Elevated Expressions of Survivin and Endoglin in Patients with Hepatic Carcinoma

Cancer Biotherapy and Radiopharmaceuticals, Volume 34, Issue 1, Page 7-12, February 2019.


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Identification and Functional Testing of Novel Interacting Protein Partners for the Stress Sensors Wsc1p and Mid2p of Saccharomyces cerevisiae

Wsc1p and Mid2p are transmembrane signaling proteins of cell wall stress in the budding yeast Saccharomyces cerevisiae. When an environmental stress compromises cell wall integrity, they activate a cell response through the Cell Wall Integrity (CWI) pathway. Studies have shown that the cytoplasmic domain of Wsc1p initiates the CWI signaling cascade by interacting with Rom2p, a Rho1-GDP-GTP exchange factor. Binding of Rom2p to the cytoplasmic tail of Wsc1p requires dephosphorylation of specific serine residues but the mechanism by which the sensor is dephosphorylated and how it subsequently interacts with Rom2p remains unclear. We hypothesize that Wsc1p and Mid2p must be physically associated with interacting proteins other than Rom2p that facilitate its interaction and regulate the activation of CWI pathway. To address this, a cDNA plasmid library of yeast proteins was expressed in bait strains bearing membrane yeast two-hybrid (MYTH) reporter modules of Wsc1p and Mid2p, and their interacting preys were recovered and sequenced. 14 previously unreported interactors were confirmed for Wsc1p and 29 for Mid2p. The interactors' functionality were assessed by cell growth assays and CWI pathway activation by western blot analysis of Slt2p/Mpk1p phosphorylation in null mutants of each interactor under defined stress conditions. The susceptibility of these strains to different stresses were tested against antifungal agents and chemicals. This study reports important novel protein interactions of Wsc1p and Mid2p that are associated with the cellular response to oxidative stress induced by Hydrogen Peroxide and cell wall stress induced by Caspofungin.

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RNAi Screen in Tribolium Reveals Involvement of F-BAR Proteins in Myoblast Fusion and Visceral Muscle Morphogenesis in Insects

In a large-scale RNAi screen in Tribolium castaneum for genes with knock-down phenotypes in the larval somatic musculature, one recurring phenotype was the appearance of larval muscle fibers that were significantly thinner than those in control animals. Several of the genes producing this knock-down phenotype corresponded to orthologs of Drosophila genes that are known to participate in myoblast fusion, particularly via their effects on actin polymerization. A new gene previously not implicated in myoblast fusion but displaying a similar thin-muscle knock-down phenotype was the Tribolium ortholog of Nostrin, which encodes an F-BAR and SH3 domain protein. Our genetic studies of Nostrin and Cip4, a gene encoding a structurally related protein, in Drosophila show that the encoded F-BAR proteins jointly contribute to efficient myoblast fusion during larval muscle development. Together with the F-Bar protein Syndapin they are also required for normal embryonic midgut morphogenesis. In addition, Cip4 is required together with Nostrin during the profound remodeling of the midgut visceral musculature during metamorphosis. We propose that these F-Bar proteins help govern proper morphogenesis particularly of the longitudinal midgut muscles during metamorphosis.

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A Large Scale Systemic RNAi Screen in the Red Flour Beetle Tribolium castaneum Identifies Novel Genes Involved in Insect Muscle Development

Although muscle development has been widely studied in Drosophila melanogaster there are still many gaps in our knowledge, and it is not known to which extent this knowledge can be transferred to other insects. To help in closing these gaps we participated in a large-scale RNAi screen that used the red flour beetle, Tribolium castaneum, as a screening platform. The effects of systemic RNAi were screened upon double-stranded RNA injections into appropriate muscle-EGFP tester strains. Injections into pupae were followed by the analysis of the late embryonic/early larval muscle patterns, and injections into larvae by the analysis of the adult thoracic muscle patterns. Herein we describe the results of the first-pass screens with pupal and larval injections, which covered ~8,500 and ~5,000 genes, respectively, of a total of ~16,500 genes of the Tribolium genome. Apart from many genes known from Drosophila as regulators of muscle development, a collection of genes previously unconnected to muscle development yielded phenotypes in larval body wall and leg muscles as well as in indirect flight muscles. We then present the main candidates from the pupal injection screen that remained after being processed through a series of verification and selection steps. Further, we discuss why distinct though overlapping sets of genes are revealed by the Drosophila and Tribolium screening approaches.

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Ion Channel Contributions to Wing Development in Drosophila melanogaster

During morphogenesis, cells communicate with each other to shape tissues and organs. Several lines of recent evidence indicate that ion channels play a key role in cellular signaling and tissue morphogenesis. However, little is known about the scope of specific ion-channel types that impinge upon developmental pathways. The Drosophila melanogaster wing is an excellent model in which to address this problem as wing vein patterning is acutely sensitive to changes in developmental pathways. We conducted a screen of 180 ion channels expressed in the wing using loss-of-function mutant and RNAi lines. Here we identify 44 candidates that significantly impacted development of the Drosophila melanogaster wing. Calcium, sodium, potassium, chloride, and ligand-gated cation channels were all identified in our screen, suggesting that a wide variety of ion channel types are important for development. Ion channels belonging to the pickpocket family, the ionotropic receptor family, and the bestrophin family were highly represented among the candidates of our screen. Seven new ion channels with human orthologs that have been implicated in human channelopathies were also identified. Many of the human orthologs of the channels identified in our screen are targets of common general anesthetics, anti-seizure and anti-hypertension drugs, as well as alcohol and nicotine. Our results confirm the importance of ion channels in morphogenesis and identify a number of ion channels that will provide the basis for future studies to understand the role of ion channels in development.

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What are the best isometric exercises of muscle potentiation?

Abstract

Purpose

The aim of this study was to follow post-activation potentiation (PAP), low-frequency fatigue (LFF), metabolic-induced fatigue and post-contractile depression (PCD) in response to different isometric muscle contraction modalities.

Methods

Young healthy men (N = 120) were randomly assigned to one of ten exercise modality groups which differed in contraction duration (5–60 s), activation pattern (intermittent or continuous contractions), activation mode (voluntary or stimulated), and intensity [maximal or submaximal (50%)]. Isometric maximal voluntary contraction (MVC), and electrically induced knee extension torque were measured at baseline and at regular intervals for 60 min after exercise.

Results

Muscle contraction modalities involving 5 s MVC were the most effective for PAP, whereas the lowest PAP effectiveness was found after the 12 × 5-MVC modality. After all of the 5–15 s MVC and 6 × 5-MVC protocols, the potentiation of the twitch rate was significantly higher than that recorded after continuous 30–60 s protocols (P < 0.001). Tetanic maximal torque (100 Hz) potentiation occurred 5 min after 15–30 s repetitive MVC modalities and after modality involving 15 electrical stimuli (P < 0.05).

Conclusions

The findings demonstrate that post-activation potentiation was most effective after brief duration continuous and repetitive MVC protocols. To understand the resultant warm-up of motor performance, it is necessary to recognize the coexistence of muscle PAP, tetanic maximal force potentiation, rapid recovery of metabolic muscle, and central muscle activation processes, as well as prolonged LFF and prolonged PCD.

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Peri-operative, intravenous clindamycin may improve the resolution rate of hypertension after Roux-en-Y gastric bypass in morbidly obese patients

Abstract

Background

Recent studies have suggested that potential aberrant alterations in the gastrointestinal microbiome contribute to the development of cardiovascular disease, specifically hypertension. Bariatric surgery produces significant sustained weight loss and hypertension resolution likely through multiple mechanisms which includes beneficial changes in the gut microbiome. We hypothesized that the type of prophylactic antibiotic given for bariatric surgery could impact the resolution rate of hypertension by altering the post-operative gastrointestinal microflora.

Methods

A retrospective analysis of adult bariatric patients who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) between 2012 and 2016 was conducted. The standard antibiotic prophylaxis was cefazolin, or clindamycin in patients with a penicillin allergy. Univariate analyses were performed comparing the differing peri-operative antibiotic treatments with resolution of hypertension at 2-week (± 1 week), 6-week (± 2 weeks), 3-month (± 2 weeks), 6-month (± 6 weeks), and 1-year (± 2 months) follow-up appointments. The criterion for resolution of hypertension was no longer requiring medication at time of follow-up.

Results

In total, 123 RYGB and 88 SG patients were included. No significant differences were found between cefazolin and clindamycin regarding hypertension resolution rates after SG. However, patients who underwent RYGB and received clindamycin had a significantly higher rate of hypertension resolution compared to cefazolin. This effect started at 2 weeks post-operatively (52.4% vs. 23.5% respectively, p = 0.008) and persisted up to the 1-year (57.9% vs. 44.0% respectively, p = 0.05).

Conclusion

Prophylactic peri-operative, intravenous clindamycin was associated with significantly increased resolution of post-operative hypertension compared to cefazolin. This finding was not observed in SG patients. Future studies are needed to confirm the mechanism of action for this novel finding is due to the differing modifications of the gastrointestinal microflora after RYGB resulting from the specific peri-operative antibiotic administered.

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Randomized controlled trial of an online problem-solving intervention following adolescent traumatic brain injury: Family outcomes

Publication date: Available online 6 February 2019

Source: Archives of Physical Medicine and Rehabilitation

Author(s): Megan E. Narad, Stacey Raj, Keith O. Yeates, H.Gerry Taylor, Michael W. Kirkwood, Terry Stancin, Shari L. Wade

Abstract

Objective

To examine parent/family outcomes of a randomized controlled trial (RCT) comparing Teen Online Problem-Solving with Family (TOPS-F), Teen Online Problem-Solving- Teen Only (TOPS-TO), or access to internet resources alone (IRC).

Design

Three-arm randomized controlled trial.

Setting

Four children's hospitals and one general medical center in Ohio and Colorado.

Participants

152 children/adolescents, 11-18 years old, hospitalized for complicated mild to severe traumatic brain injury (TBI) in the previous 18-months.

Interventions: Intervention groups: TOPS-F, TOPS-TO, and IRC.

Main Outcome Measure

Parental depression (CES-D), parental psychological distress (SCL-90-GSI), family functioning (FAD-GF), cohesiveness (PARQ) and conflict (IBQ) were assessed pre- and post-treatment. Treatment effects and the moderating effect of the number of parents in the home (single vs. two-parent families).

Results

Number of parents moderated treatment effects with effects ranging from trending to statistically significant for depression, family functioning, cohesion, and conflict. Among single parents, TOPS-TO reported better family functioning than TOPS-F, and greater cohesion and less conflict than IRC. Among two-parent families, TOPS-F reported less depression than IRC, and less depression and greater cohesion than TOPS-TO. The effect of family composition was also noted within TOPS-TO and TOPS-F. In TOPS-F, two-parent families reported less depression than single-parent families. In TOPS-TO single parents reported greater cohesion and better family functioning than two-parent families.

Conclusions

Findings support the TOPS intervention to improve family outcomes, with differential effects noted for single vs. two-parent households. The TOPS-TO format appeared more beneficial for single-parent households, while TOPS-F was more beneficial for two-parent households, highlighting the importance of considering family composition when determining the best treatment modality.

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3D-Printed Polymer/Metal Hybrid Microstructures with Ultraprecision for 3D Microcoils

3D Printing and Additive Manufacturing, Ahead of Print.


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Gene therapies in canine models for Duchenne muscular dystrophy

Abstract

Therapies for Duchenne muscular dystrophy (DMD) must first be tested in animal models to determine proof-of-concept, efficacy, and importantly, safety. The murine and canine models for DMD are genetically homologous and most commonly used in pre-clinical testing. Although the mouse is a strong, proof-of-concept model, affected dogs show more analogous clinical and immunological disease progression compared to boys with DMD. As such, evaluating genetic therapies in the canine models may better predict response at the genetic, phenotypic, and immunological levels. We review the use of canine models for DMD and their benefits as it pertains to genetic therapy studies, including gene replacement, exon skipping, and gene editing.

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Blockage of the P2X7 Receptor Attenuates Harmful Changes Produced by Ischemia and Reperfusion in the Myenteric Plexus

Abstract

Introduction

Our work analyzed the effects of a P2X7 receptor antagonist, Brilliant Blue G (BBG), on rat ileum myenteric plexus following ischemia and reperfusion (ISR) induced by 45 min of ileal artery occlusion with an atraumatic vascular clamp with 24 h (ISR 24-h group) or 14 d of reperfusion (ISR 14-d group).

Material and methods

Either BBG (50 mg/kg or 100 mg/kg, BBG50 or BBG100 groups) or saline (vehicle) was administered subcutaneously 1 h after ischemia in the ISR 24-h group or once daily for the 5 d after ischemia in the ISR 14-d group (n = 5 per group). We evaluated the neuronal density and profile area by examining the number of neutrophils in the intestinal layers, protein expression levels of the P2X7 receptor, intestinal motility and immunoreactivity for the P2X7 receptor, nitric oxide synthase, neurofilament-200, and choline acetyl transferase in myenteric neurons.

Results

The neuronal density and profile area were restored by BBG following ISR. The ischemic groups showed alterations in P2X7 receptor protein expression and the number of neutrophils in the intestine and decreased intestinal motility, all of which were recovered by BBG treatment.

Conclusion

We concluded that ISR morphologically and functionally affected the intestine and that its effects were reversed by BBG treatment, suggesting the P2X7 receptor as a therapeutic target.

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Predictive Value of Procalcitonin in Acute Severe Ulcerative Colitis: Not Quite PerfeCT?

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Real-World Experience with Tofacitinib in IBD at a Tertiary Center

Abstract

Background and Aims

Many inflammatory bowel disease (IBD) patients do not respond to medical therapy. Tofacitinib is a first-in-class, partially selective inhibitor of Janus kinase, recently approved for treating patients with ulcerative colitis (UC). We describe our experience with the use of tofacitinib for treatment of patients with moderate-to-severe IBD.

Methods

This is a retrospective, observational study of the use of tofacitinib in IBD. Patients with medically resistant IBD were treated orally with 5 mg or 10 mg twice daily. Clinical response and adverse events were assessed at 8, 26, and 52 weeks. Objective response was assessed endoscopically, radiologically, and biochemically.

Results

58 patients (53 UC, 4 Crohn's, 1 pouchitis) completed at least 8 weeks of treatment with tofacitinib. 93% of the patients previously failed treatment with anti-TNF. At 8 weeks of treatment, 21 patients (36%) achieved a clinical response, and 19 (33%) achieved clinical remission. Steroid-free remission at 8 weeks was achieved in 15 patients (26%). Of the 48 patients followed for 26 weeks, 21% had clinical, steroid-free remission. Of the 26 patients followed for 12 months, 27% were in clinical, steroid-free remission. Twelve episodes of systemic infections were noted, mostly while on concomitant steroids. One episode of herpes zoster infection was noted during follow-up.

Conclusions

In this cohort of patients with moderate-to-severe, anti-TNF resistant IBD, tofacitinib induced clinical response in 69% of the patients. 27% were in clinical, steroid-free remission by 1 year of treatment. Tofacitinib is an effective therapeutic option for this challenging patient population.

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Gastrointestinal Hemorrhage in Patients with Acute Ischemic Stroke: Should Endoscopy Be Within the Scope of Practice?

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Early Response to Corticosteroid and Baseline C-Reactive Protein Predicts Outcomes in Children with Moderate to Severe Ulcerative Colitis

Abstract

Background

Initial response to corticosteroids (CS) is recognized as a strong predictor of outcomes in ulcerative colitis (UC).

Aim

To compare outcomes of early poor responders (PR) versus good responders (GR) to initial CS at 1, 2, and 3 years from diagnosis.

Methods

In this retrospective study, we report longitudinal outcomes of children with moderate–severe UC, initiating oral/IV CS < 1 month of diagnosis and a minimum follow-up (FU) of 1 year. CS resistance (CSR) and CS dependency (CSD) were combined as PR, and those with CS-free remission (CSFR) at 6 months were GR.

Results

Of 116 children with UC, 76 (33 males) fulfilled study criteria. Median age at diagnosis was 12 years (IQR 12–14), and a median FU was 48 months (IQR 27–65). Thirty-five (46%, CSR = 10, CSD = 25) were PR, and 41 (54%) were GR. Mean relapse (2.39 vs. 1.1, p = 0.0009), acute severe UC flare-up (40% vs. 9.7%, p = 0.002), and colectomy rates (34.2% vs. 2.4%) were greater in PR versus GR, despite frequent early (< 6 months) use of azathioprine (74% vs. 27%, p = 0.004) and anti-TNFs (43% vs. 2.4%, p = 0.0001). Cumulative colectomy at 3 years was lowest in those with GR versus CSD and CSR (2.4% vs. 28% and 50% p = 0.001). On univariate analysis, CRP > 20 mg/L at diagnosis, Mayo Clinical Score > 1 at 3 months, and PR predicted colectomy. On multivariate regression, only baseline CRP > 20 mg/L predicted colectomy (HR 4.9, p = 0.03).

Conclusions

Baseline CRP and poor response to initial CS are associated with unfavorable outcomes in children with UC.

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ERCP Success Rate and Periampullary Diverticula: The Pocket Makes No Difference

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Competitive Endogenous RNA (ceRNA) Regulation Network of lncRNA–miRNA–mRNA in Colorectal Carcinogenesis

Abstract

Background

Competitive endogenous RNA (ceRNA) regulation suggested complex network of all transcript RNAs including long noncoding RNAs (lncRNAs), which can act as natural miRNA sponges to inhibit miRNA functions and modulate mRNA expression. Until now, the specific ceRNA regulatory mechanism of lncRNA–miRNA–mRNA in colorectal cancer (CRC) still remains unclear.

Materials and Methods

RNA sequencing data of 478 colon adenocarcinoma cases and 41 controls as well as 166 rectum adenocarcinoma cases and 10 controls were obtained from The Cancer Genome Atlas (TCGA) to investigate the significant changes of lncRNAs, miRNAs and mRNAs in colorectal carcinogenesis. The target lncRNAs and mRNAs of miRNAs were predicted by miRWalk. Functional and enrichment analyses were conducted by DAVID database. The lncRNA–miRNA–mRNA interaction network was constructed using Cytoscape.

Results

We constructed ceRNA regulatory networks including 22 up-regulated lncRNAs, 12 down-regulated miRNAs and 122 up-regulated mRNAs, as well as 8 down-regulated lncRNAs, 43 up-regulated miRNAs and 139 down-regulated mRNAs. The GO enrichment showed that up-regulated genes mainly enriched in biological process including organic anion transport, collagen catabolic process, wound healing, Wnt receptor signalling and in pathways of tyrosine metabolism, taurine and hypotaurine metabolism, melanogenesis and phenylalanine metabolism. For down-regulated genes, significant enrichment was found in biological process of metal ion homeostasis, transmission of nerve impulse, cell–cell signalling, transmembrane transport and in pathways of ABC transporters, neuroactive ligand–receptor interaction, retinol metabolism, nitrogen metabolism and steroid hormone biosynthesis.

Conclusion

We identified significantly altered lncRNAs, miRNAs and mRNAs in colorectal carcinogenesis, which might serve as potential biomarkers for tumorigenesis of CRC. In addition, the ceRNA regulatory network of lncRNA–miRNA–mRNA was constructed, which would elucidate novel molecular mechanisms involved in initiation and progression of CRC, thus providing promising clues for clinical diagnosis and therapy.

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Anterograde Endoscopic Ultrasound-Guided Pancreatic Duct Drainage: A Technical Review

Abstract

The advancement of pancreatic endotherapy has increased the availability of minimally invasive endoscopic pancreatic ductal drainage techniques. In this regard, familiarity with endoscopic ultrasound-guided pancreatic duct drainage (EUS-PDD) is critical for treatment of obstructed pancreatic ductal systems, especially in nonsurgical candidates and in patients desiring a minimally invasive approach. Two distinct forms of EUS-PDD exist, viz. rendezvous-assisted endoscopic retrograde pancreatography (rendezvous-assisted ERP) and anterograde EUS-PDD. Anterograde EUS-PDD refers to transmural anterograde passage of a pancreatic drainage catheter or stent directly into the main pancreatic duct, through either the gastric or enteral wall. Rendezvous-assisted ERP should be attempted after failed conventional ERP, and anterograde EUS-PDD should be considered if rendezvous-assisted ERP fails or is not technically feasible. Common clinical scenarios that fulfil these conditions are chronic pancreatitis with high-grade main pancreatic duct obstruction, surgically altered anatomy with ductal/anastomotic obstruction, pancreas divisum, and disconnected pancreatic duct syndrome. The focus of this review article is anterograde EUS-PDD and its indications, technique, and outcomes. It also provides a summary of our own experience with this procedure, and a video demonstration of the technique.

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How the “Opt-In” Option Optimizes Organ Donation Rates

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Magnesium

Mapping Oat Crown Rust Resistance Gene Pc45 Confirms Association with PcKM

Molecular mapping of crown rust resistance genes is important to effectively utilize these genes and improve breeding efficiency through marker-assisted selection. Pc45 is a major race-specific crown rust resistance gene initially identified in the wild hexaploid oat Avena sterilis in the early 1970s. This gene was transferred to cultivated oat (Avena sativa) and has been used as a differential for identification of crown rust races since 1974. Previous research identified an association between virulence to Pc45 and PcKM, a crown rust resistance gene in the varieties 'Kame' and 'Morton'. This study was undertaken to reveal the relationship between Pc45 and PcKM. Pc45 was studied in the crosses 'AC Morgan'/Pc45 and 'Kasztan'/Pc45, where Pc45 is the differential line carrying Pc45. F₂ progenies and F_2:3 families of both populations were inoculated with the crown rust isolate CR258 (race NTGG) and single gene segregation ratios were observed. SNP markers for PcKM were tested on these populations and linkage maps were generated. In addition, 17 newly developed SNP markers identified from genotyping-by-sequencing (GBS) data were mapped in these two populations, plus another three populations segregating for Pc45 or PcKM. Pc45 and PcKM mapped to the same location of Mrg08 (chromosome 12D) of the oat chromosome-anchored consensus map. These results strongly suggest that Pc45 and PcKM are the same resistance gene, but allelism (i.e., functionally different alleles of the same gene) or tight linkage (i.e., two tightly linked genes) cannot be ruled out based on the present data.

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pSBVB: A Versatile Simulation Tool To Evaluate Genomic Selection in Polyploid Species

Genomic Selection (GS) is the procedure whereby molecular information is used to predict complex phenotypes and it is standard in many animal and plant breeding schemes. However, only a small number of studies have been reported in horticultural crops, and in polyploid species in particular. In this paper, we have developed a versatile forward simulation tool, called polyploid Sequence Based Virtual Breeding (pSBVB), to evaluate GS strategies in polyploids; pSBVB is an efficient gene dropping software that can simulate any number of complex phenotypes, allowing a very flexible modeling of phenotypes suited to polyploids. As input, it takes genotype data from the founder population, which can vary from single nucleotide polymorphisms (SNP) chips up to sequence, a list of causal variants for every trait and their heritabilities, and the pedigree. Recombination rates between homeologous chromosomes can be specified, so that both allo- and autopolyploid species can be considered. The program outputs phenotype and genotype data for all individuals in the pedigree. Optionally, it can produce several genomic relationship matrices that consider exact or approximate genotype values. pSBVB can therefore be used to evaluate GS strategies in polyploid species (say varying SNP density, genetic architecture or population size, among other factors), or to optimize experimental designs for association studies. We illustrate pSBVB with SNP data from tetraploid potato and partial sequence data from octoploid strawberry, and we show that GS is a promising breeding strategy for polyploid species but that the actual advantage critically depends on the underlying genetic architecture. Source code, examples and a complete manual are freely available in GitHub https://github.com/lauzingaretti/pSBVB.

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Generation of H11-albumin-rtTA Transgenic Mice: A Tool for Inducible Gene Expression in the Liver

The modification of the mouse genome by site-specific gene insertion of transgenes and other genetic elements allows the study of gene function in different developmental stages and in the pathogenesis of diseases. Here, we generated a "genomic safe harbor" Hipp11 (H11) locus-specific knock-in transgenic mouse line in which the albumin promoter is used to drive the expression of the reverse tetracycline transactivator (rtTA) in the liver. The newly generated H11-albumin-rtTA transgenic mice were bred with tetracycline-operator-Histone-2B-green fluorescent protein (TetO-H2BGFP) mice to assess inducibility and tissue-specificity. Expression of the H2BGFP fusion protein was observed exclusively upon doxycycline (Dox) induction in the liver of H11-albumin-rtTA/TetO-H2BGFP double transgenic mice. To further analyze the ability of the Dox-inducible H11-albumin-rtTA mice to implement conditional DNA recombination, H11-albumin-rtTA transgenic mice were crossed with TetO-Cre and Ai14 mice to generate H11-albumin-rtTA/TetO-Cre/Ai14 triple transgenic mice. We successfully confirmed that the Cre-mediated recombination efficiency was as strong in Dox-induced H11-albumin-rtTA /TetO-Cre/Ai14 mice as in the control albumin-Cre/A14 mice. Finally, to characterize the expression-inducing effects of Dox in H11-albumin-rtTA/TetO-H2BGFP mice in detail, we examined GFP expression in embryos at different developmental stages and found that newly conceived H11-albumin-rtTA/TetO-H2BGFP embryos of Dox-treated pregnant female mice were expressing reporter GFP by E16.5. Our study demonstrates that these new H11-albumin-rtTA transgenic mice are a powerful and efficient tool for the temporally and spatially conditional manipulation of gene expression in the liver, and illustrates how genetic crosses with these new mice enable the generation of complex multi-locus transgenic animals for mechanistic studies.

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SNZ3 Encodes a PLP Synthase Involved in Thiamine Synthesis in Saccharomyces cerevisiae

Pyridoxal 5'-phosphate (the active form of vitamin B₆) is a cofactor that is important for a broad number of biochemical reactions and is essential for all forms of life. Organisms that can synthesize pyridoxal 5'-phosphate use either the deoxyxylulose phosphate-dependent or -independent pathway, the latter is encoded by a two-component pyridoxal 5'-phosphate synthase. Saccharomyces cerevisiae contains three paralogs of the two-component SNZ/SNO pyridoxal 5'-phosphate synthase. Past work identified the biochemical activity of Snz1p, Sno1p and provided in vivo data that SNZ1 was involved in pyridoxal 5'-phosphate biosynthesis. Snz2p and Snz3p were considered redundant isozymes and no growth condition requiring their activity was reported. Genetic data herein showed that either SNZ2 or SNZ3 are required for efficient thiamine biosynthesis in Saccharomyces cerevisiae. Further, SNZ2 or SNZ3 alone could satisfy the cellular requirement for pyridoxal 5'-phosphate (and thiamine), while SNZ1 was sufficient for pyridoxal 5'-phosphate synthesis only if thiamine was provided. qRT-PCR analysis determined that SNZ2,3 are repressed ten-fold by the presence thiamine. In total, the data were consistent with a requirement for PLP in thiamine synthesis, perhaps in the Thi5p enzyme, that could only be satisfied by SNZ2 or SNZ3. Additional data showed that Snz3p is a pyridoxal 5'-phosphate synthase in vitro and is sufficient to satisfy the pyridoxal 5'-phosphate requirement in Salmonella enterica when the medium has excess ammonia.

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Repeats of Unusual Size in Plant Mitochondrial Genomes: Identification, Incidence and Evolution

Plant mitochondrial genomes have excessive size relative to coding capacity, a low mutation rate in genes and a high rearrangement rate. They also have abundant non-tandem repeats often including pairs of large repeats which cause isomerization of the genome by recombination, and numerous repeats of up to several hundred base pairs that recombine only when the genome is stressed by DNA damaging agents or mutations in DNA repair pathway genes. Early work on mitochondrial genomes led to the suggestion that repeats in the size range from several hundred to a few thousand base pair are underrepresented. The repeats themselves are not well-conserved between species, and are not always annotated in mitochondrial sequence assemblies. We systematically identified and compared these repeats, which are important clues to mechanisms of DNA maintenance in mitochondria. We developed a tool to find and curate non-tandem repeats larger than 50bp and analyzed the complete mitochondrial sequences from 157 plant species. We observed an interesting difference between taxa: the repeats are larger and more frequent in the vascular plants. Analysis of closely related species also shows that plant mitochondrial genomes evolve in dramatic bursts of breakage and rejoining, complete with DNA sequence gain and loss. We suggest an adaptive explanation for the existence of the repeats and their evolution.

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Investigation of the Developmental Requirements of Drosophila HP1 and Insulator Protein Partner, HIPP1

Drosophila Suppressor of Hairy-wing [Su(Hw)] is a multifunctional zinc finger DNA binding protein. Transcriptional regulation by Su(Hw) is essential in the ovary and testis, where Su(Hw) functions primarily as a repressor. Recently, the HP1a and Insulator Partner Protein 1 (HIPP1) was found to extensively co-localize with Su(Hw) and other insulator binding proteins in euchromatic regions of the genome, and with Heterochromatin Protein 1a (HP1a) in heterochromatic regions. As HIPP1 is the homolog of the human co-repressor Chromodomain Y-Like (CDYL), we tested its requirement in establishing transcriptional repression in flies. To this end, we generated multiple Hipp1 null alleles and a tagged derivative of the endogenous gene (Hipp1^GFP), using CRISPR mutagenesis. We show that HIPP1 is a widely expressed nuclear protein that is dispensable for viability, as well as female and male fertility. We find that HIPP1 and HP1a display minimum co-localization in interphase cells, and HP1a-dependent transcriptional repression of several reporter genes is HIPP1-independent, indicating that HIPP1 is not essential for HP1a-dependent heterochromatin formation. Despite Su(Hw) having a major role in promoting HIPP1 occupancy in euchromatin, we show that HIPP1 is dispensable for the transcriptional and insulator functions of Su(Hw), indicating that HIPP1 is not a critical Su(Hw) cofactor. Further studies are needed to clarify the role of HIPP1 in Drosophila development.

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Determining the Genetic Architecture of Reproductive Stage Drought Tolerance in Wheat Using a Correlated Trait and Correlated Marker Effect Model

Water stress during reproductive growth is a major yield constraint for wheat (Triticum aestivum L). We previously established a controlled environment drought tolerance phenotyping method targeting the young microspore stage of pollen development. This method eliminates stress avoidance based on flowering time. We substituted soil drought treatments by a reproducible osmotic stress treatment using hydroponics and NaCl as osmolyte. Salt exclusion in hexaploid wheat avoids salt toxicity, causing osmotic stress. A Cranbrook x Halberd doubled haploid (DH) population was phenotyped by scoring spike grain numbers of unstressed (SGNCon) and osmotically stressed (SGNTrt) plants. Grain number data were analyzed using a linear mixed model (LMM) that included genetic correlations between the SGNCon and SGNTrt traits. Viewing this as a genetic regression of SGNTrt on SGNCon allowed derivation of a stress tolerance trait (SGNTol). Importantly, and by definition of the trait, the genetic effects for SGNTol are statistically independent of those for SGNCon. Thus they represent non-pleiotropic effects associated with the stress treatment that are independent of the control treatment. QTL mapping was conducted using a whole genome approach in which the LMM included all traits and all markers simultaneously. The marker effects within chromosomes were assumed to follow a spatial correlation model. This resulted in smooth marker profiles that could be used to identify positions of putative QTL. The most influential QTL were located on chromosome 5A for SGNTol (126cM; contributed by Halberd), 5A for SGNCon (141cM; Cranbrook) and 2A for SGNTrt (116cM; Cranbrook). Sensitive and tolerant population tail lines all showed matching soil drought tolerance phenotypes, confirming that osmotic stress is a valid surrogate screening method.

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Comprehensive Transcriptional Profiling of the Gastrointestinal Tract of Ruminants from Birth to Adulthood Reveals Strong Developmental Stage Specific Gene Expression

One of the most significant physiological challenges to neonatal and juvenile ruminants is the development and establishment of the rumen. Using a subset of RNA-Seq data from our high-resolution atlas of gene expression in sheep (Ovis aries) we have provided the first comprehensive characterization of transcription of the entire gastrointestinal (GI) tract during the transition from pre-ruminant to ruminant. The dataset comprises 164 tissue samples from sheep at four different time points (birth, one week, 8 weeks and adult). Using network cluster analysis we illustrate how the complexity of the GI tract is reflected in tissue- and developmental stage-specific differences in gene expression. The most significant transcriptional differences between neonatal and adult sheep were observed in the rumen complex. Comparative analysis of gene expression in three GI tract tissues from age-matched sheep and goats revealed species-specific differences in genes involved in immunity and metabolism. This study improves our understanding of the transcriptomic mechanisms involved in the transition from pre-ruminant to ruminant by identifying key genes involved in immunity, microbe recognition and metabolism. The results form a basis for future studies linking gene expression with microbial colonization of the developing GI tract and provide a foundation to improve ruminant efficiency and productivity through identifying potential targets for novel therapeutics and gene editing.

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Integrated Analysis of miRNA and mRNA Expression Profiles Reveals Functional miRNA-Targets in Development Testes of Small Tail Han Sheep

Small Tail Han Sheep is a highly valued local breed in China because of their precocity, perennial estrus, and high fecundity. The average annual lambing rate of ewes is as high as 180–270%, the semen of ram has characteristics of high yield, high density, and good motility. To reveal the key miRNAs and miRNA-targets underlying testis development and spermatogenesis in male Small Tail Han Sheep, integrated analysis of miRNA and mRNA expression profiles in 2-, 6-, and 12-month-old testes was performed by RNA-seq technology and bioinformatics methods. The results showed that total of 153 known sheep miRNAs and 2712 novel miRNAs were obtained in 2-,6 - and 12-month-old Small Tail Han Sheep testes; 5, 1, and 4 differentially expressed (DE) known sheep miRNAs, and 132, 105, and 24 DE novel miRNAs were identified in 2- vs. 6-, 6- vs. 12-, and 2- vs. 12-month-old testes, respectively. We combined miRNA results of this study and the mRNA results obtained in our previous study to predict the target mRNAs of DE known sheep miRNAs; 131, 10, and 15 target mRNAs of DE known sheep miRNAs and 76, 1, and 11 DE miRNA–targets were identified in the three groups, respectively. GO and KEGG analyses showed that: in 2- vs. 6-month-olds, the target genes of DE known sheep miRNAs were involved in 100 biological processes and 11 signaling pathways; in 6- vs. 12-month-olds, the target genes of DE known sheep miRNAs were involved in 4 biological processes; and in 2- vs. 12-month-olds, the target genes of DE known sheep miRNAs were involved in 17 biological processes and 4 signaling pathways. Three miR–target regulatory networks were constructed based on these DE miRNA–targets. The key miRNA-Targets involved in testis development and spermatogenesis were screened. 6 known sheep miRNAs and 6 novel miRNAs were selected to validate the accuracy of miRNA sequencing data by qRT-PCR. The binding sites of oar-miR-379-5p with WNT8A was validated by a dual luciferase reporter gene detection system.

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A Very Oil Yellow1 Modifier of the Oil Yellow1-N1989 Allele Uncovers a Cryptic Phenotypic Impact of Cis-regulatory Variation in Maize

Forward genetics determines the function of genes underlying trait variation by identifying the change in DNA responsible for changes in phenotype. Detecting phenotypically-relevant variation outside protein coding sequences and distinguishing this from neutral variants is not trivial; partly because the mechanisms by which DNA polymorphisms in the intergenic regions affect gene regulation are poorly understood. Here we utilized a dominant genetic reporter to investigate the effect of cis and trans-acting regulatory variation. We performed a forward genetic screen for natural variation that suppressed or enhanced the semi-dominant mutant allele Oy1-N1989, encoding the magnesium chelatase subunit I of maize. This mutant permits rapid phenotyping of leaf color as a reporter for chlorophyll accumulation, and mapping of natural variation in maize affecting chlorophyll metabolism. We identified a single modifier locus segregating between B73 and Mo17 that was linked to the reporter gene itself, which we call very oil yellow1 (vey1). Based on the variation in OY1 transcript abundance and genome-wide association data, vey1 is predicted to consist of multiple cis-acting regulatory sequence polymorphisms encoded at the wild-type oy1 alleles. The vey1 locus appears to be a common polymorphism in the maize germplasm that alters the expression level of a key gene in chlorophyll biosynthesis. These vey1 alleles have no discernable impact on leaf chlorophyll in the absence of the Oy1-N1989 reporter. Thus, the use of a mutant as a reporter for magnesium chelatase activity resulted in the detection of expression-level polymorphisms not readily visible in the laboratory.

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A Genome Wide Association Study Reveals Markers and Genes Associated with Resistance to Fusarium verticillioides Infection of Seedlings in a Maize Diversity Panel

Fusarium verticillioides infects maize, causing ear rot, yield loss and contamination by fumonisin mycotoxins. The fungus can be transmitted via kernels and cause systemic infection in maize. Maize resistance to the fungus may occur at different developmental stages, from seedling to maturity. Resistance during kernel germination is part of the plant-pathogen interaction and so far this aspect has not been investigated. In the present study, a genome wide association study (GWAS) of resistance to Fusarium during the seedling developmental stage was conducted in a maize diversity panel using 226,446 SNP markers. Seedling germination and disease phenotypes were scored on artificially inoculated kernels using the rolled towel assay. GWAS identified 164 SNPs significantly associated with the traits examined. Four SNPs were associated with disease severity score after inoculation, 153 were associated with severity in asymptomatic kernels and 7 with the difference between the severity ratings in inoculated and non-inoculated seeds. A set of genes containing or physically near the significant SNPs were identified as candidates for Fusarium resistance at the seedling stage. Functional analysis revealed that many of these genes are directly involved in plant defense against pathogens and stress responses, including transcription factors, chitinase, cytochrome P450, and ubiquitination proteins. In addition, 25 genes were found in high linkage disequilibrium with the associated SNPs identified by GWAS and four of them directly involved in disease resistance. These findings contribute to understanding the complex system of maize-F. verticillioides and may improve genomic selection for Fusarium resistance at the seedling stage.

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Optimizing Genomic Selection for a Sorghum Breeding Program in Haiti: A Simulation Study

Young breeding programs in developing countries, like the Chibas sorghum breeding program in Haiti, face the challenge of increasing genetic gain with limited resources. Implementing genomic selection (GS) could increase genetic gain, but optimization of GS is needed to account for these programs' unique challenges and advantages. Here, we used simulations to identify conditions under which genomic-assisted recurrent selection (GARS) would be more effective than phenotypic recurrent selection (PRS) in small new breeding programs. We compared genetic gain, cost per unit gain, genetic variance, and prediction accuracy of GARS (two or three cycles per year) vs. PRS (one cycle per year) assuming various breeding population sizes and trait genetic architectures. For oligogenic architecture, the maximum relative genetic gain advantage of GARS over PRS was 12–88%, which was observed only during the first few cycles. For the polygenic architecture, GARS provided maximum relative genetic gain advantage of 26–165%, and was always superior to PRS. Average prediction accuracy declines substantially after several cycles of selection, suggesting the prediction models should be updated regularly. Updating prediction models every year increased the genetic gain by up to 33–39% compared to no-update scenarios. For small populations and oligogenic traits, cost per unit gain was lower in PRS than GARS. However, with larger populations and polygenic traits cost per unit gain was up to 67% lower in GARS than PRS. Collectively, the simulations suggest that GARS could increase the genetic gain in small young breeding programs by accelerating the breeding cycles and enabling evaluation of larger populations.

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Genome-Wide Analysis of Mycoplasma dispar Provides Insights into Putative Virulence Factors and Phylogenetic Relationships

Mycoplasma dispar is an important pathogen involved in bovine respiratory disease, which causes huge economic losses worldwide. Our knowledge regarding the genomics, pathogenic mechanisms, and genetics of M. dispar is rather limited. In this study, the complete genome of M. dispar GS01 strain was sequenced using PacBio SMRT technology and first genome-wide analyzed. M. dispar GS01 has a single circular chromosome of 1,065,810 bp encoding 825 predicted proteins. Twenty-three potential virulence genes and two pathogenicity islands were identified in M. dispar. This pathogen was cytopathogenic, could form prolific biofilms, and could produce a large amount of H₂O₂. Methylation analysis revealed adenine and cytosine methylation across the genome and 13 distinct nucleotide motifs. Comparative analysis showed a high collinearity relationship between M. dispar GS01 and type strain ATCC 27140. Phylogenetic analysis demonstrated that M. dispar is genetically close to M. flocculare and M. hyopneumoniae. The data presented in this study will aid further study on the pathogenic mechanisms and evolution of M. dispar.

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A Transgenic Flock House Virus Replicon Reveals an RNAi Independent Antiviral Mechanism Acting in Drosophila Follicular Somatic Cells

The small interfering RNA (siRNA) pathway is the main and best studied invertebrate antiviral response. Other poorly characterized protein based antiviral mechanisms also contribute to the control of viral replication in insects. In addition, it remains unclear whether tissue specific factors contribute to RNA and protein-based antiviral immunity mechanisms. In vivo screens to identify such factors are challenging and time consuming. In addition, the scored phenotype is usually limited to survival and/or viral load. Transgenic viral replicons are valuable tools to overcome these limitations and screen for novel antiviral factors. Here we describe transgenic Drosophila melanogaster lines encoding a Flock House Virus-derived replicon (FHVB2eGFP), expressing GFP as a reporter of viral replication. This replicon is efficiently controlled by the siRNA pathway in most somatic tissues, with GFP fluorescence providing a reliable marker for the activity of antiviral RNAi. Interestingly, in follicular somatic cells (FSC) of ovaries, this replicon is still partially repressed in an siRNA independent manner. We did not detect replicon derived Piwi-interacting RNAs in FSCs and identified 31 differentially expressed genes between restrictive and permissive FSCs. Altogether, our results uncovered a yet unidentified RNAi-independent mechanism controlling FHV replication in FSCs of ovaries and validate the FHVB2eGFP replicon as a tool to screen for novel tissue specific antiviral mechanisms.

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Composition of the Survival Motor Neuron (SMN) Complex in Drosophila melanogaster

Spinal Muscular Atrophy (SMA) is caused by homozygous mutations in the human survival motor neuron 1 (SMN1) gene. SMN protein has a well-characterized role in the biogenesis of small nuclear ribonucleoproteins (snRNPs), core components of the spliceosome. SMN is part of an oligomeric complex with core binding partners, collectively called Gemins. Biochemical and cell biological studies demonstrate that certain Gemins are required for proper snRNP assembly and transport. However, the precise functions of most Gemins are unknown. To gain a deeper understanding of the SMN complex in the context of metazoan evolution, we investigated its composition in Drosophila melanogaster. Using transgenic flies that exclusively express Flag-tagged SMN from its native promoter, we previously found that Gemin2, Gemin3, Gemin5, and all nine classical Sm proteins, including Lsm10 and Lsm11, co-purify with SMN. Here, we show that CG2941 is also highly enriched in the pulldown. Reciprocal co-immunoprecipitation reveals that epitope-tagged CG2941 interacts with endogenous SMN in Schneider2 cells. Bioinformatic comparisons show that CG2941 shares sequence and structural similarity with metazoan Gemin4. Additional analysis shows that three other genes (CG14164, CG31950 and CG2371) are not orthologous to Gemins 6-7-8, respectively, as previously suggested. In D.melanogaster, CG2941 is located within an evolutionarily recent genomic triplication with two other nearly identical paralogous genes (CG32783 and CG32786). RNAi-mediated knockdown of CG2941 and its two close paralogs reveals that Gemin4 is essential for organismal viability.

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Yeast Models of Phosphomannomutase 2 Deficiency, a Congenital Disorder of Glycosylation

Phosphomannomutase 2 Deficiency (PMM2-CDG) is the most common monogenic congenital disorder of glycosylation (CDG) affecting at least 800 patients globally. PMM2 orthologs are present in model organisms, including the budding yeast Saccharomyces cerevisiae gene SEC53. Here we describe conserved genotype-phenotype relationships across yeast and human patients between five PMM2 loss-of-function missense mutations and their orthologous SEC53 mutations. These alleles range in severity from folding defective (hypomorph) to dimerization defective (severe hypomorph) to catalytic dead (null). We included the first and second most common missense mutations – R141H, F119L respectively– and the most common compound heterozygote genotype – PMM2^R141H/F119L – observed in PMM2-CDG patients. Each mutation described is expressed in haploid as well as homozygous and heterozygous diploid yeast cells at varying protein expression levels as either SEC53 protein variants or PMM2 protein variants. We developed a 384-well-plate, growth-based assay for use in a screen of the 2,560-compound Microsource Spectrum library of approved drugs, experimental drugs, tool compounds and natural products. We identified three compounds that suppress growth defects of SEC53 variants, F126L and V238M, based on the biochemical defect of the allele, protein abundance or ploidy. The rare PMM2 E139K protein variant is fully functional in yeast cells, suggesting that its pathogenicity in humans is due to the underlying DNA mutation that results in skipping of exon 5 and a nonfunctional truncated protein. Together, these results demonstrate that yeast models can be used to characterize known and novel PMM2 patient alleles in quantitative growth and enzymatic activity assays, and used as patient avatars for PMM2-CDG drug screens yielding compounds that could be rapidly cross-validated in zebrafish, rodent and human organoid models.

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Metformin Affects Heme Function as a Possible Mechanism of Action

Metformin elicits pleiotropic effects that are beneficial for treating diabetes, as well as particular cancers and aging. In spite of its importance, a convincing and unifying mechanism to explain how metformin operates is lacking. Here we describe investigations into the mechanism of metformin action through heme and hemoprotein(s). Metformin suppresses heme production by 50% in yeast, and this suppression requires mitochondria function, which is necessary for heme synthesis. At high concentrations comparable to those in the clinic, metformin also suppresses heme production in human erythrocytes, erythropoietic cells and hepatocytes by 30–50%; the heme-targeting drug artemisinin operates at a greater potency. Significantly, metformin prevents oxidation of heme in three protein scaffolds, cytochrome c, myoglobin and hemoglobin, with Kd values < 3 mM suggesting a dual oxidation and reduction role in the regulation of heme redox transition. Since heme- and porphyrin-like groups operate in diverse enzymes that control important metabolic processes, we suggest that metformin acts, at least in part, through stabilizing appropriate redox states in heme and other porphyrin-containing groups to control cellular metabolism.

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Complex Structural PPT1 Variant Associated with Non-syndromic Canine Retinal Degeneration

Rod and cone photoreceptors are specialized retinal neurons that have a fundamental role in visual perception, capturing light and transducing it into a neuronal signal. Aberrant functioning of rod and/or cone photoreceptors can ultimately lead to progressive degeneration and eventually blindness. In man, many rod and rod-cone degenerative diseases are classified as forms of retinitis pigmentosa (RP). Dogs also have a comparable disease grouping termed progressive retinal atrophy (PRA). These diseases are generally due to single gene defects and follow Mendelian inheritance.We collected 51 DNA samples from Miniature Schnauzers affected by PRA (average age of diagnosis ~3.9 ±1 years), as well as from 56 clinically normal controls of the same breed (average age ~6.6 ±2.8 years). Pedigree analysis suggested monogenic autosomal recessive inheritance of PRA. GWAS and homozygosity mapping defined a critical interval in the first 4,796,806 bp of CFA15. Whole genome sequencing of two affected cases, a carrier and a control identified two candidate variants within the critical interval. One was an intronic SNV in HIVEP3, and the other was a complex structural variant consisting of the duplication of exon 5 of the PPT1 gene along with a conversion and insertion (named PPT1_dci). PPT1_dci was confirmed homozygous in a cohort of 22 cases, and 12 more cases were homozygous for the CFA15 haplotype. Additionally, the variant was found homozygous in 6 non-affected dogs of age higher than the average age of onset. The HIVEP3 variant was found heterozygous (n = 4) and homozygous wild-type (n = 1) in cases either homozygous for PPT1_dci or for the mapped CFA15 haplotype. We detected the wildtype and three aberrant PPT1 transcripts in isolated white blood cell mRNA extracted from a PRA case homozygous for PPT1_dci, and the aberrant transcripts involved inclusion of the duplicated exon 5 and novel exons following the activation of cryptic splice sites. No neurological signs were detected among the dogs homozygous for the PPT1_dci variant. Therefore, we propose PPT1_dci as causative for a non-syndromic form of PRA (PRA_PPT1) that shows incomplete penetrance in Miniature Schnauzers, potentially related to the presence of the wild-type transcript. To our knowledge, this is the first case of isolated retinal degeneration associated with a PPT1 variant.

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Identifying Pseudomonas syringae Type III Secreted Effector Function via a Yeast Genomic Screen

Gram-negative bacterial pathogens inject type III secreted effectors (T3SEs) directly into host cells to promote pathogen fitness by manipulating host cellular processes. Despite their crucial role in promoting virulence, relatively few T3SEs have well-characterized enzymatic activities or host targets. This is in part due to functional redundancy within pathogen T3SE repertoires as well as the promiscuity of individual T3SEs that can have multiple host targets. To overcome these challenges, we generated and characterized a collection of yeast strains stably expressing 75 T3SE constructs from the plant pathogen Pseudomonas syringae. This collection is devised to facilitate heterologous genetic screens in yeast, a non-host organism, to identify T3SEs that target conserved eukaryotic processes. Among 75 T3SEs tested, we identified 16 that inhibited yeast growth on rich media and eight that inhibited growth on stress-inducing media. We utilized Pathogenic Genetic Array (PGA) screens to identify potential host targets of P. syringae T3SEs. We focused on the acetyltransferase, HopZ1a, which interacts with plant tubulin and alters microtubule networks. To uncover putative HopZ1a host targets, we identified yeast genes with genetic interaction profiles most similar (i.e., congruent) to the PGA profile of HopZ1a and performed a functional enrichment analysis of these HopZ1a-congruent genes. We compared the congruence analyses above to previously described HopZ physical interaction datasets and identified kinesins as potential HopZ1a targets. Finally, we demonstrated that HopZ1a can target kinesins by acetylating the plant kinesins HINKEL and MKRP1, illustrating the utility of our T3SE-expressing yeast library to characterize T3SE functions.

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A Statistical Procedure for Genome-Wide Detection of QTL Hotspots Using Public Databases with Application to Rice

Genome-wide detection of quantitative trait loci (QTL) hotspots underlying variation in many molecular and phenotypic traits has been a key step in various biological studies since the QTL hotspots are highly informative and can be linked to the genes for the quantitative traits. Several statistical methods have been proposed to detect QTL hotspots. These hotspot detection methods rely heavily on permutation tests performed on summarized QTL data or individual-level data (with genotypes and phenotypes) from the genetical genomics experiments. In this article, we propose a statistical procedure for QTL hotspot detection by using the summarized QTL (interval) data collected in public web-accessible databases. First, a simple statistical method based on the uniform distribution is derived to convert the QTL interval data into the expected QTL frequency (EQF) matrix. And then, to account for the correlation structure among traits, the QTL for correlated traits are grouped together into the same categories to form a reduced EQF matrix. Furthermore, a permutation algorithm on the EQF elements or on the QTL intervals is developed to compute a sliding scale of EQF thresholds, ranging from strict to liberal, for assessing the significance of QTL hotspots. With grouping, much stricter thresholds can be obtained to avoid the detection of spurious hotspots. Real example analysis and simulation study are carried out to illustrate our procedure, evaluate the performances and compare with other methods. It shows that our procedure can control the genome-wide error rates at the target levels, provide appropriate thresholds for correlated data and is comparable to the methods using individual-level data in hotspot detection. Depending on the thresholds used, more than 100 hotspots are detected in GRAMENE rice database. We also perform a genome-wide comparative analysis of the detected hotspots and the known genes collected in the Rice Q-TARO database. The comparative analysis reveals that the hotspots and genes are conformable in the sense that they co-localize closely and are functionally related to relevant traits. Our statistical procedure can provide a framework for exploring the networks among QTL hotspots, genes and quantitative traits in biological studies. The R codes that produce both numerical and graphical outputs of QTL hotspot detection in the genome are available on the worldwide web http://www.stat.sinica.edu.tw/chkao/.

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Off-Label Teduglutide Therapy in Non-intestinal Failure Patients with Chronic Malabsorption

Abstract

Background

Teduglutide, a glucagon-like peptide 2 analog, has demonstrated efficacy in treating adult patients with short bowel syndrome (SBS) and dependence on parenteral nutrition (PN), but its role in chronic malabsorptive states that do not necessitate PN remains uncertain.

Aims

To evaluate teduglutide use beyond its approved indications and to discuss the results of this adjunctive treatment in patients resistant to established therapy.

Results

This series reports four patients treated with teduglutide off-label. The first case had Crohn's disease (CD) with persistent colocutaneous fistulae that demonstrated complete closure after 8 months of teduglutide therapy. The second case involved a PN-dependent CD patient with persistent fistulae and intra-abdominal abscesses who weaned off PN and had a significant improvement in her nutritional status after 3 months of teduglutide therapy. The third case had CD complicated by severe malnutrition and previous PN-associated line infections, but by 9 months of teduglutide therapy, she gained 5 kg and no longer required re-initiation of PN. The fourth case had a high-output diverting ileostomy with resultant impaired healing of a stage IV decubitus ulcer, and after 2 months of therapy, the patient's pre-albumin increased by 250% and the ulcer had decreased by 40% in size.

Conclusion

The use of teduglutide might be broadened to include patients with functional SBS not meeting strict criteria for intestinal failure. Further studies should evaluate the efficacy of teduglutide in patients who may require short-term small intestine rehabilitation or who have chronically impaired absorptive capacity not yet requiring PN.

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Glypican-1 Promotes Tumorigenesis by Regulating the PTEN/Akt/β-Catenin Signaling Pathway in Esophageal Squamous Cell Carcinoma

Abstract

Background and Aims

Glypican-1 (GPC1), a cell-surface heparan sulfate proteoglycan, promotes the pathogenesis of many human cancers. This study focuses on the role of GPC1 in the promotion of cell proliferation and motility in esophageal squamous cell carcinoma (ESCC).

Methods

The expression and distribution of GPC1 were measured in tumor tissues from 248 ESCC patients using immunohistochemical (IHC) assays. Cell counting (kit-8), flow cytometry, Transwell, wound healing, IHC, and Western blotting assays were performed to examine the molecular mechanisms that underlie how GPC1 enhances cell proliferation and motility.

Results

The level of GPC1 was higher in ESCC tumor samples than in para-tumor tissues (IHC score: 5.42 ± 2.15 vs. 0.86 ± 0.96). Ectopic overexpression of GPC1 in EC9706 cells promoted cell growth and the G1/S phase transition; conversely, GPC1 knockdown in Eca109 cells attenuated cell proliferation and induced G2/M phase arrest. In addition, GPC1 upregulation enhanced ESCC cell motility and induced epithelial mesenchymal transition (EMT), as demonstrated by the aberrant expression of EMT markers. Mechanistically, we demonstrated that GPC1 increased levels of p-Akt and β-catenin and reduced PTEN expression in ESCC.

Conclusions

Our study indicated that GPC1 promotes the aggressive proliferation of ESCC cells by regulating the PTEN/Akt/β-catenin pathway. GPC1 may be a promising target for ESCC treatment.

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The FreeD module for the Lokomat facilitates a physiological movement pattern in healthy people – a proof of concept study

A contralateral pelvic drop, a transverse rotation and a lateral translation of the pelvis are essential features of normal human gait. These motions are often restricted in robot-assisted gait devices. The op...

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Micronucleus Assay for Monitoring the Genotoxic Effects of Arsenic: A Systematic Review

Publication date: Available online 6 February 2019

Source: Mutation Research/Reviews in Mutation Research

Author(s): Ju Dong, Jun-qin Wang, Qin Qian, Guo-chun Li, Dong-qin Yang, Chao Jiang

Abstract

The micronucleus (MN) assay has been used to determine the potential genotoxic effects and cancer risk in human populations exposed to arsenic. Some of these studies have found an increase in MN frequencies among exposed individuals, but different results have also been found by others. Thus, the main purpose of this study is to investigate whether MN can be used as an effective biomarker for the arsenic exposure, as well as which kind of cells show stronger effects in the MN assay upon arsenic exposure and on the MN frequency. A systematic review was conducted, the meta-analysis showed that the overall estimates of MR were 2.95 (95% confidence interval (CI): 2.00 to 4.35), 2.36 (95% CI: 1.77 to 3.15), and 2.82 (95% CI: 1.86 to 4.28) for the use of lymphocytes, buccal cells, and urothelial cells in the MN assay, respectively. Subgroup analysis showed that when the exposure method was drinking water, the MN frequencies increased significantly in lymphocytes (MR = 3.59, 95% CI: 2.30 to 5.60), in buccal cells (MR = 2.29, 95% CI: 1.69 to 3.10), and in urothelial cells (MR = 3.16, 95% CI: 2.02 to 4.97). However, when the exposure method was the occupational setting, the MN detection using lymphocytes didn't find significant differences between groups. Subgroup analysis also showed MN frequencies increased significantly in both routine-culture MN assay (MR = 2.88, 95% CI: 1.15 to 7.24) and cytokinesis-block MN assay (MR = 2.89, 95% CI: 1.84 to 4.55) when lymphocytes were used. The performance of the MN assay with different types of cells was also compared, but no significant difference was found. Therefore, it can be concluded that MN could be used as an effective biomarker for monitoring of arsenic-exposed populations, and none of the three types cells show stronger effects in the MN assay for detecting the genetic damage from arsenic.

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Editorial Board

Publication date: March 2019

Source: International Journal of Psychophysiology, Volume 137

Author(s):

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International Organization of Psychophysiology

Publication date: March 2019

Source: International Journal of Psychophysiology, Volume 137

Author(s):

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The interhemispheric miscommunication theory of auditory verbal hallucinations in schizophrenia

Publication date: Available online 7 February 2019

Source: International Journal of Psychophysiology

Author(s): Saskia Steinmann, Gregor Leicht, Christoph Mulert

Abstract

Auditory verbal hallucinations (AVH) are hallmark symptoms of schizophrenia and have been linked to abnormal activation, connectivity and integration within the auditory, language, and memory brain networks. The interhemispheric miscommunication theory of AVH is based on a steadily growing number of studies using a variety of modalities (EEG, fMRI, DTI) reporting that both altered integrity of the interhemispheric auditory pathways (Gavrilescu et al. 2010; Hubl et al. 2004; Leroux et al. 2017; Mulert et al. 2012; Wigand et al. 2014) and disturbed functional gamma-band synchrony between right and left auditory cortices (Mulert et al. 2011; Steinmann et al. 2017a) significantly contribute to abnormal auditory processing and the emergence of AVH. Moreover, initial studies using pharmacological EEG and ¹H MR Spectroscopy provided first insights into the underlying neurochemistry of AVH. It has been suggested that the observed interhemispheric gamma-band alterations might be mediated by an excitatory-to-inhibitory (E/I) imbalance due to dysfunction of N-methyl-d-aspartate receptor (NMDAR). In support, a potential NMDAR hypofunction is proposed to be compensated by increased levels of glutamate in prefrontal and auditory brain areas. In this mini-review paper, we used the levels of explanation approach and present how interhemispheric brain connectivity (brain-imaging level) corresponds to auditory perception (cognitive level), and eventually how these parameters are related to changes in neurotransmission (cellular level) and to the occurrence of AVH (clinical level). To the best of our knowledge, this is the first overview that overcomes traditional boundaries and presents converging evidence from different levels of knowledge that validate and support each other, and particularly point toward the role of an interhemispheric miscommunication in AVH.

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Corrigendum: “The transfer of 137Cs, Pu isotopes and 90Sr to bird, bat and ground-dwelling small mammal species within the Chernobyl exclusion zone”[Journal of Environmental Radioactivity Volume 153, March 2016, Pages 231-236]

Publication date: April 2019

Source: Journal of Environmental Radioactivity, Volumes 199–200

Author(s): N.A. Beresford, S. Gaschak, Andrey Maksimenko, M.D. Wood

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Editorial Board

Publication date: April 2019

Source: Journal of Environmental Radioactivity, Volumes 199–200

Author(s):

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Effect of acceleration on the rate of power development and neural activity of the leg extensors across the adult life span

Abstract

Purpose

The rate of power development (RPD) represents the capacity to rapidly generate power during a dynamic muscle contraction. As RPD is highly susceptible to aging, its decline can have important functional consequences. However, the effect of age on RPD in response to rapid changes in movement velocity (cfr. fall incidence) is not yet clear. Therefore, the present study aimed to examine the effect of age on RPD and neural drive in response to different accelerations.

Methods

Three maximal isokinetic leg extensor tests at 540°/s with different initial acceleration phases at 3200, 5700 and 7200°/s² were performed. RPD, which is the slope of the power-time curve during the acceleration phase, was calculated for 83 subjects aged between 20 and 69 years. Mean electromyography signal amplitude was determined for rectus femoris (RF), vastus lateralis (VL) and biceps femoris muscles.

Results

The average annual age-related decline rate of RPD at highest acceleration was − 2.93% and was − 1.52% and − 1.82% higher compared to lower acceleration rates (p < 0.001). This deficit can probably be explained by an age-related impairment in neural drive during the first 75 ms of the acceleration phase, as evidenced by a reduced RF and VL neuromuscular activity of − 0.30% and − 0.36% at highest versus lowest acceleration (p < 0.05).

Conclusion

These findings highlight the inability of aged individuals to quickly respond to abrupt changes in movement velocity, which requires more focus in training and prevention programs.

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The influence of local skin temperature on the sweat glands maximum ion reabsorption rate

Abstract

Purpose

Changes in mean skin temperature (T_sk) have been shown to modify the maximum rate of sweat ion reabsorption. This study aims to extend this knowledge by investigating if modifications could also be caused by local T_sk.

Methods

The influence of local T_sk on the sweat gland maximum ion reabsorption rates was investigated in ten healthy volunteers (three female and seven male; 20.8 ± 1.2 years, 60.4 ± 7.7 kg, 169.4 ± 10.4 cm) during passive heating (water-perfused suit and lower leg water immersion). In two separate trials, in a randomized order, one forearm was always manipulated to 33 °C (Neutral), whilst the other was manipulated to either 30 °C (Cool) or 36 °C (Warm) using water-perfused patches. Oesophageal temperature (T_es), forearm T_sk, sweat rate (SR), galvanic skin conductance (GSC) and salivary aldosterone concentrations were measured. The sweat gland maximum ion reabsorption rates were identified using the ∆SR threshold for an increasing ∆GSC.

Results

Thermal [T_es and body temperature (T_b)] and non-thermal responses (aldosterone) were similar across all conditions (p > 0.05). A temperature-dependent response for the sweat gland maximum ion reabsorption rates was evident between 30 °C (0.18 ± 0.10 mg/cm²/min) and 36 °C (0.28 ± 0.14 mg/cm²/min, d = 0.88, p < 0.05), but not for 33 °C (0.22 ± 0.12 mg/cm²/min), d = 0.44 and d = 0.36, p > 0.05.

Conclusion

The data indicate that small variations in local T_sk may not affect the sweat gland maximum ion reabsorption rates but when the local T_sk increases by > 6 °C, ion reabsorption rates also increase.

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Effects of exercise intensity on vascular and autonomic components of the baroreflex following glucose ingestion in adolescents

Abstract

Purpose

To investigate the effects of an oral glucose tolerance test (OGTT) on baroreflex sensitivity (BRS) in a sample of healthy adolescents, and how acute exercise bouts of different intensities alter the effects of the OGTT on BRS.

Methods

Thirteen male adolescents (14.0 ± 0.5 years) completed three conditions on separate days in a counterbalanced order: (1) high-intensity interval exercise (HIIE); (2) moderate-intensity interval exercise (MIIE); and (3) resting control (CON). At ~ 90 min following the conditions, participants performed an OGTT. Supine heart rate and blood pressure were monitored continuously at baseline, 60 min following the conditions, and 60 min following the OGTT. A cross-spectral method (LFgain) was used to determine BRS gain. Arterial compliance (AC) was assessed as the BRS vascular component. LFgain divided by AC (LFgain/AC) was used as the autonomic component.

Results

Although non-significant, LFgain moderately decreased post-OGTT when no exercise was performed (pre-OGTT = 24.4 ± 8.2 ms mmHg^− 1; post-OGTT = 19.9 ± 5.6 ms mmHg^− 1; ES = 0.64, P > 0.05). This was attributed to the decrease in LFgain/AC (pre-OGTT = 1.19 ± 0.5 ms µm^− 1; post-OGTT = 0.92 ± 0.24 ms µm^− 1; ES = 0.69, P > 0.05). Compared to CON (Δ = − 4.4 ± 8.7 ms mmHg^− 1), there were no differences for the pre–post-OGTT delta changes in LF/gain for HIIE (Δ = − 3.5 ± 8.2 ms mmHg^− 1) and MIIE (Δ = 1.3 ± 9.9 ms mmHg^− 1) had no effects on BRS following the OGTT (all ES < 0.5). Similarly, compared to CON (Δ = − 0.23 ± 0.40 ms µm^− 1) there were no differences for the pre–post-OGTT delta changes in LF/gain for HIIE (Δ = − 0.22 ± 0.49 ms µm^− 1) and MIIE (Δ = 0.13 ± 0.36 ms µm^− 1).

Conclusion

A moderate non-significant decrease in BRS was observed in adolescents following a glucose challenge with no apparent effects of exercise.

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The effects of varying gravito-inertial stressors on grip strength and hemodynamic responses in men and women

Abstract

Purpose

The body behaves as a global system with many interconnected subsystems. While the effects of a gravitational change on body responses have been extensively studied in isolation, we are not aware of any study that has examined these two types of body responses concurrently. Here, we examined how the cognitive and cardiovascular systems respond during application of varying gravito-inertial stressors in men and women.

Methods

Ten men and nine women underwent three 5-min centrifugation sessions (2.4 g at the feet, 1.5 g at the heart) in which participants rhythmically moved a hand-held object for 20 s. Grip force and hemodynamic responses were continuously measured during centrifugation and rest periods.

Result

Men optimized the modulation between grip force and the destabilizing load force, but not women. Exposure to artificial gravity induced higher heart rate and mean arterial pressure in both sexes compared to baseline. However, during artificial gravity exposure, only women decreased heart rate across sessions. Interestingly, we found that finishers of the protocol (mostly men) and Non-finishers (mostly women) exhibited divergent patterns of hemodynamic responses.

Conclusion

We speculate that the lack of grip force adaptation reported in women could be linked to the challenged hemodynamic responses during artificial gravity. By deriving a simple model to predict failure to complete the protocol, we found that mean arterial pressure—and not sex of the participant—was the most relevant factor. As artificial gravity is being proposed as a countermeasure in long-term manned missions, the observed effects in grip force adaptation and hemodynamic responses during varying gravito-inertial stressors application are particularly important.

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Spastic dystonia in stroke subjects: prevalence and features of the neglected phenomenon of the upper motor neuron syndrome

Publication date: Available online 6 February 2019

Source: Clinical Neurophysiology

Author(s): Carlo Trompetto, Antonio Currà, Luca Puce, Laura Mori, Carlo Serrati, Francesco Fattapposta, Giovanni Abbruzzese, Lucio Marinelli

Abstract

Objective

Spastic dystonia is one of the positive phenomena of the upper motor neuron syndrome (UMNS). It is characterised by the inability to relax a muscle leading to a spontaneous, although stretch-sensitive, tonic contraction. Although spastic dystonia is a recognized cause of muscle hypertonia, its prevalence among hypertonic muscles of stroke subjects has never been investigated. Differently from spasticity, which is an exaggerated stretch reflex, spastic dystonia is viewed as an efferent phenomenon, due to an abnormal central drive to motoneurons.

Methods

In 23 hemiparetic stroke subjects showing increased muscle tone of wrist flexors, surface EMG was used to investigate the presence of spontaneous, stretch-sensitive EMG activity in flexor carpi radialis.

Results

Spontaneous, stretch-sensitive EMG activity was found in 17 subjects. In the remaining 6 subjects, no spontaneous EMG activity was found.

Conclusions

The majority of stroke subjects is affected by spastic dystonia in their hypertonic wrist flexor muscles. Only a minority of subjects is affected by spasticity.

Significance

To stop spastic dystonia from being the neglected aspect of UMNS, it is essential to link its definition to increased muscle tone, as occurred for spasticity. Recognizing the real phenomena underling muscle hypertonia could improve its management.

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Brainstem avenues in Parkinson’s disease research

Publication date: Available online 6 February 2019

Source: Clinical Neurophysiology

Author(s): Matteo Bologna, Alfredo Berardelli

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Detection of REM Sleep Behaviour Disorder by Automated Polysomnography Analysis

Publication date: Available online 6 February 2019

Source: Clinical Neurophysiology

Author(s): Navin Cooray, Fernando Andreotti, Christine Lo, Mkael Symmonds, Michele T.M. Hu, Maarten De Vos

Abstract

Objective

Evidence suggests Rapid-Eye-Movement (REM) Sleep Behaviour Disorder (RBD) is an early predictor of Parkinson's disease. This study proposes a fully-automated framework for RBD detection consisting of automated sleep staging followed by RBD identification.

Methods

Analysis was assessed using a limited polysomnography montage from 53 participants with RBD and 53 age-matched healthy controls. Sleep stage classification was achieved using a Random Forest (RF) classifier and 156 features extracted from electroencephalogram (EEG), electrooculogram (EOG) and electromyogram (EMG) channels. For RBD detection, a RF classifier was trained combining established techniques to quantify muscle atonia with additional features that incorporate sleep architecture and the EMG fractal exponent.

Results

Automated multi-state sleep staging achieved a 0.62 Cohen's Kappa score. RBD detection accuracy improved by 10% to 96% (compared to individual established metrics) when using manually annotated sleep staging. Accuracy remained high (92%) when using automated sleep staging.

Conclusions

This study outperforms established metrics and demonstrates that incorporating sleep architecture and sleep stage transitions can benefit RBD detection. This study also achieved automated sleep staging with a level of accuracy comparable to manual annotation.

Significance

This study validates a tractable, fully-automated, and sensitive pipeline for RBD identification that could be translated to wearable take-home technology.

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39th Annual David W. Smith Workshop on Malformations and Morphogenesis: Abstracts of the 2018 Annual Meeting

The 39th Annual David W. Smith workshop on Malformations and Morphogenesis was held from August 24th‐29th 2018 at the Banff Centre for Arts and Creativity, Banff, Alberta, Canada. The Workshop, which honors the legacy of David W. Smith, brought together clinicians and researchers from around the world interested in congenital malformations and their underlying mechanisms of morphogenesis in this addition to this year's five themes: phenotypes and phenotyping of known, novel and emerging syndromes; treatment; epigenetics and chromatin disorders; placenta; and, gene–environment interaction. This Conference Report includes the abstracts presented at the 2018 Workshop.

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Lithic raw material acquisition and use by early Homo sapiens at Skhul, Israel

Publication date: February 2019

Source: Journal of Human Evolution, Volume 127

Author(s): Ravid Ekshtain, Christian A. Tryon

Abstract

The site of Skhul in Israel has featured prominently in discussions about the early presence of Homo sapiens outside of Africa since its excavation in the 1930s. Until now, attention has been primarily focused on the site's fossil hominins and evidence for symbolic behavior in the form of burials and rare artifacts such as pierced shells and pigment objects. We present here the results of renewed analysis of the lithic artifacts from Skhul drawn from archival collections in the United States, United Kingdom, and Israel. Although lithic artifacts form the majority of the archaeological record from the site, they have rarely been the subject of comprehensive study. Our analyses of raw material selection, use and transport combined with technological analyses of artifact production methods (1) indicate selective transport to the site of large flakes, retouched pieces, and particularly Levallois points from non-local sources, and (2) demonstrate substantial variability in raw material procurement that fails to indicate clear differences in landscape use between H. sapiens and Neanderthals.

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Cholinergic neurons in the pedunculopontine tegmental nucleus modulate breathing in rats by direct projections to the retrotrapezoid nucleus

Key points

Cholinergic projections from the PPTg to the RTN are thought to be important for sleep‐wake state dependent control of breathing. The RTN also receives cholinergic input from the postinspiratory complex. Stimulation of the PPTg increases respiratory output under control conditions, but not when muscarinic receptors in the RTN are blocked. Our data support the possibility that arousal‐dependent modulation of breathing involves recruitment of cholinergic projections from the PPTg to the RTN.

Abstract

The pedunculopontine tegmental nucleus (PPTg) in the mesopontine region has important physiological functions, including breathing control. The PPTg contains a variety of cell types including cholinergic neurons that project to the rostral aspect of the ventrolateral medulla. In addition, cholinergic signalling in the retrotrapezoid nucleus (RTN), a region that contains neurons that regulate breathing in response to changes in CO₂/H⁺, has been shown to activate chemosensitive neurons and increase inspiratory activity. Our goal is to identify the source of cholinergic input to the RTN and determine whether cholinergic signalling in this region influences baseline breathing or the ventilatory response to CO₂ in conscious male Wistar rats. Retrograde tracer Fluoro Gold injected into the RTN labelled a subset of cholinergic PPTg neurons that presumably project directly to the chemosensitive region of the RTN. In unrestrained awake rats, unilateral injection of the glutamate (10 mm ‐ 100 nl) in the PPTg decreased tidal volume (V_T), but otherwise increased respiratory rate (f_R) and net respiratory output as evidenced by an increase in ventilation (V_E). All respiratory responses elicited by PPTg stimulation were blunted by prior injection of methyl‐atropine (5 mm/50‐75 nl) into the RTN. These results show that stimulation of the PPTg can increase respiratory activity in part by cholinergic activation of chemosensitive elements of the RTN. Based on previous evidence that cholinergic PPTg projections may simultaneously activate expiratory output from the pFRG, we speculate that cholinergic signalling at the level of RTN region could also be involved in breathing regulation.

This article is protected by copyright. All rights reserved

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The increase in muscle force after 4 weeks of strength training is mediated by adaptations in motor unit recruitment and rate coding

Key points

Previous studies have indicated that several weeks of strength training is sufficient to elicit significant adaptations in the neural drive sent to the muscles. There are few data, however, on the changes elicited by strength training in the recruitment and rate coding of motor units during voluntary contractions. We show for the first time that the discharge characteristics of motor units in the tibialis anterior muscle tracked across the intervention are changed by 4 weeks of strength training with isometric voluntary contractions. The specific adaptations included significant increases in motor unit discharge rate, decreases in the recruitment‐threshold force of motor units and a similar input–output gain of the motor neurons. The findings suggest that the adaptations in motor unit function may be attributable to changes in synaptic input to the motor neuron pool or to adaptations in intrinsic motor neuron properties.

Abstract

The strength of a muscle typically begins to increase after only a few sessions of strength training. This increase is usually attributed to changes in the neural drive to muscle as a result of adaptations at the cortical or spinal level. We investigated the change in the discharge characteristics of large populations of longitudinally tracked motor units in tibialis anterior before and after 4 weeks of strength training the ankle‐dorsiflexor muscles with isometric contractions. The adaptations exhibited by 14 individuals were compared with 14 control subjects. High‐density electromyogram grids with 128 electrodes recorded the myoelectric activity during isometric ramp contractions to the target forces of 35%, 50% and 70% of maximal voluntary force. The motor unit recruitment and derecruitment thresholds, discharge rate, interspike intervals and estimates of synaptic inputs to motor neurons were assessed. The normalized recruitment‐threshold forces of the motor units were decreased after strength training (P < 0.05). Moreover, discharge rate increased by 3.3 ± 2.5 pps (average across subjects and motor units) during the plateau phase of the submaximal isometric contractions (P < 0.001). Discharge rates at recruitment and derecruitment were not modified by training (P < 0.05). The association between force and motor unit discharge rate during the ramp‐phase of the contractions was also not altered by training (P < 0.05). These results demonstrate for the first time that the increase in muscle force after 4 weeks of strength training is the result of an increase in motor neuron output from the spinal cord to the muscle.

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Aberrant cortical excitability reflects the loss of hand dexterity in musician's dystonia

Key points

Dystonia is a movement disorder characterized by abnormalities at multifaceted aspects of motor dexterity and neural functions. Evidence bridging between pathophysiology and movement abnormalities is limited. A novel finding was that in focal task‐specific dystonia (FTSD), an aberrantly reduced inhibition at the motor cortex was related to the temporal imprecision of the dexterous finger movements, whereas an elevated facilitation was associated with an abnormally sluggish transition of finger movements from flexion to extension. We newly identified two sets of behavioural–physiological covariations as hallmarks of hand FTSD, which is clinically significant because these findings provide novel evidence connecting distinct types of malfunctions within the motor cortex at rest with distinct aspects of motor dexterity degradation in FTSD patients.

Abstract

Focal task‐specific dystonia (FTSD) compromises dexterous movements. A proposed pathophysiological mechanism of FTSD involves malfunction of the motor cortex (M1). However, no evidence is yet available regarding whether and how malfunctions of M1 are responsible for the loss of motor dexterity. Here, we addressed this issue by assessing both M1 excitability and detailed movement parameters, as well as their relationships. Transcranial magnetic stimulation was applied over M1 in 20 pianists with FTSD, 20 healthy pianists and 20 non‐musicians. The patients demonstrated both reduced short‐interval intracortical inhibition (SICI) and elevated intracortical facilitation (ICF) compared with the healthy controls. This indicates that the abnormal cortical excitability reflects pathophysiology but not current skills. Hand motor dexterity was evaluated by position sensors during piano playing at two tempi. The patients showed delayed transition from finger flexion to extension at the fastest tempo and greater timing variability of the finger movements. Furthermore, multivariate analyses identified distinct sets of covariation between cortical excitability and dexterity measures. Namely, the SICI measure and ICF measure were associated with the temporal variability of the movements and the quickness of the transition from flexion to extension, respectively. Specifically, the reduced inhibition and elevated facilitation at M1 in pianists was related to the temporal imprecision and impairment of quick transitions in the sequential finger movements. The present study provides novel evidence associating M1 malfunctions with dexterity loss.

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Ivermectin and its target molecules: shared and unique modulation mechanisms of ion channels and receptors by ivermectin

 The IVM‐binding site in Cys‐loop receptors and the farnesoid X receptor (FXR), and the predicted IVM‐binding site in the P2X₄ receptor and the G‐protein‐gated inwardly rectifying K⁺ (GIRK) channel.

Abstract

Ivermectin (IVM) is an antiparasitic drug that is used worldwide and rescues hundreds of millions of people from onchocerciasis and lymphatic filariasis. It was discovered by Satoshi Ōmura and William C. Campbell, to whom the 2015 Nobel Prize in Physiology or Medicine was awarded. It kills parasites by activating glutamate‐gated Cl⁻ channels, and it also targets several ligand‐gated ion channels and receptors, including Cys‐loop receptors, P2X₄ receptors and fernesoid X receptors. Recently, we found that IVM also activates a novel target, the G‐protein‐gated inwardly rectifying K⁺ channel, and also identified the structural determinant for the activation. In this review, we aim to provide an update and summary of recent progress in the identification of IVM targets, as well as their modulation mechanisms, through molecular structures, chimeras and site‐directed mutagenesis, and molecular docking and modelling studies.

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Synaptic depression induced by postsynaptic cAMP production in the Drosophila mushroom body calyx

Key points

Synaptic potentiation in Drosophila is observed at cholinergic synapses between antennal lobe (AL) and mushroom body (MB) neurons in the adult brain; however, depression at the AL–MB synapses has not yet been identified. By ex vivo Ca²⁺ imaging in an isolated cultured Drosophila brain, we found novel activity‐dependent depression at the AL–MB synapses. The degree of Ca²⁺ responses after repetitive AL stimulation is significantly reduced in the dendritic region of MB neurons (calyx) compared with those before AL stimulation, and this reduction of Ca²⁺ responses remains for at least 30 min. The expression of rutabaga, which encodes Ca²⁺/calmodulin‐dependent adenylyl cyclase, is essential in the MB neurons for the reduction of Ca²⁺ responses in the calyx. Our study reveals that elevation of cAMP production in the calyx during repetitive AL stimulation induces the depression at the AL–MB synapses.

Abstract

Synaptic plasticity has been studied to reveal the molecular and cellular mechanisms of associative and non‐associative learning. The fruit fly Drosophila melanogaster can be used to identify the molecular mechanisms of synaptic plasticity because vast genetic information or tools are available. Here, by ex vivo Ca²⁺ imaging of an isolated cultured Drosophila brain, we examined the novel activity‐dependent synaptic depression between the projection neurons of the antennal lobe (AL) and mushroom body (MB). Ex vivo Ca²⁺ imaging analysis revealed that electrical stimulation of AL elicits Ca²⁺ responses in the dendritic (calyx) and axonal (α lobe) regions of MB neurons, and the responses are reduced after repetitive AL stimulation. Since the cAMP signalling pathway plays an important role in synaptic plasticity in invertebrates and vertebrates, we examined whether the reduction of Ca²⁺ responses is also regulated by the cAMP signalling pathway. The expression of rutabaga (rut), which encodes Ca²⁺/calmodulin‐dependent adenylyl cyclase, was essential for the reduction of Ca²⁺ responses in the calyx and α lobe. Furthermore, imaging analysis using a fluorescence resonance energy transfer‐based cAMP indicator revealed that the cAMP level increased in the wild‐type calyx during repetitive AL stimulation, whereas it decreased in rut¹mutant flies with a loss‐of‐function mutation of rut. Thus, our study suggests that an increase in postsynaptic cAMP level during repetitive AL stimulation contributes to the attenuation of inputs at AL–MB synapses.

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