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Seagrass ecosystems contain globally significant organic carbon (C) stocks. However, climate change and increasing frequency of extreme events threaten their preservation. Shark Bay, Western Australia, has the largest C stock reported for a seagrass ecosystem, containing up to 1.3% of the total C stored within the top metre of seagrass sediments worldwide. On the basis of field studies and satellite imagery, we estimate that 36% of Shark Bay’s seagrass meadows were damaged following a marine heatwave in 2010/2011. Assuming that 10 to 50% of the seagrass sediment C stock was exposed to oxic conditions after disturbance, between 2 and 9 Tg CO2 could have been released to the atmosphere during the following three years, increasing emissions from land-use change in Australia by 4–21% per annum. With heatwaves predicted to increase with further climate warming, conservation of seagrass ecosystems is essential to avoid adverse feedbacks on the climate system.

Bacterial σ factors bind RNA polymerase (E) to form holoenzyme (Eσ), conferring promoter specificity to E and playing a key role in transcription bubble formation. σ N is unique among σ factors in its structure and functional mechanism, requiring activation by specialized AAA+ ATPases. Eσ N forms an inactive promoter complex where the N-terminal σ N region I (σ N -RI) threads through a small DNA bubble. On the opposite side of the DNA, the ATPase engages σ N -RI within the pore of its hexameric ring. Here, we perform kinetics-guided structural analysis of de novo formed Eσ N initiation complexes and engineer a biochemical assay to measure ATPase-mediated σ N -RI translocation during promoter melting. We show that the ATPase exerts mechanical action to translocate about 30 residues of σ N -RI through the DNA bubble, disrupting inhibitory structures of σ N to allow full transcription bubble formation. A local charge switch of σ N -RI from positive to negative may help facilitate disengagement of the otherwise processive ATPase, allowing subsequent σ N disentanglement from the DNA bubble. Bacterial transcription with σ N requires activation by specialized AAA+ ATPases. Here, the authors visualize transient structural intermediates and engineer a biochemical assay to show that these ATPases partially unfold σ N to initiate transcription.

BackgroundMultimorbidity increases healthcare resource utilization. Little is known on specific comorbidity combinations.AimsTo identify comorbidities associated with increased resource utilization among inpatients admitted for gastrointestinal bleeding (GIB).MethodsThis retrospective cross-sectional study, 1/2010–5/2018 at the University Hospital Zurich, Switzerland, analyzed electronic health records of patients with upper (UGIB) and lower (LGIB) GIB, focusing on length of stay (LOS) and 30-day readmissions for resource use and clinical outcomes, investigated by multivariable regression adjusted for antithrombotics.ResultsOf 1101 patients, 791 had UGIB and 310 LGIB, most often melena and bleeding diverticula, respectively. In UGIB, thromboembolic events showed a trend toward 27% increased LOS (1.27; 95% confidence interval [CI] 1.00–1.61), antithrombotics independently associated with 46% increased LOS (1.46; 95% CI 1.32–1.62). Cancer (odds ratio [OR] 2.86; 95% CI 1.68–4.88) independently associated with 30-day readmissions, anemia showed a trend (OR 1.68; 95% CI 1.00–2.84). In LGIB, none of the investigated comorbidities associated with increased LOS, but antithrombotics independently associated with 25% increased LOS (1.25; 95% CI 1.07–1.46). Atrial fibrillation/flutter (OR 2.69; 95% CI 1.06–6.82) and cancer (OR 4.76; 95% CI 1.40–16.20) associated strongly with 30-day readmissions.ConclusionsIn both groups, cancer associated with 30-day readmissions, antithrombotics with increased LOS. Thromboembolic events and anemia showed clinically important trends in UGIB. Atrial fibrillation/flutter associated with 30-day readmissions in LGIB. Prospective studies are needed to investigate these complex multimorbid populations and establish appropriate guidelines.

CCAAT/enhancer binding protein alpha ( CEBPA) mutations in AML are associated with favourable prognosis and are divided into N- and C-terminal mutations. The majority of AML patients have both types of mutations. We assessed the prognostic significance of single ( n =7) and double ( n =12) CEBPA mutations among 224 AML patients. Double CEBPA mutations conferred a decisively favourable overall ( P =0.006) and disease-free survival ( P =0.013). However, clinical outcome of patients with single CEBPA mutations was not different from CEBPA wild-type patients. In a multivariable analysis, only double – but not single – CEBPA mutations were identified as independent prognostic factors. These findings indicate heterogeneity within AML patients with CEBPA mutations.

The current paradigm on leukemogenesis indicates that leukemias are propagated by leukemic stem cells. The genomic events and pathways involved in the transformation of hematopoietic precursors into leukemic stem cells are increasingly understood. This concept is based on genomic mutations or functional dysregulation of transcription factors in malignant cells of patients with acute myeloid leukemia (AML). Loss of the CCAAT/enhancer binding protein-α ( CEBPA ) function in myeloid cells in vitro and in vivo leads to a differentiation block, similar to that observed in blasts from AML patients. CEBPA alterations in specific subgroups of AML comprise genomic mutations leading to dominant-negative mutant proteins, transcriptional suppression by leukemic fusion proteins, translational inhibition by activated RNA-binding proteins, and functional inhibition by phosphorylation or increased proteasomal-dependent degradation. The PU.1 gene can be mutated or its expression or function can be blocked by leukemogenic fusion proteins in AML. Point mutations in the RUNX1/AML1 gene are also observed in specific subtypes of AML, in addition to RUNX1 being the most frequent target for chromosomal translocation in AML. These data are persuasive evidence that impaired function of particular transcription factors contributes directly to the development of human AML, and restoring their function represents a promising target for novel therapeutic strategies in AML.

One of the more fascinating features of fungus-gardening ants (Attini: Formicidae) is their fidelity to their lineage-specific fungal symbionts. Among the derived higher-attine ants (leafcutter ants and close relatives), it is thought that most leaf-cutting ants grow Attamyces fungus whereas most Trachymyrmex ants grow ‘Trachymyces’ fungus, but there exist exceptions to this clade-to-clade correspondence between ants and fungi. The exceptions are inconsistent with strict one-to-one coevolution, which suggests that ants sometimes are able to switch to novel fungi. Such switches appear to be largely constrained and ants are generally faithful to their species-specific fungi. Prior experiments demonstrated no clear fitness consequences of growing novel fungi over the short-term when the ant Trachymyrmex septentrionalis was symbiont-switched by forcing it to grow Attamyces leaf-cutter fungus. We hypothesized that long-term ant-fungal fidelity is constrained either by physiological differences among fungal species or by garden diseases that symbiont-switched ants cannot control. Repeat experiments in a different location show that T. septentrionalis colonies switched to grow Attamyces exhibit sudden declines in garden biomass and consequent fitness reductions due to garden destruction by pathogens, whereas control colonies ( Trachymyrmex ants cultivating Trachymyces fungus) do not show parallel garden declines. These patterns are mirrored in symbiont-switch experiments conducted on colonies in Trachymyrmex turrifex . Disease microbes selecting on ant-cultivar combinations therefore can constrain switches to novel cultivars and maintain combinations that are more resistant to disease.

Summary Fracture risk in type 1 diabetes (T1D) is supposed to be underestimated by bone mineral density (BMD). Individuals with T1D had more prevalent fractures in a cross-sectional study. Serum levels of pentosidine, an advanced glycation end product, and poor glycaemic control were associated with prevalent fractures independent of BMD. Introduction Type 1 diabetes (T1D) is associated with increased fracture risk. Bone mineral density (BMD) underestimates the risk of fractures in some individuals. The accumulation of advanced glycation end products (AGEs) impairs bone matrix and reduces bone strength. Methods In a cross-sectional study, 128 men and premenopausal women with T1D were evaluated. We compared traditional risk factors for fractures, BMD, parameters of bone metabolism and AGEs in individuals with and without prevalent fractures. An independent association of serum AGE levels with prevalent fractures was investigated. Results Individuals with prevalent fractures exhibited a longer duration of T1D, higher HbA1c and more diabetic-related complications. BMD at the femoral neck ( z -score −0.76 ± 0.94 vs. −0.23 ± 1.02; p  = 0.031) and total hip ( z -score −0.54 ± 0.93 vs. 0.11 ± 1.11; p  = 0.017) was lower in those with prevalent fractures. Individuals with fractures had higher pentosidine levels (164.1 ± 53.6 vs. 133.2 ± 40.4; p  = 0.002). The levels of N -ε-(carboxymethyl)-lysine (CML) and endogenous secretory receptor for AGEs (esRAGE) did not significantly differ. Multivariate logistic regression analysis adjusted for age, BMI, family history of fractures, smoking, vitamin D deficiency, BMD at lumbar spine, femoral neck and total hip identified pentosidine levels and HbA1c as independent factors associated with prevalent fractures (odds ratio 1.02, 95 % CI 1.00–1.03/pmol/ml increase of pentosidine; p  = 0.008 and odds ratio 1.93, 95 % CI 1.16–3.20 per percentage increase of HbA1c; p  = 0.011). Conclusions The pentosidine levels but not BMD are independently associated with prevalent fractures. Impaired bone quality in T1D may result from increased AGE formation.

Summary Trabecular bone score (TBS) seems to provide additive value on BMD to identify individuals with prevalent fractures in T1D. TBS did not significantly differ between T1D patients and healthy controls, but TBS and HbA1c were independently associated with prevalent fractures in T1D. A TBS cutoff <1.42 reflected prevalent fractures with 91.7 % sensitivity and 43.2 % specificity. Introduction Type 1 diabetes (T1D) increases the risk of osteoporotic fractures. TBS was recently proposed as an indirect measure of bone microarchitecture. This study aimed at investigating the TBS in T1D patients and healthy controls. Associations with prevalent fractures were tested. Methods One hundred nineteen T1D patients (59 males, 60 premenopausal females; mean age 43.4 ± 8.9 years) and 68 healthy controls matched for gender, age, and body mass index (BMI) were analyzed. The TBS was calculated in the lumbar region, based on two-dimensional (2D) projections of DXA assessments. Results TBS was 1.357 ± 0.129 in T1D patients and 1.389 ± 0.085 in controls ( p  = 0.075). T1D patients with prevalent fractures ( n  = 24) had a significantly lower TBS than T1D patients without fractures (1.309 ± 0.125 versus 1.370 ± 0.127, p  = 0.04). The presence of fractures in T1D was associated with lower TBS (odds ratio = 0.024, 95 % confidence interval (CI) = 0.001–0.875; p  = 0.042) but not with age or BMI. TBS and HbA1c were independently associated with fractures. The area-under-the curve (AUC) of TBS was similar to that of total hip BMD in discriminating T1D patients with or without prevalent fractures. In this set-up, a TBS cutoff <1.42 discriminated the presence of fractures with a sensitivity of 91.7 % and a specificity of 43.2 %. Conclusions TBS values are lower in T1D patients with prevalent fractures, suggesting an alteration of bone strength in this subgroup of patients. Reliable TBS cutoffs for the prediction of fracture risk in T1D need to be determined in larger prospective studies.

The transcription factor C/EBPα (for CCAAT/enhancer binding protein-α; encoded by the gene CEBPA ) is crucial for the differentiation of granulocytes. Conditional expression of C/EBPα triggers neutrophilic differentiation, and no mature granulocytes are observed in Cebpa -mutant mice. Here we identify heterozygous mutations in CEBPA in ten patients with acute myeloid leukemia (AML). We found that five mutations in the amino terminus truncate the full-length protein, but did not affect a 30-kD protein initiated further downstream. The mutant proteins block wild-type C/EBPα DNA binding and transactivation of granulocyte target genes in a dominant-negative manner, and fails to induce granulocytic differentiation. Ours is the first report of CEBPA mutations in human neoplasia, and such mutations are likely to induce the differentiation block found in AML.

Patients with attention deficit-hyperactivity disorder (ADHD) exhibit difficulties in multiple attentional functions. Although high heritability rates suggest a strong genetic impact, aetiological pathways from genes and environmental factors to the ADHD phenotype are not well understood. Tracking the time course of deviant task processing using event-related electrophysiological brain activity should characterize the impact of familiality on the sequence of cognitive functions from preparation to response control in ADHD. Method Preparation and response control were assessed using behavioural and electrophysiological parameters of two versions of a cued continuous performance test with varying attentional load in boys with ADHD combined type (n = 97), their non-affected siblings (n = 27) and control children without a family history of ADHD (n = 43). Children with ADHD and non-affected siblings showed more variable performance and made more omission errors than controls. The preparatory Cue-P3 and contingent negative variation (CNV) following cues were reduced in both ADHD children and their non-affected siblings compared with controls. The NoGo-P3 was diminished in ADHD compared with controls whilst non-affected siblings were located intermediate but did not differ from both other groups. No clear familiality effects were found for the Go-P3. Better task performance was further associated with higher CNV and P3 amplitudes. Impairments in performance and electrophysiological parameters reflecting preparatory processes and to some extend also for inhibitory response control, especially under high attentional load, appeared to be familially driven in ADHD and may thus constitute functionally relevant endophenotypes for the disorder.