of the inner membrane, an operation carried out by the ATP-binding cassette transporter MsbA. Although LPS binding to the inner cavity of MsbA is well established, the selectivity of MsbA-lipid interactions at other site(s) remains poorly understood. Here we use native mass spectrometry (MS) to characterize MsbA-lipid interactions and guide structural studies. We show the transporter co-purifies with copper(II) and metal binding modulates protein-lipid interactions. A 2.15 Å resolution structure of an N-terminal region of MsbA in complex with copper(II) is presented, revealing a structure reminiscent of the GHK peptide, a high-affinity copper(II) chelator. Our results demonstrate conformation-dependent lipid binding affinities, particularly for the LPS-precursor, 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo)2-lipid A (KDL). We report a 3.6 Å-resolution structure of MsbA trapped in an open, outward-facing conformation with adenosine 5’-diphosphate and vanadate, revealing a distinct KDL binding site, wherein the lipid forms extensive interactions with the transporter. Additional studies provide evidence that the exterior KDL binding site is conserved and a positive allosteric modulator of ATPase activity, serving as a feedforward activation mechanism to couple transporter activity with LPS biosynthesis.

The Influence of Anticipation of Movement Starting Time on Feedforward Activation of Trunk Muscles during Rapid Shoulder Joint Movements.

This study aimed to clarify the differences in the onset of trunk muscle activity with and without anticipation of the movement starting time during rapid shoulder movements. Ten healthy men in a relaxed upright position performed rapid 135° flexion, 135° abduction, and 45° extension of the shoulder on the dominant hand side with and without anticipation of the movement starting time. They moved their shoulder joints following a 3-s countdown and a light stimulus in the anticipation and non-anticipation conditions, respectively. Electromyography of the anterior and posterior quadratus lumborum, transversus abdominis, internal oblique, external oblique, rectus abdominis, lumbar multifidus, lumbar erector spinae on the non-dominant hand side, and the middle deltoid on the dominant hand side were measured. The onset of activity of each trunk muscle relative to the onset of the middle deltoid was calculated. Two-way analysis of variance (eight trunk muscles × two anticipation conditions) was used to compare the onset of electromyographic activity of the trunk muscles in each direction of the shoulder movement. There were significant interactions between the muscles and anticipation conditions during shoulder abduction and extension. The onset of activity in the anterior and posterior quadratus lumborum, transversus abdominis, and internal oblique occurred earlier with anticipation of the movement starting time than without anticipation during shoulder abduction and extension. The anticipation of movement starting time may contribute to a reliable center of mass control within the support base and improve lumbar spine stability by hastening the onset of activity of the deep trunk muscles.

High-fat diet induced cyclophilin B enhances STAT3/lncRNA-PVT1 feedforward loop and promotes growth and metastasis in colorectal cancer

High-fat diet (HFD) has been implicated to promote colorectal cancer (CRC). Recently, oncogene Cyclophilin B (CypB) is reported to be induced by cholesterol. However, the role of CypB in CRC carcinogenesis and metastasis associated with HFD remains unknown. In the present study, we showed that HFD-induced CypB enhances proliferation and metastasis through an inflammation-driven circuit, including Signal Transducer and Activator of Transcription 3 (STAT3)-triggered transcription of lncRNA-PVT1, and its binding with CypB that promotes activation of STAT3. CypB was found to be upregulated in CRC, which was correlated with elevated body mass index and poor prognosis. HFD induced CypB expression and proinflammatory cytokines in colon of mice. Besides, CypB restoration facilitated growth, invasion and metastasis in CRC cells both in vitro and in vivo. Moreover, RIP sequencing data identified lncRNA-PVT1 as a functional binding partner of CypB. Mechanistically, PVT1 increased the phosphorylation and nuclear translocation of STAT3 in response to IL-6, through directly interaction with CypB, which impedes the binding of Suppressors Of Cytokine Signalling 3 (SOCS3) to STAT3. Furthermore, STAT3 in turn activated PVT1 transcription through binding to its promoter, forming a regulatory loop. Finally, this CypB/STAT3/PVT1 axis was verified in TCGA datasets and CRC tissue arrays. Our data revealed that CypB linked HFD and CRC malignancy by enhancing the CypB/STAT3/PVT1 feedforward axis and activation of STAT3.

Perception and memory have distinct spatial tuning properties in human visual cortex

Reactivation of earlier perceptual activity is thought to underlie long-term memory recall. Despite evidence for this view, it is unclear whether mnemonic activity exhibits the same tuning properties as feedforward perceptual activity. Here, we leverage population receptive field models to parameterize fMRI activity in human visual cortex during spatial memory retrieval. Though retinotopic organization is present during both perception and memory, large systematic differences in tuning are also evident. Whereas there is a three-fold decline in spatial precision from early to late visual areas during perception, this pattern is not observed during memory retrieval. This difference cannot be explained by reduced signal-to-noise or poor performance on memory trials. Instead, by simulating top-down activity in a network model of cortex, we demonstrate that this property is well explained by the hierarchical structure of the visual system. Together, modeling and empirical results suggest that computational constraints imposed by visual system architecture limit the fidelity of memory reactivation in sensory cortex.

An engineered concealed IL-15-R elicits tumor-specific CD8+T cell responses through PD-1-cis delivery.

Checkpoint blockade immunotherapy releases the inhibition of tumor-infiltrating lymphocytes (TILs) but weakly induces TIL proliferation. Exogenous IL-15 could further expand TILs and thus synergize with αPD-L1 therapy. However, systemic delivery of IL-15 extensively expands peripheral NK cells, causing severe toxicity. To redirect IL-15 to intratumoral PD-1+CD8+T effector cells instead of NK cells for better tumor control and lower toxicity, we engineered an anti-PD-1 fusion with IL-15-IL-15Rα, whose activity was geographically concealed by immunoglobulin Fc region with an engineered linker (αPD-1-IL-15-R) to bypass systemic NK cells. Systematic administration of αPD-1-IL-15-R elicited extraordinary antitumor efficacy with undetectable toxicity. Mechanistically, cis-delivery of αPD-1-IL-15-R vastly expands tumor-specific CD8+T cells for tumor rejection. Additionally, αPD-1-IL-15-R upregulated PD-1 and IL-15Rβ on T cells to create a feedforward activation loop, thus rejuvenating TILs, not only resulting in tumor control in situ, but also suppressing tumor metastasis. Collectively, renavigating IL-15 to tumor-specific PD-1+CD8+T cells, αPD-1-IL-15-R elicits effective systemic antitumor immunity.

Abstract 5849: Activation of STAT3 is mediated by FGFR4 induction via SRC signaling after H. pylori infection

Abstract Background: Gastric cancer is considered the 5th most common form of cancer and 4th leading cause of cancer-related deaths worldwide. Due to the late stage of diagnosis, gastric cancer carries poor prognosis and poor overall survival. Infection with H. pylori is the strongest known risk factor. Fibroblast Growth Factor Receptor 4 (FGFR4) belongs to a family of highly conserved tyrosine kinases. This study investigated the molecular mechanism of FGFR4 regulation in response to H. pylori infection. Methods and Results: Among all the FGFRs, FGFR4 mRNA expression level was the most significantly elevated in human gastric cancer samples as compared to normal samples, using Real-time qPCR. These results were confirmed using the TCGA and Geo database analysis, confirming that FGFR4 is highly expressed in gastric cancer. Using western blot, we found that FGFR4 is significantly expressed in dysplasia and adenocarcinoma lesions in the TFF1-KO gastric cancer mouse model. Following infection with H. pylori in in-vitro (J166, 7.13) and in-vivo (PMSS1) models, we detected a significant increase in the expression of FGFR4 at the protein and mRNA levels. We also detected activation of STAT3 in human gastric cell lines and mice gastric tissues. Furthermore, analysis of FGFR4 promoter revealed several putative binding sites for STAT3. To confirm that FGFR4 expression is dependent upon STAT3 activation, we performed ChIP assay and confirmed direct functional binding of STAT3 on FGFR4 promoter. Using the FGF19, the ligand for FGFR4, we found that FGF19-FGFR4 axis played a vital role in activating STAT3 through an SRC-dependent mechanism and discovered that there is a feedforward activation loop between FGFR4 and STAT3. Functionally, we found that FGFR4 protected against H. pylori-induced DNA damage and cell death. Conclusion: Our study established a feedforward activation loop between FGFR4 and STAT3 in response to H. pylori infection and FGFR4 could be a possible druggable moiety for future therapies in gastric cancer. Citation Format: Nadeem S. Bhat, Mohammed Soutto, Xing Zhang, Zheng Chen, Shoumin Zhu, Heng Lu, Dunfa Peng, Zekuan Xu, Wael El-Rifai. Activation of STAT3 is mediated by FGFR4 induction via SRC signaling after H. pylori infection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5849.

Induction of Fibroblast Growth Factor Receptor 4 by Helicobacter pylori via Signal Transducer and Activator of Transcription 3 With a Feedforward Activation Loop Involving SRC Signaling in Gastric Cancer

Helicobacter pylori (H pylori) infection is the main risk factor for gastric cancer. The role of fibroblast growth factor receptors (FGRFs) in H pylori-mediated gastric tumorigenesis remains largely unknown. This study investigated the molecular and mechanistic links between H pylori, inflammation, and FGFR4 in gastric cancer. Cell lines, human and mouse gastric tissue samples, and gastric organoids models were implemented. Infection with H pylori was performed using invitro and invivo models. Western blot, real-time quantitative reverse-transcription polymerase chain reaction, flow cytometry, immunofluorescence, immunohistochemistry, chromatin immunoprecipitation, and luciferase reporter assays were used for molecular, mechanistic, and functional studies. Analysis of FGFR family members using The Cancer Genome Atlas data, followed by validation, indicated that FGFR4 messenger (m)RNA was the most significantly overexpressed member in human gastric cancer tissue samples (P < .001). We also detected high levels of Fgfr4 mRNA and protein in gastric dysplasia and adenocarcinoma lesions in mouse models. Infection with J166, 7.13, and PMSS1 cytotoxin-associated gene A (CagA)+ H pylori strains induced FGFR4 mRNA and protein expression in invitro and invivo models. This was associated with a concordant activation of signal transducer and activator of transcription 3 (STAT3). Analysis of the FGFR4 promoter suggested several putative binding sites for STAT3. Using chromatin immunoprecipitation assay and an FGFR-promoter luciferase reporter containing putative STAT3 binding sites and their mutants, we confirmed a direct functional binding of STAT3 on the FGFR4 promoter. Mechanistically, we also discovered a feedforward activation loop between FGFR4 and STAT3 where the fibroblast growth factor 19-FGFR4 axis played an essential role in activating STAT3 in a steroid receptor coactivator-dependent manner. Functionally, we found that FGFR4 protected against H pylori-induced DNA damage and cell death. Our findings demonstrated a link between infection, inflammation, and FGFR4 activation, where a feedforward activation loop between FGFR4 and STAT3 is established via steroid receptor coactivator in response to H pylori infection. Given the relevance of FGFR4 to the etiology and biology of gastric cancer, we propose FGFR4 as a druggable molecular vulnerability that can be tested in patients with gastric cancer.

Gamma Activation and Alpha Suppression within Human Auditory Cortex during a Speech Classification Task.

The dynamics of information flow within the auditory cortical hierarchy associated with speech processing and the emergence of hemispheric specialization remain incompletely understood. To study these questions with high spatiotemporal resolution, intracranial recordings in 29 human neurosurgical patients of both sexes were obtained while subjects performed a semantic classification task. Neural activity was recorded from posteromedial portion of Heschl's gyrus (HGPM) and anterolateral portion of Heschl's gyrus (HGAL), planum temporale (PT), planum polare, insula, and superior temporal gyrus (STG). Responses to monosyllabic words exhibited early gamma power increases and a later suppression of alpha power, envisioned to represent feedforward activity and decreased feedback signaling, respectively. Gamma activation and alpha suppression had distinct magnitude and latency profiles. HGPM and PT had the strongest gamma responses with shortest onset latencies, indicating that they are the earliest auditory cortical processing stages. The origin of attenuated top-down influences in auditory cortex, as indexed by alpha suppression, was in STG and HGAL. Gamma responses and alpha suppression were typically larger to nontarget words than tones. Alpha suppression was uniformly greater to target versus nontarget stimuli. Hemispheric bias for words versus tones and for target versus nontarget words, when present, was left lateralized. Better task performance was associated with increased gamma activity in the left PT and greater alpha suppression in HGPM and HGAL bilaterally. The prominence of alpha suppression during semantic classification and its accessibility for noninvasive electrophysiologic studies suggests that this measure is a promising index of auditory cortical speech processing.SIGNIFICANCE STATEMENT Understanding the dynamics of cortical speech processing requires the use of active tasks. This is the first comprehensive intracranial electroencephalography study to examine cortical activity within the superior temporal plane, lateral superior temporal gyrus, and the insula during a semantic classification task. Distinct gamma activation and alpha suppression profiles clarify the functional organization of feedforward and feedback processing within the auditory cortical hierarchy. Asymmetries in cortical speech processing emerge at early processing stages. Relationships between cortical activity and task performance are interpreted in the context of current models of speech processing. Results lay the groundwork for iEEG studies using connectivity measures of the bidirectional information flow within the auditory processing hierarchy.

Feedforward coactivation of trunk muscles during rapid shoulder movements.

BackgroundShoulder movements that involve unilateral and bilateral flexion, extension, abduction, and asymmetrical flexion-extension cause the activity of trunk muscles. There has not been a fixed consensus on the onset of deep trunk muscle activities including the psoas major (PM), quadratus lumborum (QL), transversus abdominis (TrA), and lumbar multifidus (MF) during shoulder movements. The purpose of this study was to measure the onset of electromyographic activity of the deep trunk muscles during rapid shoulder movements and clarify the coordinated activity pattern of the deep trunk muscles during 11 shoulder movements.MethodsThirteen men participated in this study. The onset of activity of the right deep trunk muscles (PM, QL, TrA, and MF) were measured using fine-wire electrodes, and those of the right and left deltoid (anterior, middle, and posterior) and right superficial trunk muscles (rectus abdominis, external oblique [EO], and internal oblique [IO]) were measured using surface electrodes as participants performed 6 types of unilateral, 3 types of bilateral, and 2 types of asymmetrical rapid shoulder movements. We defined feedforward activation as the onset of activity of trunk muscle before or within +50 ms onset of the deltoid muscle and feedback activation as that after +50 ms. A 1-way analysis of variance was performed to compare the onset of activity of each muscle during each shoulder movement.ResultsThe mean onset of activity of the PM (26.0 ms), QL (13.1 ms), TrA (−19.7 ms), and MF (20.4 ms) muscles demonstrated feedforward activation during left shoulder flexion. The onset of activity of the TrA (1.6-48.7 ms), rectus abdominis (−1.7 to 17.3 ms), and EO (5.6–40.8 ms) muscles demonstrated feedforward activation during left, right, and bilateral shoulder extension. The onset of activity of the PM (22.9 ms), QL (23.0 ms), TrA (18.9 ms), and EO (15.4 ms) demonstrated feedforward activation during left shoulder abduction, while that of the IO (4.4–10.9 ms) only demonstrated feedforward activation during right and bilateral shoulder abduction. The onset of activity of the TrA (−27.6 ms) and IO (−23.9 ms) demonstrated feedforward activation during left shoulder flexion-right shoulder extension, and that of the MF (33.4 ms) and EO (−17.2 ms), during left shoulder extension-right shoulder flexion.ConclusionRapid shoulder movements occur with coordinated muscle activation of the deep trunk muscles depending on the direction of shoulder movements. Feedforward activation of single or combined deep trunk muscles may facilitate rapid shoulder movements.

The Effect of Kinesio Taping on the Feedforward Activity of the Lower Limb Muscles in Elite Volleyball Players With and Without Chronic Ankle Instability Performing Single-leg Jump-landing

Purpose: The current research aims to examine the effect of taping on the feedforward activity of the lower limb muscles in elite volleyball players with and without chronic ankle instability while performing single-leg jump-landing. Methods: The electromyographic activities of the lateral gastrocnemius, tibialis anterior, peroneus longus, rectus femoris, gluteus medius, and vastus lateralis of the non-dominant leg were registered before and after taping in 26 volleyball players while performing the spike skill with single-leg landing. These volleyball players entered the research by purposive sampling. The root mean square (RMS) was employed to compute muscle activity before and after taping. The multivariate analysis of variance (MANOVA) test at P≤0.05 was utilized to analyze the data. Results: The results of the multivariate analysis of variance (MANOVA) test demonstrated that the groups did not have a significant factor in any of the variables in the feedforward phase, except for the maximum root mean square (RMS) of the peroneus longus muscle (P=0.01). Conclusion: The results showed that taping cannot improve the feedforward activity of the selected muscles during single-leg landing in people with chronic ankle instability. Therefore, it is recommended to use other methods and exercises to improve the muscle feedforward activity in these individuals during the rehabilitation phases.

Unravelling the Role of Kinases That Underpin Androgen Signalling in Prostate Cancer.

The androgen receptor (AR) signalling pathway is the key driver in most prostate cancers (PCa), and is underpinned by several kinases both upstream and downstream of the AR. Many popular therapies for PCa that target the AR directly, however, have been circumvented by AR mutation, such as androgen receptor variants. Some upstream kinases promote AR signalling, including those which phosphorylate the AR and others that are AR-regulated, and androgen regulated kinase that can also form feed-forward activation circuits to promotes AR function. All of these kinases represent potentially druggable targets for PCa. There has generally been a divide in reviews reporting on pathways upstream of the AR and those reporting on AR-regulated genes despite the overlap that constitutes the promotion of AR signalling and PCa progression. In this review, we aim to elucidate which kinases—both upstream and AR-regulated—may be therapeutic targets and require future investigation and ongoing trials in developing kinase inhibitors for PCa.

Visual speech differentially modulates beta, theta, and high gamma bands in auditory cortex.

Speech perception is a central component of social communication. Although principally an auditory process, accurate speech perception in everyday settings is supported by meaningful information extracted from visual cues. Visual speech modulates activity in cortical areas subserving auditory speech perception including the superior temporal gyrus (STG). However, it is unknown whether visual modulation of auditory processing is a unitary phenomenon or, rather, consists of multiple functionally distinct processes. To explore this question, we examined neural responses to audiovisual speech measured from intracranially implanted electrodes in 21 patients with epilepsy. We found that visual speech modulated auditory processes in the STG in multiple ways, eliciting temporally and spatially distinct patterns of activity that differed across frequency bands. In the theta band, visual speech suppressed the auditory response from before auditory speech onset to after auditory speech onset (-93 to 500 ms) most strongly in the posterior STG. In the beta band, suppression was seen in the anterior STG from -311 to -195 ms before auditory speech onset and in the middle STG from -195 to 235 ms after speech onset. In high gamma, visual speech enhanced the auditory response from -45 to 24 ms only in the posterior STG. We interpret the visual-induced changes prior to speech onset as reflecting crossmodal prediction of speech signals. In contrast, modulations after sound onset may reflect a decrease in sustained feedforward auditory activity. These results are consistent with models that posit multiple distinct mechanisms supporting audiovisual speech perception.

Trunk Angle Modulates Feedforward and Feedback Control during Single-Limb Squatting.

Trunk positioning and unexpected perturbations are high-risk conditions at the time of anterior cruciate ligament injury. The influence of trunk positioning on motor control responses to perturbation during dynamic performance is not known. We tested the influence of trunk position on feedforward and feedback control during unexpected perturbations while performing a novel single-limb squatting task. We also assessed the degree that feedforward control was predictive of feedback responses. In the flexed trunk condition, there were increased quadriceps (p < 0.026) and gluteus medius long-latency reflexes (p < 0.001) and greater quadriceps-to-hamstrings co-contraction during feedforward (p = 0.017) and feedback (p = 0.007) time bins. Soleus long-latency reflexes increased more than 100% from feedforward muscle activity regardless of trunk condition. Feedforward muscle activity differentially predicted long-latency reflex responses depending on the muscle (R2: 0.47–0.97). These findings support the concept that trunk positioning influences motor control responses to perturbation and that feedback responses may be invariant to the feedforward control strategy.

Coordinate activity of the quadratus lumborum posterior layer, lumbar multifidus, erector spinae, and gluteus medius during single-leg forward landing

This study aimed to clarify the differences in electromyographic activity between the quadratus lumborum anterior (QL-a) and posterior layers (QL-p), and the relationship among trunk muscles and gluteus medius (GMed) activities during forward landing. Thirteen healthy men performed double-leg and single-leg (ipsilateral or contralateral sides as the electromyography measurement of trunk muscles) forward landings from a 30 cm-height-box. The onset of electromyographic activity in pre-landing and the electromyographic amplitude of the unilateral QL-a, QL-p, abdominal muscles, lumbar multifidus (LMF), erector spinae (LES), and bilateral GMed were recorded. Two-way ANOVA was used to compare the onset of electromyographic activity (3 landing leg conditions × 10 muscles) and electromyographic amplitude among (3 landing leg conditions × 2 phases). The onset of QL-p was significantly earlier in contralateral-leg landing than in the double-leg and ipsilateral-leg landings. The onset of LMF and LES was significantly earlier than that of the abdominal muscles in contralateral-leg landing. QL-p activity and GMed activity on the contralateral leg side in the pre-landing were significantly higher in contralateral-leg landing than in the other leg landings. To prepare for pelvic and trunk movements after ground contact, LMF, LES, QL-p on non-support leg side, and GMed on support leg side showed early or high feedforward activation before ground contact during single-leg forward landing.