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1.
Elife ; 112022 01 12.
Article in English | MEDLINE | ID: mdl-35019838

ABSTRACT

Cold temperature is prevalent across the biosphere and slows the rates of chemical reactions. Increased catalysis has been predicted to be a dominant adaptive trait of enzymes to reduced temperature, and this expectation has informed physical models for enzyme catalysis and influenced bioprospecting strategies. To systematically test rate enhancement as an adaptive trait to cold, we paired kinetic constants of 2223 enzyme reactions with their organism's optimal growth temperature (TGrowth) and analyzed trends of rate constants as a function of TGrowth. These data do not support a general increase in rate enhancement in cold adaptation. In the model enzyme ketosteroid isomerase (KSI), there is prior evidence for temperature adaptation from a change in an active site residue that results in a tradeoff between activity and stability. Nevertheless, we found that little of the rate constant variation for 20 KSI variants was accounted for by TGrowth. In contrast, and consistent with prior expectations, we observed a correlation between stability and TGrowth across 433 proteins. These results suggest that temperature exerts a weaker selection pressure on enzyme rate constants than stability and that evolutionary forces other than temperature are responsible for the majority of enzymatic rate constant variation.


Subject(s)
Adaptation, Physiological/physiology , Cold Temperature , Enzymes/chemistry , Catalysis
2.
Cell Syst ; 12(6): 547-560, 2021 06 16.
Article in English | MEDLINE | ID: mdl-34139165

ABSTRACT

Folding a linear chain of amino acids into a three-dimensional protein is a complex physical process that ultimately confers an impressive range of diverse functions. Although recent advances have driven significant progress in predicting three-dimensional protein structures from sequence, proteins are not static molecules. Rather, they exist as complex conformational ensembles defined by energy landscapes spanning the space of sequence and conditions. Quantitatively mapping the physical parameters that dictate these landscapes and protein stability is therefore critical to develop models that are capable of predicting how mutations alter function of proteins in disease and informing the design of proteins with desired functions. Here, we review the approaches that are used to quantify protein stability at a variety of scales, from returning multiple thermodynamic and kinetic measurements for a single protein sequence to yielding indirect insights into folding across a vast sequence space. The physical parameters derived from these approaches will provide a foundation for models that extend beyond the structural prediction to capture the complexity of conformational ensembles and, ultimately, their function.


Subject(s)
Protein Folding , Proteins , Kinetics , Protein Stability , Proteins/metabolism , Thermodynamics
3.
Headache ; 60(8): 1673-1682, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32797631

ABSTRACT

OBJECTIVE: To quantify wear-off of the response to OnabotulinumtoxinA (OnabotA) treatment over the treatment cycle in chronic migraine at group and individual level. BACKGROUND: OnabotA administered quarterly is an effective treatment for chronic migraine. However, some patients report that headache recurs before the scheduled follow-up injection. METHODS: In this retrospective chart review performed in 6 university outpatient centers or private practices specialized in headache treatment, 112 patients with a ≥30% response to OnabotA who completed headache diaries over 13 weeks after OnabotA treatment were included (age [mean ± SD] 45 ± 12 years, 82% female, headache days/month at baseline 24 ± 6). RESULTS: Compared to weeks 5 to 8 after injection, headache days/week increased significantly in weeks 12 (+0.52 ± 1.96, 95% CI [0.15, 0.88], P < .009) and 13 (+1.15 ± 1.95, CI[0.79, 1.52], P < .001), demonstrating significant wear-off of the OnabotA effect. Similarly, acute medication days/week significantly increased in weeks 12 (0.38±1.67, CI [0.06, 0.69], P ≤ .027) and 13 (+0.83 ± 1.76, CI [0.49, 1.16], P < .001). At an individual level, 57 patients (51%) showed ≥30% wear-off by weeks 12 and 13, and 28 patients (25%) showed ≥30% wear-off already by weeks 10 and 11. Age, gender, OnabotA dose or cycle number, or headache center did not predict individual wear-off. CONCLUSIONS: These data show that in clinical practice, on average the response of chronic migraine patients to OnabotA injection shows a clinically significant wear-off from week 12 after treatment. About 25% of the patients experience wear-off even by weeks 10 and 11. It must be noted that wear-off detected in a real-world study on OnabotA responders can be due to wear-off of a pharmacological OnabotA effect or a placebo effect, or to regression to the mean effects. This wear-off phenomenon may negatively affect quality of life of chronic migraine patients under OnabotA treatment. The best way to counteract wear-off remains to be determined.


Subject(s)
Botulinum Toxins, Type A/pharmacokinetics , Migraine Disorders/drug therapy , Neuromuscular Agents/pharmacokinetics , Adult , Aged , Botulinum Toxins, Type A/administration & dosage , Chronic Disease , Diaries as Topic , Female , Humans , Male , Middle Aged , Neuromuscular Agents/administration & dosage , Outcome Assessment, Health Care , Retrospective Studies , Time Factors , Young Adult
4.
J Headache Pain ; 20(1): 81, 2019 Jul 15.
Article in English | MEDLINE | ID: mdl-31307383

ABSTRACT

BACKGROUND: OnabotulinumtoxinA (BOTOX®, Allergan plc, Dublin, Ireland) is approved for the preventive treatment of headaches in adult patients with chronic migraine (CM) in Australia by the country's reimbursement mechanism for medicines, the Pharmaceutical Benefits Scheme (PBS). To our knowledge, this study represents the first focused report evaluating real-world evidence of onabotulinumtoxinA treatment via the PBS in Australian clinics. METHODS: This study reviewed the medical records of adults with inadequately controlled CM from 7 private neurology practices in Australia who, beginning in March 2014, received PBS-subsidized onabotulinumtoxinA per product labelling for the first time. The primary effectiveness measure was the percentage of patients achieving a response defined by 50% or greater reduction in headache days from baseline after 2 treatment cycles. Additional data were recorded in the case report form when available and included demographics, clinical characteristics, headache severity and frequency, Headache Impact Test (HIT-6) score, medication use, and days missed of work or study at baseline, after 2 treatment cycles, and at last follow-up. Differences in mean changes from baseline were evaluated with a 1-tailed t-test or Pearson's chi-squared test (p < 0.05). RESULTS: The study population included 211 patients with a mean (SD) of 25.2 (5.3) monthly headache days at baseline. In the primary outcome analysis, 74% of patients achieved a response, with a mean (SD) of 10.6 (7.9) headache days after 2 treatment cycles (p < 0.001). Secondary effectiveness outcomes included mean (SD) reductions in HIT-6 score of - 11.7 (9.8) and - 11.8 (12.2) after 2 treatment cycles (p < 0.001) and final follow-up (p < 0.001), respectively, and mean (SD) decreases in days per month of acute pain medication use of - 11.5 (7.6) after 2 treatment cycles (p < 0.001) and - 12.7 (8.1) at final follow-up (p < 0.001). CONCLUSION: This study provides additional clinical evidence for the consistent effectiveness of onabotulinumtoxinA for the treatment of CM in Australia. This effectiveness was made evident by reductions in migraine days, severe headache days, and HIT-6 scores from baseline.


Subject(s)
Botulinum Toxins, Type A/therapeutic use , Headache/drug therapy , Headache/prevention & control , Migraine Disorders/prevention & control , Acute Pain/drug therapy , Acute Pain/prevention & control , Adult , Australia/epidemiology , Chronic Disease , Female , Headache/epidemiology , Humans , Male , Medical Records , Middle Aged , Migraine Disorders/drug therapy , Migraine Disorders/epidemiology , Randomized Controlled Trials as Topic , Retrospective Studies , Treatment Outcome
5.
Pract Neurol ; 17(1): 21-27, 2017 Jan.
Article in English | MEDLINE | ID: mdl-27974377

ABSTRACT

There is increasing awareness and interest in the complex and extensive inter-relationships between sleep disorders and neurological disorders. This review focuses on the clinical interactions between obstructive sleep apnoea and stroke, headaches, epilepsy, cognition and idiopathic Parkinson's disease. We highlight to the neurologist the importance of taking a sleep history and considering the diagnosis and treatment of obstructive sleep apnoea.


Subject(s)
Neurologists , Physician's Role , Sleep Apnea Syndromes/diagnosis , Sleep Apnea Syndromes/therapy , Epilepsy/diagnosis , Epilepsy/epidemiology , Epilepsy/therapy , Headache/diagnosis , Headache/epidemiology , Headache/therapy , Humans , Neurologists/standards , Parkinson Disease/diagnosis , Parkinson Disease/epidemiology , Parkinson Disease/therapy , Sleep Apnea Syndromes/epidemiology
6.
Mol Cell ; 59(5): 858-66, 2015 Sep 03.
Article in English | MEDLINE | ID: mdl-26340425

ABSTRACT

We describe a chemical method to label and purify 4-thiouridine (s(4)U)-containing RNA. We demonstrate that methanethiosulfonate (MTS) reagents form disulfide bonds with s(4)U more efficiently than the commonly used HPDP-biotin, leading to higher yields and less biased enrichment. This increase in efficiency allowed us to use s(4)U labeling to study global microRNA (miRNA) turnover in proliferating cultured human cells without perturbing global miRNA levels or the miRNA processing machinery. This improved chemistry will enhance methods that depend on tracking different populations of RNA, such as 4-thiouridine tagging to study tissue-specific transcription and dynamic transcriptome analysis (DTA) to study RNA turnover.


Subject(s)
MicroRNAs/chemistry , Biotin/analogs & derivatives , Cell Proliferation , Disulfides , Gene Expression Profiling/methods , HEK293 Cells , Humans , Indicators and Reagents , Mesylates , MicroRNAs/genetics , MicroRNAs/metabolism , Organic Chemistry Phenomena , RNA Processing, Post-Transcriptional , Thiouridine/chemistry
7.
Curr Pain Headache Rep ; 19(1): 468, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25416461

ABSTRACT

Sleep and headache have a complex and extensive interrelationship. This review focuses on the relationship between sleep and chronic daily headache, examining recent advances in the epidemiology and insights into possible mechanisms of this relationship as well as reviewing advances in treatment. There is a clear relationship between obstructive sleep apnoea (OSA) and snoring and morning headache, but the relationship between OSA and snoring and other primary headaches requires clarification. OSA and chronic migraine share both obesity and patent foramen ovale (PFO) as possible co-morbidities. Hypoxia does not clearly predispose to morning headache. Continuous positive airway pressure (CPAP) is an established treatment for OSA, and mixed results have been reported with regards to headache improvement with this treatment.


Subject(s)
Headache Disorders/etiology , Hypoxia/complications , Sleep Apnea, Obstructive/complications , Sleep Bruxism/complications , Sleep Deprivation/complications , Snoring/complications , Circadian Rhythm , Comorbidity , Headache Disorders/physiopathology , Humans , Hypoxia/physiopathology , Sleep Apnea, Obstructive/physiopathology , Sleep Bruxism/physiopathology , Sleep Deprivation/physiopathology , Snoring/physiopathology
8.
Med J Aust ; 189(5): 283-8, 2008 Sep 01.
Article in English | MEDLINE | ID: mdl-18759728

ABSTRACT

There is a wide array of options for migraine prophylaxis; many of the available drugs are clearly proven to be effective and yet are underused in Australia. "New" drugs which are gaining favour for migraine prophylaxis include topiramate, candesartan, gabapentin and botulinum toxin. The evidence for efficacy is excellent for topiramate and reasonably good but limited for candesartan and gabapentin. The use of botulinum toxin is controversial and has gained substantial popularity through anecdotal experience rather than convincing published evidence. Transformed or chronic migraine with medication overuse is a particularly difficult problem. New strategies to aid in medication withdrawal are reviewed. The approach to menstrual migraine and migraine with prominent aura may differ from that for typical migraine. Novel approaches are being explored for these problems.


Subject(s)
Migraine Disorders/drug therapy , Migraine Disorders/prevention & control , Australia , Cardiovascular Agents/therapeutic use , Central Nervous System Agents/therapeutic use , Glucocorticoids/therapeutic use , Humans , Migraine Disorders/etiology
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