This preliminary study tackles the assessment and treatment of autobiographical memory (AbM) in relapsing-remitting multiple sclerosis (RR-MS) patients. Our aim was to investigate cerebral activation changes, following clinical improvement of AbM due to a cognitive training based on mental visual imagery (MVI). We assessed AbM using the Autobiographical Interview (AI) in eight patients and 15 controls. The latter subjects established normative data. The eight patients showed selective defective performance on the AI. Four patients were trained cognitively and underwent pre- and post-AI and fMRI. The remaining four patients took a second AI, at the same interval, but with no intervention in between. Results showed a significant improvement of AbM performance after the facilitation programme that could not be explained by learning effects since the AI scores remained stable between the two assessments in the second group of patients. As expected, AbM improvement was accompanied by an increased cerebral activity in posterior cerebral regions in post-facilitation fMRI examination. We interpret this activation changes in terms of reflecting the emphasis made on the role of MVI in memory retrieval through the facilitation programme. These preliminary significant clinical and neuroimaging changes suggest the beneficial effects of this technique to alleviate AbM retrieval deficit in MS patients. Multiple sclerosis (MS) is a neurological disease characterised by the multifocal nature of neurological lesions in the central nervous system, which results in demyelination, white and grey matter injuries and/or atrophy . As a coHowever, very few studies have been carried out in MS to investigate autobiographical memory (AbM). Briefly stated, AbM is the capacity to relive detailed events, evoking the spatiotemporal context, in which they were encountered, as they are remembered . AbM defThe clinical conclusions of our previous work led us to consider the cerebral substrates of the documented improvement of AbM functioning following the facilitation programme.Several fMRI studies in MS have been reported, demonstrating cerebral activations during different cognitive tasks, particularly attentional processes and working memory tasks –14. ThosTherefore, the aim of the present preliminary study is to better document the mechanisms sustaining the efficacy of our MVI-based facilitation programme on AbM retrieval. To this end, we test both clinical and cerebral network changes before and after facilitation. Two sets of studies on neurocognitive relationships are relevant in the present work. In the first place, the studies showing that the AbM cerebral network is widespread and recruits predominantly the left and medial cerebral regions. Among those regions, the “core” structures are the prefrontal cortex, medial and lateral temporal cortices, parieto-occipital regions, temporoparietal junctions, and cerebellum . ConcernEight patients with definite MS according to the Mac Donald criteria  were recFifteen healthy controls were also recruited to constitute a normative database for the AbM test. Exclusion criteria for all the participants included documented psychiatric illness, neurological disorder (other than MS for the patient group), and poor knowledge of French. Demographic and clinical data for the groups of MS patients are summarized in Verbal IQ was assessed with the short form [nonverbal reasoning with the Advanced Progressive Matrices Set 1 [Anterograde memory was examined using the Rey auditory verbal learning test (RAVLT) [Executive functions were assessed using the phonological and categorical fluency tests , the Brixton Spatial Anticipation test [Information Processing Speed test from the Adult Memory Information Processing Battery (AMIPB), [language was also examined, by means of the Déno 100 test [visuoperceptual and visuospatial abilities were tested using the Silhouettes and Cube Analysis subtests from the Visual Object and Space Perception Battery (VOSP) [impact of fatigue in daily life.The following baseline tests were presented to the MS patients. ort form  of the Wort form  and nonves Set 1 . Anterog (RAVLT)  for the  (RAVLT) , 30 was ion test , the Towion test  and the ion test . Concern(AMIPB),  the Stro(AMIPB),  and the 100 test . The visy (VOSP) . Finallyy (VOSP)  was propThe autobiographical interview  , scoring for all the participants was done by one scorer (A. Ernst) and 10% of the memories were analysed by a trained second scorer (five trained students), following Levine et al.'s instructions . CoefficWe used a semistructured interview to obtain a qualitative evaluation by the patients of their AbM performance. The aim of this interview was twofold to characterise more precisely the patient's AbM difficulties as well as the potential effects of those difficulties in real life and to evaluate the benefits of the facilitation programme. This interview was adapted from the Memory Experiences Questionnaire,  from whiThe cognitive facilitation programme was constructed to alleviate AbM retrieval difficulties by means of a memory facilitation technique based on MVI. This technique was presented to the patients as a “tool” to facilitate access to a given recollection and the details associated to it. Therefore, during the MVI training sessions, patients found it increasingly easier to pay close attention to details in the mind's eye, which was used spontaneously when evoking personal recollections. Moreover, they were encouraged to try and use this technique in their everyday life and if needed, to ask questions to the neuropsychologist about the use of this tool. Treatment receipt, that is, “the extent to which the patient understands the strategies or techniques taught, and demonstrates the capacity to use them” (p. 836)  was veriscreening test was based on three sub-tests of the imagery and perception battery [The  battery : the menexternal visualization exercise included 10 verbal items that the patient had to imagine and describe. . The instruction ran as follows: “I will tell you the name of something , imagine it and describe its colour, shape, size, consistency and every detail that you see.” Each item description was checked for accuracy using a list of typical traits. For each item, the patient had to describe static aspects  and an action carried out with the item . The action was imagined to be performed either by him/herself or someone else .The construction exercise of the programme consisted in figuring out complex scenes bringing into play several characters. The goal was twofold: to increase the complexity of the scene by comparison with the previous step and to introduce several characters performing different complex actions. Five items were proposed with, for each one, a first training step and a subsequent scene construction step. During the training phase, a neuropsychologist guided the patient, starting from a general idea , to more precise subheadings . Within subheadings, detailed items were distinguished . The present step was considered to be external since the participant was asked to imagine some characters and focus primarily on them, their actions and the context of the scene rather than the patient him/herself. Responses were checked for accuracy in terms of their relation to each subheading, but no list of typical or expected responses was used. The number of headings and subheadings, as well as details produced by the patients was recorded. For the scene construction phase, an item similar to the one used in the training section was proposed .The self-visualisation exercise was the training phase that shared the most similarities with AbM since the patients were asked to visualise themselves within a given scenario, to imagine it as though they were actually living the scene and to describe whatever details, sensations or feelings came to mind. The presentation was similar to that of the previous exercise, comprising a training phase  and a scene construction phase . The difference was that the participant was asked to focus his/her attention on him/herself, that is, using internal, personal knowledge. As for the previous step, we recorded the number of headings, sub-headings and details produced by the patients.The The programme consisted in 2-hour individual sessions once a week for at least six weeks. The patients performed MVI tasks of increasing difficulty, the content of which was divided into four steps. The rate of progression through these steps was flexible and could be adapted to each patient. Completion of the entire programme required at least six sessions but additional sessions were proposed if necessary to complete the programme at the patient's rhythm of training. All over the duration of the training programme, the role of the neuropsychologist was to teach how to construct visual scenes, and to provide continuous guidance throughout the training sessions.Images were acquired using a 3T MRI scanner (Siemens Verio). The image sequence was a T2*-weighted echo planar imaging (EPI) sequence . The anterior commissure (AC) and posterior commissure (PC) were identified in the midsagittal slice, and 45 contiguous slices (each 4 mm thick) were prescribed parallel to the AC-PC plane to cover the whole brain.experimental task  consisted in the evocation of unique personal past events temporally and contextually specific, occurring over minutes or hours, but no more than one day. Thirty-two pairs of words were proposed to elicit memories , covering the same life periods than previously mentioned in the AI. Based on Addis et al., [Concerning fMRI tasks, each of them was developed in two versions, randomly allocated for each patient to before and after facilitation sessions. The  et al.,  two phascontrol task was a categorical task that included 32 pairs of words, with which patients had to construct a sentence for the construction phase . Once the sentence was constructed, they had to press on the button 1 to pursue with the elaboration phase during which patients had to repeat the same sentence and to replace only the two initial words by words of the same semantic category . The fixed duration for each trial was also 20 s. Two 4-point scales, each for 4 s, followed each trial and patients had to assess the degree of difficulty (1 = very few difficulty to 4 = very high difficulty) and the degree of pleasantness (1 = very poor pleasantness to 4 = very high pleasantness). In both tasks the last rating was followed by short periods of fixation that were of jittered duration .The It is to note that in the context of this preliminary study we focused our subsequent analyses on the construction phase of AbMs, since it reflects the access to AbMs, which according to our main hypothesis is defective in MS patients. Also, due to the small number of participants, we did not use vividness and emotional ratings for further analyses.The experimental design was organised in four sequences of eight stimuli, beginning systematically with the control task and then alternating between past events and control task conditions. At the beginning of each sequence, the name of the condition was displayed on the screen for 6 s. The presentation order of stimuli within each condition was randomised.The programming and responses collection was done with E-Prime 2 software  and responses were given on a MR-compatible four-button response box. Words were displayed on a screen in white text with a black background and viewed using a mirror incorporated in the head-coil.Prior to scanning, the tasks were explained to patients and they underwent a computerised practice trial for each task in order to be familiar to the experimental design and to the rhythm of presentation of the stimuli. They also received a more specific practice trial for the control task during which they were instructed to avoid self-implication in the sentences that they had to construct  and to try and minimise mental visual associations with the words, since these two processes were of interest for the experimental task.Immediately following scanning, a postscan interview was realised for the past events condition in order to verify the adequacy of the responses and to exclude potential nonepisodic memories before the data analysis. Thus, for each past event, patients had to indicate the type of memory  and briefly, the spatial and temporal context of the event.U = 42.00;  P = 0.24) and gender distribution . Mean scores of the number of internal details and total ratings were calculated for each recall phase and used to determine the normative data. The presence of an AbM impairment for our MS patients was determined using two measures. (i) The scores for the free recall phase owing to the free recall sensitivity to detect AbM retrieval deficit, which seems to be the memory process most involved in AbM impairment in MS patients. (ii) The mean number of internal details, which was 22.12 and total ratings, which was 8.38. These two measures assess the episodic reexperiencing ability and consequently, our MS patients' AbM performance was considered to be impaired if the mean score for internal details was ≤22.12 and the mean score for total ratings was ≤8.38 for the free recall phase.The first section of the present study aimed at providing normative data for the AI. Consequently, the healthy control group underwent a single AI assessment session. The good matching between the group of healthy controls and MS patients was verified for age  except for attentional and executive functions for which mild impairment was accepted. (ii) The AbM assessment session was carried out. To be included in the study, patients had to show AbM scores below the healthy controls' mean scores as mentioned above for internal details and total ratings for the free recall phase.Prior to inclusion, MS patients underwent a two-part screening tests. (i) The neuropsychological baseline examination (described above) to control for the absence of severe cognitive impairment other than AbM deficit. To pursue with the second part, patients had to be in the normal range on all tests . A diagram summarising the study design and progression trough the study phases is presented in The blind allocation of the patients' group could not be done since the baseline examination, the AbM assessments and the facilitation programme were conducted by the same neuropsychologist (A. Ernst). Nevertheless, to control a potential influence of the investigator awareness of the patients' group allocation, the second AI scorer was blind of the group membership, in every case. Moreover, AI reports were anonymised and memories were not supplied for scoring in the chronological order of assessment .Potential differences between the two groups of MS patients for all tests of the neuropsychological baseline assessment were analysed with the Mann-Whitney test. Concerning the AI data, the Mann-Whitney test was used to detect between-group differences for each measure  for the free recall and specific probe phases. These comparisons were carried out for the two assessment sessions. Moreover, for each measure and recall phases mentioned above, a descriptive comparison between the patients' mean scores and the normative data from the healthy controls was carried out for the two AI assessments. A within-group analysis was also realised, by means of the Wilcoxon matched pairs test, to measure the degree of AbM improvement/stability between the two assessment sessions for the experimental fMRI and the control group. This procedure was used for the number of internal details and the total ratings for the free recall and specific probe phases.t-test). For all these analyses, due to the small sample of patients, the significance threshold was set at P = 0.01, uncorrected for multiple comparisons, with a minimum extent threshold of 20 contiguously activated voxels.Preprocessing and statistical analyses were conducted using SPM5 software  . Time-seNo significant difference was observed between the two groups of patients for the neuropsychological baseline examination, except for the MADRS, for which a higher mean score was observed for the control group . Howeverfirst AI assessment, no significant difference for the mean number of internal details  nor the mean total ratings  during the free recall phase were observed between the two groups of patients. The same results were obtained for the specific probe phase . Likewise, the patients' mean scores for the specific probe phase , were below those obtained by the healthy controls .Turning to AbM performances, for the first AI assessment, the mean number of internal details and the mean total ratings obtained during the free recall phase were 18.07 and 5.58, respectively, for the experimental fMRI group and 19.22 and 5.72, respectively, for the control group. For both groups, the scores were below the mean scores established with the healthy controls (see above). In regard to the U = 0.00;  P = 0.02  and mean total ratings:  U = 0.00;  P = 0.02) and for the specific probe phase . In every case, patients included in the experimental fMRI group performed significantly better than those in the control group during the second AI assessment, which corresponded to the post-facilitation examination for the experimental fMRI group.In contrast, the scores on the second AI assessment showed significant differences between the experimental fMRI and the control groups for the free recall phase  and of the specific probe phase . Improvement of AI scores for the experimental fMRI group after facilitation condition was supported by the comparisons with those of the healthy controls. Indeed, the patient group showed a normalisation of their mean score for all the free recall phase measures  and for the specific probe phase . Conversely, the comparison of the two sessions of AI assessment for the control group showed no significant differences during the free recall phase for the number of internal details  nor the total ratings . Also during the specific probe phase, no significant differences were observed for the number of internal details  nor the total ratings . For the second AI assessment of the control group, the results of the comparisons with the healthy controls' mean scores were parallel to their first AI examination, including mean scores below those of the healthy controls for the free recall phase . For the specific probe phase, an “apparent normalisation” was observed for the mean number of internal details . Qualitative analysis revealed a punctual variation that resulted in an increased score . This observation together with the absence of a significant difference for the mean number of internal details between the two AI assessments for the control group, led us to rule out a normalisation process in this case. Moreover, no improvement was observed for the mean total ratings relative to normal controls (11.08 versus 12.47).With regard to the experimental fMRI group, the within-group analysis for before and after facilitation AI assessment highlighted a significant improvement of the patients' scores on the AI for all the measures of the free recall phase , the left inferior and superior occipital gyri , the left precuneus (BA 19) as well as of parts of the lateral temporal cortex, primarily on the left  (see The paired  39) see .The reverse comparison indicated that regions showing a greater difference in activity before the facilitation programme were exclusively located in anterior parts of the brain: the two larger clusters of differential activity were indeed located in the prefrontal cortex (PFC), the first encompassing both dorsolateral and medial aspects of the PFC, the second corresponding to the dorsolateral PFC  see .In the present preliminary study, we reported AbM performance improvement following a facilitation programme in four RR-MS patients and provided evidence of changes at the neural level. The clinical improvement was verified on the AI , which eBesides our previous study,  only thrMoreover, our preliminary fMRI findings are coherent with our retrieval-deficit hypotheses, involving a frontal lobe dysfunction , 20, in With regard to our fMRI results following the facilitation programme, they are coherent with the published reports dealing with the effects of various cognitive rehabilitation programmes on neural substrates in MS patients, that is, the presence of cerebral activation changes after cognitive intervention –17.The present fMRI findings are coherent with our hypothesis since they showed that the improved AbM performance was accompanied by cerebral activation changes during the construction processes of personal past recollections. Importantly, changes in activation were observed in posterior cerebral regions, which are known to be associated with the mental processes we trained in our MS patients, that is, MVI . MoreoveBeside these quantitative changes, the differences between the before and after facilitation semi structured interviews of patients showed positive effects in terms of a greater easiness of retrieval, a greater amount of details, a better vividness and an effective use of this technique in their daily life functioning. In addition, some patients' relatives confirmed the benefits of the facilitation programme in daily life. These last points are of importance considering that the primary goal of cognitive rehabilitation is to improve everyday life functioning in patients , 56.While these preliminary findings are of interest, we are aware of some methodological limitations that restrict the conclusions that can be drawn from this study. Despite the statistical evidence obtained for behavioural and fMRI data, our sample of patients is small and replication of these results with a larger sample would be required. Additionally, a larger sample could also give the opportunity to explore more precisely the link between the changes observed for clinical and fMRI measures. With regard to the facilitation programme, the presence of a “nursing effect” cannot be ruled out until a “placebo” group of patients is included. Furthermore, long-term follow-up measures would be valuable to examine the robustness of the treatment effects.Notwithstanding these limitations, our preliminary findings seem to be promising and encourage further investigations, all the more so that our results are in agreement with findings from previous studies which have explored the effect of cognitive rehabilitation on behavioural and neuroimaging measures in MS in diverse cognitive functions (attention,  executivFinally, this preliminary study is, to the best of our knowledge, the first neuroimaging study focusing on AbM cognitive facilitation in MS patients. Expanding this type of intervention for MS patients seems necessary due to the deleterious impact of cognitive deficit in everyday life. This is particularly the case with AbM, considering its importance in everyday life functioning , 58.


Prevent Falls  trial we aim to investigate the effectiveness of a pre-tested multi-modal intervention compared to usual care in this setting.Prevention of falls in the elderly is a public health target in many countries around the world. While a large number of trials have investigated the effectiveness of fall prevention programs, few focussed on interventions embedded in the general practice setting and its related network. In the PreFalls is a controlled multicenter prospective study with cluster-randomized allocation of about 40 general practices to an experimental or a control group. We aim to include 382 community dwelling persons aged 65 and older with an increased risk of falling. All participating general practitioners are trained to systematically assess the risk of falls using a set of validated tests. Patients from intervention practices are invited to participate in a 16-weeks exercise program with focus on fall prevention delivered by specifically trained local physiotherapists. Patients from practices allocated to the control group receive usual care. Main outcome measure is the number of falls per individual in the first 12 months . Secondary outcomes include falls in the second year, the proportion of participants falling in the first and the second year, falls associated with injury, risk of falls, fear of falling, physical activity and quality of life.Reducing falls in the elderly remains a major challenge. We believe that with its strong focus on a both systematic and realistic fall prevention strategy adapted to primary care setting PreFalls will be a valuable addition to the scientific literature in the field.NCT01032252 Among elderly people falls are a major health problem associated with significant morbidity and economic burden. Based on the available data it is estimated that about 30% to 40% of community-dwelling older persons experience at least one fall per year with a high proportion falling more often than once -3. TheseA large number of clinical trials have investigated strategies to prevent falls or injurious falls. These studies have been summarized in several systematic reviews ,10,16,17The systematic reviews ,16 raiseSeveral current guidelines ,27-29 reThe primary aim of PreFalls is to investigate whether the implementation of a multimodal intervention in the German primary care setting , consisting of 16 weeks of group exercise in combination with an individualized home training program will significantly reduce number of falls per individual and risk of falling in community-dwelling elderly with high risk of falls compared to usual care. The secondary aim is to explore effects on the incidence and frequency of fall-related injuries, on balance, strength and mobility, fear of falling and quality of life. For this study a fall is defined as "an unexpected event in which the participant comes to rest on the ground, floor or at a lower level" .PreFalls is a controlled multicenter prospective study with cluster random allocation of participating general practices to an experimental or a control group. The study is performed in two regions (greater Munich and Nuremberg areas) in Bavaria, southern Germany. Two randomisation lists are computer generated by a statistician otherwise not involved in the study. The lists are stored by the two regional study coordinators. After the definitive inclusion of a general practice into the study, the coordinator of the respective region calls the coordinator of the other region who, after registering the practice, hands out the allocation information.The study protocol was approved by the ethics board of the faculty of medicine of the Technische Universitaet Muenchen. The study design takes into account the principles set out in the Helsinki declaration . All patients have to sign informed consent forms.General practitioners interested in participating in the trial are recruited from local peer groups , from networks affiliated to the Institute for Family Medicine, Technische Universitaet Muenchen and the Institute of Sports Science and Sports, University Nuremberg/Erlangen as well as by advertising in medical journals. Participating physicians have to be licensed general practitioners working with elderly persons in a community dwelling setting. Physicians and one staff member  of each participating practice in both experimental and control group are trained in workshops lasting 3.5 hours. The workshop introduces goals, methods and logistics of the study, provides background knowledge on falls  and includes a practical training part on the methods for fall risk assessment. For the attendance of the workshop physicians gain Continuing Medical Education (CME) points.The target population of the study are community-dwelling persons aged 65 years and older with a high risk of falls. To be included at least one of the following criteria has to be met (see section measurements for a detailed description of the tests): fall within the last 12 months, fear for falling , chair-sPhysicians taking part in the study are asked to name a certified local physiotherapist or an university trained sport scientist interested to act as exercise instructor (trainer) for the fall prevention program. If the general practitioner cannot name a trainer the coordination team will identify a qualified person. If the practice is randomised to intervention program the study centre invites the trainer to a special course lasting 8 hours. The course covers the standardised evaluated intervention program -41 as weThe intervention investigated in PreFalls is a 16 week program with focus on fall prevention. It is based on a program which has been successfully tested in a previous trial  but expaTable For the full study period of 24 months participants are asked to fill in a fall diary. For each day they mark whether they fell or tripped. The monthly calendar is sent to the study coordinators during the first week of the following month in a prepaid envelope. When a fall occurs, detailed information is obtained through structured telephone interviews  subjects are asked to stand up from a standard chair with a seat height of between 40 and 50 cm, walk a distance of three meters at a normal pace, turn, walk back to the chair and sit down. Measurement of time (in seconds) begins at the word "go" and ends when the subject's back touching the backrest of the chair, with a shorter time taken indicating better balance ability and mobility ,43. The Fear of Falling is assessed with the German version of the Falls Efficacy Scale International (FES-I) , physicaSample size calculation was performed using IcebergSim software , which allows considering intracluster correlation, which is a serious issue in cluster-randomized trials.Calculations are based on assumptions regarding the proportion of individuals with at least one fall during a 12-month follow up period. Since expected numbers of falls per individual was around one , theBased on the trial by Spice et al.  we assumAnalyses of the primary endpoint, number of falls per individual within a 12 months follow up period, will be performed on base of the full-analysis set (complete information regarding the primary outcome parameter). Within this population, all subjects are considered regardless to their actual compliance and the exercise-compliance of the responsible physiotherapists respectively (intention to treat principle). The statistical analysis of the primary endpoint will be considered at a two-sided level of significance of 5%.For the confirmatory analysis of the primary endpoint, a negative binominal regression model  will be A detailed statistical analysis plan (SAP) will be defined in advance to the final analysis, to fix detailed statistical considerations with regard to further data analyses, multiple test issue, missing value imputation and sensitivity analyses.Reducing falls in the elderly remains a major challenge. Falls are common in older persons and can cause notable decreases of quality of life due to fear of falling, restricted mobility and loss of autonomy as well as large costs for health care systems -3,50,51.We believe that with its strong focus on both a systematic and realistic fall prevention strategy adapted to a primary care setting PreFalls will be a valuable addition to the scientific literature in the field.The authors declare that they have no competing interests.MS, EF, PL and WB designed and managed the study. KL was responsible for criticizing the study design. Methodological support was yield by TS, KL and AS. WB, KL, MS and EF wrote the main part of the article. TS was responsible for defining the statistical approach and writing the statistical section of the manuscript. MH and KP reviewed the manuscript and gave valuable input for improvement. Grant application was organized by MS, EF, PL and MH. All of the authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2318/11/7/prepub


SOHO satellite data reveals geophysical changes before sudden changes in the Earth's Sun-Earth environment. The influence of extragalactic changes on the Sun as well as the Sun-Earth environment seems to be both periodic and episodic. The periodic changes in terms of solar maxima and minima occur every 11 years, whereas the episodic changes can happen at any time. Episodic changes can be monitored by cosmic ray detectors as a sudden increase or decrease of activity. During these solar and cosmic anomaly periods the environment of the Earth is affected. The Star-Sun-Earth connection has the potential to influence the thermosphere, atmosphere, ionosphere and lithosphere. Initial correlation of the cosmic and Sun-Earth connection has shown the possibility of predicting earthquakes, sudden changes in atmospheric temperatures and erratic rainfall/snowfall patterns. We are continuously collecting data for different environmental parameters. Sudden heat or cold waves, tornados, erratic rainfall and snowfall are being observed and their forewarning has been attempted. Efforts have been made to understand the influence of stars and the Sun, which, although they are distant objects in space, can influence the environment of the Earth. Extragalactic cosmic rays measured as neutron counting rate, represent an energy spectrum, which is being received by the solar system from the distant stars; the particles of cosmic rays are atom –nuclei with almost light velocity , 7. The E-flux induces the variation of production of ionosphere currents. Ionosphere currents are produced by geomagnetic storms originating from the Star-Sun-Earth environment. Ionosphere current variation has a direct influence on atmospheric temperature , 11. On 2.It was not possible to explain the reason of observed solar maximum in every 11th year . However, the cosmic effect can reduce the development of sunspots as well as CME. A cloud with 1,000 atoms per cubic centimeter could compress the Sun's magnetic field to within a few AU of the Sun  , 17, 18.th October 2003 has shown its effects on the environment of the Earth. It began at approximately 1,700 UT when a Coronal Mass Ejection (CME) originating from an X10-class explosion from giant sunspot 486 struck our planet's magnetic field. Proton flux, E-flux and planetary Kp indices showed a sudden rise from 17.00 UTC on 29th October. Proton flux was more than 10 4 Mev and electron flux jumped to 106 Mev, while K-indices was at a peak value of 9. The effect of this CME was observed in crustal disturbances in seismically active parts of the earth. An earthquake of 6.8 on the Richter scale was recorded off the coast of Honshu, Japan on October 31. The Honshu area of Japan is on an active fault which makes it earthquake prone . The effect of Earth directed Coronal Mass Ejections (CME) from the Sun reveals a sensational impact on the atmosphere and geosphere. It has been observed that there is a close relationship between Kp values (Planetary Indices) and particle flux (Electron flux and Proton Flux) with the CME. The response of the magnetosphere to interplanetary shocks or pressure pulses can result in sudden injections of energetic particles into the inner magnetosphere. It has been recorded that 36 hours before the occurrence of an earthquake, Kp values and E-flux increase drastically. The phenomenon was recorded during the Kutch, Gujarat, earthquake of 2001. When the earth directed CME glances along the magnetic shield, local disturbances in the atmosphere of the Earth have been noticed. During the monsoon of 2003 there were continuous CME glances with the magnetic shield from a group of sunspots, which are responsible for the abnormal record rainfall in northern parts of India, especially Delhi, Himachal Pradesh and Haryana states, while states like Madhya Pradesh, Tamilnadu and other southern parts of India did not receive adequate rain. It has been discovered that the position of active sunspots and their effects on Earth co-ordinates are mirror images of each other. If the Earth directed CME impact is targeted on the magnetic shield it is responsible for a sudden increase in Kp, E-flux as well as Proton flux. The sudden increase in these parameters was found to be responsible for the change in geosphere. Contrary to this phenomenon atmospheric perturbation was preceded by the fall in Kp, E-flux and Proton flux. The Earth's magnetic field acts like a shield, protecting it from the constant stream of tiny particles ejected by the Sun, which is known as the ‘solar wind’. The solar wind itself is made up of hydrogen atoms, broken into their constituent pieces: protons and electrons. When electrons find routes into our atmosphere, they collide with and excite the atoms in the air. When these excited atoms release their energy, it is given out as light, creating the glowing ‘curtains’ we see as the Aurora Borealis . Protons ‘stealing’ electrons from the atoms in our atmosphere cause daytime proton auroral spots. The changes in the particle flux depend on changes in magnetic and electric fields . Particl2.1.To conclude these considerations let us look at most impressive demonstration of the influence of solar activity on the lower layers of our atmosphere. The new concepts concerning solar-terrestrial relationship research take into account the primary processes of the whole Sun-Earth system. Cyclic changes of the general atmosphere circulation are of prime interest as are the transformation and recurrence of circulation forms, which characterize planetary wave dynamics. The changes of the atmospheric pressure in geomagnetically and electronically excited cases (including the solar activity effect) in comparison to the variations in geomagnetically and electronically quiet cases.Solar-atmospheric interactions were observed more in the Northern India. The Delhi, Haryana, Meghalaya Mizorum stretch of India received more than 100% of the normal rainfall during the monsoon period of 2003.The activation of the energetically active regions occurs after the geomagnetic disturbances. The corresponding regions are Delhi-Haryana-U.P-Bihar-Bengal-Orissa-M.P-Meghalaya-Mizoram with high temperature contrasts and a vertical wind shift together with baroclinic instability.The basic disturbances appear after the geomagnetic ones in the form of the planetary wave structures with wave numbers from 3 to 4. This corresponds to the result about the selective properties of the baroclinic instability and fits the earlier obtained results on the increase of kinetic energy of such waves after the geomagnetic disturbances. Recurrence of drought after 12 years in various parts of the Earth due to irregular rain fall is due to changes in the ionosphere triggered by the change in the Electron flux during earth directed CME.One may conclude that the helio-geomagnetic activity comes out as an agent promoting permission of instability mechanisms in the atmosphere, liberation of useful potential energy and generation of vertical kinetic energy. The disturbances arisen in energetically active zones would be transported along the main zonal flow generating planetary waves.2.2.In recent years, earthquake prediction has moved from being a guessing game to more of a science. The primary obstacle to understanding earthquakes was geologists' refusal to accept the concept of tectonic plate movement . Today we know that the crust of the Earth does float on a “sea” of magma, and that earthquakes and volcanism occur primarily in those zones where one plate is rubbing against another - “fault lines”. This model is not perfect because there are often “rogue” quakes which strike in unexpected areas, but it works extraordinarily well. Nonetheless, there are certain aspects of earthquakes that lend themselves to predicting their incidence. One factor is that oscillations in the planet's magnetic field often occur right before quakes; these oscillations, as noted above, often correlate strongly with astronomical and solar events. But geologists are afraid to say something ridiculous along the lines of “sunspots cause earthquakes”, despite the fact that, in a certain sense, they do… radio wave propagation (e.g. ionospheric “whistlers”), which appears to play a role in earthquakes, and it can be studied by closely monitoring the impact of the solar wind on the ionosphere. We are interested in the sun because of the many influences it has on our lives and our environment. Beyond the obvious considerations of heat and light, some examples of these direct and indirect solar influences are the effects on short-wave radio communications, navigation, use of satellites for communication and navigation, hazards to humans and instruments in space, electrical power transmission, geomagnetic prospecting, gas pipeline monitoring, and possibly weather, seismotectonics and human and animal behavior. The Solar maximum has come again after 2000. It has been noticed that the number of sunspots are continuously on the rise. Earth directed Coronal Mass Ejections (CME) were very frequent during 2000–2002 . ContinuEarthquake lights have been reported before the Matsushiro swarms during the year 1965 to 1967 and before some recent earthquakes in China. During the Pattan earthquake (Pakistan) of December 1974, reliable forest officers and doctors far away from the earthquake epicenter observed earthquake lights coming from the sky. Before the occurrence of the Jabalpur earthquake (India) of 1997 a light source came from the sky before the occurrence of the earthquake . ExperimThe occurrence of lights during earthquakes may be explained by the sunspot activities during solar maximum. The Earth has a magnetic field with north and south poles. The magnetic field of the earth is surrounded in a region called the magnetosphere. The magnetosphere prevents most of the particles from the sun, carried in solar wind from hitting the earth. Some particles from the solar wind can enter the magnetosphere. The particles that enter from the magnetotail travel toward the Earth and create the aurora oval light shows. Dangerous particles are not able to penetrate to the Earth's surface but are forced by the magnetic field to move around the Earth. Particles gain entry through the cusps that are shaped like funnels over the polar regions or they gain entry far downstream from the Earth. The particles that enter downstream travel toward the Earth and are accelerated into the high-latitude ionosphere and produce the auroral oval light shows. Since the most intense auroras occur at solar maximum, it was once thought that the Sun hurled material out during these raised times of solar activity and that that material funneled directly into the polar cusps. However, we now understand that the electrons that cause the auroras come in downstream or from the Earth's magnetic tail. These electrons that enter at the magnetotail are energized locally within the magnetosphere. The solar wind, emanating from the Sun, injects plasma into the magnetosphere and transfers energy to it. Several times a day, the magnetosphere undergoes a disturbance called a substorm. As the substorm grows, most of the solar wind energy is dissipated within the magnetosphere, ionosphere and upper atmosphere.This disturbance ultimately causes auroral displays, the acceleration of charged particles to high energies, the emission of intense plasma waves and electromagnetic waves, and the generation of strong ionospheric currents that produce significant changes in the upper atmosphere. These waves and currents often result in severe problems on Earth with communications, power supplies, and spacecraft electronics.Other higher energy particle radiation that could pose a danger to life here on Earth is forced to drift around the Earth within two large donut-shaped regions called the radiation belts. Invisible magnetic fields are the reason that particle radiation moves in this way. Before the occurrence of the catastrophic earthquake on 26th January 2001 at Kutch, IMAGE spacecraft captured an invisible magnetic tail at Gujarat, India. This is a major precursor of the earthquake. More advanced researches should be conducted to identify the geolatitude-longitude which is likely to be affected by the magnetic tail, which may trigger earthquakes in active fault areas. A sudden rise in electron flux and planetary indices 36 hrs before 26th January 2001 earthquake of Kutch,  and its sudden fall before the occurrence of earthquake was observed. Similar observations were made in several other cases also including the Andaman Islands. Coronal Mass Ejection, increase in Kp values (more than 4), sudden increase in Kp indices and electron flux can be forewarning of seismic disturbance in earthquake prone active fault areas and other environmental changes of earth. On 24th January 2001 an Earth directed coronal mass was ejected, which took two days to reach the earth's surface and may have triggered the active fault in the Katrol Formation of Kutch to produce a major earthquake of magnitude 7.9 in Gujarat, west coast of India. This area was reported as seismically active. In the entire world, a total of 65 earthquakes have been reported on the same day. Earth directed Coronal Mass Ejection produced a suspected invisible tail of electrified gas. IMAGE spacecraft spotted the tail, which streams from earth towards Sun. The region laced by earth's magnetic field, called the magnetosphere, dominates the behavior of electrically charged particles in space near earth and shields our planet from the solar wind. Explosive events on the Sun can charge the magnetosphere with energy, generating magnetic storms that occasionally may affect the active faults in igneous/sedimentary/metamorphic geosphere and change its viscosity to trigger the shallow focus earthquake. It may be interesting to observe the series of Earth directed Coronal Mass Ejections and the occurrence of earthquakes globally. It is not a specular correlation that an earthquake of 6.0 magnitude that occurred on 11th August 2003 at Andaman Island of Indian subcontinent was preceded by a rise in Kp indices, Electron flux as well as X-ray flux.3.th December 2004 and 23rd February 2005 hailstorms and snowstorms were reported in the Northern Hemisphere, while in the tropics a sudden drop in temperature led to foggy and smoggy conditions. An earthquake measuring 9.0 of Richter scale on 26th December followed the sudden changes in the environment. An earthquake measuring 6.4 on the Richter scale occurred on Tuesday 22 February in Zarand, Kerman Province (750 KM south-east of Tehran) at 05:55 local time. Weather conditions in the region were difficult as there was heavy snowfall, resulting in a number of road blockades.It can be concluded that a sudden l drop in Kp, Electron flux, Proton flux and X-ray flux is an indication of atmospheric disturbance . This inHere I show a theoretical correlation between Starbursts, Solar minimum, Sun-Earth environment and snowfall.a)th December 2004 and 22nd-23rd February 2005. Movement of clouds, rainfall and development of fog and smog on lower altitudes of lower latitude has also been recorded on these days. Although the Sun is known to be a variable star, its total output of radiation is often assumed to be so stable and in general its' possible impact on climate is neglected. Testimony to this assumption is the term that has been employed for more than a century to describe the radiation in all wavelengths received from the Sun, the so-called solar constant, whose value at the mean Sun-Earth distance is a little over 1.37 kW / m² per unit of surface, but in truth, the solar constant varies. Earth's magnetospheric current systems are directly driven by the solar wind and are predictable in a rather deterministic sense 18. Variation in the intensity of galactic cosmic radiation observed on the ground from 1959 to 2000, The permanent component of cosmic radiation comes from the galaxy. It consists of very highly charged particles ejected by the gigantic explosions of supernova, massive stars that have reached the end of their days. These particles are atoms, which have been stripped of their electrons because of the temperatures within these giant stars. They are of different types, primarily hydrogen nuclei (protons) and helium nuclei , but also there are heavier nuclei such as iron and nickel. They travel at close to the speed of light. We see that during periods of high solar activity, the cosmic radiation is less intense, as the cosmic effect suppresses the formation of sunspots. During the impact of cosmic rays with the atmosphere of the Earth, ionization takes place. During this ionization the thermal energy is utilized to produce a regional fall in the temperature of the earth, which may lead to sudden snowfall in higher latitude and altitudes of the Earth.2 neutron counts h-1) compared to low cosmic ray flux, the chance of an overcast day increases by 20%. They also observed that during Forbursh events simultaneous decreases occur in the diffuse fraction. Cosmic ray variations are possible to correlate with geomagnetic storms, which changes the ionospheric currents and triggering of seismic activities . For hailstorm or snowstorm or heavy cloud formation it is essential that Earth's atmosphere should have a sudden increase in micro dust particles. Data of star storm shows that recent hailstorm has developed subsequently after the star storm. The reason for the weakening of the Sun's magnetic shield is the increased solar activity, which leads to a highly disordered field configuration. In the mid-1990's, during the last solar minimum, the Sun's magnetic field resembled a dipole field with well-defined magnetic poles , very much like the Earth. Unlike Earth, however, the Sun reverses its magnetic polarity every 11 years. The reversal always occurs during solar maximum. That's when the magnetic field is highly disordered, allowing more interstellar dust to enter the Solar System. It is interesting to note that in the reversed configuration after the recent solar maximum , the interstellar dust is even channeled more efficiently towards the inner Solar System. It was expected that more interstellar dust would occur from 2005 onwards, but it has appeared in December 2004. The Sun has entered the zodiac's 13th house. An interstellar wind hit our planet. It's a helium-rich breeze from the stars, flowing into the solar system from the direction of Ophiuchus. The Sun's gravity focuses the material into a cone and Earth passes through it during the first week of December. Earth was inside the cone during 25th December 2004 and 23rd February 2005. Grains of stardust are very small, about one hundredth the diameter of a human hair, hence they do not directly influence the planets of the Solar System. However, the dust particles move very fast, and produce large numbers of fragments when they impact asteroids or comets. It is, therefore, conceivable that an increase in the amount of interstellar dust in the Solar System will create more cosmic dust by collisions with asteroids and comets. It is possible that the increase of stardust in the Solar System will influence the amount of extraterrestrial material that rains down to Earth. How the Earth's surface temperature adjusts to a given change in star-solar radiation depends on the processes by which the climate system responds to variations in the energy it receives . Some of these factors amplify the effects of changes that are imposed; others reduce them. Lumped together, they make up what is called the sensitivity of the climate system, which indicates the number of degrees by which the mean-surface temperature will be raised or lowered in response to a given change, up or down, in solar and/or extra terrestrial radiation or any other climate driver. The temperature data of west USA shows a declining trend of -0.68 degree F /decade, which is considered to be anomalous in the rising trend of 0.05 deg F /decade for USA.The magnetic field around the Earth protects the planet from cosmic rays. This field is stronger when the Sun is more active i.e., emitting more ultraviolet radiation and displaying more sunspots hence fewer cosmic rays can penetrate Earths atmosphere. A direct influence of cosmic rays with the fall in temperature of whole world was observed during the years of starburst . A correThus, it is concluded that starbursts influences variables of the Sun-Earth environment, which in turn leads to climate change including snowfall. Sudden change in these variables like Kp, Proton flux and E-flux influence environment of the Earth abruptly . If E-fl


Profile-based comparison of multiple sequence alignments is a powerful methodology for the detection remote protein sequence similarity, which is essential for the inference and analysis of protein structure, function, and evolution. Accurate estimation of statistical significance of detected profile similarities is essential for further development of this methodology. Here we analyze a novel approach to estimate the statistical significance of profile similarity: the explicit consideration of background score distributions for each database template (subject).Using a simple scheme to combine and analytically approximate query- and subject-based distributions, we show that (i) inclusion of background distributions for the subjects increases the quality of homology detection; (ii) this increase is higher when the distributions are based on the scores to all known non-homologs of the subject rather than a small calibration subset of the database representatives; and (iii) these all known non-homolog distributions of scores for the subject make the dominant contribution to the improved performance: adding the calibration distribution of the query has a negligible additional effect.The construction of distributions based on the complete sets of non-homologs for each subject is particularly relevant in the setting of structure prediction where the database consists of proteins with solved 3D structure  and therefore structural relationships between proteins are known. These results point to a potential new direction in the development of more powerful methods for remote homology detection. The accuracy of detecting remote protein sequence relationships is essential for the inference and analysis of protein structure, function, and evolution. With the sample of solved structural folds growing close to the complete coverage of protein world , the abiComparing protein families, as profiles or hidden Markov models (HMMs) derived from multiple sequence alignments (MSA), rather than individual sequences, introduces information about the evolutionary constraints on sequence patterns dictated by protein structure and function, and therefore improves the quality of remote homology detection -11. The Although highly effective, this query-centered approach to the statistical significance cannot adequately reflect the uneven properties of different MSAs in the search database: subjects have different propensity to appear as a highly scored match when compared to an unrelated query. As adjustments to these propensities, multiple implicit schemes have been proposed that account for the subject's properties at the step of alignment score calculation, ranging from low-complexity filtering  to compoHere we consider an explicitly symmetrical approach to the background modeling at the step of estimating statistical significance, based on combining the background distributions for both query and subject. As a first step in this direction, we use a primitive scheme to combine query- and subject-based score distributions, and show that (i) inclusion of background distributions for the subject increases the quality of homology detection; (ii) this increase is higher when the distributions are based on the scores to all known non-homologs rather than a calibration subset of the database representatives; and (iii) these distributions make the dominant contribution to the improved performance: the removal of query-based calibration does not significantly deteriorate the performance.Distributions of scores for the comparisons of a query to real database profiles  are often used to estimate the statistical significance of a similarity between this query and any given profile. A major problem in the construction of these distributions is filtering out query homologs that should not be included in the assessment of the statistical background. As a solution to this problem, a current state-of-the-art HHsearch method , builds Although this approach provides individualized treatment of each query, it does not explicitly distinguish between various profiles in the search database, which also differ in their propensity to produce random high-scoring alignments with non-homologs. Here we consider a further development of this scheme, which involves the combination of individual background distributions for the query and each subject. Although the same calibration database can be used for both query and subjects, its composition is usually different from the search database: different folds have a different representation in the protein world, varying from a single tight sequence family to a plethora of divergent proteins as in Rossmann-type folds, TIM-barrels, imunnoglobulins, etc. As a way to preserve the structure of the search database in the background distributions, we consider constructing these distributions from the comparisons of the subject to all of its non-homologs in the search database. This approach is possible in the particular setting of structure prediction, where the database consists of proteins with solved 3D structure , which in most cases allows for a straightforward assignment of their homology relationships.As a method to produce profile-profile similarity scores, we use our recently developed scoring system implemented in PROCAIN for profile comparison . In brieFirst, we assess the E-values based on two types of background score distributions: query calibration distribution alone and mixed with a background distribution for each individual subject. We consider several ways of modeling the subject distributions that involve the comparison of a subject to different profile sets representing unrelated proteins Fig. . We use As shown in Fig. The separate evaluations of these statistical schemes on queries from different major SCOP classes are shown in Additional File To assess the role of query calibration in our symmetrized scheme, we compare the method's performance in the settings with background distributions for the subjects used alone and mixed with the calibration distribution for the query. Fig. -5 Vs 0.2808 ± 7 10-5). This result suggests that the knowledge of all subject's non-homologs is a dominant factor in the improvement of the statistical estimates. This dominance has a potential practical implication: when homology relationships between database entries are defined, the calibration of query may become unnecessary since it does not contribute to the detection accuracy.Calibration of subject alone on the set of fold representatives leads to slightly better performance than calibration of query Fig. , with thThe separate evaluations of these statistical schemes on queries from different major SCOP classes are shown in Additional File A possible explanation of this relatively weak influence of query calibration on the performance might be the difference in the sizes of score samples produced by the comparison to the calibration database (~1000 fold representatives) and all defined non-homologs in the full database (~4000 entries). In our original implementation, the scores from these two sources are mixed without additional weighting, therefore the contribution of the query calibration distribution is several fold smaller than the contribution of subject's distribution. As a control, we increase the weight of the query calibration in the mixture and observe the resulting performance Fig. . InteresThe separate evaluations of these statistical schemes on queries from different major SCOP classes are shown in Additional File Since the use of the full set of subject's non-homologs has a significant advantage over the use of the calibration subset Fig. , it is iThe separate evaluations of these statistical schemes on queries from different major SCOP classes are shown in Additional File Using MSA rather than single sequences for homology detection provides stronger similarity signals: patterns of residue usage at individual positions, conserved motifs, interdependence of residue content at different positions and other information help detecting remote relationships in the cases where individual sequences diverged beyond recognition. However, these signals create new challenges for the discrimination between MSA similarities caused by homology and produced by chance, for example by a local structural similarity involving a few SS elements in globally different proteins.The calculation of profile-profile similarity scores in PROCAIN already includes implicit consideration of both query and subject properties ,10 in a Here we analyze a novel approach to estimating statistical significance of similarity between MSAs, based on the explicit consideration of background distributions for both query and subject. In order to conduct a proof-of-principle study that would not rely on a specific statistical treatment of the data, we use a primitive mixing of PROCAIN scores and simple EVD approximations of the distributions, rather than more elaborate statistical formalisms. We find that (i) the quality of estimation of statistical significance for a given similarity score improves by incorporating information about statistical properties of the subject, and (ii) this improvement significantly increases when the full set of subject's non-homologs, rather than a subset of fold representatives, is used to infer the background distribution.Our most unexpected finding is that the improvement in the performance is dominated by using the score distributions for all non-homologs of the subject, and that considering the calibration distribution of the query has almost no additional effect Fig. . ConceptThe presented results suggest a potentially important approach to increasing the quality of remote homology detection. Effective implementation of this approach in new computational methods will require additional research in at least two areas: (i) fuller usage of the information about homology relations in the search database, for example, consideration of scores for homologs; and (ii) more detailed and accurate statistical treatment of mixed background score distributions.We present and analyze a novel approach to the estimation of statistical significance of profile-profile similarities, based on explicit consideration of both query and subject background score distributions. This approach provides a higher quality of homology detection than query calibration alone. A significant additional increase can be achieved by using the knowledge of actual homology relationships between subjects in the search database, which allows for a more representative sampling of statistical background for each subject. The presented results can serve as a basis for the development of more powerful methods for remote similarity detection.As a search database, we use the set of 4147 PSI-BLAST MSAs of homologs for SCOP domain representatives with less than 20% sequence identity that was constructed and extensively used as a part of a previously described benchmarking system . MSAs foA we calculate the set of similarity scores against all non-homologous profiles and find the mean value of this set, <s>A. Then we process this set by subtracting the mean score of the counterpart profile B from each score sAB between A and B: s'AB = sAB - <s>B. The resulting distribution of scores {s'AB} for profile A is stored. In a similar fashion, for every profile C in the calibration database, we pre-compute the set of similarity scores {sCA} against entries of the searching database and then calculate the mean value of this set, <s>C. When query profile Q is compared to profiles in the calibration database; the mean score of each profile C is subtracted from its similarity score to the query sQC: s'QC = sQC - <s>C: During the actual search, when query Q is compared to profile A in the searching database, the distributions of adjusted calibration scores for the query, {s'QC}, and for the subject, {s'AB}, are analyzed and combined according to the scheme being evaluated. The resulting distribution is fitted with EVD to estimate EVD parameters k and λ, which are then used in Karlin-Altschul formula to calculate E-value: E = kmneS-λ, where m and n are effective lengths of the two profiles and S = sQA - 0.5(<s>QC + <s>A) is the adjusted score for query against the database profile A [s'QA = sQA - <s>QC, i.e. the score adjusted on the query side by the mean of query's calibration scores, and s'AQ = sQA - <s>A, i.e. the score adjusted on the subject side by the mean of subject's scores to its non-homologs.To produce profile similarity scores, PROCAIN  complemerofile A . The latS = sQA - 0.5(<s>Q + <s>A), where <s>Q is the query's mean score against all non-homologous profiles.In the setting when the calibration database is substituted by all query's non-homologs in the search database Fig. , the queTo assess the detection quality, we build receiver operating characteristic (ROC) curves based on the results of searches use in the database of ~4000 SCOP representatives selected at 20% sequence identity of structure-based alignment described above. True and false positive definition combines expert assignments of superfamilies by SCOP and our automated SVM classifier based on multiple scores for sequence and structure similarity of the two proteins, applied as previously described . These hvs. TIM barrels). Forcing such cases to either of the two categories might bias the evaluation protocol. Therefore, following others, we use the third category of 'undefined' relations and establish the corresponding lower and higher thresholds of SVM score to define the three areas: dissimilar, unknown and similar [The resulting SVM makes a binary classification of domain pairs into the categories of similar and dissimilar. However, there is a number of domain pairs that share short regions of similarity but are poor global structural templates for each other Σi = 1nti, where ti is the number of true positives that were ranked ahead the ith false positive in the list, and T = 474929 is the total number of true positives in the dataset.ROC values and their error estimates are calculated as described in : for theAs negative controls, we build subject-based score distributions from the comparison of the subject to the set of randomized profiles produced by shuffling positions of original database profiles. To assess the contribution of predicted SS to the accuracy of the statistics, we compare the performance with the original SS assignments preserved in the randomized profiles to the performance with the artificial uniform coil SS assigned to all positions.RS generated the data , analyzed results, and drafted the manuscript. YW conceived of the original idea of using subject-based distributions and their importance for statistical estimates, as implemented it in the PROCAIN method, and generated part of the data . NG conceived of the study and participated in its design and coordination. All authors read and approved the final manuscript.Performance of statistical schemes on different SCOP classes. Supplementary Figures 1-4 (MSWord file) with ROC plots on separate SCOP classes.Click here for fileSCOP domains included in the search database. List of SCOP domain representatives included in the search database (text file).Click here for fileSCOP domains included in the calibration database. List of SCOP domain representatives included in the calibration database (text file).Click here for file


We present a simple and effective method for combining distance matrices from multiple genes on identical taxon sets to obtain a single representative distance matrix from which to derive a combined-gene phylogenetic tree. The method applies singular value decomposition (SVD) to extract the greatest common signal present in the distances obtained from each gene. The first right eigenvector of the SVD, which corresponds to a weighted average of the distance matrices of all genes, can thus be used to derive a representative tree from multiple genes. We apply our method to three well known data sets and estimate the uncertainty using bootstrap methods. Our results show that this method works well for these three data sets and that the uncertainty in these estimates is small. A simulation study is conducted to compare the performance of our method with several other distance based approaches , and we find the performances of all these approaches are comparable in the consensus setting. The computational complexity of our method is similar to that of SDM. Besides constructing a representative tree from multiple genes, we also demonstrate how the subsequent eigenvalues and eigenvectors may be used to identify if there are conflicting signals in the data and which genes might be influential or outliers for the estimated combined-gene tree. Phylogenetic analyses with individual genes will often result in conflicting topologies for the same set of taxa in the estimated evolutionary trees When a large number of taxa are examined, distance-based methods are useful tools for building a starting tree to be further refined by maximum likelihood methods. Distance-based methods typically combine the distances inferred from multiple genes to obtain a summary measure of distances for a common set of taxa. A few methods to do this have been proposed. The average consensus supertree (ACS) In this paper we consider an alternative method for deriving multiple gene tree estimates based on singular value decomposition (SVD). Stuart, Moffett and Leader We begin by transforming the dissimilarities or distances for all pairs of taxa into p-vectors where Let The distances between pairs of taxa in a phylogenetic tree can be expressed as a linear combination of the estimated branch lengths between those taxa for a given tree topology The first eigenvectors If the underlying trees of different genes are not consistent or there is large noise in the data, the direction Geometrically, each row of The major source of variability from the origin for rows of X lies on the direction Many methods for calculating pairwise distances for a gene will result in larger distances for the fast evolving genes. For example JTT based distances Typically the computational complexity of SVD for a We will quantify the ability of the SVD approach for inferring accurate trees by comparing its performance with several other distance-based approaches in the consensus setting where distance matrices combined have identical taxa. Criscuolo, et al. results section. There are 22 taxa and 25 genes with the sequence lengths of genes the same as those in the Chloroplast data set. We first generate 100 random 22-taxon trees using the standard Yule-Harding process via the R8S program Data are simulated using the same simulation protocol used by Next, to simulate the evolution of different genes corresponding to each of these simulated “true” trees, 25 “gene” trees were generated from each of these 100 trees. Note that instead of simulating DNA sequences as in Since the sites of the simulated sequences are independent, it is more sensible to use the JTT-based distances instead of SpCov-based dissimilarities. Thus we only calculate the JTT-based distance matrices. This means that there is some misspecification in the model, since the trees were simulated using the cpRev model. For each of the 100 “true” trees, we have 100 replicates. For each replicate, we constructed a combined distance matrix using each of the methods SVD, From Three different data sets are used in this paper to illustrate our method. We begin with an exploratory analysis on a non-controversial primate data set. We then apply our methods to the nematode data set published in The method is illustrated using both the common scaling spectral covariance (SpCov) based dissimilarities Hylobates agilis (gibbon), Pongo pygmaeus (orangutan), Gorilla gorilla (gorilla), Pan trogodytes (chimp) and Homo sapiens (human). It consists of thirteen mitochondrial protein-coding genes. The phylogeny for the primate data set is well established with the species tree shown as in The method is first applied to the simple primate data. The primate data set has five taxa: The four combined-gene trees from BIONJ and FITCH methods, using the first right eigenvectors of the SVD of the The top panels of For the trees estimated from the JTT-based distances the bootstrap support was evaluated from 1000 bootstrap samples obtained by sampling individual characters from sequences with replacement. A majority-rule consensus tree is computed using the CONSENSE programme in PHYLIP Caenorhabditis elegans, which is used in our analysis, as a representative nematode. Their results indicated a strong relationship between the nematode and the arthropods. However, Blair et al. The method is next applied to the more difficult nematode data set which is known to have problems with both long-branch attraction and compositional bias The top panels of The estimated combined-gene topologies have strong bootstrap support, though there is some variability within the estimated topologies of the arthropod clade. The BIONJ and FITCH majority-rule consensus trees derived from 1000 bootstrap trees for the JTT-based distances and the SpCov-based dissimilarities are shown in Amborella trichopoda within the angiosperms. The majority of analyses place Amborella as a sister taxon to the rest of the angiosperms Amborella+Nymphaea clade was found, and placed as sister to the rest of the angiosperms Calycanthus floridus, Amborella trichopoda and Nymphaea alba as sister to the rest of the angiosperm clade. Goremykin et al. Amborella in a clade with Calycanthus, which was refuted by Amborella trichopoda as sister to the rest of the angiosperms. This tree is now widely accepted. An important point to note about the controversy here is that the papers that place Amborella as basal use parsimony or maximum likelihood, while the distance methods have placed Amborella in a clade with Nymphaea. Since our method is a distance method, it may be subject to the same inclination to place Amborella in a clade with Nymphaea, and possibly Calycanthus. The reference tree for the chloroplast data As a final example, we apply the method to the larger chloroplast data set Calycanthus floridus, Amborella trichopoda and Nymphaea alba as the most basal lineage in the angiosperm clade, as given in Acorus americanus, as a sister taxon to the eudicots. The JTT-FITCH tree is the same as JTT-BIONJ within the angiosperms clade, but the JTT-FITCH tree erroneously separates the two ferns, Psilotum nudum and Adiantum capillus-veneris. This separation of two ferns is again observed in both the SpCov-BIONJ and SpCov-FITCH trees. Within the angiosperms clade, the SpCov-BIONJ and SpCov-FITCH trees both place a clade of Amborella trichopoda, Nymphaea alba and Calycanthus floridus as the most basal lineage and place one monocot, Acorus americanus, among the eudicot clade. In addition, the SpCov-FITCH tree also places Lotus corniculatus as the most basal lineage in the clade of eudicots and monocots.psaC). The first cluster consists of genes atpI, clpP, psaB, rbcL and rpoC1; the rest of the 19 genes belong to the second cluster with the direction atpI, clpP, psaB, rbcL and rpoC1 are clearly separated from the rest with a different outlier, (rps19). The direction Amborella trichopoda, Nymphaea alba and Calycanthus floridus as a sister clade to the remainder of the angiosperms, in the covariance-based chloroplast tree Triticum aestivum, Oryza sativa and Zea mays) is placed as sister to the rest of the angiosperm clade, with the clade of Calycanthus floridus, Amborella trichopoda and Nymphaea alba grouped together with Acorus americanus. Re-analysis with just the five genes atpI, clpP, psaB, rbcL and rpoC1 doesn’t result a very sensible tree, but it does place the clade of Calycanthus floridus, Amborella trichopoda and Nymphaea alba very far away from most of the other angiosperm species, which might explain why these five genes are important in placing Amborella trichopoda, Nymphaea alba and Calycanthus floridus as sister to the rest of the angiosperm clade for the analysis with the full set of genes.The existence of such controversies can be explained by the following diagnostic plots. The top panels of Amborella trichopoda, Nymphaea alba and Calycanthus floridus as sister to the rest of the angiosperm clade. Within the Amborella trichopoda, Nymphaea alba and Calycanthus floridus clade, the majority of bootstrap trees from JTT-BIONJ and JTT-FITCH place Calycanthus floridus and Amborella trichopoda as sister taxa and the majority of bootstrap trees from SpCov-BIONJ and SpCov-FITCH place Amborella trichopoda and Nymphaea alba as sister taxa. The variation in the estimated trees is fairly small with regards to the placement of most of taxa including some of those in the angiosperm clade. However, surprisingly the two taxa with the greatest variation regarding their placement in the estimated combined-gene trees are the two ferns, Psilotum nudum and Adiantum capillus-veneris. Among these bootstrap trees, Only 73% of the JTT-BIONJ, 41% of the JTT-FITCH, 33% of the SpCov-BIONJ and 0% of the SpCov-FITCH trees recover the clade of two ferns seen in the reference tree in These controversies are all again shown in the consensus trees in The results obtained from the application of the singular value decomposition method for obtaining combined-gene phylogenetic trees indicate that the performance of the method at estimating the reference tree topologies is comparable with the best other distance methods. The variability of the estimates obtained with this method was found to be mostly small, suggesting that the common signal extracted from the multiple genes using this method is fairly strong relative to noise or conflicting signals. The subsequent eigenvectors of the SVD of the distance matrix may be used as diagnostics to identify outlier genes or groups of genes with conflicting signals. The simulation results confirm that the performance of the SVD method is comparable to other existing similar types of methods. In our view, SVD provides a very simple and useful method for combining the phylogenetic signal as measured by distances across genes, and it has potential to be developed further to achieve better results due to its simplicity.As shown in the Methodology section, the SVD method provides a generalization of the least squares criterion for multiple genes to combine the phylogenetic signals. This can be easily extended to the weighted least squares criterion if the assumption that the diagonal variance matrices for the pairwise distance estimates across different genes are proportional to each other holds. In this case, denote the inverse of one diagonal variance matrix as As we observed in the methodology section, the complexity of the singular value decomposition is We have focused the SVD method on the consensus setting in this article. This is different from the focus of the methods SDM and SDM* which is to construct a distance super-matrix when missing data are present because some genes or species are less represented in databases. However, our method can be easily extended to the cases when missing data are present in the distance matrices. Multiple imputation methods based on the model assumptions or calculating the SVD and imputing the missing values iteratively are two different ways to consider. Currently we are extending the SVD method along these directions.The SVD method is based on the assumption that most genes have a consistent phylogeny signal and that the estimated branch lengths from different genes are proportional to each other. The second assumption is a strong assumption and may be violated if, for example, the rates of substitution are different for some lineages across different genes. In this case, SVD still gives a consistent topology estimate, but there is potential to improve the efficiency of the method. Instead of finding a vector to combine all phylogenetic signals across genes based on SVD, a better aim is to find the In summary, due to its simplicity, this method has potential to be further developed in multiple ways to be more robust or more efficient, and can have ability to deal with missing values.Table S1Primate Genebank numbers.(EPS)Click here for additional data file.Table S2Nematode Genebank numbers.(EPS)Click here for additional data file.Table S3Chloroplast Genebank numbers.(EPS)Click here for additional data file.