ARID5B as a critical downstream target of the TAL1 complex that activates the oncogenic transcriptional program and promotes T-cell leukemogenesis.

The oncogenic transcription factor TAL1/SCL induces an aberrant transcriptional program in T-cell acute lymphoblastic leukemia (T-ALL) cells. However, the critical factors that are directly activated by TAL1 and contribute to T-ALL pathogenesis are largely unknown. Here, we identified AT-rich interactive domain 5B (ARID5B) as a collaborating oncogenic factor involved in the transcriptional program in T-ALL. ARID5B expression is down-regulated at the double-negative 2-4 stages in normal thymocytes, while it is induced by the TAL1 complex in human T-ALL cells. The enhancer located 135 kb upstream of the ARID5B gene locus is activated under a superenhancer in T-ALL cells but not in normal T cells. Notably, ARID5B-bound regions are associated predominantly with active transcription. ARID5B and TAL1 frequently co-occupy target genes and coordinately control their expression. ARID5B positively regulates the expression of TAL1 and its regulatory partners. ARID5B also activates the expression of the oncogene MYC Importantly, ARID5B is required for the survival and growth of T-ALL cells, and forced expression of ARID5B in immature thymocytes results in thymus retention, differentiation arrest, radioresistance, and tumor formation in zebrafish. Our results indicate that ARID5B reinforces the oncogenic transcriptional program by positively regulating the TAL1-induced regulatory circuit and MYC in T-ALL, thereby contributing to T-cell leukemogenesis.

Editorial: Focus on green nanomaterials for a sustainable internet of things.

In the dynamic landscape of the Internet of Things (IoT), where smart devices are reshaping our world, nanomaterials can play a pivotal role in ensuring the IoT's sustainability. These materials are poised to redefine the development of smart devices, not only enabling cost-effective fabrication but also unlocking novel functionalities. As the IoT is set to encompass an astounding number of interconnected devices, the demand for environmentally friendly nanomaterials takes center stage. ThisFocus Issuespotlights cutting-edge research that explores the intersection of nanomaterials and sustainability. The collection delves deep into this critical nexus, encompassing a wide range of topics, from fundamental properties to applications in devices (e.g. sensors, optoelectronic synapses, energy harvesters, memory components, energy storage devices, and batteries), aspects concerning circularity and green synthesis, and an array of materials comprising organic semiconductors, perovskites, quantum dots, nanocellulose, graphene, and two-dimensional semiconductors. Authors not only showcase advancements but also delve into the sustainability profile of these materials, fostering a responsible endeavour toward a green IoT future.

Reference equations for evaluation of spirometry function tests in South Asia, and among South Asians living in other countries.

BACKGROUND: There are few data to support accurate interpretation of spirometry data in South Asia, a major global region with a high reported burden of chronic respiratory disease. METHOD: We measured lung function in 7453 healthy men and women aged ≥18 years, from Bangladesh, North India, South India, Pakistan and Sri Lanka, as part of the South Asia Biobank study. First, we assessed the accuracy of existing equations for predicting normal forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and FEV1/FVC ratio. Then, we used our data to derive (n=5589) and internally validate (n=1864) new prediction equations among South Asians, with further external validation among 339 healthy South Asians living in Singapore. RESULTS: The Global Lung Initiative (GLI) and National Health and Nutrition Examination Survey consistently overestimated expiratory volumes (best fit GLI-African American, mean±sd z-score: FEV1 -0.94±1.05, FVC -0.91±1.10; n=7453). Age, height and weight were strong predictors of lung function in our participants (p<0.001), and sex-specific reference equations using these three variables were highly accurate in both internal validation (z-scores: FEV1 0.03±0.99, FVC 0.04±0.97, FEV1/FVC -0.03±0.99) and external validation (z-scores: FEV1 0.31±0.99, FVC 0.24±0.97, FEV1/FVC 0.16±0.91). Further adjustment for study regions improves the model fit, with highest accuracy for estimation of region-specific lung function in South Asia. CONCLUSION: We present improved equations for predicting lung function in South Asians. These offer the opportunity to enhance diagnosis and management of acute and chronic lung diseases in this major global population.

Feed-forward regulatory loop driven by IRF4 and NF-κB in adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive hematological malignancy derived from mature CD4+ T-lymphocytes. Here, we demonstrate the transcriptional regulatory network driven by 2 oncogenic transcription factors, IRF4 and NF-κB, in ATL cells. Gene expression profiling of primary ATL samples demonstrated that the IRF4 gene was more highly expressed in ATL cells than in normal T cells. Chromatin immunoprecipitation sequencing analysis revealed that IRF4-bound regions were more frequently found in super-enhancers than in typical enhancers. NF-κB was found to co-occupy IRF4-bound regulatory elements and formed a coherent feed-forward loop to coordinately regulate genes involved in T-cell functions and development. Importantly, IRF4 and NF-κB regulated several cancer genes associated with super-enhancers in ATL cells, including MYC, CCR4, and BIRC3. Genetic inhibition of BIRC3 induced growth inhibition in ATL cells, implicating its role as a critical effector molecule downstream of the IRF4-NF-κB transcriptional network.

Operando Direct Observation of Filament Formation in Resistive Switching Devices Enabled by a Topological Transformation Molecule.

Conductive filaments (CFs) play a critical role in the mechanism of resistive random-access memory (ReRAM) devices. However, in situ detection and visualization of the precise location of CFs are still key challenges. We demonstrate for the first time the use of a π-conjugated molecule which can transform between its twisted and planar states upon localized Joule heating generated within filament regions, thus reflecting the locations of the underlying CFs. Customized patterns of CFs were induced and observed by the π-conjugated molecule layer, which confirmed the hypothesis. Additionally, statistical studies on filaments distribution were conducted to study the effect of device sizes and bottom electrode heights, which serves to enhance the understanding of switching behavior and their variability at device level. Therefore, this approach has great potential in aiding the development of ReRAM technology.

Day-case discharge criteria and safety of children undergoing adenoidectomy and tonsillectomy for obstructive symptoms-A systematic review.

OBJECTIVES: Obstructive sleep apnoea (OSA) is a common indication for adenoidectomy and tonsillectomy in children. Traditional practice involves overnight admission to monitor for respiratory complications. However, there is a shift towards same-day discharge in selected patients. This systematic review aims to critically evaluate day-case criteria and safety in children with OSA undergoing adenotonsillectomy. DESIGN: We performed a systematic search of EMBASE, Medline and the Cochrane library. All data collected were independently validated for accuracy. Quality assessment of included articles was performed. The protocol was registered with PROSPERO. RESULTS: A total of 15 studies were included (10 731 patients). There was heterogeneity in methods used to ascertain OSA, day-case discharge criteria and lack of prospective discharge protocol. The proportion of children considered for planned day-case surgery ranged from 28.7%-100% based on individual criteria, with an average rate of successful same-day discharge of 96.1% in these patients. The reported rates of post-operative respiratory adverse events and need for airway intervention were 0%-27.3% and 0.4%-6.8%, respectively. There was no reported mortality. The studies were considered low to medium on quality assessment. CONCLUSION: There is a lack of prospective data on day-case criteria and systematic assessment of post-operative complications in children with OSA undergoing adenoidectomy and tonsillectomy. However, current literature suggests that day-case surgery is safe in carefully selected patients. Better characterisation of patient-specific risk factors is needed to develop an optimal criteria-based timeline for safe discharge. This has the potential to improve confidence and uptake across units.

A systematic review of the feasibility and safety of day case nasal and/or palatopharyngeal surgery in patients with obstructive sleep apnoea.

INTRODUCTION: Recent guidelines suggest obstructive sleep apnoea (OSA) is not an absolute contraindication for same day discharge following surgery. The aim of this systematic review was to examine the feasibility and safety of day case nasal and/or palatopharyngeal surgery in patients with OSA. METHODS: We performed a systematic search of PubMed, EMBASE and the Cochrane library. Quality assessment of included studies was performed. The protocol of this systematic review was registered with PROSPERO (CRD42021273451). RESULTS: A total of 1836 patients from 10 observational studies were included. There were 268 (15.4%) nasal surgeries, 738 palatopharyngeal surgeries (42.4%) and 735 (42.2%) combined nasal and palatopharyngeal surgery. The majority of patients had moderate to severe OSA. A total of 860 patients (49.8%) were successfully discharged as day cases. There were no standard criteria for daycase surgery. Post-anaesthetic respiratory events were reported in 86/1750 (4.9%) patients. Oxygen desaturation was the most common respiratory event (83.7%, n = 72). There was no mortality reported. CONCLUSION: Current data suggests day surgery is feasible in carefully selected patients with OSA undergoing nasal and/or palatopharyngeal surgery. Further well-designed prospective studies with an emphasis on the systematic assessment of complications are required to establish safety and daycase criteria.

The enhancer RNA ARIEL activates the oncogenic transcriptional program in T-cell acute lymphoblastic leukemia.

The oncogenic transcription factor TAL1 regulates the transcriptional program in T-ALL. ARID5B is one of the critical downstream targets of TAL1, which further activates the oncogenic regulatory circuit in T-ALL cells. Here, we elucidated the molecular functions of the noncoding RNA, ARID5B-inducing enhancer associated long noncoding RNA (ARIEL), in T-ALL pathogenesis. We demonstrated that ARIEL is specifically activated in TAL1 + T-ALL cases, and its expression is associated with ARID5B enhancer activity. ARIEL recruits mediator proteins to the ARID5B enhancer, promotes enhancer-promoter interactions, and activates the expression of ARID5B, thereby positively regulating the TAL1-induced transcriptional program and the MYC oncogene. The TAL1 complex coordinately regulates the expression of ARIEL Knockdown of ARIEL inhibits cell growth and survival of T-ALL cells in culture and blocks disease progression in a murine xenograft model. Our results indicate that ARIEL plays an oncogenic role as an enhancer RNA in T-ALL.

Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia.

Aldehyde dehydrogenases (ALDHs) are overexpressed in various types of cancers. One of the ALDH family genes, ALDH1A2, is aberrantly expressed in more than 50% of T-cell acute lymphoblastic leukemia (T-ALL) cases. However, its molecular function and role in T-ALL pathogenesis are largely unknown. ChIP-seq and RNA-seq analyses showed that the oncogenic transcription factor TAL1 and its regulatory partners bind to the intronic regulatory element of the ALDH1A2 gene, directly inducing a T-ALL-specific isoform with enzymatic activity. ALDH1A2 was preferentially expressed in the TAL1-positive T-ALL subgroup. In T-ALL cell lines, depletion of ALDH1A2 inhibited cell viability and induced apoptosis. Interestingly, gene expression and metabolomic profiling revealed that ALDH1A2 supported glycolysis and the TCA cycle, accompanied by NADH production, by affecting multiple metabolic enzymes to promote ATP production. Depletion of ALDH1A2 increased the levels of reactive oxygen species (ROS), while ROS levels were reduced by ALDH1A2 overexpression both in vitro and in vivo. Overexpression of ALDH1A2 accelerated tumor onset and increased tumor penetrance in a zebrafish T-ALL model. Taken together, our results indicate that ALDH1A2 protects against intracellular stress and promotes T-ALL cell metabolism and survival. ALDH1A2 overexpression enables leukemic clones to sustain a hyper-proliferative state driven by oncogenes.

Switching from Ticagrelor to Clopidogrel in Asian Patients with ST-Elevated Myocardial Infarction - A Time Dependent Analysis Study.

BACKGROUND: Ticagrelor is initially prescribed after an ST-elevated myocardial infarction (STEMI) and this may be followed by a switch to clopidogrel. However, studies involving antiplatelet switching have been conflicting and only assessed at a specific switch point. The objective of this study was to investigate switching from ticagrelor to clopidogrel in an Asian population, after accounting for various switch points as in a real-world environment. METHODS: A retrospective cohort of 349 STEMI patients started on ticagrelor and aspirin were followed-up for 1 year after a percutaneous coronary intervention that was performed between June 2014 and November 2016. Patients who switched to clopidogrel were compared with those who remained on ticagrelor. Outcomes measured were major adverse cardiac and cerebrovascular events (MACCEs) and clinically significant bleeding (CSB). Cox regression analysis with switch status as a time-dependent covariate was performed. RESULTS: The switched group was not associated with MACCEs or CSB [10.0% vs. 13.8%; hazard ratio (HR) = 0.484; 95% confidence interval (CI): 0.196-1.191; p = 0.114]. There was also no significant difference when MACCEs were analyzed alone (2.3% vs. 7.7%; HR = 0.518; 95% CI: 0.137-1.957; p = 0.332). For CSB, the switched group was less likely to have an event (7.8% vs. 8.5%; HR = 0.298; 95% CI: 0.091-0.982; p = 0.047). CONCLUSIONS: This study showed no significant difference between staying on ticagrelor and switching to clopidogrel. Switching might decrease the incidence of CSB. De-escalation from ticagrelor to clopidogrel could translate to cost savings for Asian patients without compromising safety and efficacy.

Enhancer profiling identifies critical cancer genes and characterizes cell identity in adult T-cell leukemia.

A number of studies have recently demonstrated that super-enhancers, which are large cluster of enhancers typically marked by a high level of acetylation of histone H3 lysine 27 and mediator bindings, are frequently associated with genes that control and define cell identity during normal development. Super-enhancers are also often enriched at cancer genes in various malignancies. The identification of such enhancers would pinpoint critical factors that directly contribute to pathogenesis. In this study, we performed enhancer profiling using primary leukemia samples from adult T-cell leukemia/lymphoma (ATL), which is a genetically heterogeneous intractable cancer. Super-enhancers were enriched at genes involved in the T-cell activation pathway, including IL2RA/CD25, CD30, and FYN, in both ATL and normal mature T cells, which reflected the origin of the leukemic cells. Super-enhancers were found at several known cancer gene loci, including CCR4, PIK3R1, and TP73, in multiple ATL samples, but not in normal mature T cells, which implicated those genes in ATL pathogenesis. A small-molecule CDK7 inhibitor, THZ1, efficiently inhibited cell growth, induced apoptosis, and downregulated the expression of super-enhancer-associated genes in ATL cells. Furthermore, enhancer profiling combined with gene expression analysis identified a previously uncharacterized gene, TIAM2, that was associated with super-enhancers in all ATL samples, but not in normal T cells. Knockdown of TIAM2 induced apoptosis in ATL cell lines, whereas overexpression of this gene promoted cell growth. Our study provides a novel strategy for identifying critical cancer genes.

A predictive model for conversion to psychosis in clinical high-risk patients.

BACKGROUND: The authors developed a practical and clinically useful model to predict the risk of psychosis that utilizes clinical characteristics empirically demonstrated to be strong predictors of conversion to psychosis in clinical high-risk (CHR) individuals. The model is based upon the Structured Interview for Psychosis Risk Syndromes (SIPS) and accompanying clinical interview, and yields scores indicating one's risk of conversion. METHODS: Baseline data, including demographic and clinical characteristics measured by the SIPS, were obtained on 199 CHR individuals seeking evaluation in the early detection and intervention for mental disorders program at the New York State Psychiatric Institute at Columbia University Medical Center. Each patient was followed for up to 2 years or until they developed a syndromal DSM-4 disorder. A LASSO logistic fitting procedure was used to construct a model for conversion specifically to a psychotic disorder. RESULTS: At 2 years, 64 patients (32.2%) converted to a psychotic disorder. The top five variables with relatively large standardized effect sizes included SIPS subscales of visual perceptual abnormalities, dysphoric mood, unusual thought content, disorganized communication, and violent ideation. The concordance index (c-index) was 0.73, indicating a moderately strong ability to discriminate between converters and non-converters. CONCLUSIONS: The prediction model performed well in classifying converters and non-converters and revealed SIPS measures that are relatively strong predictors of conversion, comparable with the risk calculator published by NAPLS (c-index = 0.71), but requiring only a structured clinical interview. Future work will seek to externally validate the model and enhance its performance with the incorporation of relevant biomarkers.

Synthetic Lateral Metal-Semiconductor Heterostructures of Transition Metal Disulfides.

Lateral heterostructures with planar integrity form the basis of two-dimensional (2D) electronics and optoelectronics. Here we report that, through a two-step chemical vapor deposition (CVD) process, high-quality lateral heterostructures can be constructed between metallic and semiconducting transition metal disulfide (TMD) layers. Instead of edge epitaxy, polycrystalline monolayer MoS2 in such junctions was revealed to nucleate from the vertices of multilayered VS2 crystals, creating one-dimensional junctions with ultralow contact resistance (0.5 kΩ·µm). This lateral contact contributes to 6-fold improved field-effect mobility for monolayer MoS2, compared to the conventional on-top nickel contacts. The all-CVD strategy presented here hence opens up a new avenue for all-2D-based synthetic electronics.

Efficient and tumor-specific knockdown of MTDH gene attenuates paclitaxel resistance of breast cancer cells both in vivo and in vitro.

BACKGROUND: Drug resistance of paclitaxel (TAX), the first-line chemotherapy drug for breast cancer, was reported to develop in 90% of patients with breast cancer, especially metastatic breast cancer. Investigating the mechanism of TAX resistance of breast cancer cells and developing the strategy improving its therapeutic efficiency are crucial to breast cancer cure. METHODS AND RESULTS: We here report an elegant nanoparticle (NP)-based technique that realizes efficient breast cancer treatment of TAX. Using lentiviral vector-mediated gene knockdown, we first demonstrated that TAX therapeutic efficiency was closely correlated with metadherin (MTDH) gene expression in breast cancer cell lines. This finding was also supported by efficacy of TAX treatment in breast cancer patients from our clinical studies. Specifically, TAX treatment became more effective when MTDH expression was decreased in MCF-7 cancer cells by the blocking nuclear factor-kappa B (NF-κB) pathway. Based on these findings, we subsequently synthesized a polymeric NP that could co-deliver MTDH-small interfering RNA (MTDH-siRNA) and TAX into the breast cancer tumors in tumor-bearing mice. The NPs were composed of a cationic copolymer, which wrapped TAX in the inside and adsorbed the negatively charged siRNA on their surface with high drug-loading efficiency and good stability. CONCLUSIONS: NP-based co-delivery approach can effectively knock down the MTDH gene both in vitro and in vivo, which dramatically inhibits breast tumor growth, achieving effective TAX chemotherapy treatment without overt side effects. This study provides a potential therapeutic strategy for the treatment of a wide range of solid tumors highly expressing MTDH.

Chymase Level Is a Predictive Biomarker of Dengue Hemorrhagic Fever in Pediatric and Adult Patients.

Background: Most patients with dengue experience mild disease, dengue fever (DF), while few develop the life-threatening diseases dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). No laboratory tests predict DHF or DSS. We evaluated whether the serum chymase level can predict DHF or DSS in adult and pediatric patients and the influence of preexisting conditions (PECs) on chymase levels. Methods: Serum chymase levels were measured in patients presenting with undifferentiated fever to hospitals in Colombo District, Sri Lanka. The value of serum the chymase concentration and clinical signs and symptoms as predictors of DHF and/or DSS was evaluated by multivariate analysis. We assessed the influence of age, PECs, and day after fever onset on the robustness of the chymase level as a biomarker for DHF and/or DSS. Results: An elevated chymase level in acute phase blood samples was highly indicative of later diagnosis of DHF or DSS for pediatric and adult patients with dengue. No recorded PECs prevented an increase in the chymase level during DHF. However, certain PECs (obesity and cardiac or lung-associated diseases) resulted in a concomitant increase in chymase levels among adult patients with DHF. Conclusions: These results show that patients with acute dengue who present with high levels of serum chymase consistently are at greater risk of DHF. The chymase level is a robust prognostic biomarker of severe dengue for adult and pediatric patients.

Flexible Ionic-Electronic Hybrid Oxide Synaptic TFTs with Programmable Dynamic Plasticity for Brain-Inspired Neuromorphic Computing.

Emulation of biological synapses is necessary for future brain-inspired neuromorphic computational systems that could look beyond the standard von Neuman architecture. Here, artificial synapses based on ionic-electronic hybrid oxide-based transistors on rigid and flexible substrates are demonstrated. The flexible transistors reported here depict a high field-effect mobility of ≈9 cm2 V-1 s-1 with good mechanical performance. Comprehensive learning abilities/synaptic rules like paired-pulse facilitation, excitatory and inhibitory postsynaptic currents, spike-time-dependent plasticity, consolidation, superlinear amplification, and dynamic logic are successfully established depicting concurrent processing and memory functionalities with spatiotemporal correlation. The results present a fully solution processable approach to fabricate artificial synapses for next-generation transparent neural circuits.

Markers of dengue severity: a systematic review of cytokines and chemokines.

The prognosis of dengue remains a challenge in the early, objective triage of patients with dengue fever of differing severity. Circulating immuno-modulating proteins have brought new possibilities as prognostic markers of severe dengue (SD). This systematic review is devoted to understanding the potential utility of blood-based cytokines and chemokines as prognostication markers of SD based on the current literature. PubMed and Embase were searched. Of 794 candidate articles, 685 abstracts were screened against our exclusion/inclusion criteria and 25 (3.6 %) studies met the quality assessments. A total of 18 studies were retrospective observational and 2 were prospective cohort studies. Elevated IL-10, up to day 7 of fever onset, stood out as a candidate prognostic marker for SD using the 1997 and 2009 World Health Organization (WHO) case definitions. IFNγ was another potential prognostic marker of SD (1997 WHO case definition), but its levels varied between studies. Significant heterogeneity in methodologies and patient cohorts prevent ready application of IL-10 and IFNγ as prognostic markers to other dengue populations. Our results suggest that the current non-randomized studies are delivering inconsistent messages and higher-quality studies, with consistent methodologies and validation in independent patient cohorts, are needed to delineate confounding variables. Major gaps identified were full accounting and transparency of sampling days, dengue virus type, infection status and age group.

Potential for international spread of wild poliovirus via travelers.

BACKGROUND: The endgame of polio eradication is hampered by the international spread of poliovirus via travelers. In response to ongoing importations of poliovirus into polio-free countries, on 5 May 2014, WHO's Director-General declared the international spread of wild poliovirus a public health emergency of international concern. Our objective was to develop a mathematical model to estimate the international spread of polio infections. METHODS: Our model took into account polio endemicity in polio-infected countries, population size, polio immunization coverage rates, infectious period, the asymptomatic-to-symptomatic ratio, and also the probability of a traveler being infectious at the time of travel. We applied our model to three scenarios: (1) number of exportations of both symptomatic and asymptomatic polio infections out of currently polio-infected countries, (2) the risk of spread of poliovirus to Saudi Arabia via Hajj pilgrims, and (3) the importation risk of poliovirus into India. RESULTS: Our model estimated 665 polio exportations (>99 % of which were asymptomatic) from nine polio-infected countries in 2014, of which 78.3 % originated from Pakistan. Our model also estimated 21 importations of poliovirus into Saudi Arabia via Hajj pilgrims and 20 poliovirus infections imported to India in the same year. CONCLUSION: The extent of importations of asymptomatic and symptomatic polio infections is substantial. For countries that are vulnerable to polio outbreaks due to poor national polio immunization coverage rates, our newly developed model may help guide policy-makers to decide whether imposing an entry requirement in terms of proof of vaccination against polio would be justified.

What does annealing do to metal-graphene contacts?

Annealing is a postprocessing treatment commonly used to improve metal-graphene contacts with the assumption that resist residues sandwiched at the metal-graphene contacts are removed during annealing. Here, we examine this assumption by undertaking a systematic study to understand mechanisms that lead to the contact enhancement brought about by annealing. Using a soft shadow-mask, we fabricated residue-free metal-graphene contacts with the same dimensions as lithographically defined metal-graphene contacts on the same graphene flake. Both cases show comparable contact enhancement for nickel-graphene contacts after annealing treatment signifying that removal of resist residues is not the main factor for contact enhancement. It is found instead that carbon dissolves from graphene into the metal at chemisorbed Ni- and Co-graphene interfaces and leads to many end-contacts being formed between the metal and the dangling carbon bonds in the graphene, which contributes to much smaller contact resistance.