Exploring miRNA-target gene pair detection in disease with coRmiT.

A wide range of approaches can be used to detect micro RNA (miRNA)-target gene pairs (mTPs) from expression data, differing in the ways the gene and miRNA expression profiles are calculated, combined and correlated. However, there is no clear consensus on which is the best approach across all datasets. Here, we have implemented multiple strategies and applied them to three distinct rare disease datasets that comprise smallRNA-Seq and RNA-Seq data obtained from the same samples, obtaining mTPs related to the disease pathology. All datasets were preprocessed using a standardized, freely available computational workflow, DEG_workflow. This workflow includes coRmiT, a method to compare multiple strategies for mTP detection. We used it to investigate the overlap of the detected mTPs with predicted and validated mTPs from 11 different databases. Results show that there is no clear best strategy for mTP detection applicable to all situations. We therefore propose the integration of the results of the different strategies by selecting the one with the highest odds ratio for each miRNA, as the optimal way to integrate the results. We applied this selection-integration method to the datasets and showed it to be robust to changes in the predicted and validated mTP databases. Our findings have important implications for miRNA analysis. coRmiT is implemented as part of the ExpHunterSuite Bioconductor package available from https://bioconductor.org/packages/ExpHunterSuite.

Association Between COL5a1, COL11a1, and COL11a2 Gene Variations and Rotator Cuff Tendinopathy in Young Athletes.

OBJECTIVE: Tendinopathy is a prevalent condition in young athletes and in older nonathletic people. Recent tendinopathy research has shown a growing interest in the role played by genetic factors, basically genes involved in collagen synthesis and regulation, in view of collagen disorganization typically present in tendon pathologies. DESIGN: A case-control, genotype-phenotype association study. SETTING: La Ribera Hospital, Valencia, Spain. PARTICIPANTS: A group of 137 young athletes (49 with rotator cuff tendon pathology and 88 healthy counterparts) who played upper-limb-loading sports were clinically and ultrasound (US) assessed for rotator cuff tendinopathy were included. INTERVENTION: Genetic analysis was performed to determine whether there was a relationship between rotator cuff pathology and the genotype. MAIN OUTCOME MEASURES: We hypothesized that the following single nucleotide polymorphisms: COL5a1 rs12722, COL11a1 rs3753841, COL11a1 rs1676486, and COL11a2 rs1799907 would be associated with rotator cuff tendinopathy. RESULTS: A direct relationship between CC genotype and bilateral US pathological images was statistically significant (χ 2 = 0.0051) and confirmed by the Fisher test, with a correlation coefficient of 0.345 and a Cramer's v of 0.26. CONCLUSION: A significant association was found between COL5a1 rs12722 genotype and rotator cuff pathology, with the CC genotype conferring increased risk of tendon abnormalities and being associated with rotator cuff pathology.

Identification of Clinical Variants beyond the Exome in Inborn Errors of Metabolism.

Inborn errors of metabolism (IEM) constitute a huge group of rare diseases affecting 1 in every 1000 newborns. Next-generation sequencing has transformed the diagnosis of IEM, leading to its proposed use as a second-tier technology for confirming cases detected by clinical/biochemical studies or newborn screening. The diagnosis rate is, however, still not 100%. This paper reports the use of a personalized multi-omics (metabolomic, genomic and transcriptomic) pipeline plus functional genomics to aid in the genetic diagnosis of six unsolved cases, with a clinical and/or biochemical diagnosis of galactosemia, mucopolysaccharidosis type I (MPS I), maple syrup urine disease (MSUD), hyperphenylalaninemia (HPA), citrullinemia, or urea cycle deficiency. Eight novel variants in six genes were identified: six (four of them deep intronic) located in GALE, IDUA, PTS, ASS1 and OTC, all affecting the splicing process, and two located in the promoters of IDUA and PTS, thus affecting these genes' expression. All the new variants were subjected to functional analysis to verify their pathogenic effects. This work underscores how the combination of different omics technologies and functional analysis can solve elusive cases in clinical practice.

Pathogenic variants of DNAJC12 and evaluation of the encoded cochaperone as a genetic modifier of hyperphenylalaninemia.

Biallelic variants of the gene DNAJC12, which encodes a cochaperone, were recently described in patients with hyperphenylalaninemia (HPA). This paper reports the retrospective genetic analysis of a cohort of unsolved cases of HPA. Biallelic variants of DNAJC12 were identified in 20 patients (generally neurologically asymptomatic) previously diagnosed with phenylalanine hydroxylase (PAH) deficiency (phenylketonuria [PKU]). Further, mutations of DNAJC12 were identified in four carriers of a pathogenic variant of PAH. The genetic spectrum of DNAJC12 in the present patients included four new variants, two intronic changes c.298-2A>C and c.502+1G>C, presumably affecting the splicing process, and two exonic changes c.309G>T (p.Trp103Cys) and c.524G>A (p.Trp175Ter), classified as variants of unknown clinical significance (VUS). The variant p.Trp175Ter was detected in 83% of the mutant alleles, with 14 cases homozygous, and was present in 0.3% of a Spanish control population. Functional analysis indicated a significant reduction in PAH and its activity, reduced tyrosine hydroxylase stability, but no effect on tryptophan hydroxylase 2 stability, classifying the two VUS as pathogenic variants. Additionally, the effect of the overexpression of DNAJC12 on some destabilizing PAH mutations was examined and a mutation-specific effect on stabilization was detected suggesting that the proteostasis network could be a genetic modifier of PAH deficiency and a potential target for developing mutation-specific treatments for PKU.

Mechanisms responsible for neuromuscular relaxation in the gastrointestinal tract.

The enteric nervous system (ENS) is responsible for the genesis of motor patterns ensuring an appropriate intestinal transit. Enteric neurons are classified into afferent, interneuron, and motoneuron types, with the latter two being further categorized as excitatory or inhibitory, which cause smooth muscle contraction or inhibition, respectively. Muscle relaxation mechanisms are key for the understanding of physiological processes such as sphincter relaxation, gastric accommodation, or descending peristaltic reflex. Nitric oxide (NO) and ATP or a related purine represent the primary inhibitory neurotransmitters. Nitrergic neurons synthesize NO through nNOS enzyme activity. NO diffuses across the cell membrane to bind its receptor, namely, guanylyl cyclase, and then activates a number of intracellular mechanisms that ultimately result in muscle relaxation. ATP acts as an inhibitory neurotransmitter together with NO, and the purinergic P2Y1 membrane receptor has been identified as a key item in order to understand how ATP may relax intestinal smooth muscle. Although, probably, no clinician doubts the significance of NO in the pathophysiology of digestive motility, the relevance of purinergic neurotransmission is apparently much lower, as ATP has not been associated with any specific motor dysfunction yet. The goal of this review is to discuss the function of both relaxation mechanisms in order to establish the physiological grounds of potential motor dysfunctions arising from impaired intestinal relaxation.

Dynamics of inhibitory co-transmission, membrane potential and pacemaker activity determine neuromyogenic function in the rat colon.

Interaction of different neuromyogenic mechanisms determines colonic motility. In rats, cyclic depolarizations and slow waves generate myogenic contractions of low frequency (LF) and high frequency (HF), respectively. Interstitial cells of Cajal (ICC) located near the submuscular plexus (SMP) generate slow waves. Inhibitory junction potential (IJP) consists on a purinergic fast (IJPf) followed by a nitrergic slow (IJPs) component leading to relaxation. In the present study, we characterized (1) the dynamics of purinergic-nitrergic inhibitory co-transmission and (2) its contribution on prolonged inhibition of myogenic activity. Different protocols of electrical field stimulation (EFS) under different pharmacological conditions were performed to characterize electrophysiological and mechanical responses. Smooth muscle cells (SMCs) in tissue devoid of ICC-SMP had a resting membrane potential (RMP) of -40.7 ± 0.7 mV. Single pulse protocols increased purinergic and nitrergic IJP amplitude in a voltage-dependent manner (IJPfMAX = -26.4 ± 0.6 mV, IJPsMAX = -6.7 ± 0.3 mV). Trains at increasing frequencies enhanced nitrergic (k = 0.8 ± 0.2 s, IJPs∞ = -15 ± 0.5 mV) whereas they attenuated purinergic responses (k = 3.4 ± 0.6 s,IJPf∞ = -8.9 ± 0.6 mV). In tissues with intact ICC-SMP, the RMP was -50.0 ± 0.9 mV and nifedipine insensitive slow waves (10.1 ± 2.0 mV, 10.3 ± 0.5 cpm) were recorded. In these cells, (1) nitrergic and purinergic responses were reduced and (2) slow waves maintained their intrinsic frequency and increased their amplitude under nerve-mediated hyperpolarization. Based on the co-transmission process and consistent with the expected results on RMP, prolonged EFS caused a progressive reduction of LF contractions whereas HF contractions were partially insensitive. In conclusion, inhibitory neurons modulate colonic spontaneous motility and the principles determining post-junctional responses are (1) the frequency of firing that determines the neurotransmitter/receptor involved, (2) the transwall gradient and (3) the origin and nature of each myogenic activity

Transcriptomic analysis identifies dysregulated pathways and therapeutic targets in PMM2-CDG.

PMM2-CDG (MIM # 212065), the most common congenital disorder of glycosylation, is caused by the deficiency of phosphomannomutase 2 (PMM2). It is a multisystemic disease of variable severity that particularly affects the nervous system; however, its molecular pathophysiology remains poorly understood. Currently, there is no effective treatment. We performed an RNA-seq based transcriptomic study using patient-derived fibroblasts to gain insight into the mechanisms underlying the clinical symptomatology and to identify druggable targets. Systems biology methods were used to identify cellular pathways potentially affected by PMM2 deficiency, including Senescence, Bone regulation, Cell adhesion and Extracellular Matrix (ECM) and Response to cytokines. Functional validation assays using patients' fibroblasts revealed defects related to cell proliferation, cell cycle, the composition of the ECM and cell migration, and showed a potential role of the inflammatory response in the pathophysiology of the disease. Furthermore, treatment with a previously described pharmacological chaperone reverted the differential expression of some of the dysregulated genes. The results presented from transcriptomic data might serve as a platform for identifying therapeutic targets for PMM2-CDG, as well as for monitoring the effectiveness of therapeutic strategies, including pharmacological candidates and mannose-1-P, drug repurposing.

Assessment of quadriceps muscle mass by ultrasound in the postoperative period of cardiac surgery.

BACKGROUND: Patients undergoing cardiac surgery are exposed to many factors that activate catabolic and inflammatory pathways, which affect skeletal muscle and are, therefore, related to unfavorable hospital outcomes. Given the limited information on the behavior of muscle mass in critically ill patients, the objective of this study was to evaluate the impact on quantitative and qualitative measurements of quadriceps muscle mass using ultrasound after cardiac surgery. To accomplish this, a prospective, descriptive, and correlational study was conducted at a tertiary care hospital. Quadriceps muscle mass was evaluated via ultrasound in 31 adult patients in the postoperative period of cardiac surgery, with daily follow-up until postoperative day 7, as well as an assessment of associations with negative outcomes at 28 days. RESULTS: A 16% reduction in the cross-sectional area of the rectus femoris was found (95% CI 4.2-3.5 cm2; p 0.002), as well as a 24% reduction in the pennation angle of the rectus femoris (95% CI 11.1-8.4 degrees; p: 0.025). However, changes in the thickness of the rectus femoris, vastus internus, vastus lateralis, the length of the fascicle of the vastus lateralis, the pennation angle of the vastus lateralis, the sarcopenia index, and the Hekmat score were not statistically significant. There was no significant association between quadriceps muscle mass measurements and Intensive Care Unit (ICU) length stay or 28-day mortality. CONCLUSIONS: Patients in the postoperative period of cardiac surgery evaluated by ultrasound exhibit both quantitative and qualitative changes in quadriceps muscle mass. A significant reduction in muscle mass is observed but this is not associated with unfavorable outcomes.

Knowledge, Attitudes, and Practices Regarding Air Pollution among Medical Students.

Background: Air pollution has emerged as a global public health concern. Specifically, in Medellín, Colombia, episodes of elevated air pollution have been documented. Medical students' knowledge of air pollution is paramount for implementing future interventions directed toward patients. The aim of this research was to delineate the knowledge, attitudes, and practices regarding air pollution among medical students at a private university in Medellín. Methods: A cross-sectional study involving 352 medical students was conducted. A questionnaire was administered, generating scores ranging from 0 to 100, where a higher score signified better knowledge, attitudes, and practices. Data were analyzed using frequencies, summary measures, non-parametric tests, and linear regression. Results: In total, 31% rated the education received at the university on the relationship between health and air quality as fair to poor, and 81% perceived the air quality in the city as poor. The knowledge score was 77.8 (IQR 71.1-85.6), with 90% acknowledging that exposure to air pollution increases the risk of various diseases. The attitudes score was 82.1 (IQR 71.8-87.2), and 25.9% believed that air pollution is a multifactorial problem, rendering their actions ineffective. In terms of practices, the score was 50 (IQR 42.9-57.1), indicating that students either did not employ protective measures against pollution or used inappropriate practices such as masks or air purifiers. Regression analysis revealed no association between knowledge and practices. Conclusion: The findings of this study underscore that medical students possess commendable knowledge regarding the health effects of air pollution. However, their adoption of inappropriate practices for self-protection is evident. The lack of correlation between knowledge and practices highlights the necessity of educational initiatives to be complemented by regulatory and cultural interventions.

In vitro motor patterns and electrophysiological changes in patients with colonic diverticular disease.

PURPOSE: The underlying mechanism responsible for motility changes in colonic diverticular disease (DD) is still unknown. In the present study, our aim was to investigate the structural and in vitro motor changes in the sigmoid colon of patients with DD. METHODS: Muscle bath, microelectrodes and immunohistochemical techniques were performed with samples obtained from the left and sigmoid colon of patients with DD and compared with those of patients without DD. RESULTS: The amplitude and area under the curve of the spontaneous rhythmic phasic contractions were greatly reduced in patients with DD whereas their frequency and tone remained unaltered. Electrical field stimulation induced a neurally mediated, enhanced ON-contraction (amplitude) in patients with DD and increased the duration of latency of OFF-contractions. The resting membrane potential of smooth muscle cells was hyperpolarized and the amplitude of the inhibitory junction potential was increased in patients with DD. In contrast, no significant histological differences were observed in patients with DD as smooth muscle (circular and longitudinal layers), interstitial cells of Cajal, glial cells and myenteric neurons densities remained unaltered. CONCLUSIONS: Sigmoid strips from patients with asymptomatic DD showed an altered motor pattern with reduced spontaneous motility and enhanced neurally mediated colonic responses involving both excitatory and inhibitory motor pathways. No major neural and muscular structural elements were detected at this stage of the disease. These findings could be valuable in understanding the pathophysiology of this prevalent digestive disease.

Static Postural Control during Single-Leg Stance in Endurance, Team and Combat Athletes from the Spanish National Sport Technification Program.

In the context of pediatric physical exercise, the analysis of factors affecting postural control (PC) provides insight into the development of sport-specific motor skills. This study aims to evaluate the static PC during single-leg stance in endurance, team and combat athletes from the Spanish National Sport Technification Program. A total of 29 boys and 32 girls, aged 12 to 16 years old, were recruited. Centre of pressure (CoP) was measured on a force platform in standing position for 40 s under two sensorial and leg dominance conditions. Girls showed lower MVeloc (p < 0.001), MFreq (p > 0.001) and Sway (p < 0.001) values than boys in both sensorial conditions (open and closed eyes). The highest values in all PC variables were observed with eyes closed in both genders (p < 0.001). Sway values were lower in boys combat-athletes compared to endurance athletes in two sensorial conditions and with non-dominant leg (p < 0.05). Young athletes in their teens enrolled in a Sport Technification Program have shown differences in PC when comparing different visual conditions, sport disciplines and gender. This study opens a window to a better understanding of the determinants of PC during single-leg stance as a critical element in the sport specialization of young athletes.

Purinergic neuromuscular transmission is absent in the colon of P2Y(1) knocked out mice.

Purinergic and nitrergic co-transmission is the dominant mechanism responsible for neural-mediated smooth muscle relaxation in the gastrointestinal tract. The aim of the present paper was to test whether or not P2Y(1) receptors are involved in purinergic neurotransmission using P2Y(1)(−/−) knock-out mice. Tension and microelectrode recordings were performed on colonic strips. In wild type (WT) animals, electrical field stimulation (EFS) caused an inhibitory junction potential (IJP) that consisted of a fast IJP (MRS2500 sensitive, 1 µm) followed by a sustained IJP (N(ω)-nitro-L-arginine (L-NNA) sensitive, 1 mm). The fast component of the IJP was absent in P2Y(1)(−/−) mice whereas the sustained IJP (L-NNA sensitive) was recorded. In WT animals, EFS-induced inhibition of spontaneous motility was blocked by the consecutive addition of L-NNA and MRS2500. In P2Y(1)(−/−) mice, EFS responses were completely blocked by L-NNA. In WT and P2Y(1)(−/−) animals, L-NNA induced a smooth muscle depolarization but 'spontaneous' IJP (MRS2500 sensitive) could be recorded in WT but not in P2Y(1)(−/−) animals. Finally, in WT animals, 1 µm MRS2365 caused a smooth muscle hyperpolarization that was blocked by 1 µm MRS2500. In contrast, 1 µm MRS2365 did not modify smooth muscle resting membrane potential in P2Y(1)(−/−) mice. ß-Nicotinamide adenine dinucleotide (ß-NAD, 1 mm) partially mimicked the effect of MRS2365. We conclude that P2Y(1) receptors mediate purinergic neurotransmission in the gastrointestinal tract and ß-NAD partially fulfils the criteria to participate in rodent purinergic neurotransmission. The P2Y(1)(−/−) mouse is a useful animal model to study the selective loss of purinergic neurotransmission.

Comparison among plaque assay, tissue culture infectious dose (TCID50) and real-time RT-PCR for SARS-CoV-2 variants quantification.

Background and Objectives: SARS-CoV-2 variants of concern (VOC) and interest (VOI) pose a significant threat to public health because the rapid change in the SARS-CoV-2 genome can alter viral phenotypes such as virulence, transmissibility and the ability to evade the host response. Hence, SARS-CoV-2 quantification techniques are essential for timely diagnosis and follow-up. Besides, they are vital to understanding viral pathogenesis, antiviral evaluation, and vaccine development. Materials and Methods: Five isolates of SARS-CoV-2: D614G strain (B.1), three VOC (Alpha, Gamma and Delta), and one VOI (Mu) were used to compare three techniques for viral quantification, plaque assay, median tissue culture infectious dose (TCID50) and real-time RT-PCR. Results: Plaque assay showed viral titers between 0.15 ± 0.01×107 and 1.95 ± 0.09×107 PFU/mL while viral titer by TCID50 assay was between 0.71 ± 0.01×106 to 4.94 ± 0.80×106 TCID50/mL for the five SARS-CoV-2 isolates. The PFU/mL titer obtained by plaque and the calculated from TCID50 assays differed by 0.61 log10, 0.59 log10, 0.59 log10 and 0.96 log10 for Alfa, Gamma, Delta, and Mu variants (p≤0.0007), respectively. No differences were observed for the D614G strain. Real-time PCR assay exhibited titers ranging from 0.39 ± 0.001×108 to 3.38 ± 0.04×108 RNA copies/µL for all variants. The relation between PFU/mL and RNA copies/mL was 1:29800 for D614G strain, 1:11700 for Alpha, 1:8930 for Gamma, 1:12500 for Delta, and 1:2950 for Mu. Conclusion: TCID50 assay was comparable to plaque assay for D614G but not for others SARS-CoV-2 variants. Our data demonstrated a correlation among PFU/mL and E gene RNA copies/µL, units of measure commonly used to quantify the viral load in diagnostic and research fields. The results suggest that the proportion of infectious virions in vitro changes depending on the SARS-CoV-2 variant, being Mu, the variant reaching a higher viral titer with fewer viral copies.

Gene expression analysis method integration and co-expression module detection applied to rare glucide metabolism disorders using ExpHunterSuite.

High-throughput gene expression analysis is widely used. However, analysis is not straightforward. Multiple approaches should be applied and methods to combine their results implemented and investigated. We present methodology for the comprehensive analysis of expression data, including co-expression module detection and result integration via data-fusion, threshold based methods, and a Naïve Bayes classifier trained on simulated data. Application to rare-disease model datasets confirms existing knowledge related to immune cell infiltration and suggest novel hypotheses including the role of calcium channels. Application to simulated and spike-in experiments shows that combining multiple methods using consensus and classifiers leads to optimal results. ExpHunter Suite is implemented as an R/Bioconductor package available from https://bioconductor.org/packages/ExpHunterSuite . It can be applied to model and non-model organisms and can be run modularly in R; it can also be run from the command line, allowing scalability with large datasets. Code and reports for the studies are available from https://github.com/fmjabato/ExpHunterSuiteExamples .

Evaluating, Filtering and Clustering Genetic Disease Cohorts Based on Human Phenotype Ontology Data with Cohort Analyzer.

Exhaustive and comprehensive analysis of pathological traits is essential to understanding genetic diseases, performing precise diagnosis and prescribing personalized treatments. It is particularly important for disease cohorts, as thoroughly detailed phenotypic profiles allow patients to be compared and contrasted. However, many disease cohorts contain patients that have been ascribed low numbers of very general and relatively uninformative phenotypes. We present Cohort Analyzer, a tool that measures the phenotyping quality of patient cohorts. It calculates multiple statistics to give a general overview of the cohort status in terms of the depth and breadth of phenotyping, allowing us to detect less well-phenotyped patients for re-examining or excluding from further analyses. In addition, it performs clustering analysis to find subgroups of patients that share similar phenotypic profiles. We used it to analyse three cohorts of genetic diseases patients with very different properties. We found that cohorts with the most specific and complete phenotypic characterization give more potential insights into the disease than those that were less deeply characterised by forming more informative clusters. For two of the cohorts, we also analysed genomic data related to the patients, and linked the genomic data to the patient-subgroups by mapping shared variants to genes and functions. The work highlights the need for improved phenotyping in this era of personalized medicine. The tool itself is freely available alongside a workflow to allow the analyses shown in this work to be applied to other datasets.

Metagenomics of mine tailing rhizospheric communities and its selection for plant establishment towards bioremediation.

Mining operations often generate tailing dams that contain toxic residues and are a source of contamination when left unconfined. The establishment of a plant community over the tailings has been proposed as a containment strategy known as phytostabilization. Previously, we described naturally occurring mine tailing colonizing plants such as Acacia farnesiana, Brickellia coulteri, Baccharis sarothroides, and Gnaphalium leucocephalum without finding local adaptation. We explored the rhizosphere microbes as contributors in plant establishment and described both the culturable and in situ diversity of rhizospheric bacteria using the 16S rRNA gene and metagenomic shotgun sequencing. We built a synthetic community (SC) of culturable rhizosphere bacteria from the mine tailings. The SC was then the foundation for a serial passes experiment grown in plant-derived nutrient sources, selecting for heavy metals tolerance, community cooperation, and competition. The outcome of the serial passes was named the 'final synthetic community' (FSC). Overall, diversity decreased from in situ uncultivable microbes from roots (399 bacteria genera) to the cultivated communities (291 genera), the SC (94 genera), and the lowest diversity was in the FSC (43 genera). Metagenomic diversity clustered into 94,245 protein families, where we found plant growth promotion-related genes such as the csgBAC and entCEBAH, coded in a metagenome-assembled genome named Kosakonia sp. Nacozari. Finally, we used the FSC to inoculate mine tailing colonizing plants in a greenhouse experiment. The plants with the FSC inocula observed higher relative plant growth rates in sterile substrates. The FSC presents promising features that might make it useful for phytostabilization tailored strategies.

Purinergic and nitrergic neuromuscular transmission mediates spontaneous neuronal activity in the rat colon.

Nitric oxide (NO) and ATP mediate smooth muscle relaxation in the gastrointestinal tract. However, the involvement of these neurotransmitters in spontaneous neuronal activity is unknown. The aim of the present work was to study spontaneous neuromuscular transmission in the rat midcolon. Microelectrode experiments were performed under constant stretch both in circular and longitudinal directions. Spontaneous inhibitory junction potentials (sIJP) were recorded. Tetrodotoxin (1 microM) and apamin (1 microM) depolarized smooth muscle cells and inhibited sIJP. N(omega)-nitro-l-arginine (l-NNA, 1 mM) depolarized smooth muscle cells but did not modify sIJP. In contrast, the P2Y(1) antagonist MRS-2500 (1 microM) did not modify the resting membrane potential (RMP) but reduced sIJP (IC(50) = 3.1 nM). Hexamethonium (200 microM), NF-023 (10 microM), and ondansetron (1 microM) did not modify RMP and sIJP. These results correlate with in vitro (muscle bath) and in vivo (strain gauges) data where l-NNA but not MRS-2500 induced a sustained increase of spontaneous motility. We concluded that, in the rat colon, inhibitory neurons regulate smooth muscle RMP and cause sIJP. In vitro, the release of inhibitory neurotransmitters is independent of nicotinic, P2X, and 5-hydroxytryptamine type 3 receptors. Neuronal NO causes a sustained smooth muscle hyperpolarization that is responsible for a constant inhibition of spontaneous motility. In contrast, ATP acting on P2Y(1) receptors is responsible for sIJP but does not mediate inhibitory neural tone. ATP and NO have complementary physiological functions in the regulation of gastrointestinal motility.

New and potential strategies for the treatment of PMM2-CDG.

BACKGROUND: Mutations in the PMM2 gene cause phosphomannomutase 2 deficiency (PMM2; MIM# 212065), which manifests as a congenital disorder of glycosylation (PMM2-CDG). Mutant PMM2 leads to the reduced conversion of Man-6-P to Man-1-P, which results in low concentrations of guanosine 5'-diphospho-D-mannose, a nucleotide-activated sugar essential for the construction of protein oligosaccharide chains. To date the only therapeutic options are preventive and symptomatic. SCOPE OF REVIEW: This review covers the latest advances in the search for a treatment for PMM2-CDG. MAJOR CONCLUSIONS: Treatments based on increasing Man-1-P levels have been proposed, along with the administration of different mannose derivates, employing enzyme inhibitors or repurposed drugs to increase the synthesis of GDP-Man. A single repurposed drug that might alleviate a severe neurological symptom associated with the disorder is now in clinical use. Proof of concept also exists regarding the use of pharmacological chaperones and/or proteostatic regulators to increase the concentration of hypomorphic PMM2 mutant proteins. GENERAL SIGNIFICANCE: The ongoing challenges facing the discovery of drugs to treat this orphan disease are discussed.

Functional neuromuscular impairment in severe intestinal dysmotility.

BACKGROUND: Chronic intestinal pseudo-obstruction (CIPO) and enteric dysmotility (ED) are severe intestinal motility disorders usually associated with underlying neuromuscular abnormalities. OBJECTIVE: To evaluate the in vitro neuromuscular function of patients with severe intestinal motility disorders. METHODS: Full-thickness intestinal biopsies (16 jejunum and 3 ileum) obtained from patients with CIPO (n = 10) and ED (n = 9) were studied using muscle bath and microelectrode techniques. Control samples (n = 6 ileum and n = 6 jejunum) were used to establish the range of normality. KEY RESULTS: Fourteen parameters were defined to assess muscle contractility and nerve-muscle interaction: five to evaluate smooth muscle and interstitial cells of Cajal (ICC) and nine to evaluate inhibitory neuromuscular transmission. For each sample, a parameter was scored 0 if the value was inside the normal range or a value of 1 if it was outside. Patients' samples (CIPO/ED) had more abnormal parameters than controls (P < 0.001 for both jejunum and ileum). Functional abnormalities were found to be heterogeneous. The most prevalent abnormality was a decreased purinergic neuromuscular transmission, which was detected in 43.8% of jejunal samples. CONCLUSIONS AND INFERENCES: Abnormalities of neuromuscular intestinal function are detected in vitro in severe intestinal dysmotility. However, consistent with the heterogeneity of the disease pathophysiology, functional impairment cannot be attributed to a single mechanism. Specifically, defects of purinergic neuromuscular transmission may have an important role in motility disorders of the gastrointestinal tract.

Vínculos, autonomía y salud mental en adultos jóvenes del proceso de reintegración en Colombia / Bonds, autonomy and mental health in young adults of the reintegration process in Colombia

Este artículo busca explorar la construcción de los vínculos, su relación con el desarrollo de la autonomía y las problemáticas de salud mental de adultos jóvenes excombatientes de grupos armados que hacen parte del proceso de reintegración en Colombia. Se analizaron 3977 registros de la Encuesta Multimodal Psicosocial (EMP) correspondientes a adultos jóvenes entre los 18 y 24 años, que fueron aplicadas en desarrollo del proceso de reincorporación. Se aplicaron dos métodos de análisis estadísticos complementarios: el método de Componentes Principales (ACP) y un método Jerárquico aglomerativo. En el análisis de los procesos vinculares se encontró que en un grupo alrededor de un 80 % de los casos registra haber experimentado rupturas vinculares importantes a causa de la violencia, el abandono temprano y/o vivir en contextos de conflicto y violencia. En cuanto al análisis de los procesos de autonomía, se encontró que un grupo correspondiente al 70 % reporta no contar con las capacidades para garantizar su autonomía y calidad de vida, pasando por condiciones de precarización laboral con riesgo a incurrir en redes de delincuencia. Y un 39 % reporta coincidir alta disposición de riesgo en sus procesos vinculares y de autonomía.

This article seeks to explore the construction of bonds, their relation with the development of autonomy and the mental health problems of young adult ex-combatants of armed groups who are part of the reintegration process in Colombia. A total of 3977 records of the Psychosocial Multimodal Questionnaire (PMS) corresponding to young adults between 18 and 24 years old, which were applied in the development of the reincorporation process, were analyzed. Two complementary statistical analysis methods were applied: The Principal Components Method (PCA) and an agglomerative Hierarchical method. In the analysis of bonding processes, it was found that, in one group, about 80% of the cases recorded having experienced significant bonding ruptures due to violence, early abandonment and/or living in contexts of conflict and violence. Regarding the analysis of the processes of autonomy, a group corresponding to 70% reported not having the capacities to guarantee their autonomy and quality of life, going through conditions of job insecurity with the risk of incurring in criminal networks. And 39% report a high risk disposition in their relationship and autonomy processes.