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Panic disorder (PD) may increase the likelihood of suicidal ideation and behaviors because of psychiatric comorbidities such as major depressive disorder (MDD). However, research has yet to demonstrate a direct relationship between PD and suicide mortality.
Method
Using data from Taiwan’s National Health Insurance Research Database, we identified 171,737 individuals with PD and 686,948 age- and sex-matched individuals without PD during 2003–2017. We assessed the risk of suicide within the same period. Psychiatric comorbidities such as schizophrenia, bipolar disorder, MDD, obsessive-compulsive disorder (OCD), autism, alcohol use disorder (AUD), and substance use disorder (SUD) were also evaluated. Time-dependent Cox regression models were used to compare the risk of suicide in different groups after adjustment for demographic data and psychiatric comorbidities.
Results
Our Cox regression model revealed that PD was an independent risk factor for suicide (hazard ratio [HR] = 1.85, 95% confidence interval [CI] = 1.59–2.14), regardless of psychiatric comorbidities. Among all comorbidities, MDD with PD was associated with the highest risk of suicide (HR = 6.08, 95% CI = 5.48–6.74), followed by autism (HR = 4.52, 95% CI = 1.66–12.29), schizophrenia (HR = 3.34, 95% CI = 2.7–4.13), bipolar disorder (HR = 3.20, 95% CI = 2.71–3.79), AUD (HR = 2.99, 95% CI = 2.41–3.72), SUD (HR = 2.82, 95% CI = 2.28–3.47), and OCD (HR = 2.10, 95% CI = 1.64–2.67).
Discussion
PD is an independent risk factor for suicide. Psychiatric comorbidities (i.e. schizophrenia, bipolar disorder, MDD, OCD, AUD, SUD, and autism) with PD increase the risk of suicide.
In contemporary neuroimaging studies, it has been observed that patients with major depressive disorder (MDD) exhibit aberrant spontaneous neural activity, commonly quantified through the amplitude of low-frequency fluctuations (ALFF). However, the substantial individual heterogeneity among patients poses a challenge to reaching a unified conclusion.
Methods
To address this variability, our study adopts a novel framework to parse individualized ALFF abnormalities. We hypothesize that individualized ALFF abnormalities can be portrayed as a unique linear combination of shared differential factors. Our study involved two large multi-center datasets, comprising 2424 patients with MDD and 2183 healthy controls. In patients, individualized ALFF abnormalities were derived through normative modeling and further deconstructed into differential factors using non-negative matrix factorization.
Results
Two positive and two negative factors were identified. These factors were closely linked to clinical characteristics and explained group-level ALFF abnormalities in the two datasets. Moreover, these factors exhibited distinct associations with the distribution of neurotransmitter receptors/transporters, transcriptional profiles of inflammation-related genes, and connectome-informed epicenters, underscoring their neurobiological relevance. Additionally, factor compositions facilitated the identification of four distinct depressive subtypes, each characterized by unique abnormal ALFF patterns and clinical features. Importantly, these findings were successfully replicated in another dataset with different acquisition equipment, protocols, preprocessing strategies, and medication statuses, validating their robustness and generalizability.
Conclusions
This research identifies shared differential factors underlying individual spontaneous neural activity abnormalities in MDD and contributes novel insights into the heterogeneity of spontaneous neural activity abnormalities in MDD.
Research evidence has established an association of obsessive-compulsive disorder (OCD) with suicidal thoughts and suicide attempts. However, further investigation is required to determine whether individuals with OCD have higher risk of death by suicide compared with those without OCD.
Methods
Of the entire Taiwanese population, between 2003 and 2017, 56,977 individuals with OCD were identified; they were then matched at a 1:4 ratio with 227,908 non-OCD individuals on the basis of their birth year and sex. Suicide mortality was assessed between 2003 and 2017 for both groups. Time-dependent Cox regression models were used to investigate the difference in suicide risk between individuals with versus without OCD.
Results
After adjustment for major psychiatric comorbidities (i.e., schizophrenia, bipolar disorder and major depressive disorder), the OCD group had higher risk of suicide (hazard ratio: 1.97, 95% confidence interval: 1.57–2.48) during the follow-up compared with the comparison group. Furthermore, OCD severity, as indicated by psychiatric hospitalizations due to OCD, was positively correlated with suicide risk.
Conclusions
Regardless of the existence of major psychiatric comorbidities, OCD was found to be an independent risk factor for death by suicide. A suicide prevention program specific to individuals with OCD may be developed in clinical practice in the future.
The Secretarybird Sagittarius serpentarius is a charismatic raptor of the grasslands and open savannas of Africa. Evidence of widespread declines across the continent has led to the assessment that the species is at risk of becoming extinct. Southern Africa was identified as a remaining stronghold for the species, but the status of this population requires reassessment. To determine the status of the species in South Africa, Lesotho, and Eswatini, we analysed data from a citizen science project, the Southern African Bird Atlas Project (SABAP). We implemented novel time-to-detection modelling, as well as summarisation of changes in reporting rates, using standard metrics, to determine the trajectory of the population. To cross-validate our findings, we used data from another citizen science project, the Coordinated Avifaunal Roadcounts (CAR) project. While our results were in agreement with previous studies that have reported significant declines when comparing SABAP1 (1987–1992) and SABAP2 (2007 and onwards), all analysis pathways that examined data within the SABAP2 period only, as well as CAR data from this period, failed to show an alarming declining trend over this more recent time period. We did, however, find some evidence for decreases in Secretarybird abundance in urban grid cells. We used random forest models to predict probability of occurrence, as well as probability of abundance (reporting rates) for the assessed region and provided population estimates based on these analysis pathways. Continued monitoring and conservation efforts are required to guard this population stronghold.
Pebrine disease, caused by Nosema bombycis (Nb) infection in silkworms, is a severe and long-standing disease that threatens sericulture. As parasitic pathogens, a complex relationship exists between microsporidia and their hosts at the mitochondrial level. Previous studies have found that the translocator protein (TSPO) is involved in various biological functions, such as membrane potential regulation, mitochondrial autophagy, immune responses, calcium ion channel regulation, and cell apoptosis. In the present study, we found that TSPO expression in silkworms (BmTSPO) was upregulated following Nb infection, leading to an increase in cytoplasmic calcium, adenosine triphosphate, and reactive oxygen species levels. Knockdown and overexpression of BmTSPO resulted in the promotion and inhibition of Nb proliferation, respectively. We also demonstrated that the overexpression of BmTSPO promotes host cell apoptosis and significantly increases the expression of genes involved in the immune deficiency and Janus kinase-signal transducer and the activator of the transcription pathways. These findings suggest that BmTSPO activates the innate immune signalling pathway in silkworms to regulate Nb proliferation. Targeting TSPO represents a promising approach for the development of new treatments for microsporidian infections.
This study proposes a novel super-resolution (or SR) framework for generating high-resolution turbulent boundary layer (TBL) flow from low-resolution inputs. The framework combines a super-resolution generative adversarial neural network (SRGAN) with down-sampling modules (DMs), integrating the residual of the continuity equation into the loss function. The DMs selectively filter out components with excessive energy dissipation in low-resolution fields prior to the super-resolution process. The framework iteratively applies the SRGAN and DM procedure to fully capture the energy cascade of multi-scale flow structures, collectively termed the SRGAN-based energy cascade reconstruction framework (EC-SRGAN). Despite being trained solely on turbulent channel flow data (via ‘zero-shot transfer’), EC-SRGAN exhibits remarkable generalization in predicting TBL small-scale velocity fields, accurately reproducing wavenumber spectra compared to direct numerical simulation (DNS) results. Furthermore, a super-resolution core is trained at a specific super-resolution ratio. By leveraging this pretrained super-resolution core, EC-SRGAN efficiently reconstructs TBL fields at multiple super-resolution ratios from various levels of low-resolution inputs, showcasing strong flexibility. By learning turbulent scale invariance, EC-SRGAN demonstrates robustness across different TBL datasets. These results underscore the potential of EC-SRGAN for generating and predicting wall turbulence with high flexibility, offering promising applications in addressing diverse TBL-related challenges.
The comorbidity between schizophrenia (SCZ) and inflammatory bowel disease (IBD) observed in epidemiological studies is partially attributed to genetic overlap, but the magnitude of shared genetic components and the causality relationship between them remains unclear.
Methods
By leveraging large-scale genome-wide association study (GWAS) summary statistics for SCZ, IBD, ulcerative colitis (UC), and Crohn's disease (CD), we conducted a comprehensive genetic pleiotropic analysis to uncover shared loci, genes, or biological processes between SCZ and each of IBD, UC, and CD, independently. Univariable and multivariable Mendelian randomization (MR) analyses were applied to assess the causality across these two disorders.
Results
SCZ genetically correlated with IBD (rg = 0.14, p = 3.65 × 10−9), UC (rg = 0.15, p = 4.88 × 10−8), and CD (rg = 0.12, p = 2.27 × 10−6), all surpassed the Bonferroni correction. Cross-trait meta-analysis identified 64, 52, and 66 significantly independent loci associated with SCZ and IBD, UC, and CD, respectively. Follow-up gene-based analysis found 11 novel pleiotropic genes (KAT5, RABEP1, ELP5, CSNK1G1, etc) in all joint phenotypes. Co-expression and pathway enrichment analysis illustrated those novel genes were mainly involved in core immune-related signal transduction and cerebral disorder-related pathways. In univariable MR, genetic predisposition to SCZ was associated with an increased risk of IBD (OR 1.11, 95% CI 1.07–1.15, p = 1.85 × 10−6). Multivariable MR indicated a causal effect of genetic liability to SCZ on IBD risk independent of Actinobacteria (OR 1.11, 95% CI 1.06–1.16, p = 1.34 × 10−6) or BMI (OR 1.11, 95% CI 1.04–1.18, p = 1.84 × 10−3).
Conclusions
We confirmed a shared genetic basis, pleiotropic loci/genes, and causal relationship between SCZ and IBD, providing novel insights into the biological mechanism and therapeutic targets underlying these two disorders.
Previous studies have revealed an association between dietary factors and atopic dermatitis (AD). To explore whether there was a causal relationship between diet and AD, we performed Mendelian randomisation (MR) analysis. The dataset of twenty-one dietary factors was obtained from UK Biobank. The dataset for AD was obtained from the publicly available FinnGen consortium. The main research method was the inverse-variance weighting method, which was supplemented by MR‒Egger, weighted median and weighted mode. In addition, sensitivity analysis was performed to ensure the accuracy of the results. The study revealed that beef intake (OR = 0·351; 95 % CI 0·145, 0·847; P = 0·020) and white bread intake (OR = 0·141; 95 % CI 0·030, 0·656; P = 0·012) may be protective factors against AD. There were no causal relationships between AD and any other dietary intake factors. Sensitivity analysis showed that our results were reliable, and no heterogeneity or pleiotropy was found. Therefore, we believe that beef intake may be associated with a reduced risk of AD. Although white bread was significant in the IVW analysis, there was large uncertainty in the results given the wide 95 % CI. Other factors were not associated with AD in this study.
An O2 oxidation and freeze-dry procedure has been used to synthesize birnessite through the oxidation of Mn2+ in alkali media. The effects of O2 flow rate, the fluxion velocity of reaction suspension, the reaction temperature, pretreatment the reaction solutions with N2, and the hydration conditions on the purity of birnessite, the crystallinity, the ion-exchange properties, and the phase transformation of intermediate phases were examined. Buserite with a 1 nm basal spacing, produced after the oxidation, is transformed to 0.7 nm Na birnessite by complete freeze drying. Increasing the fluxion velocity of the reaction suspension and the O2 flow rate facilitated oxidation of Mn(OH)2. Prephase I (a phase related to hausmannite, γ-Mn3O4 (Luo and Suib, 1997; Luo et al., 1998), and feitknechtite (β-MnOOH) were formed as intermediates during the synthesis. Mechanical stirring was used to change the fluxion velocity of the reactive suspension. When the speed of stirring and the O2 flow rate were raised to 250 rpm and 3.0 L/min, respectively, or 450 rpm and 2.0 L/min, respectively, birnessite was the only phase in the final product. Irrespective of temperature in other reactions, pure birnessite was synthesized as long as the temperature during the initial mixing of the reaction solutions was maintained below 10°C. Increasing the reaction temperature led to a larger crystal size, better crystallinity and lower surface area. The pretreatment of solutions with N2 or O2 had little effect on the synthesis; synthesized birnessites had the same purity (100%) as, and similar crystallinity to, that of the no-pretreatment control. Dehydration of the buserite by freeze drying and heating at 60°C did not affect the production of birnessite; however, the latter caused partial loss of ion-exchange capacity with Mg2+. The pathways of the birnessite formation in this study might be:
(1) Mn(OH)2 (amorphous) → feitknechtite → buserite → birnessite, and
Mn(OH)2 existed in an X-ray amorphous state, not in the form of ‘pyrochroite’, during the synthesis.
The adopted conditions for synthesis of pure birnessite were NaOH to Mn molar ratio of 13.7, O2 flow rate of 2 L/min and oxidation for 5 h during vigorous stirring at 450 rpm at room temperature. The birnessite synthesized had a hexagonal platy morphology with good crystallinity, an average composition of Na0.25MnO2.07.0.66H2O, and a surface area of 38 m2/g.
Todorokite is a common Mn oxide (with a tunnel structure) in the Earth surface environment, and can be obtained by hydrothermal treatment or refluxing process from precursor buserite with a layered structure. Several chemical reaction conditions for the phase transformation from Na-buserite to todorokite at atmospheric pressure were investigated, including temperature, pH, crystallinity of precursor Na-buserite, the amount of the interlayer Mg2+ of the Mg-buserite and clay minerals. The results showed that the conversion rate and crystallinity of todorokite decreased with falling temperature, and Mg-buserite could not be completely transformed to todorokite at lower temperatures (40°C). The poorly crystalline Na-buserite could be converted into todorokite more easily than highly crystalline Na-buserite. Todorokite can be prepared at pH 5–9, but the rate of conversion and crystallinity of todorokite did vary with pH in the order: neutral ≈ alkali > acidic. The conversion rate of todorokite decreased with decreasing interlayer Mg2+ content of the Mg-buserite. The presence of montmorillonite or goethite slowed the formation reaction of todorokite in the refluxing process, and the reaction time was prolonged when the amounts of those minerals were increased.
The role of Mn oxide in the abiotic formation of humic substances has been well demonstrated. However, information on the effect of crystal structure and surface-chemical characteristics of Mn oxide on this process is limited. In the present study, hexagonal and triclinic birnessites, synthesized in acidic and alkali media, were used to study the influence of the crystal-structure properties of birnessites on the oxidative polymerization of hydroquinone and to elucidate the catalytic mechanism of birnessites in the abiotic formation of humic-like polymers in hydroquinone-birnessite systems. The intermediate and final products formed in solution and solid-residue phases were identified by UV/Visible spectroscopy, atomic absorption spectrometry, Fourier-transform infrared spectroscopy, X-ray diffraction, solid-phase microextraction-gaschromatography-mas ss pectrometry, ion chromatography, and ultrafiltration. The degree of oxidative polymerization of hydroquinone wasenhanced with increase in the interlayer hydrated H+, the average oxidation state (AOS), and the specific surface area of birnessites. The nature of the functional groups of the humic-like polymers formed was, however, almost identical when hydroquinone was catalyzed by hexagonal and triclinic birnessites with similar AOS of Mn. The results indicated that crystal structure and surface-chemistry characteristics have significant influence on the oxidative activity of birnessites and the degree of polymerization of hydroquinone, but have little effect on the abiotic formation mechanism of humic-like polymers. The proposed oxidative polymerization pathway for hydroquinone isthat, asit approachesthe birnessite, it formsp recursor surface complexes. Asa strong oxidant, birnessite accepts an electron from hydroquinone, which is oxidized to 1,4-benzoquinone. The coupling, cleavage, polymerization, and decarboxylation reactionsaccompany the generation of 1,4-benzoquinone, lead to the release of CO2 and carboxylic acid fragments, the generation of rhodochrosite, and the ultimate formation of humic-like polymers. These findings are of fundamental significance in understanding the catalytic role of birnessite and the mechanism for the abiotic formation of humic substances in nature.
Preterm children with very low birthweight (VLBW) / extremely low birthweight (ELBW) with normal early development had been found poorer executive functions (EFs) at preschool-age (Ni, Huang & Guo, 2011). The previous study found that the risks of deficits in EFs at preschool-age of preterm children can be attenuated by more supportive home environment (Taylor & Clark, 2016). However, former studies didn't investigate the effect of birthweight and home environment on cognitive EFs of preterm children simultaneously, especially those with normal early development. The present study aims to investigate the predictive effect of birthweight and home environment on the cognitive EFs of VLBW / ELBW preterm children.
Participants and Methods:
The preterm children were recruited from the Premature Baby Foundation of Taiwan. Inclusion criteria were their scores of Bayley Scales of Infant and Toddler Development, second or third edition at 12 and 24 months, and Wechsler Preschool and Primary Scale of Intelligence, Revised Edition at 5 years old were higher than 70. Exclusion criteria were visual impairment, hearing impairment, and cerebral palsy. There was a total of 287 preterm children with age 6 recruited in the present study. Preterm children were then divided into VLBW group (n=202, birthweight between 1001-1500g) and ELBW group (n=85, birthweight less than 1000g). The typical children included 89 term-born healthy and typically developing children with age 6, who were recruited from comparable social status families in the community. Four types of cognitive EFs including 22 indicators were assessed. Inhibition ability including 8 indicators was assessed through Comprehensive Nonverbal Attention Test Battery (CNAT), cognitive flexibility including 6 indicators was assessed through Wisconsin Card Sorting Test (WCST), working memory including 2 indicators was assessed through Digit Span Subtest of Wechsler Intelligence Scale for Children-IV (WISC-IV) and Knox's Cube Test (KCT), planning ability including 6 indicators was assessed through Tower of London (ToL). The home environment was assessed through Home Observation for Measurement of the Environment (HOME), Revised edition. Data were analyzed with Stepwise Regression.
Results:
Results showed that the regression model with birthweight significantly predicted 83.3% of planning ability indicators, 83.3% of cognitive flexibility indicators, and 50% of working memory indicators. Among indicators mentioned above, birthweight has been found the greatest predictive effect on summation-of score of ToL (R2=.04, p<.001). The regression model with HOME significantly predicted 66.7% of planning ability indicators, 16.7% of cognitive flexibility indicators, and 12.5% of inhibition ability indicators. Among the indicators mentioned above, HOME has been found the greatest predictive effect on rule-1 of ToL (R2=.027, p=.001). The regression model with birthweight and HOME significantly predicted 50% of planning ability indicators. Among indicators mentioned above, the regression model has been found the greatest predictive effect on summation-of-score of ToL (R2=.061, p<.001).
Conclusions:
Both birthweight and home environment have been found significantly predicted different types of cognitive EFs at preschool-age of VLBW / ELBW preterm children with normal early development. Though the home environment doesn't have such a great predictive effect as birthweight is, both birthweight and home environment are significant predictors of planning ability.
There is growing evidence that gray matter atrophy is constrained by normal brain network (or connectome) architecture in neuropsychiatric disorders. However, whether this finding holds true in individuals with depression remains unknown. In this study, we aimed to investigate the association between gray matter atrophy and normal connectome architecture at individual level in depression.
Methods
In this study, 297 patients with depression and 256 healthy controls (HCs) from two independent Chinese dataset were included: a discovery dataset (105 never-treated first-episode patients and matched 130 HCs) and a replication dataset (106 patients and matched 126 HCs). For each patient, individualized regional atrophy was assessed using normative model and brain regions whose structural connectome profiles in HCs most resembled the atrophy patterns were identified as putative epicenters using a backfoward stepwise regression analysis.
Results
In general, the structural connectome architecture of the identified disease epicenters significantly explained 44% (±16%) variance of gray matter atrophy. While patients with depression demonstrated tremendous interindividual variations in the number and distribution of disease epicenters, several disease epicenters with higher participation coefficient than randomly selected regions, including the hippocampus, thalamus, and medial frontal gyrus were significantly shared by depression. Other brain regions with strong structural connections to the disease epicenters exhibited greater vulnerability. In addition, the association between connectome and gray matter atrophy uncovered two distinct subgroups with different ages of onset.
Conclusions
These results suggest that gray matter atrophy is constrained by structural brain connectome and elucidate the possible pathological progression in depression.
Drawing on the emerging literature in translanguaging theory and research, the Element provides a comprehensive analysis of the embedded model of translanguaging-in-interpreting and interpreting-in-translanguaging from theoretical and practical perspectives, buttressed by evidence from an exploratory empirical investigation. To achieve this goal, the authors first trace the emergence and historical development of the key concepts and basic tenets of translanguaging and interpreting separately and then combined. This is followed by reviews of relevant literature, synthesizing how translanguaging theories and research methods can be applied in specific domains of interpreting studies, such as community and public service interpreting. An integrated account of translanguaging and interpreting is proposed and elaborated. The theoretical and methodological implications of this integrative perspective are teased out, with a view to illuminating interpreting theory, pedagogy and instruction.
An example of a nonfinitely based involution monoid of order five has recently been discovered. We confirm that this example is, up to isomorphism, the unique smallest among all involution monoids.
The production of broadband, terawatt terahertz (THz) pulses has been demonstrated by irradiating relativistic lasers on solid targets. However, the generation of extremely powerful, narrow-band and frequency-tunable THz pulses remains a challenge. Here, we present a novel approach for such THz pulses, in which a plasma wiggler is elaborated by a table-top laser and a near-critical density plasma. In such a wiggler, the laser-accelerated electrons emit THz radiations with a period closely related to the plasma thickness. The theoretical model and numerical simulations predict that a THz pulse with a laser–THz energy conversion of over 2.0%, an ultra-strong field exceeding 80 GV/m, a divergence angle of approximately 20° and a center frequency tunable from 4.4 to 1.5 THz can be generated from a laser of 430 mJ. Furthermore, we demonstrate that this method can work across a wide range of laser and plasma parameters, offering potential for future applications with extremely powerful THz pulses.
In this paper, we study the behaviours of the commutators $[\vec b,\,T]$ generated by multilinear Calderón–Zygmund operators $T$ with $\vec b=(b_1,\,\ldots,\,b_m)\in L_{\rm loc}(\mathbb {R}^n)$ on weighted Hardy spaces. We show that for some $p_i\in (0,\,1]$ with $1/p=1/p_1+\cdots +1/p_m$, $\omega \in A_\infty$ and $b_i\in \mathcal {BMO}_{\omega,p_i}$ ($1\le i\le m$), which are a class of non-trivial subspaces of ${\rm BMO}$, the commutators $[\vec b,\,T]$ are bounded from $H^{p_1}(\omega )\times \cdots \times H^{p_m}(\omega )$ to $L^p(\omega )$. Meanwhile, we also establish the corresponding results for a class of maximal truncated multilinear commutators $T_{\vec b}^*$.
Evidence suggests a familial coaggregation of major psychiatric disorders, including schizophrenia, bipolar disorder, major depression (MDD), autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). Those disorders are further related to suicide and accidental death. However, whether death by suicide may coaggregate with accidental death and major psychiatric disorders within families remains unclear.
Aims
To clarify the familial coaggregation of deaths by suicide with accidental death and five major psychiatric disorders.
Method
Using a database linked to the entire Taiwanese population, 68 214 first-degree relatives of individuals who died by suicide between 2003 and 2017 and 272 856 age- and gender-matched controls were assessed for the risks of death by suicide, accidental death and major psychiatric disorders.
Results
A Poisson regression model showed that the first-degree relatives of individuals who died by suicide were more likely to die by suicide (relative risk RR = 4.61, 95% CI 4.02–5.29) or accident (RR = 1.62, 95% CI 1.43–1.84) or to be diagnosed with schizophrenia (RR = 1.53, 95% CI 1.40–1.66), bipolar disorder (RR = 1.99, 95% CI 1.83–2.16), MDD (RR = 1.98, 95% CI 1.89–2.08) or ADHD (RR = 1.34, 95% CI 1.24–1.44).
Conclusions
Our findings identified a familial coaggregation of death by suicide with accidental death, schizophrenia, major affective disorders and ADHD. Further studies would be required to elucidate the pathological mechanisms underlying this coaggregation.
Drawing on recent developments from translanguaging theory, we argue in this chapter that translating and interpreting are by default translanguaging practices of meaning-making, during which process multilayered “translanguaging spaces” are being constantly and accumulatively created by dynamic interactional “moments” (Li, 2011) between the translator/interpreter and the external environment within the broader social–cultural contexts. These emerging insights from the key tenets of the translanguaging lens give rise to the construction of a unified theory of translating and interpreting aptitude consisting of a Macro level, Meso level, and Micro level (i.e., the 3M model), each level subsuming multiple interplaying elements interacting dynamically to generate multilayered translanguaging spaces of meaning-making.