Modelling Mandarin tone perception-production link through critical perceptual cues.

Theoretical accounts posit a close link between speech perception and production, but empirical findings on this relationship are mixed. To explain this apparent contradiction, a proposed view is that a perception-production relationship should be established through the use of critical perceptual cues. This study examines this view by using Mandarin tones as a test case because the perceptual cues for Mandarin tones consist of perceptually critical pitch direction and noncritical pitch height cues. The defining features of critical and noncritical perceptual cues and the perception-production relationship of each cue for each tone were investigated. The perceptual stimuli in the perception experiment were created by varying one critical and one noncritical perceptual cue orthogonally. The cues for tones produced by the same group of native Mandarin participants were measured. This study found that the critical status of perceptual cues primarily influenced within-category and between-category perception for nearly all tones. Using cross-domain bidirectional statistical modelling, a perception-production link was found for the critical perceptual cue only. A stronger link was obtained when within-category and between-category perception data were included in the models as compared to using between-category perception data alone, suggesting a phonetically and phonologically driven perception-production relationship.

METTL16 promotes liver cancer stem cell self-renewal via controlling ribosome biogenesis and mRNA translation.

BACKGROUND: While liver cancer stem cells (CSCs) play a crucial role in hepatocellular carcinoma (HCC) initiation, progression, recurrence, and treatment resistance, the mechanism underlying liver CSC self-renewal remains elusive. We aim to characterize the role of Methyltransferase 16 (METTL16), a recently identified RNA N6-methyladenosine (m6A) methyltransferase, in HCC development/maintenance, CSC stemness, as well as normal hepatogenesis. METHODS: Liver-specific Mettl16 conditional KO (cKO) mice were generated to assess its role in HCC pathogenesis and normal hepatogenesis. Hydrodynamic tail-vein injection (HDTVi)-induced de novo hepatocarcinogenesis and xenograft models were utilized to determine the role of METTL16 in HCC initiation and progression. A limiting dilution assay was utilized to evaluate CSC frequency. Functionally essential targets were revealed via integrative analysis of multi-omics data, including RNA-seq, RNA immunoprecipitation (RIP)-seq, and ribosome profiling. RESULTS: METTL16 is highly expressed in liver CSCs and its depletion dramatically decreased CSC frequency in vitro and in vivo. Mettl16 KO significantly attenuated HCC initiation and progression, yet only slightly influenced normal hepatogenesis. Mechanistic studies, including high-throughput sequencing, unveiled METTL16 as a key regulator of ribosomal RNA (rRNA) maturation and mRNA translation and identified eukaryotic translation initiation factor 3 subunit a (eIF3a) transcript as a bona-fide target of METTL16 in HCC. In addition, the functionally essential regions of METTL16 were revealed by CRISPR gene tiling scan, which will pave the way for the development of potential inhibitor(s). CONCLUSIONS: Our findings highlight the crucial oncogenic role of METTL16 in promoting HCC pathogenesis and enhancing liver CSC self-renewal through augmenting mRNA translation efficiency.

RNA m6A reader YTHDF2 facilitates precursor miR-126 maturation to promote acute myeloid leukemia progression.

As the most common internal modification of mRNA, N6-methyladenosine (m6A) and its regulators modulate gene expression and play critical roles in various biological and pathological processes including tumorigenesis. It was reported previously that m6A methyltransferase (writer), methyltransferase-like 3 (METTL3) adds m6A in primary microRNAs (pri-miRNAs) and facilitates its processing into precursor miRNAs (pre-miRNAs). However, it is unknown whether m6A modification also plays a role in the maturation process of pre-miRNAs and (if so) whether such a function contributes to tumorigenesis. Here, we found that YTHDF2 is aberrantly overexpressed in acute myeloid leukemia (AML) patients, especially in relapsed patients, and plays an oncogenic role in AML. Moreover, YTHDF2 promotes expression of miR-126-3p (also known as miR-126, as it is the main product of precursor miR-126 (pre-miR-126)), a miRNA that was reported as an oncomiRNA in AML, through facilitating the processing of pre-miR-126 into mature miR-126. Mechanistically, YTHDF2 recognizes m6A modification in pre-miR-126 and recruits AGO2, a regulator of pre-miRNA processing, to promote the maturation of pre-miR-126. YTHDF2 positively and negatively correlates with miR-126 and miR-126's downstream target genes, respectively, in AML patients, and forced expression of miR-126 could largely rescue YTHDF2/Ythdf2 depletion-mediated suppression on AML cell growth/proliferation and leukemogenesis, indicating that miR-126 is a functionally important target of YTHDF2 in AML. Overall, our studies not only reveal a previously unappreciated YTHDF2/miR-126 axis in AML and highlight the therapeutic potential of targeting this axis for AML treatment, but also suggest that m6A plays a role in pre-miRNA processing that contributes to tumorigenesis.

Multi-modal cross-linguistic perception of Mandarin tones in clear speech.

Clearly enunciated speech (relative to conversational, plain speech) involves articulatory and acoustic modifications that enhance auditory-visual (AV) segmental intelligibility. However, little research has explored clear-speech effects on the perception of suprasegmental properties such as lexical tone, particularly involving visual (facial) perception. Since tone production does not primarily rely on vocal tract configurations, tones may be less visually distinctive. Questions thus arise as to whether clear speech can enhance visual tone intelligibility, and if so, whether any intelligibility gain can be attributable to tone-specific category-enhancing (code-based) clear-speech cues or tone-general saliency-enhancing (signal-based) cues. The present study addresses these questions by examining the identification of clear and plain Mandarin tones with visual-only, auditory-only, and AV input modalities by native (Mandarin) and nonnative (English) perceivers. Results show that code-based visual and acoustic clear tone modifications, although limited, affect both native and nonnative intelligibility, with category-enhancing cues increasing intelligibility and category-blurring cues decreasing intelligibility. In contrast, signal-based cues, which are extensively available, do not benefit native intelligibility, although they contribute to nonnative intelligibility gain. These findings demonstrate that linguistically relevant visual tonal cues are existent. In clear speech, such tone category-enhancing cues are incorporated with saliency-enhancing cues across AV modalities for intelligibility improvements.

TET2-mediated mRNA demethylation regulates leukemia stem cell homing and self-renewal.

TET2 is recurrently mutated in acute myeloid leukemia (AML) and its deficiency promotes leukemogenesis (driven by aggressive oncogenic mutations) and enhances leukemia stem cell (LSC) self-renewal. However, the underlying cellular/molecular mechanisms have yet to be fully understood. Here, we show that Tet2 deficiency significantly facilitates leukemogenesis in various AML models (mediated by aggressive or less aggressive mutations) through promoting homing of LSCs into bone marrow (BM) niche to increase their self-renewal/proliferation. TET2 deficiency in AML blast cells increases expression of Tetraspanin 13 (TSPAN13) and thereby activates the CXCR4/CXCL12 signaling, leading to increased homing/migration of LSCs into BM niche. Mechanistically, TET2 deficiency results in the accumulation of methyl-5-cytosine (m5C) modification in TSPAN13 mRNA; YBX1 specifically recognizes the m5C modification and increases the stability and expression of TSPAN13 transcripts. Collectively, our studies reveal the functional importance of TET2 in leukemogenesis, leukemic blast cell migration/homing, and LSC self-renewal as an mRNA m5C demethylase.

QKI shuttles internal m7G-modified transcripts into stress granules and modulates mRNA metabolism.

N7-methylguanosine (m7G) modification, routinely occurring at mRNA 5' cap or within tRNAs/rRNAs, also exists internally in messenger RNAs (mRNAs). Although m7G-cap is essential for pre-mRNA processing and protein synthesis, the exact role of mRNA internal m7G modification remains elusive. Here, we report that mRNA internal m7G is selectively recognized by Quaking proteins (QKIs). By transcriptome-wide profiling/mapping of internal m7G methylome and QKI-binding sites, we identified more than 1,000 high-confidence m7G-modified and QKI-bound mRNA targets with a conserved "GANGAN (N = A/C/U/G)" motif. Strikingly, QKI7 interacts (via C terminus) with the stress granule (SG) core protein G3BP1 and shuttles internal m7G-modified transcripts into SGs to regulate mRNA stability and translation under stress conditions. Specifically, QKI7 attenuates the translation efficiency of essential genes in Hippo signaling pathways to sensitize cancer cells to chemotherapy. Collectively, we characterized QKIs as mRNA internal m7G-binding proteins that modulate target mRNA metabolism and cellular drug resistance.

Barriers and shortcomings in access to cardiovascular management and prevention for familial hypercholesterolemia during the COVID-19 pandemic.

Familial hypercholesterolemia (FH) is a hereditary condition caused by mutations in the lipid pathway. The goal in managing FH is to reduce circulating low-density lipoprotein cholesterol and, therefore, reduce the risk of developing atherosclerotic cardiovascular disease (ASCVD). Because FH patients were considered high risk groups due to an increased susceptible for contracting COVID-19 infection, we hypothesized whether the effects of the pandemic hindered access to cardiovascular care. In this review, we conducted a literature search in databases Pubmed/Medline and ScienceDirect. We included a comprehensive analysis of findings from articles in English related and summarized the effects of the pandemic on cardiovascular care through direct and indirect effects. During the COVID-19 pandemic, FH patients presented with worse outcomes and prognosis, especially those that have suffered from early ASCVD. This caused avoidance in seeking care due to fear of transmission. The pandemic severely impacted consultations with lipidologists and cardiologists, causing a decline in lipid profile evaluations. Low socioeconomic communities and ethnic minorities were hit the hardest with job displacements and lacked healthcare coverage respectively, leading to treatment nonadherence. Lock-down restrictions promoted sedentary lifestyles and intake of fatty meals, but it is unclear whether these factors attenuated cardiovascular risk in FH. To prevent early atherogenesis in FH patients, universal screening programs, telemedicine, and lifestyle interventions are important recommendations that could improve outcomes in FH patients. However, the need to research in depth on the disproportionate impact within different subgroups should be the forefront of FH research.

Phosphorylation stabilized TET1 acts as an oncoprotein and therapeutic target in B cell acute lymphoblastic leukemia.

Although the overall survival rate of B cell acute lymphoblastic leukemia (B-ALL) in childhood is more than 80%, it is merely 30% in refractory/relapsed and adult patients with B-ALL. This demonstrates a need for improved therapy targeting this subgroup of B-ALL. Here, we show that the ten-eleven translocation 1 (TET1) protein, a dioxygenase involved in DNA demethylation, is overexpressed and plays a crucial oncogenic role independent of its catalytic activity in B-ALL. Consistent with its oncogenic role in B-ALL, overexpression of TET1 alone in normal precursor B cells is sufficient to transform the cells and cause B-ALL in mice within 3 to 4 months. We found that TET1 protein is stabilized and overexpressed because of its phosphorylation mediated by protein kinase C epsilon (PRKCE) and ATM serine/threonine kinase (ATM), which are also overexpressed in B-ALL. Mechanistically, TET1 recruits STAT5B to the promoters of CD72 and JCHAIN and promotes their transcription, which in turn promotes B-ALL development. Destabilization of TET1 protein by treatment with PKC or ATM inhibitors (staurosporine or AZD0156; both tested in clinical trials), or by pharmacological targeting of STAT5B, greatly decreases B-ALL cell viability and inhibits B-ALL progression in vitro and in vivo. The combination of AZD0156 with staurosporine or vincristine exhibits a synergistic effect on inhibition of refractory/relapsed B-ALL cell survival and leukemia progression in PDX models. Collectively, our study reveals an oncogenic role of the phosphorylated TET1 protein in B-ALL independent of its catalytic activity and highlights the therapeutic potential of targeting TET1 signaling for the treatment of refractory/relapsed B-ALL.

Risk stratification of sudden cardiac death in asymptomatic female Brugada syndrome patients: A literature review.

BACKGROUND AND OBJECTIVES: Risk stratification in Brugada syndrome remains a difficult problem. Given the male predominance of this disease and their elevated risks of arrhythmic events, affected females have received less attention. It is widely known that symptomatic patients are at increased risk of sudden cardiac death (SCD) than asymptomatic patients, while this might be true in the male population; recent studies have shown that this association might not be significant in females. Over the past few decades, numerous markers involving clinical symptoms, electrocardiographic (ECG) indices, and genetic tests have been explored, with several risk-scoring models developed so far. The objective of this study is to review the current evidence of clinical and ECG markers as well as risk scores on asymptomatic females with Brugada syndrome. FINDINGS: Gender differences in ECG markers, the yield of genetic findings, and the applicability of risk scores are highlighted. CONCLUSIONS: Various clinical, electrocardiographic, and genetic risk factors are available for assessing SCD risk amongst asymptomatic female BrS patients. However, due to the significant gender discrepancy in BrS, the SCD risk amongst females is often underestimated, and there is a lack of research on female-specific risk factors and multiparametric risk scores. Therefore, multinational studies pooling female BrS patients are needed for the development of a gender-specific risk stratification approach amongst asymptomatic BrS patients.

METTL16 drives leukemogenesis and leukemia stem cell self-renewal by reprogramming BCAA metabolism.

N6-methyladenosine (m6A), the most prevalent internal modification in mammalian mRNAs, is involved in many pathological processes. METTL16 is a recently identified m6A methyltransferase. However, its role in leukemia has yet to be investigated. Here, we show that METTL16 is a highly essential gene for the survival of acute myeloid leukemia (AML) cells via CRISPR-Cas9 screening and experimental validation. METTL16 is aberrantly overexpressed in human AML cells, especially in leukemia stem cells (LSCs) and leukemia-initiating cells (LICs). Genetic depletion of METTL16 dramatically suppresses AML initiation/development and maintenance and significantly attenuates LSC/LIC self-renewal, while moderately influencing normal hematopoiesis in mice. Mechanistically, METTL16 exerts its oncogenic role by promoting expression of branched-chain amino acid (BCAA) transaminase 1 (BCAT1) and BCAT2 in an m6A-dependent manner and reprogramming BCAA metabolism in AML. Collectively, our results characterize the METTL16/m6A/BCAT1-2/BCAA axis in leukemogenesis and highlight the essential role of METTL16-mediated m6A epitranscriptome and BCAA metabolism reprograming in leukemogenesis and LSC/LIC maintenance.

Comparison of Sodium-Glucose Cotransporter-2 Inhibitor and Dipeptidyl Peptidase-4 Inhibitor on the Risks of New-Onset Atrial Fibrillation, Stroke and Mortality in Diabetic Patients: A Propensity Score-Matched Study in Hong Kong.

OBJECTIVE: To compare the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2Is) and dipeptidyl peptidase-4 inhibitors (DPP4Is) on adverse outcomes in diabetic patients in Hong Kong. METHODS: This was a retrospective population-based cohort study of type 2 diabetes mellitus patients (n = 72,746) treated with SGLT2I or DPP4I between January 1, 2015, and December 31, 2020, in Hong Kong. Patients with exposure to both DPP4I and SGLT2I therapy, without complete demographics or mortality data, or who had prior atrial fibrillation (AF) were excluded. The study outcomes were new-onset AF, stroke/transient ischemic attack, cardiovascular mortality and all-cause mortality. Propensity score matching (1:1 ratio) between SGLT2I and DPP4I users was performed. RESULTS: The unmatched study cohort included 21,713 SGLT2I users and 39,510 DPP4I users (total: n = 61,233 patients; 55.37% males, median age: 62.7 years [interquartile range (IQR): 54.6-71.9 years]). Over a median follow-up of 2030 (IQR: 1912-2117) days, 2496 patients (incidence rate [IR]: 4.07%) developed new-onset AF, 2179 patients (IR: 3.55%) developed stroke/transient ischemic attack, 1963 (IR: 3.20%) died from cardiovascular causes and 6607 patients (IR: 10.79%) suffered from all-cause mortality. After propensity score matching (SGLT2I: n = 21,713; DPP4I: n = 21,713), SGLT2I users showed lower incidence of new-onset AF (1.96% vs. 2.78%, standardized mean difference [SMD] = 0.05), stroke (1.80% vs. 3.52%, SMD = 0.11), cardiovascular mortality (0.47% vs. 1.56%, SMD = 0.11) and all-cause mortality (2.59% vs. 7.47%, SMD = 0.22) compared to DPP4I users. Cox regression found that SGLT2I users showed lower risk of new-onset AF (hazard ratio [HR]: 0.68, 95% confidence interval [CI]: [0.56, 0.83], P = 0.0001), stroke (HR: 0.64, 95% CI: [0.53, 0.79], P < 0.0001), cardiovascular mortality (HR: 0.39, 95% CI: [0.27, 0.56], P < 0.0001) and all-cause mortality (HR: 0.44, 95% CI: [0.37, 0.51], P < 0.0001) after adjusting for significant demographics, past comorbidities, medications and laboratory tests. CONCLUSIONS: Based on real-world data of type 2 diabetic patients in Hong Kong, SGLT2I use was associated with lower risk of incident AF, stroke/transient ischemic attack, and cardiovascular and all-cause mortality outcomes compared to DPP4I use.

Clinical characteristics, risk factors and outcomes of cancer patients with COVID-19: A population-based study.

INTRODUCTION: Cancer patients may be susceptible to poorer outcomes in COVID-19 infection owing to the immunosuppressant effect of chemotherapy/radiotherapy and cancer growth, along with the potential for nosocomial transmission due to frequent hospital admissions. METHODS: This was a population-based retrospective cohort study of COVID-19 patients who presented to Hong Kong public hospitals between 1 January 2020 and 8 December 2020. The primary outcome was a composite endpoint of requirement for intubation, ICU admission and 30-day mortality. RESULTS: The following study consisted of 6089 COVID-19 patients (median age 45.9 [27.8.1-62.7] years; 50% male), of which 142 were cancer subjects. COVID-19 cancer patients were older at baseline and tended to present with a higher frequency of comorbidities, including diabetes mellitus, hypertension, chronic obstructive pulmonary disease, ischemic heart disease, ventricular tachycardia/fibrillation and gastrointestinal bleeding (p < 0.05). These subjects also likewise tended to present with higher serum levels of inflammatory markers, including D-dimer, lactate dehydrogenase, high sensitivity troponin-I and C-reactive protein. Multivariate Cox regression showed that any type of cancer presented with an almost four-fold increased risk of the primary outcome (HR: 3.77; 95% CI: 1.63-8.72; p < 0.002) after adjusting for significant demographics, Charlson comorbidity index, number of comorbidities, past comorbidities and medication history. This association remained significant when assessing those with colorectal (HR: 5.07; 95% CI: 1.50-17.17; p < 0.009) and gastrointestinal malignancies (HR: 3.79; 95% CI: 1.12-12.88; p < 0.03), but not with lung, genitourinary, or breast malignancies, relative to their respective cancer-free COVID-19 counterparts. CONCLUSIONS: COVID-19 cancer patients are associated with a significantly higher risk of intubation, ICU admission and/or mortality.

Predictive value of neutrophil-to-lymphocyte ratio for atrial fibrillation and stroke in type 2 diabetes mellitus: The Hong Kong Diabetes Study.

INTRODUCTION: Neutrophil-to-lymphocyte ratio (NLR) is a routinely available biomarker that reflects systemic inflammation. The study evaluated the predictive value of NLR for ischemic stroke and atrial fibrillation (AF) in patients with type 2 diabetes mellitus. METHODS: This was a population-based cohort study of patients with type 2 diabetes mellitus and complete blood count tests at baseline between 1 January 1st, 2009, and 31 December, 2009, at government-funded hospitals/clinics in Hong Kong. Follow-up was until 31 December, 2019, or death. RESULTS: A total of 85,351 patients (age = 67.6 ± 13.2 years old, male = 48.8%, follow-up = 3101 ± 1441 days) were included. Univariable Cox regression found that increased NLR at quartiles 2, 3 and 4 was significantly associated with higher risks of new-onset ischemic stroke (hazard ratio [HR]: 1.28 [1.20-1.37], p < .001, HR: 1.41 [1.32-1.51], p < .001 and HR: 1.38 [1.29-1.47], p < .001) and AF (HR: 1.09 [1.02-1.17], p < .015; HR: 1.28 [1.20-1.37], p < .001; HR: 1.39 [1.31-1.49], p < .001) compared to quartile 1. On multivariable analysis, NLR remained a significant predictor of ischemic stroke risk for quartiles 2 and 3 (quartile 2: HR: 1.14 [1.05, 1.22], p = .001; quartile 3: HR: 1.14 [1.06, 1.23], p < .001) but not quartile 4 (HR: 1.08 [0.994, 1.17], p = .070). NLR was not predictive of AF after adjusting for confounders (quartile 2: HR: 0.966 [0.874, 1.07], p = .499; quartile 3: HR: 0.978 [0.884, 1.08], p = .661; quartile 4: HR: 1.05 [0.935, 1.16], p = .462). CONCLUSION: NLR is a significant predictor of new-onset ischaemic stroke after adjusting for significant confounders in Chinese type 2 diabetes patients.

Spiked Helmet Electrocardiographic Sign-A Systematic Review of Case Reports.

First reported in 2011, the spiked helmet sign (SHS) is an electrocardiographic pattern of ST-segment elevation anecdotally associated with poor prognosis. This study aims to systematically evaluate the electrocardiographic characteristics, clinical presentations, and outcomes of all cases of SHS reported in the literature. PubMed, Scopus, Web of Science, and EMBASE were searched electronically from their inception until November 2022. The Joanna Briggs Institute Critical Appraisal Checklist for Case Reports was used to critically appraise included studies. Studies written in English describing at least one patient with SHS were included. Altogether, 26 case reports or series describing 39 patients with SHS were included. All included studies were rated of acceptable quality. Associated conditions were heterogeneous, with intracranial hemorrhagic complications being the most common (9 patients), followed by pneumothorax (6 patients) or severe pneumonia (4 patients), bowel ischemia or obstruction (6 patients), and autonomic dysfunction (3 patients with Takotsubo cardiomyopathy and 3 patients with spinal injury, cocaine overuse, and stellate gangliectomy). Two patients had multiple complications and 12 other patients suffered from sepsis, myocardial infarction, etc. Clinical outcomes were reported for 32 patients, of whom 19 (59%) died during hospitalization (6 patients with pneumothorax or pneumonia, 4 patients with intracranial hemorrhagic complications, 2 patients with bowel ischemia or obstruction, and 7 patients due to other reasons). SHS may be associated with poor prognosis, necessitating its prompt recognition by clinicians and swift evaluation for underlying causes. Larger studies are needed to elucidate its prevalence, clinical implications, and precipitating mechanisms.

The Impact of Cardiac Comorbidity Sequence at Baseline and Mortality Risk in Type 2 Diabetes Mellitus: A Retrospective Population-Based Cohort Study.

Introduction: The presence of multiple comorbidities increases the risk of all-cause mortality, but the effects of the comorbidity sequence before the baseline date on mortality remain unexplored. This study investigated the relationship between coronary heart disease (CHD), atrial fibrillation (AF) and heart failure (HF) through their sequence of development and the effect on all-cause mortality risk in type 2 diabetes mellitus. Methods: This study included patients with type 2 diabetes mellitus prescribed antidiabetic/cardiovascular medications in public hospitals of Hong Kong between 1 January 2009 and 31 December 2009, with follow-up until death or 31 December 2019. The Cox regression was used to identify comorbidity sequences predicting all-cause mortality in patients with different medication subgroups. Results: A total of 249,291 patients (age: 66.0 ± 12.4 years, 47.4% male) were included. At baseline, 7564, 10,900 and 25,589 patients had AF, HF and CHD, respectively. Over follow-up (3524 ± 1218 days), 85,870 patients died (mortality rate: 35.7 per 1000 person-years). Sulphonylurea users with CHD developing later and insulin users with CHD developing earlier in the disease course had lower mortality risks. Amongst insulin users with two of the three comorbidities, those with CHD with preceding AF (hazard ratio (HR): 3.06, 95% CI: [2.60−3.61], p < 0.001) or HF (HR: 3.84 [3.47−4.24], p < 0.001) had a higher mortality. In users of lipid-lowering agents with all three comorbidities, those with preceding AF had a higher risk of mortality (AF-CHD-HF: HR: 3.22, [2.24−4.61], p < 0.001; AF-HF-CHD: HR: 3.71, [2.66−5.16], p < 0.001). Conclusions: The sequence of comorbidity development affects the risk of all-cause mortality to varying degrees in diabetic patients on different antidiabetic/cardiovascular medications.

SOX9 and SOX10 control fluid homeostasis in the inner ear for hearing through independent and cooperative mechanisms.

The in vivo mechanisms underlying dominant syndromes caused by mutations in SRY-Box Transcription Factor 9 (SOX9) and SOX10 (SOXE) transcription factors, when they either are expressed alone or are coexpressed, are ill-defined. We created a mouse model for the campomelic dysplasia SOX9Y440X mutation, which truncates the transactivation domain but leaves DNA binding and dimerization intact. Here, we find that SOX9Y440X causes deafness via distinct mechanisms in the endolymphatic sac (ES)/duct and cochlea. By contrast, conditional heterozygous Sox9-null mice are normal. During the ES development of Sox9Y440X/+ heterozygotes, Sox10 and genes important for ionic homeostasis are down-regulated, and there is developmental persistence of progenitors, resulting in fewer mature cells. Sox10 heterozygous null mutants also display persistence of ES/duct progenitors. By contrast, SOX10 retains its expression in the early Sox9Y440X/+ mutant cochlea. Later, in the postnatal stria vascularis, dominant interference by SOX9Y440X is implicated in impairing the normal cooperation of SOX9 and SOX10 in repressing the expression of the water channel Aquaporin 3, thereby contributing to endolymphatic hydrops. Our study shows that for a functioning endolymphatic system in the inner ear, SOX9 regulates Sox10, and depending on the cell type and target gene, it works either independently of or cooperatively with SOX10. SOX9Y440X can interfere with the activity of both SOXE factors, exerting effects that can be classified as haploinsufficient/hypomorphic or dominant negative depending on the cell/gene context. This model of disruption of transcription factor partnerships may be applicable to congenital deafness, which affects ∼0.3% of newborns, and other syndromic disorders.

Efficacy of vasopressin, steroid, and epinephrine protocol for in-hospital cardiac arrest resuscitation: a systematic review and meta-analysis of randomized controlled trials with trial sequential analysis.

OBJECTIVES: To assess the effect of vasopressin, steroid and epinephrine (VSE) combination therapy on return of spontaneous circulation (ROSC) after in-hospital cardiac arrest (IHCA), and test the conclusiveness of evidence using trial sequential analysis (TSA). METHODS: The systematic search included PubMed, EMBASE, Scopus, and Cochrane Central Register of Controlled Trials. Randomized controlled trials (RCTs) that included adult patients with IHCA, with at least one group receiving combined VSE therapy were selected. Data was extracted independently by two reviewers. The main outcome of interest was ROSC. Other outcomes included survival to hospital discharge or survival to 30 and 90 days, with good neurological outcomes. RESULTS: We included a total of three RCTs (n = 869). Results showed that VSE combination therapy increased ROSC (risk ratio = 1.41; 95% CI: 1.25-1.59) as compared to placebo. TSA demonstrated that the existing evidence is conclusive. This was also validated by the alpha-spending adjusted relative risk (1.32 [1.16, 1.49], P < 0.0001). Other outcomes could not be meta-analysed due to differences in timeframe in the included studies. CONCLUSIONS: VSE combination therapy administered in cardiopulmonary resuscitation led to improved rates of ROSC. Future trials of VSE therapy should evaluate survival to hospital discharge, neurological function and long-term survival.

RNA N6 -methyladenosine reader YTHDC1 is essential for TGF-beta-mediated metastasis of triple negative breast cancer.

RNA N6 -methyladenosine (m6A) modification and its regulators fine tune gene expression and contribute to tumorigenesis. This study aims to uncover the essential role and the underlying molecular mechanism(s) of the m6A reader YTHDC1 in promoting triple negative breast cancer (TNBC) metastasis. METHODS: In vitro and in vivo models were employed to determine the pathological function of YTHDC1 in TNBC metastasis. To identify bona fide YTHDC1 target RNAs, we conducted RNA-seq, m6A-seq, and RIP-seq, followed by integrative data analysis and validation assays. RESULTS: By analyzing The Cancer Genome Atlas (TCGA) dataset, we found that elevated expression of YTHDC1 is positively correlated with poor prognosis in breast cancer patients. Using a mammary fat pad mouse model of TNBC, YTHDC1 significantly promoted lung metastasis of TNBC cells. Through multiple transcriptome-wide sequencing and integrative data analysis, we revealed dysregulation of metastasis-related pathways following YTHDC1 depletion and identified SMAD3 as a bona fide YTHDC1 target RNA. Depletion of YTHDC1 caused nuclear retention of SMAD3 mRNA, leading to lower SMAD3 protein levels. Loss of YTHDC1 led to impaired TGF-ß-induced gene expression, leading to inhibition of epithelial-mesenchymal transition (EMT) and suppressed TNBC cell migration and invasion. SMAD3 overexpression was able to restore the response to TGF-ß in YTHDC1 depleted TNBC cells. Furthermore, we demonstrated that the oncogenic role of YTHDC1 is mediated through its recognition of m6A as m6A-binding defective mutants of YTHDC1 were unable to rescue the impaired cell migration and invasion of YTHDC1 knockout TNBC cells. CONCLUSIONS: We show that YTHDC1 plays a critical oncogenic role in TNBC metastasis through promoting the nuclear export and expression of SMAD3 to augment the TGF-ß signaling cascade. Overall, our study demonstrates that YTHDC1 is vital for TNBC progression by enhancing TNBC cell survival and TGF-ß-mediated EMT via SMAD3 to enable the formation of distant metastasis and highlights the therapeutic potential of targeting the YTHDC1/m6A/SMAD3 axis for TNBC treatment.

Development of an Electronic Frailty Index for Predicting Mortality and Complications Analysis in Pulmonary Hypertension Using Random Survival Forest Model.

Background: The long-term prognosis of the cardio-metabolic and renal complications, in addition to mortality in patients with newly diagnosed pulmonary hypertension, are unclear. This study aims to develop a scalable predictive model in the form of an electronic frailty index (eFI) to predict different adverse outcomes. Methods: This was a population-based cohort study of patients diagnosed with pulmonary hypertension between January 1st, 2000 and December 31st, 2017, in Hong Kong public hospitals. The primary outcomes were mortality, cardiovascular complications, renal diseases, and diabetes mellitus. The univariable and multivariable Cox regression analyses were applied to identify the significant risk factors, which were fed into the non-parametric random survival forest (RSF) model to develop an eFI. Results: A total of 2,560 patients with a mean age of 63.4 years old (interquartile range: 38.0-79.0) were included. Over a follow-up, 1,347 died and 1,878, 437, and 684 patients developed cardiovascular complications, diabetes mellitus, and renal disease, respectively. The RSF-model-identified age, average readmission, anti-hypertensive drugs, cumulative length of stay, and total bilirubin were among the most important risk factors for predicting mortality. Pair-wise interactions of factors including diagnosis age, average readmission interval, and cumulative hospital stay were also crucial for the mortality prediction. Patients who developed all-cause mortality had higher values of the eFI compared to those who survived (P < 0.0001). An eFI ≥ 9.5 was associated with increased risks of mortality [hazard ratio (HR): 1.90; 95% confidence interval [CI]: 1.70-2.12; P < 0.0001]. The cumulative hazards were higher among patients who were 65 years old or above with eFI ≥ 9.5. Using the same cut-off point, the eFI predicted a long-term mortality over 10 years (HR: 1.71; 95% CI: 1.53-1.90; P < 0.0001). Compared to the multivariable Cox regression, the precision, recall, area under the curve (AUC), and C-index were significantly higher for RSF in the prediction of outcomes. Conclusion: The RSF models identified the novel risk factors and interactions for the development of complications and mortality. The eFI constructed by RSF accurately predicts the complications and mortality of patients with pulmonary hypertension, especially among the elderly.