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1.
Eur J Haematol ; 2024 Apr 05.
Article in English | MEDLINE | ID: mdl-38577720

ABSTRACT

BACKGROUND: Having a haematological condition can adversely affect the quality of life (QoL) of family members/partners of patients. It is important to measure this often ignored burden in order to implement appropriate supportive interventions. OBJECTIVE: To measure current impact of haematological conditions on the QoL of family members/partners of patients, using the Family Reported Outcome Measure-16 (FROM-16). METHODS: A cross-sectional study, recruited online through patient support groups, involved UK family members/partners of people with haematological conditions completing the FROM-16. RESULTS: 183 family members/partners (mean age = 60.5 years, SD = 13.2; females = 62.8%) of patients (mean age = 64.1, SD = 12.8; females = 46.4%) with 12 haematological conditions completed the FROM-16. The FROM-16 mean total score was 14.0 (SD = 7.2), meaning 'a moderate effect on QoL'. The mean FROM-16 scores of family members of people with multiple myeloma (mean = 15.8, SD = 6.3, n = 99) and other haematological malignancies (mean = 13.9, SD = 7.8, n = 29) were higher than of people with pernicious anaemia (mean = 10.7, SD = 7.5, n = 47) and other non-malignant conditions (mean = 11, SD = 7.4, n = 56, p < .01). Over one third (36.1%, n = 183) of family members experienced a 'very large effect' (FROM-16 score>16) on their quality of life. CONCLUSIONS: Haematological conditions, in particular those of malignant type, impact the QoL of family members/partners of patients. Healthcare professionals can now, using FROM-16, identify those most affected and should consider how to provide appropriate holistic support within routine practice.

2.
J Patient Rep Outcomes ; 8(1): 38, 2024 Mar 26.
Article in English | MEDLINE | ID: mdl-38530614

ABSTRACT

BACKGROUND: The FROM-16 is a generic family quality of life (QoL) instrument that measures the QoL impact of patients' disease on their family members/partners. The study aimed to assess the responsiveness of FROM-16 to change and determine Minimal Important Change (MIC). METHODS: Responsiveness and MIC for FROM-16 were assessed prospectively with patients and their family members recruited from outpatient departments of the University Hospital Wales and University Hospital Llandough, Cardiff, United Kingdom. Patients completed the EQ-5D-3L and a global severity question (GSQ) online at baseline and at 3-month follow-up. Family members completed FROM-16 at baseline and a Global Rating of Change (GRC) in addition to FROM-16 at follow-up. Responsiveness was assessed using the distribution-based (effect size-ES, standardized response mean -SRM) and anchor-based (area under the receiver operating characteristics curve ROC-AUC) approaches and by testing hypotheses on expected correlation strength between FROM-16 change score and patient assessment tools (GSQ and EQ-5D). Cohen's criteria were used for assessing ES. The AUC ≥ 0.7 was considered a good measure of responsiveness. MIC was calculated using anchor-based (ROC analysis and adjusted predictive modelling) and distribution methods based on standard deviation (SD) and standard error of the measurement (SEM). RESULTS: Eighty-three patients with 15 different health conditions and their relatives completed baseline and follow-up questionnaires and were included in the responsiveness analysis. The mean FROM-16 change over 3 months = 1.43 (SD = 4.98). The mean patient EQ-5D change over 3 months = -0.059 (SD = 0.14). The responsiveness analysis showed that the FROM-16 was responsive to change (ES = 0.2, SRM = 0.3; p < 0.01). The ES and SRM of FROM-16 change score ranged from small (ES = 0.2; SRM = 0.3) for the distribution-based method to large (ES = 0.8, SRM = 0.85) for anchor-based methods. The AUC value was above 0.7, indicating good responsiveness. There was a significant positive correlation between the FROM-16 change scores and the patient's disease severity change scores (p < 0.001). The MIC analysis was based on data from 100 family members of 100 patients. The MIC value of 4 was suggested for FROM-16. CONCLUSIONS: The results of this study confirm the longitudinal validity of FROM-16 which refers to the degree to which an instrument is able to measure change in the construct to be measured. The results yield a MIC value of 4 for FROM-16. These psychometric attributes of the FROM-16 instrument are useful in both clinical research as well as clinical practice.


Subject(s)
Patient Reported Outcome Measures , Quality of Life , Humans , Surveys and Questionnaires , United Kingdom , Wales
3.
Mol Psychiatry ; 28(11): 4693-4706, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37726451

ABSTRACT

Early life adversity (ELA) causes aberrant functioning of neural circuits affecting the health of an individual. While ELA-induced behavioural disorders resulting from sensory and cognitive disabilities can be assessed clinically, the neural mechanisms need to be probed using animal models by employing multi-pronged experimental approaches. As ELA can alter sensory perception, we investigated the effect of early weaning on murine olfaction. By implementing go/no-go odour discrimination paradigm, we observed olfactory learning and memory impairments in early life stressed (ELS) male mice. As olfactory bulb (OB) circuitry plays a critical role in odour learning, we studied the plausible changes in the OB of ELS mice. Lowered c-Fos activity in the external plexiform layer and a reduction in the number of dendritic processes of somatostatin-releasing, GABAergic interneurons (SOM-INs) in the ELS mice led us to hypothesise the underlying circuit. We recorded reduced synaptic inhibitory feedback on mitral/tufted (M/T) cells, in the OB slices from ELS mice, explaining the learning deficiency caused by compromised refinement of OB output. The reduction in synaptic inhibition was nullified by the photo-activation of ChR2-expressing SOM-INs in ELS mice. The role of SOM-INs was revealed by learning-dependent refinement of Ca2+dynamics quantified by GCaMP6f signals, which was absent in ELS mice. Further, the causal role of SOM-INs involving circuitry was investigated by optogenetic modulation during the odour discrimination learning. Photo-activating these neurons rescued the ELA-induced learning deficits. Conversely, photo-inhibition caused learning deficiency in control animals, while it completely abolished the learning in ELS mice, confirming the adverse effects mediated by SOM-INs. Our results thus establish the role of specific inhibitory circuit in pre-cortical sensory area in orchestrating ELA-dependent changes.


Subject(s)
Adverse Childhood Experiences , Olfactory Bulb , Mice , Male , Animals , Olfactory Bulb/metabolism , Interneurons/metabolism , Neurons/metabolism , Somatostatin/metabolism
4.
Front Neurosci ; 17: 1180868, 2023.
Article in English | MEDLINE | ID: mdl-37404465

ABSTRACT

Neuronal morphological characterization and behavioral phenotyping in mouse models help dissecting neural mechanisms of brain disorders. Olfactory dysfunctions and other cognitive problems were widely reported in asymptomatic carriers and symptomatic patients infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). This led us to generate the knockout mouse model for Angiotensin Converting Enzyme-2 (ACE2) receptor, one of the molecular factors mediating SARS-CoV-2 entry to the central nervous system, using CRISPR-Cas9 based genome editing tools. ACE2 receptors and Transmembrane Serine Protease-2 (TMPRSS2) are widely expressed in the supporting (sustentacular) cells of human and rodent olfactory epithelium, however, not in the olfactory sensory neurons (OSNs). Hence, acute inflammation induced changes due to viral infection in the olfactory epithelium may explain transient changes in olfactory detectabilities. As ACE2 receptors are expressed in different olfactory centers and higher brain areas, we studied the morphological changes in the olfactory epithelium (OE) and olfactory bulb (OB) of ACE2 KO mice in comparison with wild type animals. Our results showed reduced thickness of OSN layer in the OE, and a decrease in cross-sectional area of glomeruli in the OB. Aberrations in the olfactory circuits were revealed by lowered immunoreactivity toward microtubule associated protein 2 (MAP2) in the glomerular layer of ACE2 KO mice. Further, to understand if these morphological alterations lead to compromised sensory and cognitive abilities, we performed an array of behavioral assays probing their olfactory subsystems' performances. ACE2 KO mice exhibited slower learning of odor discriminations at the threshold levels and novel odor identification impairments. Further, ACE2 KO mice failed to memorize the pheromonal locations while trained on a multimodal task implying the aberrations of neural circuits involved in higher cognitive functions. Our results thus provide the morphological basis for the sensory and cognitive disabilities caused by the deletion of ACE2 receptors and offer a potential experimental approach to study the neural circuit mechanisms of cognitive impairments observed in long COVID.

5.
Curr Res Neurobiol ; 4: 100081, 2023.
Article in English | MEDLINE | ID: mdl-36919010

ABSTRACT

Quantifying olfactory impairments can facilitate early detection of Coronavirus disease 2019 (COVID-19). Despite being a debated topic, many reports provide evidence for the neurotropism of SARS-CoV-2. However, a sensitive, specific, and accurate non-invasive method for quantifying persistent neurological impairments is missing to date. To quantify olfactory detectabilities and neurocognitive impairments in symptomatic COVID-19 patients during and post-infection periods, we used a custom-built olfactory-action meter (OAM) providing accurate behavioral readouts. Ten monomolecular odors were used for quantifying olfactory detectabilities and two pairs of odors were employed for olfactory matching tests. We followed cohorts of healthy subjects, symptomatic patients, and recovered subjects for probing olfactory learning deficits, before the Coronavirus Omicron variant was reported in India. Our method identifies severe and persistent olfactory dysfunctions in symptomatic patients during COVID-19 infection. Symptomatic patients and recovered subjects showed significant olfactory learning deficits during and post-infection periods, 4-18 months, in comparison to healthy subjects. On comparing olfactory fitness, we found differential odor detectabilities and olfactory function scores in symptomatic patients and asymptomatic carriers. Our results indicate probable long-term neurocognitive deficits in COVID-19 patients imploring the necessity of long-term tracking during post-infection period. Differential olfactory fitness observed in symptomatic patients and asymptomatic carriers demand probing mechanisms of potentially distinct infection routes.

6.
Chemistry ; 29(7): e202202622, 2023 Feb 01.
Article in English | MEDLINE | ID: mdl-36325647

ABSTRACT

Demystifying the sulfation code of glycosaminoglycans (GAGs) to induce precise homing of nanoparticles in tumor cells or neurons influences the development of a potential drug- or gene-delivery system. However, GAGs, particularly heparan sulfate (HS) and chondroitin sulfate (CS), are structurally highly heterogeneous, and synthesizing well-defined HS/CS composed nanoparticles is challenging. Here, we decipher how specific sulfation patterns on HS and CS regulate receptor-mediated homing of nanoprobes in primary and secondary cells. We discovered that aggressive cancer cells such as MDA-MB-231 displayed a strong uptake of GAG-nanoprobes compared to mild or moderately aggressive cancer cells. However, there was no selectivity towards the GAG sequences, thus indicating the presence of more than one form of receptor-mediated uptake. However, U87 cells, olfactory bulb, and hippocampal primary neurons showed selective or preferential uptake of CS-E-coated nanoprobes compared to other GAG-nanoprobes. Furthermore, mechanistic studies revealed that the 4,6-O-disulfated-CS nanoprobe used the CD44 and caveolin-dependent endocytosis pathway for uptake. These results could lead to new opportunities to use GAG nanoprobes in nanomedicine.


Subject(s)
Chondroitin Sulfates , Glycosaminoglycans , Glycosaminoglycans/metabolism , Heparitin Sulfate/metabolism
7.
FASEB J ; 35(9): e21836, 2021 09.
Article in English | MEDLINE | ID: mdl-34407246

ABSTRACT

Memorizing pheromonal locations is critical for many mammalian species as it involves finding mates and avoiding competitors. In rodents, pheromonal information is perceived by the main and accessory olfactory systems. However, the role of somatosensation in context-dependent learning and memorizing of pheromone locations remains unexplored. We addressed this problem by training female mice on a multimodal task to locate pheromones by sampling volatiles emanating from male urine through the orifices of varying dimensions or shapes that are sensed by their vibrissae. In this novel pheromone location assay, female mice' preference toward male urine scent decayed over time when they were permitted to explore pheromones vs neutral stimuli, water. On training them for the associations involving olfactory and whisker systems, it was established that they were able to memorize the location of opposite sex pheromones, when tested 15 days later. This memory was not formed either when the somatosensory inputs through whisker pad were blocked or when the pheromonal cues were replaced with that of same sex. The association between olfactory and somatosensory systems was further confirmed by the enhanced expression of the activity-regulated cytoskeleton protein. Furthermore, the activation of main olfactory bulb circuitry by pheromone volatiles did not cause any modulation in learning and memorizing non-pheromonal volatiles. Our study thus provides the evidence for associations formed between different sensory modalities facilitating the long-term memory formation relevant to social and reproductive behaviors.


Subject(s)
Discrimination Learning/physiology , Odorants/analysis , Olfactory Perception/physiology , Pheromones/analysis , Smell/physiology , Vibrissae/physiology , Animals , Female , Male , Memory/physiology , Mice , Olfactory Bulb/metabolism , Size Perception/physiology
8.
Front Synaptic Neurosci ; 12: 551691, 2020.
Article in English | MEDLINE | ID: mdl-33304264

ABSTRACT

In the vertebrate olfactory bulb (OB), axonless granule cells (GC) mediate self- and lateral inhibitory interactions between mitral/tufted cells via reciprocal dendrodendritic synapses. Locally triggered release of GABA from the large reciprocal GC spines occurs on both fast and slow time scales, possibly enabling parallel processing during olfactory perception. Here we investigate local mechanisms for asynchronous spine output. To reveal the temporal and spatial characteristics of postsynaptic ion transients, we imaged spine and adjacent dendrite Ca2 +- and Na+-signals with minimal exogenous buffering by the respective fluorescent indicator dyes upon two-photon uncaging of DNI-glutamate in OB slices from juvenile rats. Both postsynaptic fluorescence signals decayed slowly, with average half durations in the spine head of t1 / 2_Δ[Ca2 +]i ∼500 ms and t1 / 2_Δ[Na+]i ∼1,000 ms. We also analyzed the kinetics of already existing data of postsynaptic spine Ca2 +-signals in response to glomerular stimulation in OB slices from adult mice, either WT or animals with partial GC glutamate receptor deletions (NMDAR: GluN1 subunit; AMPAR: GluA2 subunit). In a large subset of spines the fluorescence signal had a protracted rise time (average time to peak ∼400 ms, range 20 to >1,000 ms). This slow rise was independent of Ca2 + entry via NMDARs, since similarly slow signals occurred in ΔGluN1 GCs. Additional Ca2 + entry in ΔGluA2 GCs (with AMPARs rendered Ca2 +-permeable), however, resulted in larger ΔF/Fs that rose yet more slowly. Thus GC spines appear to dispose of several local mechanisms to promote asynchronous GABA release, which are reflected in the time course of mitral/tufted cell recurrent inhibition.

9.
EClinicalMedicine ; 28: 100575, 2020 Nov.
Article in English | MEDLINE | ID: mdl-33083773

ABSTRACT

BACKGROUND: COVID-19 threatens the global community because a large fraction of infected people are asymptomatic, yet can effectively transmit SARS-CoV-2. Finding and isolating these silent carriers is a crucial step in confining the spread of the disease. A sudden loss of the sense of smell has been self-reported by COVID-19 patients across different countries, consistent with expression of the molecular factors mediating SARS-CoV-2 uptake into human olfactory epithelial supporting cells. However, precise quantification of olfactory loss in asymptomatic COVID-19 carriers is missing to date. METHODS: To quantify olfactory functions in asymptomatic COVID-19 patients, we designed an olfactory-action meter that determines detectability indices at different odor concentrations and an olfactory matching accuracy score using monomolecular odors. The optimization of test parameters allowed us to reliably and accurately assess olfactory deficits in a patient within 20 minutes. FINDINGS: Measurement of detection indices at low concentrations revealed a 50% reduction in asymptomatic COVID-19 carriers. Further, patients with better detection scores showed significantly reduced olfactory matching accuracies compared to normal healthy subjects. Our quantification of olfactory loss, considering all parameters, identified 82% of the asymptomatic SARS-CoV-2 carriers with olfactory deficits. However, on subjective evaluation, only 15% of the patients noticed a compromised ability to smell. INTERPRETATION: Compromised olfactory fitness can serve as a strong basis for identifying asymptomatic COVID-19 patients. Detailed design specifications and protocols provided here should enable the development of a sensitive, fast, and economical screening strategy that can be administered to large populations to prevent the rapid spread of COVID-19. FUNDING: This work was supported by the DBT - Wellcome Trust India Alliance intermediate grant (IA/I/14/1/501,306 to N.A.) and UGC NET Fellowship (A.B.). All the funding sources played no roles in the study.

10.
Cell Rep ; 28(11): 2966-2978.e5, 2019 09 10.
Article in English | MEDLINE | ID: mdl-31509755

ABSTRACT

The olfactory environment is first represented by glomerular activity patterns in the olfactory bulb. It remains unclear how these representations intersect with sampling behavior to account for the time required to discriminate odors. Using different chemical classes, we investigate glomerular representations and sniffing behavior during olfactory decision-making. Mice rapidly discriminate odorants and learn to increase sniffing frequency at a fixed latency after trial initiation, independent of odor identity. Relative to the increase in sniffing frequency, monomolecular odorants are discriminated within 10-40 ms, while binary mixtures require an additional 60-70 ms. Intrinsic imaging of glomerular activity in anesthetized and awake mice reveals that Euclidean distance between activity patterns and the time needed for discriminations are anti-correlated. Therefore, the similarity of glomerular patterns and their activation strengths, rather than sampling behavior, define the extent of neuronal processing required for odor discrimination, establishing a neural metric to predict olfactory discrimination time.


Subject(s)
Behavior, Animal/physiology , Discrimination, Psychological/physiology , Olfactory Bulb/physiology , Olfactory Pathways/physiology , Smell/physiology , Action Potentials/physiology , Animals , Discrimination, Psychological/drug effects , Learning/drug effects , Learning/physiology , Mice , Mice, Inbred C57BL , Odorants , Olfactory Bulb/drug effects , Olfactory Pathways/drug effects , Reaction Time/physiology , Wakefulness/drug effects , Wakefulness/physiology
11.
Dis Esophagus ; 32(6)2019 Jun 01.
Article in English | MEDLINE | ID: mdl-30561584

ABSTRACT

Delayed gastric emptying (DGE) is a common morbidity that affects 10%-50% of Ivor-Lewis gastroesophagectomy (ILGO) patients. DGE management is variable with no gold standard prevention or treatment. We conducted a study to assess the effectiveness of intraoperative pyloric botulinum toxin injection in preventing DGE. All patients undergoing an ILGO for curative intent, semi-mechanical anastomosis, and enhanced recovery between 1st December 2011 and 30th June 2017 were included. Patients with pyloroplasties were excluded and botulinum toxin was routinely given from the 2nd April 2016. We compared botulinum toxin injection (BOTOX) against no intervention (NONE) for patient demographics, adjuvant therapy, surgical approach, DGE incidence, length of stay (LOS), and complications. Additionally, we compared pneumonia risk, anastomotic leak rate, and LOS in DGE versus non-DGE patients. DGE was defined using nasogastric tube input/output differences and chest X-ray appearance according to an algorithm adopted in our unit, which were retrospectively applied. There were 228 patients: 65 (28.5%) received botulinum toxin and 163 (71.5%) received no intervention. One hundred twenty-four (54.4%) operations were performed laparoscopically, of which 11 (4.8%) were converted to open procedures, and 104 (45.6%) were open operations. DGE incidence was 11 (16.9%) in BOTOX and 29 (17.8%) in NONE, P = 0.13. Medical management was required in 14 of 228 (6.1%) cases: 3 (4.6%) in BOTOX and 11 (4.8%) in NONE. Pyloric dilatation was required in 26 of 228 (11.4%): 8 of 65 (12.3%) in the BOTOX and 18 of 163 (11.0%) in NONE. There were no significant differences between groups and requirement for intervention, P = 0.881. Overall median LOS was 10 (6.0-75.0) days: 9 (7.0-75.0) in BOTOX and 10 (6.0-70.0) in NONE, P = 0.516. In non-DGE versus DGE patients, median LOS was 9 (6-57) versus 14 (7-75) days (P < 0.0001), pneumonia incidence of 27.7% versus 30.0% (P = 0.478), and anastomotic leak rate of 2.1% versus 10.0% (P = 0.014). Overall leak rate was 3.5%. Overall complication rate was 67.1%, including minor/mild complications. There were 43 of 65 (66.2%) in BOTOX and 110 of 163 (67.5%) in NONE, P = 0.482. In-hospital mortality was 1 (0.44%), 30-day mortality was 2 (0.88%), 90-day mortality was 5 (2.2%), and there were no 30-day readmissions. Intraoperative pyloric botulinum toxin injections were ineffective in preventing DGE (BOTOX vs. NONE: 16.9% vs. 17.8%) or reducing postoperative complications. DGE was relatively common (17.5%) with 11.4% of patients requiring postoperative balloon dilatation. DGE also resulted in prolonged LOS (increase from 9 to 14 days) and significant increase in leak rate from 2.1% to 10.0%. A better understanding of DGE will guide assessment, investigation, and management of the condition.


Subject(s)
Botulinum Toxins, Type A/administration & dosage , Gastroparesis/prevention & control , Neuromuscular Agents/administration & dosage , Pylorus , Adult , Aged , Aged, 80 and over , Anastomotic Leak/etiology , Esophagectomy/adverse effects , Esophagectomy/methods , Female , Gastrectomy/adverse effects , Gastrectomy/methods , Gastroparesis/etiology , Gastroparesis/therapy , Hospital Mortality , Humans , Injections , Intraoperative Care , Length of Stay , Male , Middle Aged , Pneumonia/etiology , Retrospective Studies
12.
Ann Med Surg (Lond) ; 30: 13-17, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29946453

ABSTRACT

BACKGROUND: Laparoscopic common bile duct exploration (LCBDE) has emerged as a recommended alternative to endoscopic retrograde cholangiopancreatography (ERCP) for the management of choledocholithiasis. However, its use in the elderly has been limited, and evidence of its safety and efficacy in these patients is yet to be established. This study describes our experience of LCBDE in elderly patients, analysing the safety and efficacy of this technique in comparison to younger patients. METHODS: All patients undergoing laparoscopic cholecystectomy (LC) with LCBDE for choledocholithiasis in our unit between January 2015 and January 2017 were included. Data pertaining to patient demographics, comorbidities, investigations, operative technique and outcomes were analysed. Patients were divided into 2 groups based on age (Group A:<65 years vs Group B: >/ = 65 years) for comparative analysis. RESULTS: 124 patients (Group A: 65, Group B: 59) were included. Group B were more co-morbid and had a higher ASA grade than Group A. However, there was no significant difference between groups in rates of conversion to open or complications, including bile leak (3.1% vs 5.1%, p = 0.67), retained stone (4.6% vs 1.7%, p = 0.62), or complications according to Clavien-Dindo classification (p = 0.78). Re-intervention rates were also similar between groups (7.7% vs 3.4%, p = 0.44 and 3.1% vs 3.4%, p = 1.0 respectively), as was length of stay. CONCLUSION: Despite higher frequency of comorbidities and ASA grade, LCBDE in elderly patients is safe and effective, and has similar outcomes to younger patients. Therefore elderly patients with choledocholithiasis should be offered LCBDE as an alternative to ERCP.

13.
J R Soc Interface ; 14(130)2017 05.
Article in English | MEDLINE | ID: mdl-28566511

ABSTRACT

The damselfly Pseudolestes mirabilis reflects brilliant white on the ventral side of its hindwings and a copper-gold colour on the dorsal side. Unlike many previous investigations of odonate wings, in which colour appearances arise either from multilayer interference or from wing-membrane pigmentation, the whiteness on the wings of P. mirabilis results from light scattered by a specialized arrangement of flattened waxy fibres and the copper-gold colour is produced by pigment-based filtering of this light scatter. The waxy fibres responsible for this optical signature effectively form a structure that is disordered in two dimensions and this also gives rise to distinct optical linear polarization. It is a structure that provides a mechanism enabling P. mirabilis to display its bright wing colours efficiently for territorial signalling, both passively while perched, in which the sunlit copper-gold upperside is presented against a highly contrasting background of foliage, and actively in territorial contests in which the white underside is also presented. It also offers a template for biomimetic high-intensity broadband reflectors that have a pronounced polarization signature.


Subject(s)
Light , Odonata/anatomy & histology , Polarography , Wings, Animal/anatomy & histology , Animals , Behavior, Animal , Color , Territoriality
14.
Phys Chem Chem Phys ; 19(32): 21287-21296, 2017 Aug 16.
Article in English | MEDLINE | ID: mdl-28597880

ABSTRACT

The p53 tumour suppressor is a transcription activator that signals for cell cycle arrest and apoptosis. In its active form p53 is a tetramer, with each monomer organised in domains with different degrees of structural stability, ranging from the well folded DNA-binding domain (DBD) and tetramerization domain (TET), to the intrinsically disordered transactivation domain (TAD), and extreme C-terminal domain (CTD). Compared to all other domains, the structure/function relationship of the p53-CTD within the full-length p53 tetramer is still poorly understood due to its high degree of conformational disorder. Meanwhile, the structure of p53-CTD-like peptides has been well characterized when in complex with a variety of receptors, where, as other intrinsically disordered regions (IDR), it adopts specific, while diverse, conformations. Receptor-specific folding is likely to occur upon binding, either from a random coil, or as a result of an initial recognition of a pre-formed structural motif, known as molecular recognition feature (MoRF), selected by the receptor within the conformational ensemble of the IDP in solution. In this latter case, MoRFs act as nucleation sites, favouring the initiation of the folding process within the binding site. In this work we show the results of over 20 µs of cumulative molecular dynamics (MD) simulations of a 22 residue peptide unbound in solution with sequence corresponding to the p53-CTD 367-388 section. Such extensive sampling allowed us to identify and characterize the structure of specific sets of minimal structural MoRFs within the p53-CTD peptide conformational ensemble at equilibrium. These motifs are short, involving only 3 to 4 residues, and specifically localized within the peptide sequence. Corresponding patterns of secondary structure propensity along the p53-CTD sequence are also predicted by disorder prediction calculations. Based on these findings we discuss how the structural complementarity of specific minimal structural MoRFs to the binding site of different receptors could regulate the p53-CTD binding promiscuity.


Subject(s)
Molecular Dynamics Simulation , Tumor Suppressor Protein p53/chemistry , Amino Acid Sequence , Protein Binding , Protein Domains , Protein Structure, Secondary , S100 Calcium Binding Protein beta Subunit/chemistry , S100 Calcium Binding Protein beta Subunit/metabolism , Tumor Suppressor Protein p53/metabolism
15.
Ann R Coll Surg Engl ; 98(8): e165-e167, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27652796

ABSTRACT

Radial head dislocations are common in children who fall onto outstretched hands. We present a case of medial radial head dislocation without a concomitant ulna fracture in a 14-year-old girl and the long-term sequelae of the injury.


Subject(s)
Elbow Injuries , Radius/injuries , Adolescent , Elbow Joint/diagnostic imaging , Elbow Joint/surgery , Female , Humans , Joint Dislocations/diagnostic imaging , Joint Dislocations/surgery , Open Fracture Reduction , Radiography , Radius/diagnostic imaging , Radius/surgery , Tomography, X-Ray Computed , Ulna Fractures/complications , Ulna Fractures/diagnosis , Ulna Fractures/diagnostic imaging , Ulna Fractures/surgery
16.
Nat Neurosci ; 18(10): 1474-1482, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26301325

ABSTRACT

Neuronal pattern separation is thought to enable the brain to disambiguate sensory stimuli with overlapping features, thereby extracting valuable information. In the olfactory system, it remains unknown whether pattern separation acts as a driving force for sensory discrimination and the learning thereof. We found that overlapping odor-evoked input patterns to the mouse olfactory bulb (OB) were dynamically reformatted in the network on the timescale of a single breath, giving rise to separated patterns of activity in an ensemble of output neurons, mitral/tufted (M/T) cells. Notably, the extent of pattern separation in M/T assemblies predicted behavioral discrimination performance during the learning phase. Furthermore, exciting or inhibiting GABAergic OB interneurons, using optogenetics or pharmacogenetics, altered pattern separation and thereby odor discrimination learning in a bidirectional way. In conclusion, we propose that the OB network can act as a pattern separator facilitating olfactory stimulus distinction, a process that is sculpted by synaptic inhibition.


Subject(s)
Discrimination Learning/physiology , Olfactory Bulb/physiology , Olfactory Perception/physiology , Animals , Immunohistochemistry , Male , Mice , Mice, Inbred C57BL , Microscopy, Confocal , Olfactory Pathways/physiology
17.
J R Soc Interface ; 12(103)2015 Feb 06.
Article in English | MEDLINE | ID: mdl-25540236

ABSTRACT

The dorsal surfaces of the hindwings of the dragonfly Rhyothemis resplendens (Odonata: Libellulidae) reflect a deep blue from the multilayer structure in its wing membrane. The layers within this structure are not flat, but distinctly 'wrinkled', with a thickness of several hundred nanometres and interwrinkle crest distances of 5 µm and greater. A comparison between the backscattered light from R. resplendens and a similar, but un-'wrinkled' multilayer in the damselfly Matronoides cyaneipennis (Odonata: Calopterygidae) shows that the angle over which incident light is backscattered is increased by the wrinkling in the R. resplendens structure. Whereas the reflection from the flat multilayer of M. cyaneipennis is effectively specular, the reflection from the wrinkled R. resplendens multilayer spans 1.47 steradians (equivalent to ±40° for all azimuthal angles). This property enhances the visibility of the static wing over a broader angle range than is normally associated with a smooth multilayer, thereby markedly increasing its conspicuousness.


Subject(s)
Insecta/anatomy & histology , Wings, Animal/anatomy & histology , Animals
18.
Elife ; 3: e02109, 2014 Mar 18.
Article in English | MEDLINE | ID: mdl-24642413

ABSTRACT

Sensory inputs are remarkably organized along all sensory pathways. While sensory representations are known to undergo plasticity at the higher levels of sensory pathways following peripheral lesions or sensory experience, less is known about the functional plasticity of peripheral inputs induced by learning. We addressed this question in the adult mouse olfactory system by combining odor discrimination studies with functional imaging of sensory input activity in awake mice. Here we show that associative learning, but not passive odor exposure, potentiates the strength of sensory inputs up to several weeks after the end of training. We conclude that experience-dependent plasticity can occur in the periphery of adult mouse olfactory system, which should improve odor detection and contribute towards accurate and fast odor discriminations. DOI: http://dx.doi.org/10.7554/eLife.02109.001.


Subject(s)
Learning , Neuronal Plasticity , Smell , Animals , Long-Term Potentiation , Mice , Odorants , Sensory Receptor Cells/physiology
20.
Opt Lett ; 38(20): 4174-7, 2013 Oct 15.
Article in English | MEDLINE | ID: mdl-24321952

ABSTRACT

The synchronization of chaotic lasers and the optical phase synchronization of light originating in multiple coupled lasers have both been extensively studied. However, the interplay between these two phenomena, especially at the network level, is unexplored. Here, we experimentally compare these phenomena by controlling the heterogeneity of the coupling delay times of two lasers. While chaotic lasers exhibit deterioration in synchronization as the time delay heterogeneity increases, phase synchronization is found to be independent of heterogeneity. The experimental results are found to be in agreement with numerical simulations for semiconductor lasers.


Subject(s)
Lasers , Nonlinear Dynamics
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