Biomedical subjects

Paul Thompson

Publications and source records attributed to Paul Thompson.

At least 19 recordsLinked to original sources

PubMed2026

Sex-specific biological aging clocks across organs and omics.

Sex differentially shapes aging, neurodevelopment and neurodegenerative diseases such as Alzheimer's disease (AD). However, most biological aging clocks (artificial intelligence-predicted age minus chronological age) were trained on sex-pooled samples and implicitly assume sex invariance.Here we developed 38 sex-specific biological aging clocks across 15 organ systems. We first demonstrate the importance of sex-stratified training for constructing sex-specific healthy normative references and then reveal marked divergence between female and male clocks. Key genetic parameters and Mendelian randomization results indicate that organ-specific aging liability and its relationships to cardiometabolic, endocrine and mental traits are configured differently in females and males. Proteomic analyses identify distinct, organ-resolved synaptic, immune, vascular and metabolic networks that differentially track female and male biological aging. In longitudinal survival analyses, sex-specific clocks predict whole-body systemic diseases and all-cause mortality in a sex-dependent and organ-dependent manner. Further analyses reveal sex-dependent associations between the brain aging clock and cognitive decline trajectory during a preclinical AD clinical trial. Sex-stratified clocks may offer distinct value by defining biological age against sex-appropriate normative references and revealing sex-dependent genetic, molecular and clinical signatures that pooled models may obscure. Meanwhile, sex-pooled and sex-interaction approaches remain valuable, as human aging and disease also share fundamental biological similarities between females and males. Together, these findings reveal sex-specific biological aging signatures in aging, AD and systemic health, highlighting the need for explicitly sex-stratified modeling approaches.

Journal Article↗

PubMed2006

Anomalous sylvian fissure morphology in Williams syndrome.

The unusual sensitivity and attraction to auditory stimuli in people with Williams syndrome (WS) has been hypothesized to be the consequence of atypical development of brain regions surrounding the Sylvian fissure. Planum temporale surface area, which is determined in part by Sylvian fissure patterning, was examined in 42 WS and 40 control participants to determine if anomalous Sylvian fissure morphology is present in WS. WS participants had significantly reduced leftward asymmetry of the planum temporale compared to control participants, due to a significant expansion in the size of the right planum temporale. The increased right planum temporale size was largely due to WS participants (24%) who had a right hemisphere Sylvian fissure that coursed horizontally and failed to ascend into the parietal lobe. This sulcal pattern is unusual in the right hemisphere and is more commonly found in the left hemisphere of typically developing individuals. There were no control participants with this type of right hemisphere Sylvian fissure pattern. The right hemisphere Sylvian fissure sulcal patterns were also related to a measure of cortical complexity and the amount of right hemisphere occipital lobe volume, suggesting that intrinsic genetic influences leading to anomalous visual system development in WS have widespread influences on cortical morphology that are similar in manner to extrinsic embryonic visual system lesions.

Adult↗

PubMed2006

The 1988 and 2002 phocine distemper virus epidemics in European harbour seals.

We present new and revised data for the phocine distemper virus (PDV) epidemics that resulted in the deaths of more than 23 000 harbour seals Phoca vitulina in 1988 and 30,000 in 2002. On both occasions the epidemics started at the Danish island of Anholt in central Kattegat, and subsequently spread to adjacent colonies in a stepwise fashion. However, this pattern was not maintained throughout the epidemics and new centres of infection appeared far from infected populations on some occasions: in 1988 early positive cases were observed in the Irish Sea, and in 2002 the epidemic appeared in the Dutch Wadden Sea, 6 wk after the initiation of the outbreak at Anholt Island. Since the harbour seal is a rather sedentary species, such 'jumps' in the spread among colonies suggest that another vector species could have been involved. We discussed the role of sympatric species as disease vectors, and suggested that grey seal populations could act as reservoirs for PDV if infection rates in sympatric species are lower than in harbour seals. Alternatively, grey seals could act as subclinical infected carriers of the virus between Arctic and North Sea seal populations. Mixed colonies of grey and harbour seal colonies are found at all locations where the jumps occurred. It seems likely that grey seals, which show long-distance movements, contributed to the spread among regions. The harbour seal populations along the Norwegian coast and in the Baltic escaped both epidemics, which could be due either to genetic differences among harbour seal populations or to immunity. Catastrophic events such as repeated epidemics should be accounted for in future models and management strategies of wildlife populations.

Age Factors↗

PubMed2006

Quantitative analysis of bottlenose dolphin movement patterns and their relationship with foraging.

1. Broad-scale telemetry studies have greatly improved our understanding of the ranging patterns and habitat-use of many large vertebrates. However, there often remains considerable uncertainty over the function of different areas or the factors influencing habitat selection. Further insights into these processes can be obtained through analyses of finer scale movement patterns. For example, search behaviour may be modified in response to prey distribution and abundance. 2. In this study, quantitative analysis techniques are applied to the movements of bottlenose dolphins, recorded from land using a theodolite, to increase our understanding of their foraging strategies. Movements were modelled as a correlated random walk (CRW) and a biased random walk (BRW) to identify movement types and using a first-passage time (FPT) approach, which quantifies the time allocated to different areas and identifies the location and spatial scale of intensive search effort. 3. Only a quarter of the tracks were classed as CRW movement. Turning angle and directionality appeared to be key factors in determining the type of movement adopted. A high degree of overlap in search effort between separate movement paths indicated that there were small key sites (0.3 km radius) within the study area (4 km(2)). Foraging behaviour occurred mainly within these intensive search areas, indicating that they were feeding sites. 4. This approach provides a quantitative method of identifying important foraging areas and their spatial scale. Such techniques could be applied to movement paths for a variety of species derived from telemetry studies and increase our understanding of their foraging strategies.

Animals↗

PubMed2005

Age-related morphology trends of cortical sulci.

The age-related trends of the width and the depth of major cortical sulci were studied in normal adults. Ninety healthy subjects (47 males, 43 females) age 20-82 years were evaluated. Measurements of average sulcal width and depth in 14 prominent sulcal structures per hemisphere were performed with high-resolution anatomical MRI. The average sulcal width increased at a rate of about 0.7 mm/decade, while the average sulcal depth decreased at a rate of about 0.4 mm/decade. Sulcal age-related trends were found to be highly influenced by gender in the superior temporal, collateral, and cingulate sulci (P < 0.05), with males showing more pronounced age-related change in sulcal width than females. Sulcal structures located in multimodal cortical areas showed more profound age-related changes than sulcal structures in unimodal cortical areas (P < 0.05).

Adult↗

PubMed2005

Structural analysis of a highly acetylated protein using a curved-field reflectron mass spectrometer.

Matrix-assisted laser desorption/ionization mass spectrometry and tandem mass spectrometry (MS/MS) were used to determine the multiple acetylation sites in the histone acetyltransferase (HAT): p300-HAT. Partial cleavage of the peptides containing acetylated lysine residues by trypsin provided a set of nested sequences that enabled us to determine that multiple acetylation occurs on the same molecule. At the same time, cleavages resulting in a terminal unacetylated lysine suggested that not all of these sites are fully modified. Using MS and MS/MS, we were able to characterize both the unmodified and acetylated tryptic peptides covering more than 82% of the protein.

Acetylation↗

PubMed2005

Nondisease genetic testing: reporting of muscle SNPs shows effects on self-concept and health orientation scales.

The purpose of this study was to assess the impact of genetic self-knowledge (nondisease genotype information) on individual self-concept and Health Orientation Scale (HOS). Adult volunteers (n=257) were recruited from an ongoing genetic association study identifying muscle quantitative trait loci (QTLs). Participants completed psychosocial assessments before and after 12 weeks of resistance training of the nondominant arm. At study exit, a genetic counselor informed participants of genetic test results on three to four genes that have an association with muscle-related traits, and counseled subjects on the potential significance of these findings. The second psychosocial assessment was performed immediately following this counseling session. The Tennessee Self-Concept Scale v.2 (TSCS:2) and the HOS showed female subjects to have a significantly greater positive change between first and second assessments, relative to male subjects. Most self-concept subscales improved significantly, when 'neutral' genotypes (no anticipated beneficial or deleterious impact) were reported, compared to positive genotypes. TSCS:2 subscales showing improvement included: total (P=0.013); physical (P=0.004); satisfaction (P=0.019); and behavioral (P=0.047). HOS subscales showing improvement included health image concern (P=0.006); and health expectations (P=0.047). In conclusion, these results suggest that genetic self-knowledge affects self-concept, consistent with the 'attribution' theory. Individuals who received neutral genetic information attributed positive changes from the exercise program to their own abilities, while those who received positive information were more likely to attribute positive changes to their genetics. This study is limited by the ability to determine the direction of the impact of nondisease genetic information presented to participants.

Adult↗

PubMed2005

An in-service evaluation of hip protector use in residential homes.

BACKGROUND: The establishment of a hip protector service has allowed us to study eligibility, acceptability and compliance with use, reasons for non-use, and the effect of dementia, confusion, incontinence and risk of falling. METHODS: All residents in all residential homes in Poole were assessed at baseline. All eligible residents were offered 1 week's trial of protectors and those who wished to continue were given a set of protectors. Compliance was assessed at 3, 6 and 12 months. Percentages shown for compliance exclude those who died, were transferred, had lost data or in whom follow-up was not yet completed. RESULTS: Over 18 months, 873 residents from 47 homes were identified (mean age 88 years, female:male 4.5:1). Of these, 745 were considered eligible to wear protectors (86%) and 535 agreed to wear them after 1 week (72%). Compliance over 12 months was 78%. Most wearers wore protectors every day. At 3 months, 83% of demented compared to 73% of not demented residents (P = 0.023), 86% of always confused, 77% of sometimes confused and 72% of never confused (P < 0.009) and 82% of incontinent compared to 73% of continent residents (P = 0.024) were wearing hip protectors. There was a positive linear trend between the risk of falling and compliance (P = 0.048). CONCLUSIONS: The results suggest that there is a 48% chance of a resident wearing the protectors after 1 year. The higher compliance among those with dementia, confusion, incontinence and at high risk of falling supports the concept that hip protectors are worn by those at greatest risk of fracture.

Accidental Falls↗

PubMed2004

Modulation of the ligand binding properties of the transcription repressor NmrA by GATA-containing DNA and site-directed mutagenesis.

NmrA is a negative transcription-regulating protein that binds to the C-terminal region of the GATA transcription-activating protein AreA. The proposed molecular mechanism of action for NmrA is to inhibit AreA binding to its target promoters. In contrast to this proposal, we report that a C-terminal fragment of AreA can bind individually to GATA-containing DNA and NmrA and that in the presence of a mixture of GATA-containing DNA and NmrA, the AreA fragment binds preferentially to the GATA-containing DNA in vitro. These observations are consistent with NmrA acting by an indirect route, such as by controlling entry into the nucleus. Deletion of the final nine amino acids of a C-terminal fragment of AreA does not affect NmrA binding. Wild-type NmrA binds NAD(+)(P+) with much greater affinity than NAD(P)H, despite the lack of the consensus GXXGXXG dinucleotide-binding motif. However, introducing the GXXGXXG sequence into the NmrA double mutant N12G/A18G causes an approximately 13-fold increase in the KD for NAD+ and a 2.3-fold increase for NADP+. An H37W mutant in NmrA designed to increase the interaction with the adenine ring of NAD+ has a decrease in KD of approximately 4.5-fold for NAD+ and a marginal 24% increase for NADP+. The crystal structure of the N12G/A18G mutant protein shows changes in main chain position as well as repositioning of H37, which disrupts contacts with the adenine ring of NAD+, changes which are predicted to reduce the binding affinity for this dinucleotide. The substitutions E193Q/D195N or Q202E/F204Y in the C-terminal domain of NmrA reduced the affinity for a C-terminal fragment of AreA, implying that this region of the protein interacts with AreA.

Base Sequence↗

PubMed2004

Efficacy of extended-release niacin with lovastatin for hypercholesterolemia: assessing all reasonable doses with innovative surface graph analysis.

BACKGROUND: Combination therapy to improve the total lipid profile may achieve greater coronary risk reductions than lowering low-density lipoprotein cholesterol (LDL-C) alone. A new extended-release niacin (niacin ER)/lovastatin tablet substantially lowers LDL-C, triglyceride, and lipoprotein(a) levels and raises high-density lipoprotein cholesterol (HDL-C) level. We evaluated these serum lipid responses to niacin ER/lovastatin at all clinically reasonable doses. METHODS: Men (n = 85) and women (n = 79) with type IIa or IIb primary hyperlipidemia after diet were randomized among 5 parallel treatment arms. Each arm had 5 sequential 4-week treatment periods: niacin ER (starting at 500 mg/d, increasing in 500-mg increments to 2500 mg/d); lovastatin (starting at 10 mg, increasing to 20 mg, then 40 mg/d); and 3 combinations arms, each with a constant lovastatin dose and escalating niacin ER doses. RESULTS: For primary comparisons, mean LDL-C level reductions from baseline were greater with niacin ER/lovastatin (1500/20 mg) than with lovastatin (20 mg) (35% vs 22%, P<.001) and with niacin ER/lovastatin (2000/40 mg) than with lovastatin (40 mg) (46% vs 24%, P<.001). Each 500-mg increase in niacin ER, on average, decreased LDL-C levels an additional 4% and increased HDL-C levels 8%. The maximum recommended dose (2000/40 mg/d) increased HDL-C levels 29% and decreased LDL-C levels 46%, triglyceride levels 38%, and lipoprotein(a) levels 14%. All lipid responses were dose dependent and generally additive. Graphs of the dose-response relationships as 3-dimensional surfaces documented the strength and consistency of these responses. CONCLUSIONS: Niacin ER/lovastatin combination therapy substantially improves 4 major lipoprotein levels associated with atherosclerotic disease. Dose-response surfaces provide a practical guide for dose selection.

Delayed-Action Preparations↗

PubMed2004

Implicit brain imaging.

We describe how implicit surface representations can be used to solve fundamental problems in brain imaging. This kind of representation is not only natural following the state-of-the-art segmentation algorithms reported in the literature to extract the different brain tissues, but it is also, as shown in this paper, the most appropriate one from the computational point of view. Examples are provided for finding constrained special curves on the cortex, such as sulcal beds, regularizing surface-based measures, such as cortical thickness, and for computing warping fields between surfaces such as the brain cortex. All these result from efficiently solving partial differential equations (PDEs) and variational problems on surfaces represented in implicit form. The implicit framework avoids the need to construct intermediate mappings between 3-D anatomical surfaces and parametric objects such planes or spheres, a complex step that introduces errors and is required by many other cortical processing approaches.

Algorithms↗

PubMed2004

Evidence-based update of chemotherapy options for metastatic colorectal cancer.

Colorectal carcinoma is one of the most common malignancies in the Western world. Although fluorouracil (5-FU) has been used for over 40 years, only in the last decade has its value been recognized in the treatment of advanced colorectal cancer. Early randomized studies explored the best possible doses and schedules of 5-FU and its modulators such as folinic acid or leucovorin (LV) in combination with respect to efficacy and side-effects. The development of oral fluoropyrimidines, in particular capecitabine, has made chemotherapy further accessible and acceptable. The introduction of newer cytotoxics irinotecan and oxaliplatin has achieved a significant improvement in survival rates with manageable toxicity. With appropriate selection of patients and proper sequencing of currently most efficient regimens, median survival durations of around 20 months can now be reached. Novel targeted therapies (bevacizumab, cetuximab and cyclooxygenase-2 (COX-2) inhibitors) in combination with most efficient chemotherapy regimens will probably push the median survival beyond the 2-year mark. The present article is an overview of most important studies that have substantially changed the approach to metastatic colorectal cancer and have given the patients and clinicians a wider range of options for treating this illness.

Antibodies, Monoclonal↗

PubMed2004

Laparoscopy in the management of colorectal cancer metastatic to the liver.

BACKGROUND: This investigation was undertaken to define the value of laparoscopy in the staging of patients with colorectal carcinoma metastatic to the liver. METHODS: The clinical details of 59 consecutive patients with colorectal liver metastases undergoing laparoscopy prior to planned hepatectomy were entered prospectively on a computerized database. All patients were staged preoperatively with thin slice (5-7 mm) helical computed tomography chest, abdomen and pelvis. Synchronous metastases were defined as those found during, or on imaging carried out within 1 month of, colorectal resection. Criteria for laparoscopic unresectability were: (i) histologically proven extrahepatic disease; (ii) bilateral inflow or outflow involvement; (iii) the presence of cirrhosis in patients requiring an extended resection (lobectomy or greater); or (iv) hepatic metastases involving more than six hepatic segments. RESULTS: In 24 patients with synchronous metastases (median age 65 years, range 32-81 years) all were resectable on laparoscopic criteria, of whom 21 were resected. Extrahepatic disease was found at laparotomy in three patients. In 35 patients with metachronous metastases (median age 64 years, range 32-81 years) laparoscopy could not be performed in five patients because of adhesions, and three patients were deemed unresectable on laparoscopic criteria. Of the remaining 27 patients, 25 underwent resection while two proved unresectable. Overall eight of 54 evaluable patients had unresectable disease and laparoscopy correctly identified three patients. CONCLUSIONS: Following computed tomography scan, 15% of patients with metastatic colorectal carcinoma will be found to have unresectable disease. Laparoscopy will identify approximately half. Laparoscopy is of no greater value in staging synchronous versus metachronous metastases.

Adult↗

PubMed2003

The Auckland Breast Cancer Register: a special project of the Auckland Breast Cancer Study Group.

AIMS: The Auckland Breast Cancer Register (ABCR) has been established in response to the need for a comprehensive database of breast cancer cases from the Auckland area. METHODS: The database records patient demographics, diagnosis, treatment options, prognosis and long-term outcome (annual follow up). Data from 1204 cases, recorded between June 2000 and June 2002 are reported. RESULTS: The major findings are that 34% of women had breast cancer detected by screening only (47% in the group eligible for free screening within the Breast Screen Aotearoa screening programme); 84% of patients had invasive carcinoma; 13% had ductal carcinoma in situ (DCIS); and 3% fine needle aspiration only. Forty nine per cent of invasive tumours were < or =2 cm. Grade 3 tumours were found in 53% of patients under 40 years old compared with 26.8% 40 years or older. Mastectomy was performed in 56% of patients with invasive cancer and 33% of those with DCIS. Axillary surgery was performed in 94% of patients with invasive cancer and 39% had involved nodes. Seventy nine per cent of patients were referred for an opinion from an oncologist. Radiotherapy was given to 77% of these patients, chemotherapy to 33%, and hormone therapy to 57%. CONCLUSIONS: The ABCR will provide essential healthcare information that will lead to better understanding of breast cancer in Auckland and more effective delivery of the clinical resources available in the Auckland region.

Adult↗

PubMed2003

PPARgamma activation enhances cell surface ENaCalpha via up-regulation of SGK1 in human collecting duct cells.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor that belongs to the nuclear receptor family that plays a critical role in adipocyte differentiation and lipid metabolism. Here we report for the first time that PPARgamma is expressed in human renal cortical collecting ducts (CCD), segments of the nephor involved in regulation of sodium and water homeostasis via action of the epithelial sodium channel (ENaC). ENaC activity is regulated by the hormones aldosterone and insulin, primarily through co-ordinate actions on serum and glucocorticoid regulated kinase 1 (SGK1). We show that SGK1 activity is stimulated by treatment of a human CCD cell line with PPARgamma agonists, paralleled by an increase in SGK1 mRNA that is abolished by pretreatment with a specific PPARgamma antagonist, and that this leads to increased levels of cell surface ENaCalpha. Electrophoretic mobility shift assays suggest that these effects are caused by binding of PPARgamma to a specific response element in the SGK1 promoter. Our results identify SGK1 as a target for PPARgamma and suggest a novel role for PPARgamma in regulation of sodium re-absorption in the CCD via stimulation of ENaC activity. This pathway may play a role in sodium retention caused by activation of PPARgamma in man.

Cell Line↗

PubMed2003

The negative transcriptional regulator NmrA discriminates between oxidized and reduced dinucleotides.

NmrA, a transcription repressor involved in the regulation of nitrogen metabolism in Aspergillus nidulans,is a member of the short-chain dehydrogenase reductase superfamily. Isothermal titration calorimetry and differential scanning calorimetry have been used to show NmrA binds NAD+ and NADP+ with similar affinity (average KD 65 microM) but has a greatly reduced affinity for NADH and NADPH (average KD 6.0 mM). The structure of NmrA in a complex with NADP+ reveals how repositioning a His-37 side chain allows the different conformations of NAD+ and NADP+ to be accommodated. Modeling NAD(P)H into NmrA indicated that steric clashes, attenuation of electrostatic interactions, and loss of aromatic ring stacking can explain the differing affinities of NAD(P)+/NAD(P)H. The ability of NmrA to discriminate between the oxidized and reduced forms of the dinucleotides may be linked to a possible role in redox sensing. Isothermal titration calorimetry demonstrated that NmrA and a C-terminal fragment of the GATA transcription factor AreA interacted with a 1:1 stoichiometry and an apparent KD of 0.26 microM. NmrA was unable to bind the nitrogen metabolite repression signaling molecules ammonium or glutamine.

Aspergillus nidulans↗

PubMed2003

Early and late neurodevelopmental influences in the prodrome to schizophrenia: contributions of genes, environment, and their interactions.

Both early (i.e., pre- and perinatal periods) and late (i.e., adolescent period) neurodevelopmental processes are thought to participate in the etiology and pathophysiology of schizophrenia. However, whether markers of these processes would be expected to predict an imminent onset of psychosis, as is hoped in the current generation of prodromal research programs, depends on whether their disruptions result from genetic factors shared by patients and some of their unaffected relatives, nongenetic factors specific to those who manifest the illness phenotype, or combinations of these sets of influences. Here we present recent work deriving primarily from high-risk and family-study (i.e., "genetic high-risk") designs, which provide a framework for investigating the neural changes that may occur proximally to the initial onset of psychosis. This work indicates that some of the alterations in brain function and structure in schizophrenia are primarily genetically mediated and also appear in some of patients' unaffected first degree relatives, while other alterations are present in individuals who manifest the illness phenotype but not in relatives at genetic risk (Cannon et al. 2002a, 2002c; Van Erp et al. 2002). Whereas the primarily genetically mediated deficits shared by at-risk but nonsymptomatic relatives are not likely to show differential change in the premorbid period and may be necessary but clearly not sufficient for the development of psychotic symptoms, the deficits specific to patients who manifest the illness phenotype are good candidates for marking the neurobiological processes associated with the emergence of psychotic symptoms at the time of schizophrenia onset. Preliminary results from longitudinal studies of individuals ascertained initially in a prodromal (i.e., "clinical high-risk") state appear to be interpretable within this framework. A number of questions arising from this line of inquiry need to be addressed in the current generation of prodromal research programs: To what extent do the neural systems affected by early and late neurodevelopmental influences overlap? Is there likely to be a schizophrenia-related disturbance in the processes associated with adolescent brain maturation, or are these maturational processes themselves intact, participating in psychosis onset only indirectly, by promoting a neurobiological context in which the early neurodevelopmental disturbances can be expressed in psychotic symptoms? What pattern of changes observable from in vivo imaging studies is consistent with a reduction in neuropil volume? We develop a framework for addressing these questions and evaluating their implications for understanding the roles of early and late neurodevelopmental influences in the etiology and pathophysiology of schizophrenia.

Adult↗

PubMed2003

Does soccer headgear attenuate the impact when heading a soccer ball?

UNLABELLED: There is increasing concern that repetitive blows to the head, such as those from heading a soccer ball, can cause measurable cognitive impairment. Reducing acceleration of impact could reduce neurologic sequelae. OBJECTIVE: To measure the effectiveness of four different types of soccer headgear in reducing the acceleration of impact. METHODS: A standard magnesium headform was instrumented with a triaxial accelerometer. A soccer ball was propelled at the headform at three different speeds known to occur in soccer play: 9, 12, and 15 m/sec (20, 26, and 34 mph). The main outcome was the peak acceleration of the headform associated with these impacts with and without protective headgear. RESULTS: Peak accelerations were found in a range from 144 m/s(2) to 289 m/s(2) (14.67-29.5 G, G = 9.81 m/s(2)). Using multivariate analysis of variance (MANOVA) methods to compare the headbands and controls, there was no significant difference in the measured accelerations at the center of gravity with or without headgear (p = 0.50). However, the interaction term of headbands, pressure, and speed was significant at F = 5.51 and p = 0.00001. Using contrasts within conditions, some headbands were found to cause a decrease in peak acceleration at the highest speed and pressure. CONCLUSIONS: Currently available headgear for soccer heading shows little ability to attenuate impact during simulated soccer heading. However, statistically significant decreases are present at the highest speeds and pressures tested, suggesting the headbands may play a role in decreasing impact for more forceful blows.

Acceleration↗