Carotid body dysregulation contributes to Long COVID symptoms.

BACKGROUND: The symptoms of long COVID, which include fatigue, breathlessness, dysregulated breathing, and exercise intolerance, have unknown mechanisms. These symptoms are also observed in heart failure and are partially driven by increased sensitivity of the carotid chemoreflex. As the carotid body has an abundance of ACE2 (the cell entry mechanism for SARS-CoV-2), we investigated whether carotid chemoreflex sensitivity was elevated in participants with long COVID. METHODS: Non-hositalised participants with long-COVID (n = 14) and controls (n = 14) completed hypoxic ventilatory response (HVR; the measure of carotid chemoreflex sensitivity) and cardiopulmonary exercise tests. Parametric and normally distributed data were compared using Student's unpaired t-tests or ANOVA. Nonparametric equivalents were used where relevant. Peason's correlation coefficient was used to examine relationships between variables. RESULTS: During cardiopulmonary exercise testing the VE/VCO2 slope (a measure of breathing efficiency) was higher in the long COVID group (37.8 ± 4.4) compared to controls (27.7 ± 4.8, P = 0.0003), indicating excessive hyperventilation. The HVR was increased in long COVID participants (-0.44 ± 0.23 l/min/ SpO2%, R2 = 0.77 ± 0.20) compared to controls (-0.17 ± 0.13 l/min/SpO2%, R2 = 0.54 ± 0.38, P = 0.0007). The HVR correlated with the VE/VCO2 slope (r = -0.53, P = 0.0036), suggesting that excessive hyperventilation may be related to carotid body hypersensitivity. CONCLUSIONS: The carotid chemoreflex is sensitised in long COVID and may explain dysregulated breathing and exercise intolerance in these participants. Tempering carotid body excitability may be a viable treatment option for long COVID patients.

Patients with long COVID suffer from breathlessness during exercise, leading to exercise intolerance. We know that SARS-CoV-2, the virus that causes COVID-19, can infect carotid bodies which is a small sensory organ that sends signals to the brain for regulating breathing and blood pressure. This is called the carotid chemoreflex. However, it is not clear if SARS-CoV-2 infection affects carotid chemoreflex. Here, we examine whether the normal functioning of carotid chemoreflex is disrupted in non-hospitalised patients with long COVID and if this is linked to excessive breathing during exercise. Our study shows that carotid chemoreflex is more sensitive in long COVID patients, who are otherwise healthy. The carotid bodies could be a good therapeutic target for treating breathlessness in patients with long COVID.

Aging in females is associated with changes in respiratory modulation of sympathetic nerve activity and blood pressure.

Sympathetic nerve activity (SNA) is tightly coupled with the respiratory cycle. In healthy human males, respiratory modulation of SNA does not change with age. However, it is unclear how this modulation is affected by age in females. We investigated whether respiratory sympathetic modulation is altered in healthy postmenopausal (PMF) versus premenopausal female (YF), and younger male (YM) adults, and determined its relationship to resting blood pressure. Muscle SNA (MSNA; microneurography), respiration (transducer belt), ECG, and continuous blood pressure were measured in 12 YF, 13 PMF, and 12 YM healthy volunteers. Respiratory modulation of MSNA was quantified during two phases of the respiratory cycle: mid-late expiration and inspiration/postinspiration. All groups showed respiratory modulation of MSNA (P < 0.0005). There was an interaction between the respiratory phase and group for MSNA [bursts/100 heartbeats (HB) (P = 0.004) and bursts/min (P = 0.029)], with smaller reductions in MSNA during inspiration observed in PMF versus the other groups. Respiratory modulation of blood pressure was also reduced in PMF versus YF (6 [2] vs. 12 [9] mmHg, P = 0.008) and YM (13 [13] mmHg, P = 0.001, median [interquartile range]). The magnitude of respiratory sympathetic modulation was related to resting blood pressure in PMF only, such that individuals with less modulation had greater resting blood pressure. The data indicate that aging in postmenopausal females is associated with less inspiratory inhibition of MSNA. This correlated with a higher resting blood pressure in PMF only. Thus, the reduced modulation of MSNA could contribute to the age-related rise in blood pressure that occurs in females.NEW & NOTEWORTHY The current study demonstrates that respiratory modulation of sympathetic nerve activity (SNA) is reduced in healthy postmenopausal (PMF) versus premenopausal females (YF). Furthermore, respiratory sympathetic modulation was negatively related to resting blood pressure in postmenopausal females, such that blood pressure was greater in individual with less modulation. Reduced respiratory sympathetic modulation may have implications for the autonomic control of blood pressure in aging postmenopausal females, by contributing to age-related sympathetic activation and reducing acute, respiratory-linked blood pressure variation.

Phonological parafoveal pre-processing in children reading English sentences.

Although previous research has shown that, in English, both adult and teenage readers parafoveally pre-process phonological information during silent reading, to date, no research has been conducted to investigate such processing in children. Here we used the boundary paradigm during silent sentence reading, to ascertain whether typically developing English children, like adults, parafoveally process words phonologically. Participants' eye movements (adults: n = 48; children: n = 48) were recorded as they read sentences which contained, in preview, correctly spelled words (e.g., cheese), pseudohomophones (e.g., cheeze), or spelling controls (e.g., cheene). The orthographic similarity of the target words available in preview was also manipulated to be similar (e.g., cheese/cheeze/cheene) or dissimilar (e.g., queen/kween/treen). The results indicate that orthographic similarity facilitated both adults' and children's pre-processing. Moreover, children parafoveally pre-processed words phonologically very early in processing. The children demonstrated a pseudohomophone advantage from preview that was broadly similar to the effect displayed by the adults, although the orthographic similarity of the pseudohomophone previews was more important for the children than the adults. Overall, these results provide strong evidence for phonological recoding during silent English sentence reading in 8-9-year-old children.

The importance of the first letter in children's parafoveal preprocessing in English: Is it phonologically or orthographically driven?

For both adult and child readers of English, the first letter of a word plays an important role in lexical identification. Using the boundary paradigm during silent sentence reading, we examined whether the first-letter bias in parafoveal preprocessing is phonologically or orthographically driven and whether this differs between skilled adult and beginner child readers. Participants read sentences that contained either a correctly spelled word in preview (identity; e.g., "circus"), a preview letter string that maintained the phonology but manipulated the orthography of the first letter (P + O- preview; e.g., "sircus"), or a preview letter string that manipulated both the phonology and the orthography of the first letter (P- O- preview; e.g., "wircus"). There was a cost associated with manipulating the first letter of the target words in preview for both adults and children. Critically, during first-pass reading, both adult and child readers displayed similar reading times between P + O- and P- O- previews. This shows that the first-letter bias is driven by orthographic encoding and that the first letter's orthographic code in preview is crucial for efficient, early processing of phonology. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Pro-inflammatory role of Wnt/ß-catenin signaling in endothelial dysfunction.

Background: Endothelial dysfunction is a critical component of both atherosclerotic plaque formation and saphenous vein graft failure. Crosstalk between the pro-inflammatory TNF-α-NFκB signaling axis and the canonical Wnt/ß-catenin signaling pathway potentially plays an important role in regulating endothelial dysfunction, though the exact nature of this is not defined. Results: In this study, cultured endothelial cells were challenged with TNF-α and the potential of a Wnt/ß-catenin signaling inhibitor, iCRT-14, in reversing the adverse effects of TNF-α on endothelial physiology was evaluated. Treatment with iCRT-14 lowered nuclear and total NFκB protein levels, as well as expression of NFκB target genes, IL-8 and MCP-1. Inhibition of ß-catenin activity with iCRT-14 suppressed TNF-α-induced monocyte adhesion and decreased VCAM-1 protein levels. Treatment with iCRT-14 also restored endothelial barrier function and increased levels of ZO-1 and focal adhesion-associated phospho-paxillin (Tyr118). Interestingly, inhibition of ß-catenin with iCRT-14 enhanced platelet adhesion in cultured TNF-α-stimulated endothelial cells and in an ex vivo human saphenous vein model, most likely via elevating levels of membrane-tethered vWF. Wound healing was moderately retarded by iCRT-14; hence, inhibition of Wnt/ß-catenin signaling may interfere with re-endothelialisation in grafted saphenous vein conduits. Conclusion: Inhibition of the Wnt/ß-catenin signaling pathway with iCRT-14 significantly recovered normal endothelial function by decreasing inflammatory cytokine production, monocyte adhesion and endothelial permeability. However, treatment of cultured endothelial cells with iCRT-14 also exerted a pro-coagulatory and moderate anti-wound healing effect: these factors may affect the suitability of Wnt/ß-catenin inhibition as a therapy for atherosclerosis and vein graft failure.

Obesity and diabetes are major risk factors for epicardial adipose tissue inflammation.

BACKGROUNDEpicardial adipose tissue (EAT) directly overlies the myocardium, with changes in its morphology and volume associated with myriad cardiovascular and metabolic diseases. However, EAT's immune structure and cellular characterization remain incompletely described. We aimed to define the immune phenotype of EAT in humans and compare such profiles across lean, obese, and diabetic patients.METHODSWe recruited 152 patients undergoing open-chest coronary artery bypass grafting (CABG), valve repair/replacement (VR) surgery, or combined CABG/VR. Patients' clinical and biochemical data and EAT, subcutaneous adipose tissue (SAT), and preoperative blood samples were collected. Immune cell profiling was evaluated by flow cytometry and complemented by gene expression studies of immune mediators. Bulk RNA-Seq was performed in EAT across metabolic profiles to assess whole-transcriptome changes observed in lean, obese, and diabetic groups.RESULTSFlow cytometry analysis demonstrated EAT was highly enriched in adaptive immune (T and B) cells. Although overweight/obese and diabetic patients had similar EAT cellular profiles to lean control patients, the EAT exhibited significantly (P ≤ 0.01) raised expression of immune mediators, including IL-1, IL-6, TNF-α, and IFN-γ. These changes were not observed in SAT or blood. Neither underlying coronary artery disease nor the presence of hypertension significantly altered the immune profiles observed. Bulk RNA-Seq demonstrated significant alterations in metabolic and inflammatory pathways in the EAT of overweight/obese patients compared with lean controls.CONCLUSIONAdaptive immune cells are the predominant immune cell constituent in human EAT and SAT. The presence of underlying cardiometabolic conditions, specifically obesity and diabetes, rather than cardiac disease phenotype appears to alter the inflammatory profile of EAT. Obese states markedly alter EAT metabolic and inflammatory signaling genes, underlining the impact of obesity on the EAT transcriptome profile.FUNDINGBarts Charity MGU0413, Abbott, Medical Research Council MR/T008059/1, and British Heart Foundation FS/13/49/30421 and PG/16/79/32419.

Aneurysm severity is suppressed by deletion of CCN4.

Patients with abdominal aortic aneurysms are frequently treated with high-risk surgery. A pharmaceutical treatment to reverse aneurysm progression could prevent the need for surgery and save both lives and healthcare resources. Since CCN4 regulates cell migration, proliferation and apoptosis, processes involved in aneurysm progression, it is a potential regulator of aneurysm progression. We investigated the role of CCN4 in a mouse aneurysm model, using apolipoprotein-E knockout (ApoE-/-) mice fed high fat diet and infused with Angiotensin II (AngII). Blood pressure was similarly elevated in CCN4-/-ApoE-/- mice and CCN4+/+ApoE-/- mice (controls) in response to AngII infusion. Deletion of CCN4 significantly reduced the number of ruptured aortae, both thoracic and abdominal aortic area, and aneurysm grade score, compared to controls. Additionally, the frequency of vessel wall remodelling and the number of elastic lamina breaks was significantly suppressed in CCN4-/-ApoE-/- mice compared to controls. Immunohistochemistry revealed a significantly lower proportion of macrophages, while the proportion of smooth muscle cells was not affected by the deletion of CCN4. There was also a reduction in both proliferation and apoptosis in CCN4-/-ApoE-/- mice compared to controls. In vitro studies showed that CCN4 significantly increased monocyte adhesion beyond that seen with TNFα and stimulated macrophage migration by more than threefold. In summary, absence of CCN4 reduced aneurysm severity and improved aortic integrity, which may be the result of reduced macrophage infiltration and cell apoptosis. Inhibition of CCN4 could offer a potential therapeutic approach for the treatment of aneurysms.

Eye-movement control during learning and scanning of Landolt-C stimuli: Exposure frequency effects and spacing effects in a visual search task.

We examined whether typical frequency effects observed in normal reading would also occur in a target search task using non-linguistic Landolt-C stimuli. In an initial learning session, we simulated development of frequency effects by controlling exposures participants received of Landolt-C clusters during learning. In a subsequent scanning session, we manipulated the cluster demarcation form of linear strings of Landolt-C clusters (i.e., spaced vs. unspaced vs. shaded unspaced). Participants were required to scan and search for pre-learnt target clusters that were embedded in longer Landolt-C strings. During learning, frequency effects were successfully simulated such that targets with more exposures received shorter fixation time than those with fewer exposures. Participants were unable to successfully detect the pre-learnt targets when they were embedded in the strings during scanning. No evidence of frequency effects was observed in the scanning session. In contrast, eye-movement control was significantly influenced by cluster demarcation form, with increased difficulty for unspaced strings, less for shaded strings, and least for spaced strings. Furthermore, typical landing position distributions that occur in reading of spaced languages also occurred during scanning of spaced Landolt-C strings but not for the shaded or the unspaced strings. In conclusion, exposure frequency effects were successfully simulated during learning but did not carry over to target search during scanning of Landolt-C strings. Possible reasons why frequency effects did not occur in the scanning session are discussed.

Eye-movement control during learning and scanning of English pseudoword stimuli: Exposure frequency effects and spacing effects in a visual search task.

Wang et al. (Attention, Perception, and Psychophysics, in press, 2021) reported a Landolt-C learning and scanning experiment. In a learning session, they simulated exposure frequency effects successfully by training participants to learn target Landolt-C clusters with different exposures. The rate of learning high-frequency (HF) targets were greater than that of learning low-frequency (LF) targets. In a subsequent scanning session, participants were required to scan text-like Landolt-C strings to detect whether any pre-learnt target was embedded in the strings. The Landolt-C strings were displayed under different spacing formats (i.e., spaced format, unspaced format, and unspaced shaded format). However, the simulated exposure frequency effect did not occur in the scanning session. Wang et al. argued one straightforward reason for this might be because participants failed to maintain the memory of pre-learnt target to the scanning session. In the current study, we employed the same learning and scanning paradigm to investigate whether exposure frequency would occur in a target search task by using easier learning materials - pseudoword stimuli. The learning of pseudoword stimuli was much more successful than Landolt-C stimuli. Interestingly, however, we found a very different rate of learning effect such that the rate of learning LF targets was greater than HF targets. To our surprise, we did not find any influence of exposure frequency on eye movements during scanning even when participants were able to identify pre-learnt pseudowords in strings. Learning rate effect, exposure frequency effects, and saccadic targeting during the scanning of strings under different spacing formats are discussed in this paper.

The influence of children's reading ability on initial letter position encoding during a reading-like task.

Previous studies exploring the cost of reading sentences with words that have two transposed letters in adults showed that initial letter transpositions caused the most disruption to reading, indicating the important role that initial letters play in lexical identification (e.g., Rayner et al., 2006). Regarding children, it is not clear whether differences in reading ability would affect how they encode letter position information as they attempt to identify misspelled words in a reading-like task. The aim of this experiment was to explore how initial-letter position information is encoded by children compared to adults when reading misspelled words, containing transpositions, during a reading-like task. Four different conditions were used: control (words were correctly spelled), TL12 (letters in first and second positions were transposed), TL13 (letters in first and third positions were transposed), and TL23 (letters in second and third positions were transposed). Results showed that TL13 condition caused the most disruption, whereas TL23 caused the least disruption to reading of misspelled words. Although disruption for the TL13 condition was quite rapid in adults, the immediacy of disruption was less so for the TL23 and TL12 conditions. For children, effects of transposition also occurred quite rapidly but were longer lasting. The time course was particularly extended for the less skilled relative to the more skilled child readers. This pattern of effects suggests that both adults and children with higher, relative to lower, reading ability encode internal letter position information more flexibly to identify misspelled words, with transposed letters, during a reading-like task. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Parafoveal pre-processing in children reading English: The importance of external letters.

Although previous research has demonstrated that for adults external letters of words are more important than internal letters for lexical processing during reading, no comparable research has been conducted with children. This experiment explored, using the boundary paradigm during silent sentence reading, whether parafoveal pre-processing in English is more affected by the manipulation of external letters or internal letters, and whether this differs between skilled adult and beginner child readers. Six previews were generated: identity (e.g., monkey); external letter manipulations where either the beginning three letters of the word were substituted (e.g., rackey) or the last three letters of the word were substituted (e.g., monhig); internal letter manipulations; e.g., machey, mochiy); and an unrelated control condition (e.g., rachig). Results indicate that both adults and children undertook pre-processing of words in their entirety in the parafovea, and that the manipulation of external letters in preview was more harmful to participants' parafoveal pre-processing than internal letters. The data also suggest developmental change in the time course of pre-processing, with children's pre-processing delayed compared to that of adults. These results not only provide further evidence for the importance of external letters to parafoveal processing and lexical identification for adults, but also demonstrate that such findings can be extended to children.

HIF1α activation in dendritic cells under sterile conditions promotes an anti-inflammatory phenotype through accumulation of intracellular lipids.

Obesity is among the leading causes of elevated cardiovascular disease mortality and morbidity. Adipose tissue dysfunction, insulin resistance and inflammation are recognized as important risk factors for the development of cardiovascular disorders in obesity. Hypoxia appears to be a key factor in adipose tissue dysfunction affecting not only adipocytes but also immune cell function. Here we examined the effect of hypoxia-induced transcription factor HIF1α activation on classical dendritic cell (cDCs) function during obesity. We found that deletion of Hif1α on cDCs results in enhanced adipose-tissue inflammation and atherosclerotic plaque formation in a mouse model of obesity. This effect is mediated by HIF1α-mediated increased lipid synthesis, accumulation of lipid droplets and alter synthesis of lipid mediators. Our findings demonstrate that HIF1α activation in cDCs is necessary to control vessel wall inflammation.

The role of phonology in lexical access in teenagers with a history of dyslexia.

We examined phonological recoding during silent sentence reading in teenagers with a history of dyslexia and their typically developing peers. Two experiments are reported in which participants' eye movements were recorded as they read sentences containing correctly spelled words (e.g., church), pseudohomophones (e.g., cherch), and spelling controls (e.g., charch). In Experiment 1 we examined foveal processing of the target word/nonword stimuli, and in Experiment 2 we examined parafoveal pre-processing. There were four participant groups-older teenagers with a history of dyslexia, older typically developing teenagers who were matched for age, younger typically developing teenagers who were matched for reading level, and younger teenagers with a history of dyslexia. All four participant groups showed a pseudohomophone advantage, both from foveal processing and parafoveal pre-processing, indicating that teenagers with a history of dyslexia engage in phonological recoding for lexical identification during silent sentence reading in a comparable manner to their typically developing peers.

The Changing Role of Phonology in Reading Development.

Processing of both a word's orthography (its printed form) and phonology (its associated speech sounds) are critical for lexical identification during reading, both in beginning and skilled readers. Theories of learning to read typically posit a developmental change, from early readers' reliance on phonology to more skilled readers' development of direct orthographic-semantic links. Specifically, in becoming a skilled reader, the extent to which an individual processes phonology during lexical identification is thought to decrease. Recent data from eye movement research suggests, however, that the developmental change in phonological processing is somewhat more nuanced than this. Such studies show that phonology influences lexical identification in beginning and skilled readers in both typically and atypically developing populations. These data indicate, therefore, that the developmental change might better be characterised as a transition from overt decoding to abstract, covert recoding. We do not stop processing phonology as we become more skilled at reading; rather, the nature of that processing changes.

Reading sentences of words with rotated letters: An eye movement study.

Participants' eye movements were measured as they read sentences in which individual letters within words were rotated. Both the consistency of direction and the magnitude of rotation were manipulated (letters rotated all in the same direction, or alternately clockwise and anti-clockwise, by 30° or 60°). Each sentence included a target word that was manipulated for frequency of occurrence. Our objectives were threefold: To quantify how change in the visual presentation of individual letters disrupted word identification, and whether disruption was consistent with systematic change in visual presentation; to determine whether inconsistent letter transformation caused more disruption than consistent letter transformation; and to determine whether such effects were comparable for words that were high and low frequency to explore the extent to which they were visually or linguistically mediated. We found that disruption to reading was greater as the magnitude of letter rotation increased, although even small rotations affected processing. The data also showed that alternating letter rotations were significantly more disruptive than consistent rotations; this result is consistent with models of lexical identification in which encoding occurs over units of more than one adjacent letter. These rotation manipulations also showed significant interactions with word frequency on the target word: Gaze durations and total fixation duration times increased disproportionately for low-frequency words when they were presented at more extreme rotations. These data provide a first step towards quantifying the relative contribution of the spatial relationships between individual letters to word recognition and eye movement control in reading.

Comments on: "What Is Developmental Dyslexia?" Brain Sci. 2018, 8, 26. The Relationship between Eye Movements and Reading Difficulties.

We are writing in response to the review article: Stein. J. (2018). What is Developmental Dyslexia? Brain Sciences, 8, 26, doi:10.3390/brainsci8020026. We consider that the section entitled, "Eye Movement Control", presents a misleading characterisation of current empirical and theoretical understanding. We outline five specific points relating to Stein's views on eye movement control and developmental dyslexia with which we disagree and conclude that disruption to oculomotor behaviour occurs as a consequence of processing difficulty that individuals with dyslexia experience as they engage in reading.

Binocular advantages for parafoveal processing in reading.

During reading, binocular visual input results in superior performance and is particularly important in the pre-processing of parafoveal text prior to direct fixation. It is not yet clear whether binocular vision in the parafovea is necessary for accurate saccadic targeting, or for efficient pre-processing of upcoming text, prior to direct fixation. In the present sentence reading experiment, we used a dichoptic gaze-contingent moving window paradigm in order to establish 1) how much parafoveal binocular input is necessary for fluent reading and 2) which aspect of parafoveal processing is more reliant on binocular vision. Eye movement measures revealed that reading was disrupted unless word N + 1 was entirely binocular in the parafovea, though no additional benefit was observed when word N + 2 was also binocular. Additionally, while fixation durations and reading times were clearly affected by the manipulation, similarly pronounced changes in binocular saccadic parameters such as accuracy, speed, amplitude and velocity were not observed. We concluded that the disruption to reading caused by presenting monocular text to the right of fixation cannot be attributed to difficulties in targeting binocular saccacdes, but instead results from a decreased efficiency in the pre-processing of parafoveal text. These results provide further demonstration for the importance of binocular vision during written text processing.

Phonological processing during silent reading in teenagers who are deaf/hard of hearing: an eye movement investigation.

There has been considerable variability within the literature concerning the extent to which deaf/hard of hearing individuals are able to process phonological codes during reading. Two experiments are reported in which participants' eye movements were recorded as they read sentences containing correctly spelled words (e.g., church), pseudohomophones (e.g., cherch), and spelling controls (e.g., charch). We examined both foveal processing and parafoveal pre-processing of phonology for three participant groups-teenagers with permanent childhood hearing loss (PCHL), chronological age-matched controls, and reading age-matched controls. The teenagers with PCHL showed a pseudohomophone advantage from both directly fixated words and parafoveal preview, similar to their hearing peers. These data provide strong evidence for phonological recoding during silent reading in teenagers with PCHL.

The role of character positional frequency on Chinese word learning during natural reading.

Readers' eye movements were recorded to examine the role of character positional frequency on Chinese lexical acquisition during reading and its possible modulation by word spacing. In Experiment 1, three types of pseudowords were constructed based on each character's positional frequency, providing congruent, incongruent, and no positional word segmentation information. Each pseudoword was embedded into two sets of sentences, for the learning and the test phases. In the learning phase, half the participants read sentences in word-spaced format, and half in unspaced format. In the test phase, all participants read sentences in unspaced format. The results showed an inhibitory effect of character positional frequency upon the efficiency of word learning when processing incongruent pseudowords both in the learning and test phase, and also showed facilitatory effect of word spacing in the learning phase, but not at test. Most importantly, these two characteristics exerted independent influences on word segmentation. In Experiment 2, three analogous types of pseudowords were created whilst controlling for orthographic neighborhood size. The results of the two experiments were consistent, except that the effect of character positional frequency was absent in the test phase in Experiment 2. We argue that the positional frequency of a word's constituent characters may influence the character-to-word assignment in a process that likely incorporates both lexical segmentation and identification.