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Abstract Recent studies have suggested that mRNA internal m7G and its writer protein METTL1 are closely related to cell metabolism and cancer regulation. Here, we identify that IGF2BP family proteins IGF2BP1-3 can preferentially bind internal mRNA m7G. Such interactions, especially IGF2BP3 with m7G, could promote the degradation of m7G target transcripts in cancer cells. IGF2BP3 is more responsive to changes of m7G modification, while IGF2BP1 prefers m6A to stabilize the bound transcripts. We also demonstrate that p53 transcript, TP53, is m7G-modified at its 3’UTR in cancer cells. In glioblastoma, the methylation level and the half lifetime of the modified transcript could be modulated by tuning IGF2BP3, or by site-specific targeting of m7G through a dCas13b-guided system, resulting in modulation of cancer progression and chemosensitivity.

IntroductionSecond language learning is a multifaceted task that benefits across numerous neurocognitive domains including central auditory processing. Existing cross-sectional and longitudinal data show that performance on tests of central auditory processing [central auditory tests (CATs)] worsens with HIV infection. Second language learning may modify this relationship. To explore the relationship between second language learning, central auditory processing, and its interaction with HIV, we assessed the effect of learning English as a second language on CATs among children both living with and without HIV (CLWH/CLWOH) in Dar es Salaam, Tanzania.MethodsThree hundred and seventy-two native Kiswahili speaking children aged 3-10 years old (196 CLWOH, 176 CLWH) were enrolled. Participants completed questionnaires about English language learning, socioeconomic status (SES), and health history. Three central auditory tests-the Triple Digit Test (TDT), the Staggered Spondaic Word Test (SSW), and the Hearing-In-Noise Test (HINT)-were used to assess each participant's central auditory processing abilities. Multivariate linear regression was used to assess the effect of written and spoken English language learning at home and in school on CATs with age, HIV-status, and SES included in each model.ResultsHIV status, age, and SES were all significant predictors of all three central auditory tests, with CLWH performing significantly worse on all three CATs than CLWOH. Children actively learning spoken and written English at home had significantly better central auditory processing abilities on the TDT compared to children not actively learning English at home (p < 0.01) independent of HIV status, age, and SES. Children learning spoken and written English at school performed significantly better on the HINT (p < 0.05) than those not actively learning English at school.DiscussionLearning English at home and learning English in school were associated with improved central auditory performance independent of HIV status, SES, and age. These findings also underscore the significance of second language acquisition as a potential mechanism of improving central auditory function within a Kiswahili-speaking cohort. This study found differences in central auditory processing between children exposed to English at home and in school, suggesting differences in language learning in both settings mediated by SES, and this benefit exists regardless of HIV status.

The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase Mg2+/Mn2+-dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of PPM1D are found across several human cancers making it a relevant pharmacological target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of PPM1D, uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in PPM1D-mutant cells. Altogether, our results demonstrate a role for SOD1 in the survival of PPM1D-mutant leukemia cells and highlight a new potential therapeutic strategy against PPM1D-mutant cancers.

Abstract Objective Alzheimer's disease (AD) is a major health concern for aging adults with Down syndrome (DS), but conventional diagnostic techniques are less reliable in those with severe baseline disability. Likewise, acquisition of magnetic resonance imaging to evaluate cerebral atrophy is not straightforward, as prolonged scanning times are less tolerated in this population. Computed tomography (CT) scans can be obtained faster, but poor contrast resolution limits its function for morphometric analysis. We implemented an automated analysis of CT scans to characterize differences across dementia stages in a cross‐sectional study of an adult DS cohort. Methods CT scans of 98 individuals were analyzed using an automatic algorithm. Voxel‐based correlations with clinical dementia stages and AD plasma biomarkers (phosphorylated tau‐181 and neurofilament light chain) were identified, and their dysconnectomic patterns delineated. Results Dementia severity was negatively correlated with gray (GM) and white matter (WM) volumes in temporal lobe regions, including parahippocampal gyri. Dysconnectome analysis revealed an association between WM loss and temporal lobe GM volume reduction. AD biomarkers were negatively associated with GM volume in hippocampal and cingulate gyri. Interpretation Our automated algorithm and novel dysconnectomic analysis of CT scans successfully described brain morphometric differences related to AD in adults with DS, providing a new avenue for neuroimaging analysis in populations for whom magnetic resonance imaging is difficult to obtain.

Background Artificial intelligence platforms, like Viz.ai with large vessel occlusion detection, have been used for disease detection and interprovider communication. Whether this software expedites patient transfer and evaluation for treatment needs further exploration. Methods A single‐center retrospective registry was queried for patients with acute large vessel occlusion of the intracranial internal carotid, middle cerebral M1 or M2 segments, or basilar artery treated in a comprehensive stroke network (8 spokes, 1 hub) for 6 months pre‐ and post‐implementation of the Viz large vessel occlusion platform (excluding a 1‐month “washout” period). Robust regression was used to summarize time from initial hospital contact to arterial puncture (primary outcome) between periods, with prespecified subgroup analyses, which were assessed using interaction terms. Results Of the 132 patients (n = 58 preintervention), there were nonsignificantly fewer patients undergoing endovascular therapy in the postintervention period (86.2% preintervention versus 73.0% postintervention; P = 0.07). Among patients who underwent endovascular therapy (n = 50 preintervention, n = 54 postintervention), there was a nonsignificant reduction in time from first contact to arterial puncture (median 155 minute preintervention versus 116 minute postintervention; P = 0.10); however, this became significant in adjusted robust regression accounting for stroke severity, age, Alberta Stroke Program Early Computed Tomography Scale score, daytime versus nighttime and weekend versus weekday arrival, and use of perfusion imaging (β −20.9 [95% CI, −40.5 to −1.4)]. There was also a significant interaction observed for the association between spoke versus hub arrival and the Viz large vessel occlusion period, with shorter intervals observed for transferred patients (n = 32 preintervention with a median of 169 versus 142 minutes for n = 33 postintervention; Pinteraction

Background Prior studies have shown benefit for endovascular therapy (EVT) in patients with large‐vessel occlusion and severe deficits, as captured by the National Institutes of Health Stroke Scale (NIHSS). However, the benefit of EVT in patients with NIHSS score of

Background Prior studies have shown benefit for endovascular therapy (EVT) in patients with large‐vessel occlusion and severe deficits, as captured by the National Institutes of Health Stroke Scale. However the benefit of EVT in patients with National Institutes of Health Stroke Scale score

Abstract Separating deuterium from hydrogen isotope mixtures is of vital importance to develop nuclear energy industry, as well as other isotope-related advanced technologies. As one of the most promising alternatives to conventional techniques for deuterium purification, kinetic quantum sieving using porous materials has shown a great potential to address this challenging objective. From the knowledge gained in this field; it becomes clear that a quantum sieve encompassing a wide range of practical features in addition to its separation performance is highly demanded to approach the industrial level. Here, the rational design of an ultra-microporous squarate pillared titanium oxide hybrid framework has been achieved, of which we report the comprehensive assessment towards practical deuterium separation. The material not only displays a good performance combining high selectivity and volumetric uptake, reversible adsorption-desorption cycles, and facile regeneration in adsorptive sieving of deuterium, but also features a cost-effective green scalable synthesis using chemical feedstock, and a good stability (thermal, chemical, mechanical and radiolytic) under various working conditions. Our findings provide an overall assessment of the material for hydrogen isotope purification and the results represent a step forward towards next generation practical materials for quantum sieving of important gas isotopes.

Introduction Tandem Lesions (TLs) pose unique challenges in the endovascular management of acute ischemic stroke.(1) The absence of anterograde blood flow in the carotid occluded segment may limit the effectiveness of endovascular interventions, resulting in delayed reperfusion or suboptimal recanalization.(2,3) Thus, the presence of unpaired blood flow through the ICA in the context of TLs is believed to exacerbate the extension of ischemic lesions. (4,5) This study compared the clinical and procedural outcomes of patients with TLs and extracranial internal carotid artery occlusion versus those with stenosis. Methods A retrospective analysis was performed on a multicenter cohort of patients with TLs who underwent endovascular treatment. The patients were categorized into two groups: those with extracranial ICA stenosis and those with occlusion. Clinical outcomes, including functional independence, hemorrhagic events, and procedural time metrics including puncture to reperfusion time were assessed. Sensitivity analyses were conducted to evaluate these differences segregating patients according to varying degrees of stenosis, and in pre‐specified subgroups. Results A total of 513 patients with TLs were included in the study. 281 (54.8%) presented with ICA occlusion, and 232 (45.2%) presented stenosis >=70% (Table 1). The comparison between the stenosis and occlusion groups revealed no significant differences in the main outcomes, including mTICI 2c‐3 (47.5% vs. 50.6%, aOR 1.07, 95% CI 0.70‐1.64, p=.751) (Figure 1), mRS 0‐2 at 90 days (43.6% vs. 48.9%, aOR 0.79, 95% CI 0.52‐1.20, p=.271), sICH rates (4.7% vs. 5.6%, aOR 0.72, 95% CI 0.31‐1.71, p=.458), and puncture to reperfusion time (58 [40‐80.5] vs. 52.5 [35.2‐80], ratio 1.04, 95% CI 0.88‐1.23, p=.64). Similar analyses performed comparing different degrees of stenosis and occlusion, and in patients treated with the antegrade approach only, did not show significant differences either. Conclusion Our findings indicate that although more severe degrees of stenosis or occlusion of the ICA prolong the time from puncture to reperfusion, no significant differences in clinical outcomes exist. The clinical implications of these findings need to be further evaluated to fully comprehend the specific needs of patients affected by TLs.

Background For acute proximal intracranial artery occlusions, contact aspiration may be more effective than stent‐retriever for first‐line reperfusion therapy. Due to the lack of data regarding medium vessel occlusion thrombectomy, we evaluated outcomes according to first‐line technique in a large, multicenter registry. Methods Imaging, procedural, and clinical outcomes of patients with acute proximal medium vessel occlusions (M2, A1, or P1) or distal medium vessel occlusions (M3, A2, P2, or further) treated at 37 sites in 10 countries were analyzed according to first‐line endovascular technique (stent‐retriever versus aspiration). Multivariable logistic regression and propensity‐score matching were used to estimate the odds of the primary outcome, expanded Thrombolysis in Cerebral Infarction score of 2b–3 (“successful recanalization”), as well as secondary outcomes (first‐pass effect, expanded Thrombolysis in Cerebral Infarction 2c‐3, intracerebral hemorrhage, and 90‐day modified Rankin scale, 90‐day mortality) between treatment groups. Results Of the 440 included patients (44.5% stent‐retriever versus 55.5% aspiration), those treated with stent‐retriever had lower baseline Alberta Stroke Program Early Computed Tomography Scale scores (median 8 versus 9; P

Background and study aims Z-POEM is now an established therapy for symptomatic Zenker’s diverticulum (ZD). Short-term follow-up of up to 1-year post Z-POEM suggests excellent efficacy and safety; however, long-term outcomes are not known. Thus, we sought to report on longer-term outcomes (≥ 2 years) following Z-POEM for treatment of ZD. Patients and methods This was an International multicenter retrospective study at eight institutions across North America, Europe, and Asia over a 5-year period (from December 3, 2015 to March 13, 2020) of patients who underwent Z-POEM for management of ZD with a minimum 2-year follow-up. The primary outcome was clinical success, defined as improvement in dysphagia score to ≤ 1 without need for further procedures during the first 6 months. Secondary outcomes included rate of recurrence in patients initially meeting clinical success, rate of reintervention, and adverse events (AEs). Results A total of 89 patients (male 57.3 %, mean age 71 ± 12 years) underwent Z-POEM for treatment of ZD (mean diverticulum size was 3.4 ± 1.3 cm). Technical success was achieved in 97.8 % of patients (n = 87) with a mean procedure time of 43.8 ± 19.2 minutes. The median post-procedure hospital stay was 1 day. There were eight AEs (9 %) (3 mild, 5 moderate). Overall, clinical success was achieved in 84 patients (94 %). Mean dysphagia, regurgitation, and respiratory scores all improved dramatically from 2.1 ± 0.8, 2.8 ± 1.3, and 1.8 ± 1.6 pre-procedure to 0.13 ± 0.5, 0.11 ± 0.5, and 0.05 ± 0.4, respectively, post-procedure at most recent follow-up (all P

Introduction Large vessel occlusion (LVO) and dehydration are both independently associated with poor functional outcomes and increased odds of mortality in acute ischemic stroke. Dehydration has previously been shown to affect collateral blood flow in LVO stroke, but it is unclear if this leads to worsened clinical outcomes. Methods A stroke center registry (10/2019‐12/2021) of consecutive adults who had undergone successful endovascular therapy (EVT, with thrombolysis in cerebral infarction score 2b/3) for anterior circulation LVO (ICA, M1, or M2) was queried. Dehydration on presentation was defined using laboratory surrogates: blood urea nitrogen/creatinine ratio >15 or serum osmolality >296 mOsm/kg. The primary outcome was a favorable shift in 90‐day modified Rankin Scale (mRS) using a proportional odds model, adjusting for age, pre‐stroke mRS, National Institutes of Health Stroke Scale (NIHSS), and Alberta Stroke Program Early Computed Tomography Scale (ASPECTS). Secondary outcomes included early improvement in 24h NIHSS. Results Of the 318 patients with anterior LVO who underwent EVT, 206 (65%) met criteria for dehydration, and 181 (87.9%) had both mRS and ASPECTS data available. Younger age, lower NIHSS, lower mRS, and higher ASPECTS were all strongly and independently associated with a favorable shift in 90d mRS. Dehydrated patients had similar changes in 24‐hr NIHSS scores (‐5 [interquartile range, IQR ‐10 to 0] vs. ‐5 [IQR ‐8 to 0], p = 0.37). Dehydration was not associated with a less favorable shift in 90‐day mRS (odds ratio [OR] 0.74, 95% confidence interval [CI] 0.41‐1.33), which remained non‐significant after multivariable adjustment (OR 1.46, 95%CI 0.74‐2.86). With serum osmolality assessed continuously, higher serum osm was associated with a less favorable shift in mRS at 90d (OR 0.95, 95%CI 0.92‐0.99, p = 0.009), but this did not persist after multivariable adjustment (p = 0.92) and was driven by the association between higher osmolality and age (r = 0.24, p(bonferroni)< 0.01) and pre‐stroke mRS (r = 0.20, p(bonferroni) = 0.04). Conclusions There was no association between dehydration and lower odds of early clinical improvement or long‐term functional recovery following successful endovascular thrombectomy.

Introduction Prior studies have elucidated a relationship between nonstenotic plaque in patients with cryptogenic embolic (cortical) infarcts, however it is unclear if nonstenotic carotid plaque is relevant in subcortical infarct patterns. Methods A nested cohort of consecutive patients with anterior, unilateral, subcortical infarcts without an identifiable embolic source were identified from a prospective stroke registry (September 2019 ‐ June 2021). Patients with extracranial stenosis >50% were excluded. Patients with computed tomography angiography were included and comparisons made according to infarct pattern being lacunar (single lesion < 1.5cm on computed tomography [CT] or < 2.0cm on diffusion weighted imaging [DWI]) versus cryptogenic (≥ 1.5cm on CT or ≥ 2.0cm on DWI, or scattered subcortical lesions). Prevalence estimates for cervical internal carotid artery (ICA) plaque presence were estimated with 95% confidence intervals (CI), and differences in plaque thickness and features were compared between sides. Results Of the 1684 who were screened, 141 met inclusion criteria (n = 80 due to small vessel disease, n = 61 cryptogenic). The median age was 66y (interquartile range, IQR 58–73) and National Institutes of Health Stroke Scale score was 3 (IQR 1–5). There was a higher probability of finding excess plaque ipsilateral to the stroke (41.1%, 95%CI 33.3‐49.3%) than finding excess contralateral plaque (29.1%, 95%CI 22.2‐37.1%; p = 0.03), but this was driven by patients with cryptogenic infarcts (excess ipsilateral vs. contralateral plaque frequency of 49.2% vs. 14.8%, p< 0.001) and not lacunar disease (35.0% vs. 40.0%, p = 0.51). Conclusions The probability of finding ipsilateral, nonstenotic carotid plaque in patients with subcortical cryptogenic strokes exceeds the probability of contralateral plaque and is driven by larger subcortical infarcts, classically defined as being cryptogenic. Approximately 1 in 3 unilateral anterior subcortical infarcts may be due to nonstenotic ICA plaque.

Memory normally declines with ageing and these age-related cognitive changes are associated with changes in brain structure. Episodic memory retrieval has been widely studied during ageing, whereas learning has received less attention. Here we examined the neural correlates of episodic learning rate in ageing. Our study sample consisted of 982 cognitively healthy female and male older participants from the Vallecas Project cohort, without a clinical diagnosis of mild cognitive impairment or dementia. The learning rate across the three consecutive recall trials of the verbal memory task (Free and Cued Selective Reminding Test) recall trials was used as a predictor of grey matter (GM) using voxel-based morphometry, and WM microstructure using tract-based spatial statistics on fractional anisotropy (FA) and mean diffusivity (MD) measures. Immediate Recall improved by 1.4 items per trial on average, and this episodic learning rate was faster in women and negatively associated with age. Structurally, hippocampal and anterior thalamic GM volume correlated positively with learning rate. Learning also correlated with the integrity of WM microstructure (high FA and low MD) in an extensive network of tracts including bilateral anterior thalamic radiation, fornix, and long-range tracts. These results suggest that episodic learning rate is associated with key anatomical structures for memory functioning, motivating further exploration of the differential diagnostic properties between episodic learning rate and retrieval in ageing.

Background and study aims The utility of digital single- operator cholangiopancreatoscopy (D-SOCP) in surgically altered anatomy (SAA) is limited. We aimed to evaluate the technical success and safety of D-SOCP in patients SAA. Patients and methods Patients with SAA who underwent D-SOCP between February 2015 and June 2020 were retrospectively evaluated. Technical success was defined as completing the intended procedure with the use of D-SOCP. Results Thirty-five patients underwent D-SOCP (34 D-SOC, 1 D-SOP). Bilroth II was the most common type of SAA (45.7 %), followed by Whipple reconstruction (31.4 %). Twenty-three patients (65.7 %) patients had prior failed ERCP due to the presence of complex biliary stone (52.2 %). A therapeutic duodenoscope was utilized in the majority of the cases (68.6 %), while a therapeutic gastroscope (22.7 %) or adult colonoscope (8.5 %) were used in the remaining procedures. Choledocholithiasis (61.2 %) and pancreatic duct calculi (3.2 %) were the most common indications for D-SOCP. Technical success was achieved in all 35 patients (100 %) and majority (91.4 %) requiring a single session. Complex interventions included electrohydraulic or laser lithotripsy, biliary or pancreatic stent placement, stricture dilation, and target tissue biopsies. Two mild adverse events occurred (pancreatitis and transient bacteremia). Conclusions In SAA, D-SOCP is a safe and effective modality to diagnose and treat complex pancreatobiliary disorders, especially in cases where standard ERCP attempts may fail.

DNA Methyltransferase 3 A (DNMT3A) is an important facilitator of differentiation of both embryonic and hematopoietic stem cells. Heterozygous germline mutations in DNMT3A lead to Tatton-Brown-Rahman Syndrome (TBRS), characterized by obesity and excessive height. While DNMT3A is known to impact feeding behavior via the hypothalamus, here we investigated a role in adipocyte progenitors utilizing heterozygous knockout mice that recapitulate cardinal TBRS phenotypes. These mice become morbidly obese due to adipocyte enlargement and tissue expansion. Adipose tissue in these mice exhibited defects in preadipocyte maturation and precocious activation of inflammatory gene networks, including interleukin-6 signaling. Adipocyte progenitor cell lines lacking DNMT3A exhibited aberrant differentiation. Furthermore, mice in which Dnmt3a was specifically ablated in adipocyte progenitors showed enlarged fat depots and increased progenitor numbers, partly recapitulating the TBRS obesity phenotypes. Loss of DNMT3A led to constitutive DNA hypomethylation, such that the DNA methylation landscape of young adipocyte progenitors resemble that of older wild-type mice. Together, our results demonstrate that DNMT3A coordinates both the central and local control of energy storage required to maintain normal weight and prevent inflammatory obesity.

Background and aims: Mouse models of colitis have been used to study the pathogenesis of inflammatory bowel disease (IBD) and for pre-clinical development of therapeutic agents. Various epigenetic pathways have been shown to play important regulatory roles in IBD. Reversible N6-methyladenosine (m6A) methylation represents a new layer of post-transcriptional gene regulation that affects a variety of biological processes. We aim to study how deletion of a critical component of m6A writer complex, METTL14, in T cells affects the development of colitis. Methods: Conditional Mettl14 was lineage specifically deleted with CD4-regulated Cre in T cells. Colitis phenotype was determined by H&E staining, colon weight-to-length ratio and cytokine expression. We additionally utilized T cell transfer model of colitis and adoptive transfer of regulatory T cells. Mice were treated with antibiotics to determine if the colitis could be attenuated. Results: METTL14 deficiency in T cells induced spontaneous colitis in mice. This was characterized by increased inflammatory cell infiltration, increased colonic weight-to-length ratio and increased Th1 and Th17 cytokines. The colitis development was due to dysfunctional regulatory T (Treg) cells, as adoptive transfer of WT Treg cells attenuated the colitis phenotype. The METTL14-deficient Treg cells have decreased RORγt expression compared with WT controls. METTL14 deficiency caused impaired induction of naïve T cells into induced Treg cells. Antibiotic treatment notably attenuated the colitis development. Conclusion: Here we report a new mouse model of spontaneous colitis based on perturbation of RNA methylation in T cells. The colitis is T cell-mediated and dependent on the microbiome. This model represents a new tool for elucidating pathogenic pathways, studying the contribution of intestinal microbiome and preclinical testing of therapeutic agents for inflammatory bowel disease.

Background and study aims Current endoscopic methods of treating gastric fistulas are either too complex or have high rates of recurrence. We aimed to provide a novel endoscopic method for robust fistula closure. Patients and methods This was a single-center, retrospective study of five patients who underwent multi-layer endoscopic suturing for closing of a chronic fistula (> 4 weeks). Devitalization of the fistula tract was achieved with argon plasma coagulation, followed by endoscopic suturing of the fistula. Then, endoscopic suturing of the gastric wall surrounding the fistula was performed, creating an overlay of healthy gastric mucosa around the fistula. Results Technical success (fistula closure on the day of the procedure) was achieved in all five patients, with no complications. After a median follow up of 5 months (range 2–23 months), there was a 100 % clinical success rate (no fistula recurrence). Conclusions Our single-operator method of multi-layer endoscopic suturing provides a robust fistula closure with minimal to no risk of recurrence. In light of limitations of current fistula closure methods, further investigations are warranted to better define long-term outcomes with it compared to alternative methods.

Among over 150 distinct RNA modifications, N6-methyladenosine (m6A) and adenosine-to-inosine (A-to-I) RNA editing represent 2 of the most studied modifications on mammalian mRNAs. Although both modifications occur on adenosine residues, knowledge on potential functional crosstalk between these 2 modifications is still limited. Here, we show that the m6A modification promotes expression levels of the ADAR1, which encodes an A-to-I RNA editing enzyme, in response to interferon (IFN) stimulation. We reveal that YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) mediates up-regulation of ADAR1; YTHDF1 is a reader protein that can preferentially bind m6A-modified transcripts and promote translation. Knockdown of YTHDF1 reduces the overall levels of IFN-induced A-to-I RNA editing, which consequently activates dsRNA-sensing pathway and increases expression of various IFN-stimulated genes. Physiologically, YTHDF1 deficiency inhibits virus replication in cells through regulating IFN responses. The A-to-I RNA editing activity of ADAR1 plays important roles in the YTHDF1-dependent IFN responses. Therefore, we uncover that m6A and YTHDF1 affect innate immune responses through modulating the ADAR1-mediated A-to-I RNA editing.

Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth disorder caused by germline heterozygous mutations in the DNA methyltransferase DNMT3A. DNMT3A is a critical regulator of hematopoietic stem cell (HSC) differentiation and somatic DNMT3A mutations are frequent in hematologic malignancies and clonal hematopoiesis. Yet, the impact of constitutive DNMT3A mutation on hematopoiesis in TBRS is undefined. In order to establish how constitutive mutation of DNMT3A impacts blood development in TBRS we gathered clinical data and analyzed blood parameters in 18 individuals with TBRS. We also determined the distribution of major peripheral blood cell lineages by flow cytometric analyses. Our analyses revealed non-anemic macrocytosis, a relative decrease in lymphocytes and increase in neutrophils in TBRS individuals compared to unaffected controls. We were able to recapitulate these hematologic phenotypes in multiple murine models of TBRS and identified rare hematological and non-hematological malignancies associated with constitutive Dnmt3a mutation. We further show that loss of DNMT3A in TBRS is associated with an altered DNA methylation landscape in hematopoietic cells affecting regions critical to stem cell function and tumorigenesis. Overall, our data identify key hematopoietic effects driven by DNMT3A mutation with clinical implications for individuals with TBRS and DNMT3A-associated clonal hematopoiesis or malignancies.

Summary: The RNA N6-methyladenosine (m6A) methylation is installed by the METTL3-METTL14 methyltransferase complex. This modification has critical regulatory roles in various biological processes. Here, we report that deletion of Mettl14 dramatically reduces mRNA m6A methylation in developing B cells and severely blocks B cell development in mice. Deletion of Mettl14 impairs interleukin-7 (IL-7)-induced pro-B cell proliferation and the large-pre-B-to-small-pre-B transition and causes dramatic abnormalities in gene expression programs important for B cell development. Suppression of a group of transcripts by cytoplasmic m6A reader YTHDF2 is critical to the IL-7-induced pro-B cell proliferation. In contrast, the block in the large-pre-B-to-small-pre-B transition is independent of YTHDF1 or YTHDF2 but is associated with a failure to properly upregulate key transcription factors regulating this transition. Our data highlight the important regulatory roles of the RNA m6A methylation and its reader proteins in early B cell development.

Background: The overwhelming need and interest in global surgery has led to increasing numbers of international surgery resident rotations. Despite the validity of global surgical education, financial and logistical barriers remain when implementing these international rotations. The Mount Sinai Department of Surgery, New York, USA, established an international resident rotation in 2005. Here, we describe some of the costs and barriers to establishing and maintaining a global surgery rotation with the aim of providing a guideline for academic institutions interested in building an international rotation. Methods: This study is a retrospective review of the international rotation with the Hospital Jose Maria Cabral y Báez (Cabral) in Santiago, Dominican Republic. The exchange programme is an opportunity for two resident doctors from Dominican Republic to join Mount Sinai third year residents in a 1-month surgical rotation. We reviewed data collected from budgets, financial investments, resident and programme director experiences, and formal agreements between the two institutions. Findings: With the Mount Sinai funding, there have been three residents from the Dominican Republic who have completed an exchange rotation at the Mount Sinai Hospital. An optimum international site requires a balanced alliance between the US academic institution and the international site. The Cabral and Mount Sinai collaborative partnership allows residents from both institutions to benefit from the exchange of experiences and surgical practices. Site selection is contingent on: hospital infrastructure (eg, operative variety and volume, faculty oversight); suitable living accommodations that allow personal safety, access to food, running water, electricity, and an internet connection; and overcoming language barriers. Successful implementation requires a time commitment from staff at both institutions. The monthly operational cost of this programme is US$3530, with 37% for visiting resident accommodation, 30% for transport, 20% for visiting resident expenses, and 13% for health and communication expenses. The time required by the US programme director includes an annual trip to the international rotation site and approximately 100 h per year, which includes monthly orientations and debriefings, and research. Finally, this programme requires adherence to Accreditation Council for Graduate Medical Education and Residency Review Committee guidelines. Interpretation: Global academic surgery combines surgery with education, clinical service, research, and advocacy in resource-limited settings. Mitigation of logistical barriers and addressing financial costs allows for successful global academic surgery programmes. Funding: None

Reinforced concrete (RC) members in critical structures, such as bridge piers, high-rise buildings, and offshore facilities, are vulnerable to impact loads throughout their service life. For example, vehicle collisions, accidental loading, or unpredicted attacks could occur. The numerical models presented in this paper are shown to adequately replicate the impact behaviour and damage process of fibre-reinforced polymer (FRP)-strengthened concrete-filled steel tube (CFST) columns and Reinforced Concrete slabs. Validated models are developed using Abaqus/Explicit by reproducing the results obtained from experimental testing on bare CFST and RC slab members. Parameters relating to the FRP and material components are investigated to determine the influence on structural behaviour. The innovative method of using the dissipated energy approach for structural evaluation provides an assessment of the effective use of FRP and material properties to enhance the dynamic response. The outcome of the evaluation, including the geometrical, material, and contact properties modelling, shows that there is an agreement between the numerical and experimental behaviour of the selected concrete members. The experimentation shows that the calibration of the models is a crucial task, which was considered and resulted in matching the force–displacement behaviour and achieving the same maximum impact force and displacement values. Different novel and complicated Finite Element Models were comprehensively developed. The developed numerical models could precisely predict both local and global structural responses in the different reinforced concrete members. The application of the current numerical techniques can be extended to design structural members where there are no reliable practical guidelines on both national and international levels.

Esophageal squamous cell carcinoma (ESCC) is the second common cancer in Henan province and is well-known for aggressiveness and dismal prognosis. Adjuvant therapies, chemotherapy, radiotherapy and endoscopic treatment have not improved survival rates in patients with late stage esophageal carcinoma. All-trans retinoic acid (ATRA) is the active ingredient of Vitamin A and affects a wide spectrum of biological processes including development, growth, neural function, immune function, reproduction, and vision. It is one of the most potent therapeutic agents used for treating cancers, especially lung adenocarcinomas. ATRA inhibits metastatic potential and angiogenesis in several tumor models. We investigated the effects of ATRA on the expression of angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2) and receptor Tie-2 in EC1 cells in vitro. We also assessed the growth and migration of EC1 cells in vitro. ATRA treatment caused 29.5% and 40.3% reduction of the growth of EC1 cells after 24 hours and 48 hours, relative to the control. ATRA plus fluorouracil treatment reduced the viability more strongly than either drug alone, indicating an additive effect. Moreover, ATRA decreased EC1 migration by 87%. Furthermore, ATRA treatment led to a marked decrease of the transcript levels of Ang-1, Ang-2, Tie-2, VEGF, and VEGF receptors, as assessed by real-time RT-PCR. Importantly, the protein levels of Ang-1, Ang-2 and Tie-2 were reduced by ATRA treatment. In vivo, we found ATRA treatment suppressed the tumor growth and improved the cachexia of mice. Importantly, ATRA treatment decreased the expression of CD31, Ang-1, Ang-2 and Tie-2 in subcutaneous tumors of EC1 cells. Collectively, our findings demonstrate that ATRA exhibits a dose- and temporal-dependent effect on the metastatic behavior, suppresses the angiopoietin-Tie2 pathway and inhibits angiogenesis and the progression of xenograft tumors of EC1 cells.

Enterprises nowadays strive to keep transforming their business processes in accordance with the fastchanging customer demands so as to survive the intense global competition. In an attempt to provide practitioners with an insight into ERP implementation and the resulting business performances, this paper investigate how a successful ERP implementation can help transform enterprises processes. Case based research which is based on an in-depth observation under managerial and practitioner situation. A case study at a precession engineering company is conducted to evaluate the feasibility of the proposed strategic enterprise information model. This paper focuses on the implementation of Sales & Marketing and Warehouse modules of an ERP system. The key performance indicators are used to evaluate how the ERP implementation can improve the business processes. It is found that ERP helps to improve data visibility and improve on-time delivery but less effective on improving employee productivity. This research proposes an enterprise information model to exploit what strategy should be formulate and how ERP tactic can be implemented in company to enhance enterprise competitive advantages. The strategic enterprise information model is formulated based on our in-depth case study and ERP consultant's experience.

Cell-based therapies to treat skeletal muscle disease are limited by the poor survival of donor myoblasts, due in part to acute hypoxic stress. After confirming that the microenvironment of transplanted myoblasts is hypoxic, we screened a kinase inhibitor library in vitro and identified five kinase inhibitors that protected myoblasts from cell death or growth arrest in hypoxic conditions. A systematic, combinatorial study of these compounds further improved myoblast viability, showing both synergistic and additive effects. Pathway and target analysis revealed CDK5, CDK2, CDC2, WEE1, and GSK3β as the main target kinases. In particular, CDK5 was the center of the target kinase network. Using our recently developed statistical method based on elastic net regression we computationally validated the key role of CDK5 in cell protection against hypoxia. This method provided a list of potential kinase targets with a quantitative measure of their optimal amount of relative inhibition. A modified version of the method was also able to predict the effect of combinations using single-drug response data. This work is the first step towards a broadly applicable system-level strategy for the pharmacology of hypoxic damage.

BACKGROUND: Hepatic steatosis is a major risk factor for graft failure in liver transplantation. Hepatic steatosis shows a greater negative influence on graft function following prolonged cold ischaemia. As the impact of steatosis on hepatocyte metabolism during extended cold ischaemia is not well-described, we compared markers of metabolic capacity and mitochondrial function in steatotic and lean livers following clinically relevant durations of cold preservation. METHODS: Livers from 10-week old leptin-deficient obese (ob/ob, n = 9) and lean C57 mice (n = 9) were preserved in ice-cold University of Wisconsin solution. Liver mitochondrial function was then assessed using high resolution respirometry after 1.5, 3, 5, 8, 12, 16 and 24 hours of storage. Metabolic marker enzymes for anaerobiosis and mitochondrial mass were also measured in conjunction with non-bicarbonate tissue pH buffering capacity. RESULTS: Ob/ob and lean mice livers showed severe (>60%) macrovesicular and mild (

Introduction: Second language learning is a multifaceted task that benefits across numerous neurocognitive domains including central auditory processing. Existing cross-sectional and longitudinal data show that performance on tests of central auditory processing [central auditory tests (CATs)] worsens with HIV infection. Second language learning may modify this relationship. To explore the relationship between second language learning, central auditory processing, and its interaction with HIV, we assessed the effect of learning English as a second language on CATs among children both living with and without HIV (CLWH/CLWOH) in Dar es Salaam, Tanzania. Methods: Three hundred and seventy-two native Kiswahili speaking children aged 3-10 years old (196 CLWOH, 176 CLWH) were enrolled. Participants completed questionnaires about English language learning, socioeconomic status (SES), and health history. Three central auditory tests-the Triple Digit Test (TDT), the Staggered Spondaic Word Test (SSW), and the Hearing-In-Noise Test (HINT)-were used to assess each participant's central auditory processing abilities. Multivariate linear regression was used to assess the effect of written and spoken English language learning at home and in school on CATs with age, HIV-status, and SES included in each model. Results: HIV status, age, and SES were all significant predictors of all three central auditory tests, with CLWH performing significantly worse on all three CATs than CLWOH. Children actively learning spoken and written English at home had significantly better central auditory processing abilities on the TDT compared to children not actively learning English at home (p < 0.01) independent of HIV status, age, and SES. Children learning spoken and written English at school performed significantly better on the HINT (p < 0.05) than those not actively learning English at school. Discussion: Learning English at home and learning English in school were associated with improved central auditory performance independent of HIV status, SES, and age. These findings also underscore the significance of second language acquisition as a potential mechanism of improving central auditory function within a Kiswahili-speaking cohort. This study found differences in central auditory processing between children exposed to English at home and in school, suggesting differences in language learning in both settings mediated by SES, and this benefit exists regardless of HIV status. [ABSTRACT FROM AUTHOR]

Superagers are elderly individuals with the memory ability of people 30 years younger and provide evidence that age-related cognitive decline is not inevitable. In a sample of 64 superagers (mean age, 81.9; 59% women) and 55 typical older adults (mean age, 82.4; 64% women) from the Vallecas Project, we studied, cross-sectionally and longitudinally over 5 years with yearly follow-ups, the global cerebral white matter status as well as region-specific white matter microstructure assessment derived from diffusivity measures. Superagers and typical older adults showed no difference in global white matter health (total white matter volume, Fazekas score, and lesions volume) cross-sectionally or longitudinally. However, analyses of diffusion parameters revealed the better white matter microstructure in superagers than in typical older adults. Cross-sectional differences showed higher fractional anisotropy (FA) in superagers mostly in frontal fibers and lower mean diffusivity (MD) in most white matter tracts, expressed as an anteroposterior gradient with greater group differences in anterior tracts. FA decrease over time is slower in superagers than in typical older adults in all white matter tracts assessed, which is mirrored by MD increases over time being slower in superagers than in typical older adults in all white matter tracts except for the corticospinal tract, the uncinate fasciculus, and the forceps minor. The better preservation of white matter microstructure in superagers relative to typical older adults supports resistance to age-related brain structural changes as a mechanism underpinning the remarkable memory capacity of superagers, while their regional aging pattern is in line with the last-in-first-out hypothesis. [ABSTRACT FROM AUTHOR]