Draft genome sequence of Acetobacter aceti strain 1023, a vinegar factory isolate

The genome sequence of Acetobacter aceti 1023, an acetic acid bacterium adapted to traditional vinegar fermentation, comprises 3.0 Mb (chromosome plus plasmids). A. aceti 1023 is closely related to the cocoa fermenter Acetobacter pasteurianus 386B but possesses many additional insertion sequence elements

Diagnosis and management of food allergies: new and emerging options: a systematic review

It is reported that 6% of children and 3% of adults have food allergies, with studies suggesting increased prevalence worldwide over the last few decades. Despite this, our diagnostic capabilities and techniques for managing patients with food allergies remain limited. We have conducted a systematic review of literature published within the last 5 years on the diagnosis and management of food allergies. While the gold standard for diagnosis remains the double-blind, placebo-controlled food challenge, this assessment is resource intensive and impractical in most clinical situations. In an effort to reduce the need for the double-blind, placebo-controlled food challenge, several risk-stratifying tests are employed, namely skin prick testing, measurement of serum-specific immunoglobulin E levels, component testing, and open food challenges. Management of food allergies typically involves allergen avoidance and carrying an epinephrine autoinjector. Clinical research trials of oral immunotherapy for some foods, including peanut, milk, egg, and peach, are under way. While oral immunotherapy is promising, its readiness for clinical application is controversial. In this review, we assess the latest studies published on the above diagnostic and management modalities, as well as novel strategies in the diagnosis and management of food allergy

How big is big enough? Toward a sustainable future by examining alternatives to the conventional economic growth paradigm

This study addresses how the sustainability crisis may be overcome by using alternatives to the conventional economic growth paradigm. Based on a literature review, the paper identifies and discusses three alternatives, namely negative, zero and positive economic growth. These alternatives are compared from a feasibility and policy perspective in relation to the transition toward sustainable development. The three alternatives are associated with very far‐reaching sets of policies that have different focal points with regard to how the paradigm shift from the conventional growth paradigm can be realized. All these alternatives, however, challenge the effectiveness of market forces. The shortcomings of the alternatives (resistance to voluntary transition with negative or zero growth, no proper consideration of the rebound effect for positive growth) hinder the transition and must be further addressed by policy‐makers in public and private sectors, as well as by civil society

Comparison of echocardiographic methods for calculating left ventricular mass in elite rugby football league athletes and the impact on chamber geometry

Background: Recommendations for the echocardiographic assessment of left ventricular (LV) mass in the athlete suggest the use of the linear method using a two-tiered classification system (2TC). The aims of this study were to compare the linear method and the area-length (A-L) method for LV mass in elite rugby football league (RFL) athletes and to establish how any differences impact the classification of LV geometry using 2TC and four-tier (4TC) classification systems. Methods: Two hundred and twenty (220) male RFL athletes aged 25 ± 5 (14–34 years) were recruited. All athletes underwent echocardiography and LV mass was calculated by the American Society of Echocardiography (ASE) corrected Linear equation (2D) and the A-L method. Left ventricular mass Index (LVMi) was used with relative wall thickness to determine geometry in the 2TC and with concentricity and LV end diastolic volume index for the 4TC. Method specific recommended cut-offs were utilised. Results: Higher values of absolute (197 ± 34 vs. 181 ± 34 g; p < 0.0001) and indexed (92 ± 13 vs. 85 ± 13 g/m2; p < 0.0001) measures of LV mass were obtained from A-L compared to the linear method. Normal LV geometry was demonstrated in 98.2% and 80% of athletes whilst eccentric hypertrophy in 1.4% and 19.5% for linear and A-L respectively. Both methods provided 0.5% as having concentric remodelling and 0% as having concentric hypertrophy. Allocation to the 4TC resulted in 97% and 80% with normal geometry, 0% and 8.6% with eccentric dilated hypertrophy, 0% and 7.7% with eccentric non-dilated hypertrophy, 1.4% and 0.5% with concentric remodelling and 1.4% and 3% with concentric non-dilated hypertrophy for linear and A-L methods respectively. No participants had concentric dilated hypertrophy from either methods. Conclusion: The linear and A-L method for calculation of LV mass in RFL athletes are not interchangeable with significantly higher values obtained using A-L method impacting on geometry classification. More athletes present with eccentric hypertrophy using 2TC and eccentric dilated/non-dilated using 4TC. Further studies should be aimed at establishing the association of A-L methods of LV mass and application of the 4TC to the multi-factorial demographics of the athlete

KDM3A coordinates actin dynamics with intraflagellar transport to regulate cilia stability

Cilia assembly and disassembly are coupled to actin dynamics, ensuring a coherent cellular response during environmental change. How these processes are integrated remains undefined. The histone lysine demethylase KDM3A plays important roles in organismal homeostasis. Loss-of-function mouse models of Kdm3a phenocopy features associated with human ciliopathies, whereas human somatic mutations correlate with poor cancer prognosis. We demonstrate that absence of KDM3A facilitates ciliogenesis, but these resulting cilia have an abnormally wide range of axonemal lengths, delaying disassembly and accumulating intraflagellar transport (IFT) proteins. KDM3A plays a dual role by regulating actin gene expression and binding to the actin cytoskeleton, creating a responsive "actin gate" that involves ARP2/3 activity and IFT. Promoting actin filament formation rescues KDM3A mutant ciliary defects. Conversely, the simultaneous depolymerization of actin networks and IFT overexpression mimics the abnormal ciliary traits of KDM3A mutants. KDM3A is thus a negative regulator of ciliogenesis required for the controlled recruitment of IFT proteins into cilia through the modulation of actin dynamics.</p

Targeting of Epigenetic Co-dependencies Enhances Anti-AML Efficacy of Menin Inhibitor in AML with MLL1-R or Mutant NPM1

Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy, which is responsible for therapy-refractory AML relapse

Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1

Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy, which is responsible for therapy-refractory AML relapse

Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)

Treatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1