Constraints on the evolution of azole resistance in plant pathogenic fungi

The durability of azole fungicides in controlling agriculturally important pathogenic fungi is unique amongst modern single site fungicides. Today, azoles are still relied on to control pathogens of many crops including cereals, fruits and vegetables, canola and soybeans. Significantly, this widespread use continues despite many reports of azole-resistant fungal strains. In this review, recent reports of azole resistance and the mechanisms associated with resistant phenotypes are discussed. The example of the complex evolution of the azole target sterol 14-demethylase (CYP51) enzyme in modern European populations of the wheat pathogen Mycosphaerella graminicola is used to describe the quantitative and epistatic effects on fungicide sensitivity and enzyme function of target site mutations, and to explore the hypothesis that constraints on CYP51 evolution have ensured the longevity of azoles. In addition, the threats posed by alternative resistance mechanisms causing cross-resistance to all azoles or even unrelated fungicides are discussed, and postulations are made on how using new genomic technologies to gain a greater understanding of azole resistance evolution should enhance the ability to control azole-resistant strains of plant pathogenic fungi in the future

A multi-exon deletion within WWOX is associated with a 46,XY disorder of sex development

Disorders of sex development (DSD) are congenital conditions where chromosomal, gonad or genital development is atypical. In a significant proportion of 46,XY DSD cases it is not possible to identify a causative mutation, making genetic counseling difficult and potentially hindering optimal treatment. Here, we describe the analysis of a 46,XY DSD patient that presented at birth with ambiguous genitalia. Histological analysis of the surgically removed gonads showed bilateral undifferentiated gonadal tissue and immature testis, both containing malignant germ cells. We screened genomic DNA from this patient for deletions and duplications using an Illumina whole-genome SNP microarray. This analysis revealed a heterozygous deletion within the WWOX gene on chromosome 16, removing exons 6-8. Analysis of parental DNA showed that the deletion was inherited from the mother. cDNA analysis confirmed that the deletion maintained the reading frame, with exon 5 being spliced directly onto exon 9. This deletion is the first description of a germline rearrangement affecting the coding sequence of WWOX in humans. Previously described Wwox knockout mouse models showed gonadal abnormalities, supporting a role for WWOX in human gonad development

Preoperative Exercise Training to Prevent Postoperative Pulmonary Complications in Adults Undergoing Major Surgery. A Systematic Review and Meta-analysis with Trial Sequential Analysis.

Rationale: Poor preoperative physical fitness and respiratory muscle weakness are associated with postoperative pulmonary complications (PPCs) that result in prolonged hospital length of stay and increased mortality.Objectives: To examine the effect of preoperative exercise training on the risk of PPCs across different surgical settings.Methods: We searched MEDLINE, Web of Science, Embase, the Physiotherapy Evidence Database, and the Cochrane Central Register, without language restrictions, for studies from inception to July 2020. We included randomized controlled trials that compared patients receiving exercise training with those receiving usual care or sham training before cardiac, lung, esophageal, or abdominal surgery. PPCs were the main outcome; secondary outcomes were preoperative functional changes and postoperative mortality, cardiovascular complications, and hospital length of stay. The study was registered with PROSPERO (International Prospective Register of Systematic Reviews).Results: From 29 studies, 2,070 patients were pooled for meta-analysis. Compared with the control condition, preoperative exercise training was associated with a lower incidence of PPCs (23 studies, 1,864 patients; relative risk, 0.52; 95% confidence interval [CI], 0.41 to 0.66; grading of evidence, moderate); Trial Sequential Analysis confirmed effectiveness, and there was no evidence of difference of effect across surgeries, type of training (respiratory muscles, endurance or combined), or preoperative duration of training. At the end of the preoperative period, exercise training resulted in increased peak oxygen uptake (weighted mean difference [WMD], +2 ml/kg/min; 99% CI, 0.3 to 3.7) and higher maximal inspiratory pressure (WMD, +12.2 cm H <sub>2</sub> O; 99% CI, 6.3 to 18.2). Hospital length of stay was shortened (WMD, -2.3 d; 99% CI, -3.82 to -0.75) in the intervention group, whereas no difference was found in postoperative mortality.Conclusions: Preoperative exercise training improves physical fitness and reduces the risk of developing PPCs while minimizing hospital resources use, regardless of the type of intervention and surgery performed.Systematic review registered with https://www.crd.york.ac.uk/prospero/ (CRD 42018096956)

MicroRNA MIR396 regulates the switch between stem cells and transit-amplifying cells in arabidopsis roots

To ensure an adequate organ mass, the daughters of stem cells progress through a transit-amplifying phase displaying rapid cell division cycles before differentiating. Here, we show that Arabidopsis thaliana microRNA miR396 regulates the transition of root stem cells into transit-amplifying cells by interacting with GROWTH-REGULATING FACTORs (GRFs). The GRFs are expressed in transit-amplifying cells but are excluded from the stem cells through inhibition by miR396. Inactivation of the GRFs increases the meristem size and induces periclinal formative divisions in transit-amplifying cells. The GRFs repress PLETHORA (PLT) genes, regulating their spatial expression gradient. Conversely, PLT activates MIR396 in the stem cells to repress the GRFs. We identified a pathway regulated by GRF transcription factors that represses stem cell-promoting genes in actively proliferating cells, which is essential for the progression of the cell cycle and the orientation of the cell division plane. If unchecked, the expression of the GRFs in the stem cell niche suppresses formative cell divisions and distorts the organization of the quiescent center. We propose that the interactions identified here between miR396 and GRF and PLT transcription factors are necessary to establish the boundary between the stem cell niche and the transit-amplifying region.Fil: Rodriguez Virasoro, Ramiro Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Ercoli, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Debernardi, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Breakfield, Natalie W.. University of Duke; Estados UnidosFil: Mecchia, Martin Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Sabatini, Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Cools, Toon. University of Ghent; BélgicaFil: De Veylder, Lieven. University of Ghent; BélgicaFil: Benfey, Philip N.. University of Duke; Estados UnidosFil: Palatnik, Javier Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentin

Decoding the neural substrates of reward-related decision making with functional MRI

Although previous studies have implicated a diverse set of brain regions in reward-related decision making, it is not yet known which of these regions contain information that directly reflects a decision. Here, we measured brain activity using functional MRI in a group of subjects while they performed a simple reward-based decision-making task: probabilistic reversal-learning. We recorded brain activity from nine distinct regions of interest previously implicated in decision making and separated out local spatially distributed signals in each region from global differences in signal. Using a multivariate analysis approach, we determined the extent to which global and local signals could be used to decode subjects' subsequent behavioral choice, based on their brain activity on the preceding trial. We found that subjects' decisions could be decoded to a high level of accuracy on the basis of both local and global signals even before they were required to make a choice, and even before they knew which physical action would be required. Furthermore, the combined signals from three specific brain areas (anterior cingulate cortex, medial prefrontal cortex, and ventral striatum) were found to provide all of the information sufficient to decode subjects' decisions out of all of the regions we studied. These findings implicate a specific network of regions in encoding information relevant to subsequent behavioral choice