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Genetics Jul 2021Changes in gene regulation at multiple levels may comprise an important share of the molecular changes underlying adaptive evolution in nature. However, few studies have...
Changes in gene regulation at multiple levels may comprise an important share of the molecular changes underlying adaptive evolution in nature. However, few studies have assayed within- and between-population variation in gene regulatory traits at a transcriptomic scale, and therefore inferences about the characteristics of adaptive regulatory changes have been elusive. Here, we assess quantitative trait differentiation in gene expression levels and alternative splicing (intron usage) between three closely related pairs of natural populations of Drosophila melanogaster from contrasting thermal environments that reflect three separate instances of cold tolerance evolution. The cold-adapted populations were known to show population genetic evidence for parallel evolution at the SNP level, and here we find evidence for parallel expression evolution between them, with stronger parallelism at larval and adult stages than for pupae. We also implement a flexible method to estimate cis- vs trans-encoded contributions to expression or splicing differences at the adult stage. The apparent contributions of cis- vs trans-regulation to adaptive evolution vary substantially among population pairs. While two of three population pairs show a greater enrichment of cis-regulatory differences among adaptation candidates, trans-regulatory differences are more likely to be implicated in parallel expression changes between population pairs. Genes with significant cis-effects are enriched for signals of elevated genetic differentiation between cold- and warm-adapted populations, suggesting that they are potential targets of local adaptation. These findings expand our knowledge of adaptive gene regulatory evolution and our ability to make inferences about this important and widespread process.
Topics: Acclimatization; Animals; Cold Temperature; Drosophila Proteins; Drosophila melanogaster; Evolution, Molecular; Models, Genetic
PubMed: 33989401
DOI: 10.1093/genetics/iyab077 -
Human Molecular Genetics Oct 2022Linkage disequilibrium and the incomplete regulatory annotation of the noncoding genome complicates the identification of functional noncoding genetic variants and their...
Linkage disequilibrium and the incomplete regulatory annotation of the noncoding genome complicates the identification of functional noncoding genetic variants and their causal association with disease. Current computational methods for variant prioritization have limited predictive value, necessitating the application of highly parallelized experimental assays to efficiently identify functional noncoding variation. Here, we summarize two distinct approaches, massively parallel reporter assays and CRISPR-based pooled screens and describe their flexible implementation to characterize human noncoding genetic variation at unprecedented scale. Each approach provides unique advantages and limitations, highlighting the importance of multimodal methodological integration. These multiplexed assays of variant effects are undoubtedly poised to play a key role in the experimental characterization of noncoding genetic risk, informing our understanding of the underlying mechanisms of disease-associated loci and the development of more robust predictive classification algorithms.
Topics: Humans; Genome; Genomics; Linkage Disequilibrium; Algorithms; Genome-Wide Association Study
PubMed: 36057282
DOI: 10.1093/hmg/ddac194 -
Frontiers in Systems Neuroscience 2021Maintaining a balance between excitatory and inhibitory activity is an essential feature of neural networks of the neocortex. In the face of perturbations in the levels... (Review)
Review
Maintaining a balance between excitatory and inhibitory activity is an essential feature of neural networks of the neocortex. In the face of perturbations in the levels of excitation to cortical neurons, synapses adjust to maintain excitatory-inhibitory (EI) balance. In this review, we summarize research on this EI homeostasis in the neocortex, using stroke as our case study, and in particular the loss of excitation to distant cortical regions after focal lesions. Widespread changes following a localized lesion, a phenomenon known as diaschisis, are not only related to excitability, but also observed with respect to functional connectivity. Here, we highlight the main findings regarding the evolution of excitability and functional cortical networks during the process of post-stroke recovery, and how both are related to functional recovery. We show that cortical reorganization at a global scale can be explained from the perspective of EI homeostasis. Indeed, recovery of functional networks is paralleled by increases in excitability across the cortex. These adaptive changes likely result from plasticity mechanisms such as synaptic scaling and are linked to EI homeostasis, providing a possible target for future therapeutic strategies in the process of rehabilitation. In addition, we address the difficulty of simultaneously studying these multiscale processes by presenting recent advances in large-scale modeling of the human cortex in the contexts of stroke and EI homeostasis, suggesting computational modeling as a powerful tool to tie the meso- and macro-scale processes of recovery in stroke patients.
PubMed: 35082606
DOI: 10.3389/fnsys.2021.806544 -
Frontiers in Neuroscience 2021Recent studies have found that troponin T parallels the structural and functional decay of peripheral nerves at the level of the lower limbs in patients with type 2...
Fractional Anisotropy and Troponin T Parallel Structural Nerve Damage at the Upper Extremities in a Group of Patients With Prediabetes and Type 2 Diabetes - A Study Using 3T Magnetic Resonance Neurography.
BACKGROUND
Recent studies have found that troponin T parallels the structural and functional decay of peripheral nerves at the level of the lower limbs in patients with type 2 diabetes (T2D). The aim of this study was to determine whether this finding can also be reproduced at the level of the upper limbs.
METHODS
Ten patients with fasting glucose levels >100 mg/dl (five with prediabetes and five with T2D) underwent magnetic resonance neurography of the right upper arm comprising T2-weighted and diffusion weighted sequences. The fractional anisotropy (FA), an indicator for the structural integrity of peripheral nerves, was calculated in an automated approach for the median, ulnar, and radial nerve. All participants underwent additional clinical, serological, and electrophysiological assessments.
RESULTS
High sensitivity Troponin T (hsTNT) and HbA1c were negatively correlated with the average FA of the median, ulnar and radial nerve ( = -0.84; = 0.002 and = -0.68; = 0.032). Both FA and hsTNT further showed correlations with items of the Michigan Hand Outcome Questionnaire ( = -0.76; = 0.010 and = 0.87; = 0.001, respectively). A negative correlation was found for hsTNT and HbA1c with the total Purdue Pegboard Test Score ( = -0.87; = 0.001 and = -0.68; = 0.031).
CONCLUSION
This study is the first to find that hsTNT and HbA1c are associated with functional and structural parameters of the nerves at the level of the upper limbs in patients with impaired glucose tolerance and T2D. Our results support the hypothesis that hyperglycemia-related microangiopathy, represented by elevated hsTNT levels, is a contributor to nerve damage in diabetic polyneuropathy.
PubMed: 35140582
DOI: 10.3389/fnins.2021.741494 -
BMC Biotechnology Jan 2022The present study intends to optimize the processing technology for the wine-processing of Rhizoma Coptidis, using alkaloids as indicators.
BACKGROUND
The present study intends to optimize the processing technology for the wine-processing of Rhizoma Coptidis, using alkaloids as indicators.
METHOD
In the present study, the Box-Behnken design method was adopted to optimize the processing technology for Rhizoma Coptidis, using the alkaloid component quantities as the index. 100 g of Rhizoma Coptidis slices and 12.5 g of Rhizoma Coptidis wine were used. After full mixing, box-Behnken design method was used to optimize the processing time, processing temperature and processing time of coptis chinensis by taking alkaloid content as index. After mixing well, these components were fried in a container at 125 °C for 6 min and exhibited good parallelism.
RESULTS
The content of alkaloids in coptis chinensis was the highest after roasting at 125 °C for 6 min. The characteristic components were berberine hydrochloride, and the relative content was about 15.96%. And showed good parallelism. The effective components of Rhizoma Coptidis were primarily alkaloids.
CONCLUSION
The optimized processing technology for Rhizoma Coptidis is good.
Topics: Alkaloids; Chromatography, High Pressure Liquid; Coptis; Drugs, Chinese Herbal; Rhizome; Technology
PubMed: 35031033
DOI: 10.1186/s12896-021-00731-5 -
Chimia Apr 2023RNA splicing, the removal of introns and ligation of exons, is a crucial process during mRNA maturation. Group II introns are large ribozymes that self-catalyze their...
RNA splicing, the removal of introns and ligation of exons, is a crucial process during mRNA maturation. Group II introns are large ribozymes that self-catalyze their splicing, as well as their transposition. They are living fossils of spliceosomal introns and eukaryotic retroelements. The yeast mitochondrial Sc.ai5γ is the first identified and best-studied self-splicing group II intron. A combination of biochemical, biophysical, and computational tools enables studying its catalytic properties, structure, and dynamics, while also serving to develop new therapeutic and biotechnological tools. We survey the history of group II intron studies paralleling the trends in RNA methodology with Sc.ai5γ in the spotlight.
Topics: Introns; Biophysics; Biotechnology; Catalysis; Mitochondria
PubMed: 38047803
DOI: 10.2533/chimia.2023.235 -
Frontiers in Neuroscience 2020Studying the structural alterations occurring during diseases of the nervous system requires imaging heterogeneous cell populations at the circuit, cellular and... (Review)
Review
Studying the structural alterations occurring during diseases of the nervous system requires imaging heterogeneous cell populations at the circuit, cellular and subcellular levels. Recent advancements in brain tissue clearing and expansion methods allow unprecedented detailed imaging of the nervous system through its entire scale, from circuits to synapses, including neurovascular and brain lymphatics elements. Here, we review the state-of-the-art of brain tissue clearing and expansion methods, mentioning their main advantages and limitations, and suggest their parallel implementation for circuits-to-synapses brain imaging using conventional (diffraction-limited) light microscopy -such as confocal, two-photon and light-sheet microscopy- to interrogate the cellular and molecular basis of neurodegenerative diseases. We discuss recent studies in which clearing and expansion methods have been successfully applied to study neuropathological processes in mouse models and postmortem human brain tissue. Volumetric imaging of cleared intact mouse brains and large human brain samples has allowed unbiased assessment of neuropathological hallmarks. In contrast, nanoscale imaging of expanded cells and brain tissue has been used to study the effect of protein aggregates on specific subcellular structures. Therefore, these approaches can be readily applied to study a wide range of brain processes and pathological mechanisms with cellular and subcellular resolution in a time- and cost-efficient manner. We consider that a broader implementation of these technologies is necessary to reveal the full landscape of cellular and molecular mechanisms underlying neurodegenerative diseases.
PubMed: 33122983
DOI: 10.3389/fnins.2020.00914 -
Molecular Biology and Evolution Sep 2021Population genetic theory predicts that small effective population sizes (Ne) and restricted gene flow limit the potential for local adaptation. In particular, the...
Population genetic theory predicts that small effective population sizes (Ne) and restricted gene flow limit the potential for local adaptation. In particular, the probability of evolving similar phenotypes based on shared genetic mechanisms (i.e., parallel evolution), is expected to be reduced. We tested these predictions in a comparative genomic study of two ecologically similar and geographically codistributed stickleback species (viz. Gasterosteus aculeatus and Pungitius pungitius). We found that P. pungitius harbors less genetic diversity and exhibits higher levels of genetic differentiation and isolation-by-distance than G. aculeatus. Conversely, G. aculeatus exhibits a stronger degree of genetic parallelism across freshwater populations than P. pungitius: 2,996 versus 379 single nucleotide polymorphisms located within 26 versus 9 genomic regions show evidence of selection in multiple freshwater populations of G. aculeatus and P. pungitius, respectively. Most regions involved in parallel evolution in G. aculeatus showed increased levels of divergence, suggestive of selection on ancient haplotypes. In contrast, haplotypes involved in freshwater adaptation in P. pungitius were younger. In accordance with theory, the results suggest that connectivity and genetic drift play crucial roles in determining the levels and geographic distribution of standing genetic variation, providing evidence that population subdivision limits local adaptation and therefore also the likelihood of parallel evolution.
Topics: Animals; Fresh Water; Gene Flow; Genetic Drift; Genome; Smegmamorpha
PubMed: 33956140
DOI: 10.1093/molbev/msab144 -
JMIR Research Protocols May 2023Obsessive-compulsive disorder (OCD) is a psychiatric syndrome characterized by unwanted and repetitive thoughts and repeated ritualistic compulsions for decreasing...
BACKGROUND
Obsessive-compulsive disorder (OCD) is a psychiatric syndrome characterized by unwanted and repetitive thoughts and repeated ritualistic compulsions for decreasing distress. Symptoms can cause severe distress and functional impairment. OCD affects 2% to 3% of the population and is ranked within the 10 leading neuropsychiatric causes of disability. Cortico-striatal-thalamo-cortical circuitry dysfunction has been implicated in OCD, including altered brain activation and connectivity. Complex glutamatergic signaling dysregulation within cortico-striatal circuitry has been proposed in OCD. Data obtained by several studies indicate reduced glutamatergic concentrations in the anterior cingulate cortex, combined with overactive glutamatergic signaling in the striatum and orbitofrontal cortex. A growing number of randomized controlled trials have assessed the utility of different glutamate-modulating drugs as augmentation medications or monotherapies for OCD, including refractory OCD. However, there are relevant variations among studies in terms of patients' treatment resistance, comorbidity, age, and gender. At present, 4 randomized controlled trials are available on the efficacy of memantine as an augmentation medication for refractory OCD.
OBJECTIVE
Our study's main purpose is to conduct a double-blind, randomized, parallel-group, placebo-controlled, monocenter trial to assess the efficacy and safety of memantine as an augmentative agent to a selective serotonin reuptake inhibitor in the treatment of moderate to severe OCD. The study's second aim is to evaluate the effect of memantine on cognitive functions in patients with OCD. The third aim is to investigate if responses to memantine are modulated by variables such as gender, symptom subtypes, and the duration of untreated illness.
METHODS
Investigators intend to conduct a double-blind, randomized, parallel-group, placebo-controlled, monocenter trial to assess the efficacy and safety of memantine as an augmentative agent to a selective serotonin reuptake inhibitor in the treatment of patients affected by severe refractory OCD. Participants will be rated via the Yale-Brown Obsessive Compulsive Scale at baseline and at 2, 4, 6, 8, 10, and 12 months. During the screening period and T4 and T6 follow-up visits, all participants will undergo an extensive neuropsychological evaluation. The 52-week study duration will consist of 4 distinct periods, including memantine titration and follow-up periods.
RESULTS
Recruitment has not yet started. The study will be conducted from June 2023 to December 2024. Results are expected to be available in January 2025. Throughout the slow-titration period, we will observe the minimum effective dose of memantine, and the follow-up procedure will detail its residual efficacy after drug withdrawal.
CONCLUSIONS
The innovation of this research proposal is not limited to the evaluation of the efficacy and safety of memantine as an augmentation medication for OCD. We will also test if memantine acts as a pure antiobsessive medication or if memantine's ability to improve concentration and attention mimics an antiobsessive effect.
TRIAL REGISTRATION
ClinicalTrials.gov NCT05015595; https://clinicaltrials.gov/ct2/show/NCT05015595.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)
PRR1-10.2196/39223.
PubMed: 37166948
DOI: 10.2196/39223 -
BMJ Open Sep 2023Chronic non-cancer pain (CNCP) treatment's primary goal is to maintain physical and mental functioning while improving quality of life. Opioid use in CNCP patients has...
Effect and safety of listening to music or audiobooks as a coadjuvant treatment for chronic pain patients under opioid treatment: a study protocol for an open-label, parallel-group, randomised, controlled, proof-of-concept clinical trial in a tertiary hospital in the Barcelona South Metropolitan...
BACKGROUND
Chronic non-cancer pain (CNCP) treatment's primary goal is to maintain physical and mental functioning while improving quality of life. Opioid use in CNCP patients has increased in recent years, and non-pharmacological interventions such as music listening have been proposed to counter it. Unlike other auditive stimuli, music can activate emotional-regulating and reward-regulating circuits, making it a potential tool to modulate attentional processes and regulate mood. This study's primary objective is to provide the first evidence on the distinct (separate) effects of music listening as a coadjuvant maintenance analgesic treatment in CNCP patients undergoing opioid analgesia.
METHODS AND ANALYSIS
This will be a single-centre, phase II, open-label, parallel-group, proof-of-concept randomised clinical trial with CNCP patients under a minimum 4-week regular opioid treatment. We plan to include 70 consecutive patients, which will be randomised (1:1) to either the experimental group (active music listening) or the control group (active audiobooks listening). During 28 days, both groups will listen daily (for at least 30 min and up to 1 hour) to preset playlists tailored to individual preferences.Pain intensity scores at each visit, the changes (differences) from baseline and the proportions of responders according to various definitions based on pain intensity differences will be described and compared between study arms. We will apply longitudinal data assessment methods (mixed generalised linear models) taking the patient as a cluster to assess and compare the endpoints' evolution. We will also use the mediation analysis framework to adjust for the effects of additional therapeutic measures and obtain estimates of effect with a causal interpretation.
ETHICS AND DISSEMINATION
The study protocol has been reviewed, and ethics approval has been obtained from the Bellvitge University Hospital Institutional Review Board, L'Hospitalet de Llobregat, Barcelona, Spain. The results from this study will be actively disseminated through manuscript publications and conference presentations.
TRIAL REGISTRATION NUMBER
NCT05726266.
Topics: Humans; Chronic Pain; Analgesics, Opioid; Tertiary Care Centers; Music; Quality of Life; Sound Recordings; Cancer Pain; Randomized Controlled Trials as Topic; Clinical Trials, Phase II as Topic
PubMed: 37696633
DOI: 10.1136/bmjopen-2023-074948