Causal Discovery and Optimal Experimental Design for Genome-Scale Biological Network Recovery.

Causal discovery of genome-scale networks is important for identifying pathways from genes to observable traits -e.g. differences in cell function, disease, drug resistance and others. Causal learners based on graphical models rely on interventional samples to orient edges in the network. However, these models have not been shown to scale up the size of the genome, which are on the order of 103-104 genes. We introduce a new learner, SP-GIES, that jointly learns from interventional and observational datasets and achieves almost 4x speedup against an existing learner for 1,000 node networks. SP-GIES achieves an AUC-PR score of 0.91 on 1,000 node networks, and scales up to 2,000 node networks - this is 4x larger than existing works. We also show how SP-GIES improves downstream optimal experimental design strategies for selecting interventional experiments to perform on the system. This is an important step forward in realizing causal discovery at scale via autonomous experimental design.

Distinct mechanoreceptor pezo-1 isoforms modulate food intake in the nematode Caenorhabditis elegans.

Two PIEZO mechanosensitive cation channels, PIEZO1 and PIEZO2, have been identified in mammals, where they are involved in numerous sensory processes. While structurally similar, PIEZO channels are expressed in distinct tissues and exhibit unique properties. How different PIEZOs transduce force, how their transduction mechanism varies, and how their unique properties match the functional needs of the tissues they are expressed in remain all-important unanswered questions. The nematode Caenorhabditis elegans has a single PIEZO ortholog (pezo-1) predicted to have 12 isoforms. These isoforms share many transmembrane domains but differ in those that distinguish PIEZO1 and PIEZO2 in mammals. We used transcriptional and translational reporters to show that putative promoter sequences immediately upstream of the start codon of long pezo-1 isoforms predominantly drive green fluorescent protein (GFP) expression in mesodermally derived tissues (such as muscle and glands). In contrast, sequences upstream of shorter pezo-1 isoforms resulted in GFP expression primarily in neurons. Putative promoters upstream of different isoforms drove GFP expression in different cells of the same organs of the digestive system. The observed unique pattern of complementary expression suggests that different isoforms could possess distinct functions within these organs. We used mutant analysis to show that pharyngeal muscles and glands require long pezo-1 isoforms to respond appropriately to the presence of food. The number of pezo-1 isoforms in C. elegans, their putative differential pattern of expression, and roles in experimentally tractable processes make this an attractive system to investigate the molecular basis for functional differences between members of the PIEZO family of mechanoreceptors.

A Consecutive Case Series of Rescue Intubations With the Articulating Total Control Introducer for Precision Tracheal Access.

Effective rescue after failed intubation is important to limit the number of attempts and patient risk. Nothing is known about the Total Control Introducer's (TCI) effectiveness as an intubation rescue device. A single system's airway management database was studied. The TCI was used for rescue in 34 cases. Overall success was 33 of 34 (97%). First-pass success was 32 of 33 (97%). First-pass rescue was successful in 12 of 12 (100%) after video and direct laryngoscopy had failed. In this case series, the TCI was found to be a highly effective rescue technique after failed direct and video laryngoscopy.

Assessing the Evidence of Micronutrients on Depression among Children and Adolescents: An Evidence Gap Map.

There is some evidence indicating that nutrition may have the ability to prevent, treat, and/or influence the severity of depression. The aims of this evidence gap map (EGM) are to provide an overview and to determine evidence gaps in the existing research on micronutrients and their impact on depression among children and adolescents. We conducted a comprehensive search in multiple databases of primary and secondary literature assessing the impact of micronutrients on depression-related outcomes such as unipolar depression, major depressive disorders, dysthymia, acute depression, and mood disorders. Abstracts and full-text articles were dual-screened based on predefined eligibility criteria. A total of 30 primary research publications were included in the EGM. About 47% of included studies focused on late adolescents (15-19 y), ∼40% on early adolescents (10-14 y), and ∼13% on children aged 6-9 y. Among the included studies, 8 studies examined a single micronutrient intervention and 22 studies examined micronutrient concentrations (either intake or serum), and their impact on depression. The most frequently studied micronutrients were vitamin D (n = 8), zinc (n = 8), iron (n = 6), folate (n = 7), and vitamin B-12 (n = 5). More longitudinal studies and trials are needed to determine the role of micronutrients in the etiology and treatment of depression among children and adolescents.

Bacterial genus-specific tolerance for YdcI expression.

The bacterial ydcI gene encodes a highly conserved transcriptional regulatory protein found in a wide range of Gram-negative bacteria and is involved in a number of Salmonella enterica serovar Typhimurium phenotypes. Given its high conservation, the YdcI protein has the potential for studies and applications across bacterial genera. However, no studies have been performed with YdcI outside of S. Typhimurium. Here we report that different Gram-negative genera display dramatically different tolerances for YdcI expression. In non-tolerant genera, YdcI expression results in rapid loss of cell viability several log-fold in magnitude, and the viability loss is observed at YdcI levels that are physiologically relevant. The N-terminal and C-terminal halves can be exchanged between the S. Typhimurium and Escherichia coli YdcI proteins with the resulting proteins still displaying the differential tolerance phenotype. Comparison of YdcI expression from the respective chromosomal gene in S. Typhimurium and E. coli revealed much lower levels in E. coli suggesting that this species has evolved a lower endogenous YdcI expression level and does not tolerate increases above this level. Expression of YdcI resulted in increased sensitivity to a range of antibiotics indicating the possibility that this protein could augment antibacterial strategies in non-tolerant genera. Overall, the results indicate vastly different outcomes for YdcI expression depending on bacterial genus and unmask differences in YdcI expression, regulation, target interactions, and/or YdcI regulon activity in different bacteria. The results also impact future work on YdcI when the protein is being studied/expressed in different Gram-negative genera.

A series of vectors with alternative antibiotic resistance markers for use in lambda Red recombination.

A target bacterial strain of interest for use in Red-based recombineering may already encode resistance to antibiotic markers used with current Red recombination tools such that the resistance cannot be removed. Such cases include those where markers are needed to maintain an unstable genetic element co-resident in the strain or those where the genetic source of resistance is not known. We report the availability of PCR templates with FRT-flanked mutagenesis cassettes and plasmids encoding Red recombination functions that contain marker combinations not currently available on widely disseminated lambda Red molecular reagents. The functionality of these convenient alternative tools is demonstrated.