Abnormal molecular signatures of inflammation, energy metabolism, and vesicle biology in human Huntington disease peripheral tissues

BACKGROUND: A major challenge in neurodegenerative diseases concerns identifying biological disease signatures that track with disease progression or respond to an intervention. Several clinical trials in Huntington disease (HD), an inherited, progressive neurodegenerative disease, are currently ongoing. Therefore, we examine whether peripheral tissues can serve as a source of readily accessible biological signatures at the RNA and protein level in HD patients. RESULTS: We generate large, high-quality human datasets from skeletal muscle, skin and adipose tissue to probe molecular changes in human premanifest and early manifest HD patients—those most likely involved in clinical trials. The analysis of the transcriptomics and proteomics data shows robust, stage-dependent dysregulation. Gene ontology analysis confirms the involvement of inflammation and energy metabolism in peripheral HD pathogenesis. Furthermore, we observe changes in the homeostasis of extracellular vesicles, where we find consistent changes of genes and proteins involved in this process. In-depth single nucleotide polymorphism data across the HTT gene are derived from the generated primary cell lines. CONCLUSIONS: Our ‘omics data document the involvement of inflammation, energy metabolism, and extracellular vesicle homeostasis. This demonstrates the potential to identify biological signatures from peripheral tissues in HD suitable as biomarkers in clinical trials. The generated data, complemented by the primary cell lines established from peripheral tissues, and a large panel of iPSC lines that can serve as human models of HD are a valuable and unique resource to advance the current understanding of molecular mechanisms driving HD pathogenesis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-022-02752-5

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Stream types of the Lake Kinneret (Sea of Galilee) watershed

<p>The Lake Kinneret watershed (LKW) is an important freshwater resource in Israel, providing a myriad of water-dependent ecosystem services. Presently, environmental monitoring of the LKW is focused mainly on water quality and quantity parameters, but neglects biology. To fill this gap, a reference-based biological monitoring scheme is being developed. This approach requires a description of stream types, i.e. clusters of streams that naturally share similar environmental conditions, to help identify type-specific reference conditions and their associated communities. Here, we present the first stream typology for the entire LKW. Using a compilation of data layers of regional climate (precipitation and air temperature), local geology (volcanic, carbonic, and organic), and geomorphology (elevation, size, and slope), we have differentiated altogether nine stream types: small and mid-sized basaltic streams (41.6 and 2% of the entire catchment, respectively), small and mid-sized calcareous streams (36.4 and 2.9%), small organic streams (6.8%), and montane streams (6.5%). In addition, due to its size, the Jordan River is divided into three section-types: the karstic upper Jordan (6.3 km), the organic section of the Hula Valley (HV) (13.1 km), and the basaltic canyon-like section (16.9 km that stretches between the HV and the Lake Kinneret). Although Israel is not obligated to comply with the EU Water Framework Directive, this work constitutes an important step towards the development of the first bioassessment scheme for the LKW.</p

Fast-to-Slow Transition of Skeletal Muscle Contractile Function and Corresponding Changes in Myosin Heavy and Light Chain Formation in the R6/2 Mouse Model of Huntington’s Disease

<div><p>Huntington´s disease (HD) is a hereditary neurodegenerative disease resulting from an expanded polyglutamine sequence (poly-Q) in the protein huntingtin (HTT). Various studies report atrophy and metabolic pathology of skeletal muscle in HD and suggest as part of the process a fast-to-slow fiber type transition that may be caused by the pathological changes in central motor control or/and by mutant HTT in the muscle tissue itself. To investigate muscle pathology in HD, we used R6/2 mice, a common animal model for a rapidly progressing variant of the disease expressing exon 1 of the mutant human gene. We investigated alterations in the extensor digitorum longus (EDL), a typical fast-twitch muscle, and the soleus (SOL), a slow-twitch muscle. We focussed on mechanographic measurements of excised muscles using single and repetitive electrical stimulation and on the expression of the various myosin isoforms (heavy and light chains) using dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of whole muscle and single fiber preparations. In EDL of R6/2, the functional tests showed a left shift of the force-frequency relation and decrease in specific force. Moreover, the estimated relative contribution of the fastest myosin isoform MyHC IIb decreased, whereas the contribution of the slower MyHC IIx isoform increased. An additional change occurred in the alkali MyLC forms showing a decrease in 3f and an increase in 1f level. In SOL, a shift from fast MyHC IIa to the slow isoform I was detectable in male R6/2 mice only, and there was no evidence of isoform interconversion in the MyLC pattern. These alterations point to a partial remodeling of the contractile apparatus of R6/2 mice towards a slower contractile phenotype, predominantly in fast glycolytic fibers.</p></div

Summary of myosin light chain (MyLC) distribution (fractional content) in EDL and SOL muscles of male and female R6/2 mice and WT controls.

<p>Summary of myosin light chain (MyLC) distribution (fractional content) in EDL and SOL muscles of male and female R6/2 mice and WT controls.</p

Summary of myosin light chain (MyLC) distribution (fractional content) in EDL and SOL muscles of male and female R6/2 mice and WT controls.

<p>Summary of myosin light chain (MyLC) distribution (fractional content) in EDL and SOL muscles of male and female R6/2 mice and WT controls.</p

Lower force and slowed kinetics of contraction in R6/2.

<p>(A) Mean twitch force (left panel) and specific force (i.e. normalized by cross sectional area; right panel) compared in EDL and SOL muscles of WT (n = 15 and n = 15, respectively) and R6/2 (n = 10 and n = 10, respectively). (B) Comparison of half time of relaxation (t_1/2, left panel) and time to peak (t_peak, right panel). (C) Comparison of force frequency relations. Error bars indicate SEM.</p

Relative content of myosin light chain isoforms in WT and R6/2 muscle.

<p>(A) Examples showing Roti®-Blue-stained gels exhibiting MyLC bands that were evaluated in the analysis. See also <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0166106#pone.0166106.s002" target="_blank">S2 Fig</a></b>. (B) Relative amounts of the indicated MyLC isoforms in EDL of WT and R6/2, respectively, separated in results from female (left panel) and male specimen (right panel). (C) Relative amounts of the indicated MyLC isoforms in SOL of WT and R6/2, respectively, separated in results from female (left panel) and male (right panel) specimen. Error bars indicate SEM. n = 10 to 12 mice.</p

MyHC determination in single muscle fibers.

<p>Muscle fiber composition for EDL was assessed on a single fiber basis. For this MyHC were extracted from 6 to 15 randomly selected, intact fibers per muscle sample. (A) Examples showing Roti®-Blue-stained MyHC bands from selected single fiber SDS PAGE gels. Fibers were classified as Type IIB and IIX when a single band could be detected and as mixed IIB/X when both bands were detectable, irrespective of staining intensity. (B) Relative contribution (fractional number) of pooled fibers (59 fibers of 5 R6/2 mice and 89 fibers of 7 WT mice) exhibiting expression of MyHC IIb, IIx or both. Distributions of fibers amongst the types IIB, IIX and mixed type IIB/X differed significantly between WT and R6/2 mice (p = 0.02) indicating a different muscle fiber composition of R6/2 EDL muscle with more mixed-type fibers. Bars show relative frequencies; error bars show confidence intervals for binomial proportions (i.e. fibers of respective type vs. all other fibers) (95% CI).</p

Summary of muscle contractile properties.

<p>Summary of muscle contractile properties.</p