The gene encoding Arabidopsis acyl-CoA-binding protein 3 is pathogen inducible and subject to circadian regulation

In Arabidopsis thaliana, acyl-CoA-binding protein 3 ( ACBP3), one of six ACBPs, is unique in terms of the C-terminal location of its acyl-CoA-binding domain. It promotes autophagy-mediated leaf senescence and confers resistance to Pseudomonas syringae pv. tomato DC3000. To understand the regulation of ACBP3, a 1.7 kb 5'-flanking region of ACBP3 and its deletion derivatives were characterized using β-glucuronidase (GUS) fusions. A 374 bp minimal fragment (–151/+223) could drive GUS expression while a 1698 bp fragment (–1475/+223) conferred maximal activity. Further, histochemical analysis on transgenic Arabidopsis harbouring the largest (1698 bp) ACBP3pro::GUS fusion displayed ubiquitous expression in floral organs and vegetative tissues (vascular bundles of leaves and stems), consistent with previous results showing that extracellularly localized ACBP3 functions in plant defence. A 160 bp region (–434/–274) induced expression in extended darkness and caused down-regulation in extended light. Electrophoretic mobility shift assay (EMSA) and DNase I footprinting assay showed that the DNA-binding with one finger box (Dof-box, –341/–338) interacted specifically with leaf nuclear proteins from dark-treated Arabidopsis, while GT-1 (–406/–401) binds both dark- and light-treated Arabidopsis, suggesting that Dof and GT-1 motifs are required to mediate circadian regulation of ACBP3. Moreover, GUS staining and fluorometric measurements revealed that a 109 bp region (–543/–434) was responsive to phytohormones and pathogens. An S-box of AT-rich sequence (–516/–512) was identified to bind nuclear proteins from pathogen-infected Arabidopsis leaves, providing the basis for pathogen-inducible regulation of ACBP3 expression. Thus, three cis-responsive elements (Dof, GT-1, and the S-box) in the 5'-flanking region of ACBP3 are proven functional in the regulation of ACBP3

Chronic kidney disease, severe arterial and arteriolar sclerosis and kidney neoplasia: on the spectrum of kidney involvement in MELAS syndrome

<p>Abstract</p> <p>Background</p> <p>MELAS syndrome (MIM ID#540000), an acronym for Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes, is a genetically heterogeneous mitochondrial disorder with protean manifestations and occasional kidney involvement. Interest in the latter is rising due to the identification of cases with predominant kidney involvement and to the hypothesis of a link between mitochondrial DNA and kidney neoplasia.</p> <p>Case presentation</p> <p>We report the case of a 41-year-old male with full blown MELAS syndrome, with lactic acidosis and neurological impairment, affected by the "classic" 3243A > G mutation of mitochondrial DNA, with kidney cancer. After unilateral nephrectomy, he rapidly developed severe kidney functional impairment, with nephrotic proteinuria. Analysis of the kidney tissue at a distance from the two tumor lesions, sampled at the time of nephrectomy was performed in the context of normal blood pressure, recent onset of diabetes and before the appearance of proteinuria. The morphological examination revealed a widespread interstitial fibrosis with dense inflammatory infiltrate and tubular atrophy, mostly with thyroidization pattern. Vascular lesions were prominent: large vessels displayed marked intimal fibrosis and arterioles had hyaline deposits typical of hyaline arteriolosclerosis. These severe vascular lesions explained the different glomerular alterations including ischemic and obsolescent glomeruli, as is commonly observed in the so-called "benign" arteriolonephrosclerosis. Some rare glomeruli showed focal segmental glomerulosclerosis; as the patient subsequently developed nephrotic syndrome, these lesions suggest that silent ischemic changes may result in the development of focal segmental glomerulosclerosis secondary to nephron loss.</p> <p>Conclusions</p> <p>Nephron loss may trigger glomerular sclerosis, at least in some cases of MELAS-related nephropathy. Thus the incidence of kidney disease in the "survivors" of MELAS syndrome may increase as the support therapy of these patients improves.</p

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [&lt;1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None

Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

XGBoost, a Machine Learning Method, Predicts Neurological Recovery in Patients with Cervical Spinal Cord Injury

The accurate prediction of neurological outcomes in patients with cervical spinal cord injury (SCI) is difficult because of heterogeneity in patient characteristics, treatment strategies, and radiographic findings. Although machine learning algorithms may increase the accuracy of outcome predictions in various fields, limited information is available on their efficacy in the management of SCI. We analyzed data from 165 patients with cervical SCI, and extracted important factors for predicting prognoses. Extreme gradient boosting (XGBoost) as a machine learning model was applied to assess the reliability of a machine learning algorithm to predict neurological outcomes compared with that of conventional methodology, such as a logistic regression or decision tree. We used regularly obtainable data as predictors, such as demographics, magnetic resonance variables, and treatment strategies. Predictive tools, including XGBoost, a logistic regression, and a decision tree, were applied to predict neurological improvements in the functional motor status (ASIA [American Spinal Injury Association] Impairment Scale [AIS] D and E) 6 months after injury. We evaluated predictive performance, including accuracy and the area under the receiver operating characteristic curve (AUC). Regarding predictions of neurological improvements in patients with cervical SCI, XGBoost had the highest accuracy (81.1%), followed by the logistic regression (80.6%) and the decision tree (78.8%). Regarding AUC, the logistic regression showed 0.877, followed by XGBoost (0.867) and the decision tree (0.753). XGBoost reliably predicted neurological alterations in patients with cervical SCI. The utilization of predictive machine learning algorithms may enhance personalized management choices through pre-treatment categorization of patients

Gender equality in global health leadership: Cross-sectional survey of global health graduates

Women comprise two-thirds of the global-health (GH) workforce but are underrepresented in leadership. GH departments are platforms to advance gender equality in GH leadership. Using a survey of graduates from one GH department, we compared women’s and men’s post-training career agency and GH employment and assessed whether gender gaps in training accounted for gender gaps in career outcomes. Master-of-Public-Health (MPH) and mid-career-fellow alumni since 2010 received a 31-question online survey. Forty-four per cent of MPH alum and 24% of fellows responded. Using logistic regression, we tested gender gaps in training satisfaction, career agency, and GH employment, unadjusted and adjusted for training received. Women (N = 293) reported lower satisfaction with training (M7.6 vs 8.2) and career agency (leadership ability: M6.3 vs 7.4) than men (N = 60). Women more often than men acquired methods-related skills (95% vs 78%), employment recommendations (42% vs 18%), and group membership. Men more often than women acquired leadership training (43% vs 23%), award recommendations (53% vs 17%), and conference support (65% vs 35%). Women and men had similar odds of GH employment. Accounting for confounders and gender-gaps in training eliminated gender gaps in five of six career-agency outcomes. Panel studies of women’s and men’s career trajectories in GH are needed