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S90-01A - Fundamental SOA & Service-Oriented Computing - Dump Information

Vendor : SOA
Exam Code : S90-01A
Exam Name : Fundamental SOA & Service-Oriented Computing
Questions and Answers : 100 Q & A
Updated On : April 24, 2019
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S90-01A Questions and Answers

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S90-01A Fundamental SOA & Service-Oriented Computing

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S90-01A exam Dumps Source : Fundamental SOA & Service-Oriented Computing

Test Code : S90-01A
Test Name : Fundamental SOA & Service-Oriented Computing
Vendor Name : SOA
Q&A : 100 Real Questions

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Pullman and SoA call on govt to handle on-line book piracy | killexams.com Real Questions and Pass4sure dumps

published April eight, 2019 by using Mark Chandler

Society of Authors president Philip Pullman and 32 different main writers have referred to as on the executive to address “the blight” of online publication piracy.

Society of Authors president Philip Pullman and 32 other leading writers have called on the executive to handle “the blight” of on-line book piracy.

An open letter to business Secretary Greg Clark, signed by way of Pullman, Hilary Mantel, Malorie Blackman and Kazuo Ishiguro among others, warns piracy websites are getting increasingly frequent.  

The letter argues “online ebook piracy has the expertise to damage the reputable booklet market and make it even harder for authors to make a dwelling from their work".

Citing research by the intellectual Property office that a sixth of e-books read online in the UK in 2017 were pirated, the authors warned piracy could lead on to new writing drying up and impact the uk’s already struggling library gadget.

They spoke of greater mighty motion turned into essential to handle breaches of copyright and have claled for a meeting with Clark to focus on their issues.

Pullman observed: “online piracy of books, track, and other expressions of the human spirit must be accurately understood: it’s an offence towards moral justice. It’s the very contrary of freedom of speech, since it acts to avoid those who create attractiveness, talents, consolation or pride from incomes even a modest living from their efforts. The law of copyright is among the bastions of civilized dwelling, but the acid rain of on-line piracy is slowly dissolving some thing we thought turned into set in stone. definitely it is going to be a simple obligation of any decent executive to look after the rights of those that support to create what civilization is.”

among the many signatories became Joanne Harris, who last month called for publishers to take online pirates to court docket after a storm of complaints about web site Ebooks Bike.

The letter in full:

we are writing related to on-line ebook piracy. we're British authors and contributors of the Council of the Society of Authors.

we are worried that sites providing illegal downloads of books are getting increasingly general. research by means of the highbrow Property office found that a sixth of e-books read online within the UK in 2017 - round four million books - were pirated. We don't are looking to provide any of those websites publicity by means of naming them here, however they could effortlessly be found.   

Authors aren't requested for permission earlier than their work seems on these sites, and they do not receive any remuneration. Authors’ salary are in decline and a lot of are struggling financially. A survey performed by means of the Authors’ Licensing and amassing Society (ALCS) in 2018 found that the median revenue of a UK writer from their writing became simply £10,500 per annum.

The increase of on-line publication piracy has the advantage to damage the reputable booklet market and make it even more durable for authors to make a dwelling from their work. this will hurt writers and readers alike – if authors can no longer afford to jot down, the deliver of new writing will inevitably dry up. It could also cause extra damage to our library service (which does pay authors, each for the purchase of books and, via PLR, every time a ebook is lent), at a time when libraries are already facing cuts and closures throughout the nation.

the uk’s excellent literary heritage has always been underpinned through a strong copyright regime. sadly, this regime isn't revered by on-line pirates, who flagrantly infringe copyright law by means of both copying our books and providing them for down load. As Secretary of State whose branch has responsibility for copyright and piracy, we are calling on you to take action against the blight of online ebook piracy.  

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Auditory sensory reminiscence span for duration is severely curtailed in women with Rett syndrome | killexams.com Real Questions and Pass4sure dumps

The current information demonstrate that contributors with RTT produce the MMN response for the shortest 450 ms SOA condition, albeit attenuated and delayed, indicating that they have somewhat preserved skill to build an auditory sensory memory illustration for period and to discriminate length deviance when a series of auditory indicators is offered at a fast stimulation expense. youngsters, these sensory reminiscence traces for tone duration appear to have a appreciably foreshortened temporal span in RTT, as evident by means of the extremely extraordinary absence of a detectable MMN at longer SOAs of 900 and 1800ms.

The presence of an MMN to auditory period deviance in the existing analyze corresponds with our old findings the usage of a pitch deviance paradigm, where the presence of an MMN pointed to the neural skill to characterize frequency deviations in RTT albeit that the pitch-evoked MMN become morphologically ordinary and extensively delayed in that study9. The presence of a length-evoked MMN right here in a similar fashion suggests the neural potential to existing length deviants. nonetheless, the proven fact that the period MMN is absent at slower presentation prices might also suggest that sensory memory for this simple auditory feature is extra impacted in RTT than is frequency illustration. it's price noting, although, that in our prior analyze, best a single frequency manipulation became used to generate the MMN, and that the difference between the average and deviant (503 versus 996 Hz) become very gigantic and therefore highly detectable. unlike the latest analyze, we didn't parametrically vary the electricity of the memory hint, either through changing the presentation rate or with the aid of narrowing the frequency difference. Taken collectively, both studies suggest that whereas MMN is relatively preserved in RTT when the stimulation parameters are such that the deviation, be it in duration or pitch, is large and highly detectable, as soon as the equipment is taxed to any diploma, giant deficits begin to demonstrate themselves. evidently, it can be important to observe up with parametric studies to examine the bounds of the auditory sensory reminiscence equipment in RTT for these and different basic auditory elements (i.e., frequency, duration, region, and loudness).

it's also price mentioning that the specificity of impaired MMN to the longer SOA situations suggests that the MMN discount turned into unlikely led to by elements akin to attention or motivation, which beneath definite restricted instances are favourite to modulate MMN amplitude32. The intact MMN in the fastest situation, and the proven fact that the blocks with different SOAs have been equally dispensed within experimental session certainly exhibit that it is the ability to preserve sensory reminiscence representations of period over longer durations it really is decreased in RTT.

Our analyze additionally confirmed an increase in MMN amplitude with age in the TD community, consistent with previous findings33. Noteworthy, the rate of MMN maturation was identical across SOAs, indicating that while period discrimination capability continues to be establishing from childhood into adulthood, the skill to preserve auditory sensory memory representations is already above 2 s in the age range of the members during this look at (6–26 years ancient). This outcome is in line with prior work showing that auditory sensory reminiscence for frequency can final for at least three s in 6-year-historic children34. In standard development, there is a gradual raise in the duration of sensory memory with construction, such that no MMN is observed in little ones more youthful than 2 years historical when SOAs are longer than 1 s, in 4-yr-historic toddlers when SOAs are longer than 2 s, or in 6-year-old toddlers with SOAs longer than three s. however, the MMN is well known in every of these agencies with faster presentation rates34,35,36.

One viable implication of the indisputable fact that patients with RTT confirmed no reliable MMN at 900 ms, is that their sensory memory systems may have stagnated at a developmental stage appropriate with that of a 1–2-12 months-ancient TD child. it's during this age range that patients with RTT usually adventure developmental arrest that affects cognitive and motor features, including language skills. one more measure of basic auditory characteristic up to now examined in RTT is the brainstem frequency following response, which measures responses which are section-locked to the frequency of a periodic stimulus. Galbraith and colleagues, working with adults with RTT, discovered that the capability to entrain external excessive-frequency modulation become at a level extra according to child maturation degrees considered in TDs37. therefore, it should be would becould very well be advised that auditory system maturation is also halted at an early developmental stage.

One may argue that the decay in sensory reminiscence could be particular to period representation, given that old stories have advised that memory representation for duration decays greater swiftly with getting older and cognitive decline than does frequency representation38,39,forty. In our previous study of RTT sufferers, MMN facts advised that the lifetime of frequency representation is as a minimum 900 ms, longer than observed right here for length, but as outlined, that become the only SOA employed in that study9. even so, it's a distinct opportunity that the duration equipment is more susceptible than the frequency illustration equipment, and this might also relate to the separable cortical circuits accountable for generating these two kinds of the MMN26. Whereas the most important mills of the frequency MMN are found in hierarchically early primary auditory cortex as well as fronto-parietal regions, a extra complicated set of areas changed into involved in producing the duration MMN, together with secondary auditory cortex and a more extended set of fronto-parietal generators. it is plausible that larger-order cortical areas are greater impacted via the disease than are early areas, and that it follows that procedures reliant on these bigger-order areas can be greater inclined. youngsters, that we haven't yet parametrically dissimilar the presentation charges for frequency deviations inside the equal cohort, leaves this an open query for now.

The MMN measures in our analyze have been no longer concerning RTT severity as measured by the RSSS. while the RSSS accumulates all aspects of RTT symptomatology and is in keeping with observational and scientific symptoms, the MMN is an aim measure of auditory sensory reminiscence. The absence of correlation between the two measures suggests that cognitive and perceptual deficits, which are difficult to assess by the use of behavioral strategies, may be impartial from core motor signs. accordingly, our neurophysiological measure offers critical additional information about auditory perceptual and cognitive brain function in sufferers with RTT that isn't directly involving the at the moment used clinical measures of RTT severity. Importantly, it also has implications for speech and language comprehension.

The attenuated reminiscence span, as measured through MMN to stimulation with distinct SOAs is attribute of a couple of neurological conditions. MMN generation is crucially based on the suitable functioning of NMDA receptors, as proven through animal reviews as well as pharmacological stories in match adults and sufferers with schizophrenia41,42. NMDA abnormalities have also been implicated in RTT. In a small put up-mortem examine that blanketed 9 impartial RTT samples from prefrontal cortex, Blue and colleagues reported that NMDA receptor density turned into expanded in samples from more youthful women (2–8 years historical), while it changed into decreased in samples from older women (up to 30 years of age)43. similar biphasic shifts within the direction of this NMDA effect with age were proven in prefrontal brain areas of a RTT animal model44. while there turned into no age-connected change in MMN alterations across condition in our RTT sufferers, most of them have been older than 8 years. NMDA receptor dysfunction has additionally been reported in fit elderly subjects and people with Alzheimer’s disease45, which have both additionally been shown to demonstrate shortened sensory memory39,46,47,forty eight. therefore, the absence of MMN in RTT for longer SOAs and the obvious discount of MMN for the shortest SOA might, in concept, be linked to reduced NMDA receptor binding. similar to what we see right here, sufferers with schizophrenia display reduced MMN even with short SOAs of 450–500 ms49,50. on the other hand, realizing the position of NMDA receptors in modulating the span of sensory memory traces in distinctive neurological issues wants additional investigation.

The oddball paradigm with distinct SOAs can also be with ease carried out in animals. The animal model of RTT, both with total Mecp2 knockout or deficient Mecp2 in selected neuronal subtypes11,fifty one, is a probably very constructive tool to track down the neurophysiological and molecular mechanisms underlying the drastic decay in auditory sensory reminiscence illustration over longer durations that we report during this look at, as well as to investigate its response to medication. taking into account that such profound deficits in sensory memory could be of essential magnitude for language acquisition, the index of MMN attenuation with increasing SOA may also be a very promising biomarker not handiest for RTT subjects, however also for other neurodevelopmental problems.

analyze limitations

A hindrance of the latest analyze is the wide age-latitude of the contributors, due to the fact that auditory responses continue to mature with ordinary construction across the age-latitude tested33,52. although age became correlated with MMN amplitude in the TD community, it changed into no longer linked to manipulations of stimulus cost. This means that community changes viewed as a characteristic of presentation cost have been no longer plagued by age, however quite, characterize frank transformations in mind feature in RTT. A 2nd challenge is that mutation subtype could not be with ease examined right here as a result of the exceptionally restricted sample size. Neither were we able to believe skills adjustments as a function of classic versus odd Rett phenotype. both of those distinctions could be of wonderful hobby as this work progresses. We should additionally well known that listening to testing turned into not conducted on the time of EEG acquisition in sufferers with RTT due to difficulties in assessing it during this inhabitants. besides the fact that children, the presence of an MMN for the shortest SOA within the RTT neighborhood, naturally shows that they could realize and decode auditory suggestions. ultimately, non-invasive recordings comparable to those performed here can not shed light on the mechanisms during which MECP2 protein loss leads to auditory cortical processing deficits. Work the use of an identical paradigms in murine models of RTT may be tremendously instructive in this regard11,53.


Slovenia recollects ambassador from Croatia over spying experiences | killexams.com Real Questions and Pass4sure dumps

The Slovenian foreign affairs ministry has recalled the nation’s ambassador to Croatia for consultations following reviews that Croatian representatives tried to affect the reporting of a Slovenian media outlet on the actions of the Croatian intelligence in Slovenia.

family members between Croatia and Slovenia were deteriorating in the closing few years seeing that both countries were unable to settle a border dispute. Croatia refuses to settle for the July 2017 permanent courtroom of Arbitration (PCA) ruling giving Slovenia access to the high seas via Piran Bay, claiming the manner was corrupted. Zagreb’s stance is that it's going to not settle for the ruling after a Slovenian official turned into discovered trying to have an impact on the outcome again in 2015.

native media pronounced earlier in April that the leaked cellphone recordings that ended in Croatia declaring the border arbitration corrupted had been made by way of the Croatian Intelligence company (SOA).

Excerpts from a leaked tape had been posted by Croatian day by day Jutarnji list in July 2015. They seem to exhibit the Slovenian representative within the arbitration tribunal, Jernej Sekolec, discussing approach with Simona Drenik, the Slovenian finance ministry’s consultant earlier than the court. The transcripts revealed disclosure of personal suggestions and a joint plan to have an effect on different judges.

Days after the unlock of the tapes, the Croatian parliament voted unanimously in favour of withdrawing from the arbitration. Croatia’s then best minister Zoran Milanovic told MPs that whereas the tribunal may also proceed to work, “we won't recognize any of its decisions”.

Slovenian media now document that Croatian officers tried to impact the reporting of industrial broadcaster POP television on the activities of the Croatian intelligence provider, STA information company reported. On April eight, POP television mentioned that the Croatian government had used an middleman to try to prevent the news portal from revealing the proven fact that SOA turned into answerable for the wiretapping in the border dispute.

“these days, inadmissible activities of the Croatian secret provider targeting Croatia’s neighbours, Slovenia amongst them, had been made public. In democratic Europe and the area at huge, overseas interference and pressure exerted on editorial policies are deemed unacceptable. The Croatian ambassador, Boris Grigić, has been summoned to the international ministry, and Slovenia's ambassador to Croatia, Smiljana Knez, recalled for consultations,” the Slovenian foreign affairs minister observed in a statement.

moreover, Slovenian prime Minister Marjan Sarec known as a session of the nation’s country wide safety Council.

“Any pressures on the media are inadmissible and opposite to the simple ideas of democracy. If such pressures are carried out through a foreign govt, this suggests an immense democratic deficit and a shift far from the basic European values,” he stated.

The Croatian executive has rejected the allegations made by means of Slovenia, while SOA known as the experiences in the Slovenian media “untrue and tendentious fabrications”, according to complete Croatia information.


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Pullman and SoA call on government to tackle online book piracy | killexams.com real questions and Pass4sure dumps

Published April 8, 2019 by Mark Chandler

Society of Authors president Philip Pullman and 32 other leading writers have called on the government to tackle “the blight” of online book piracy.

Society of Authors president Philip Pullman and 32 other leading writers have called on the government to tackle “the blight” of online book piracy.

An open letter to Business Secretary Greg Clark, signed by Pullman, Hilary Mantel, Malorie Blackman and Kazuo Ishiguro among others, warns piracy sites are becoming increasingly prevalent.  

The letter argues “online book piracy has the potential to damage the legitimate book market and make it even harder for authors to make a living from their work".

Citing research by the Intellectual Property Office that a sixth of e-books read online in the UK in 2017 were pirated, the authors warned piracy could lead to new writing drying up and impact the UK’s already struggling library system.

They said more robust action was needed to tackle breaches of copyright and have claled for a meeting with Clark to discuss their concerns.

Pullman said: “Online piracy of books, music, and other expressions of the human spirit needs to be properly understood: it’s an offence against moral justice. It’s the very opposite of freedom of speech, because it acts to prevent those who create beauty, knowledge, consolation or delight from earning even a modest living from their efforts. The law of copyright is one of the bastions of civilized living, but the acid rain of online piracy is slowly dissolving something we thought was set in stone. Surely it should be a fundamental duty of any decent government to defend the rights of those who help to create what civilization is.”

Among the signatories was Joanne Harris, who last month called for publishers to take online pirates to court after a storm of complaints about website Ebooks Bike.

The letter in full:

We are writing regarding online book piracy. We are British authors and members of the Council of the Society of Authors.

We are concerned that websites offering illegal downloads of books are becoming increasingly prevalent. Research by the Intellectual Property Office found that a sixth of e-books read online in the UK in 2017 - around four million books - were pirated. We do not want to give any of these sites publicity by naming them here, but they can easily be found.   

Authors are not asked for permission before their work appears on these sites, and they do not receive any remuneration. Authors’ earnings are in decline and many are struggling financially. A survey carried out by the Authors’ Licensing and Collecting Society (ALCS) in 2018 found that the median earnings of a UK author from their writing was just £10,500 per annum.

The growth of online book piracy has the potential to damage the legitimate book market and make it even harder for authors to make a living from their work. This will harm writers and readers alike – if authors can no longer afford to write, the supply of new writing will inevitably dry up. It could also cause further damage to our library service (which does pay authors, both for the purchase of books and, through PLR, every time a book is lent), at a time when libraries are already facing cuts and closures across the country.

The UK’s great literary heritage has always been underpinned by a robust copyright regime. Unfortunately, this regime is not respected by online pirates, who flagrantly infringe copyright law by both copying our books and offering them for download. As Secretary of State whose department has responsibility for copyright and piracy, we are calling on you to take action against the blight of online book piracy.  

We would be happy to meet to discuss further and we look forward to hearing from you.


Can APIs help UK economy after Brexit? | killexams.com real questions and Pass4sure dumps

In today’s interconnected and complex global economy, the digital landscape is driving the change led by application programmable interfaces (APIs). APIs play a major role in shifting industries toward further servitisation and utilisation of both internal and external capabilities and resources to create innovative knowledge-based services.

The idea of APIs fundamentally emerged with the development of service-oriented architecture (SOA) and the decoupling mechanism in web services which enabled more applications and data to be streamlined and integrated beyond single organisation boundaries.

The promises were this technology would enable people to develop apps using their domain expertise without having to worry too much about advanced programming skills.  Furthermore, APIs helped in building digital societies where the physical and digital worlds are fused. By using APIs, acquiring functions and data became much easier in an open digital ecosystem where millions of APIs are either available for free or for small fees.

Currently, the UK is operating under the EU market law and trading internationally is governed through EU regulations. Exposing local SMEs to an ever-expanding global market without preparation is extremely risky.  Government will find it difficult to prepare the market for the Brexit aftershock, taking into account that the global economy is dynamic, there is high fluctuation in the availability of resources, capabilities, services, and prices.

After the nation voted to leave the EU,  fundamental economic changes were expected. For example, if the UK decided not to stay within the single market (the European Economic Area) it is likely trade will fall more, leading to a 2.6% decrease in income per person (The independent, 2016).

Many international companies were expected to leave the UK (some already have) as they  lose competitive advantages of being in the single market, where they avoid  trade tariffs, which in return will cause a loss of job opportunities.

In the same way,  UK-based companies might lose competitive advantages in offering products and services to European countries, due to both added tariffs and a manpower scarcity.

Potentially, UK-based companies will lose the advantages of accessing cheap labour from Southern and Eastern European countries, and profit margins will decline.

Nevertheless, many organisations worldwide are fully virtualising their capabilities and services with an intention to make them available for wider customers. By doing this, business  collaborations and relations will strengthen, on a win-win basis.

It is crucial to explore the how APIs can potentially support local businesses, in particular SMEs, in utilising global resources to maximise benefits and reduce cost. APIs can offer the required agility to handle fluctuation in the global economic landscape.

API-based solution to rectify the impact

Develop a tool that utilises APIs in order to help SMEs  connect with the global business ecosystem. The tools provide real-time data and decision-support for where and when to purchase a) services, b) capabilities, and c) resources. Equally, it will provide a decision-support mechanism as to who, when and where to sell the same. It will maximise SMEs’ competitiveness by allowing them to discover both their strengths and weaknesses. Typically, a firm will consume (import data and functions) and expose APIs (export data and functions).The proposal here focuses on consumed APIs and suggests the following features should enhance the tool capability:

  • APIs connect the tool to micro and macroeconomic data sources, where some are available freely (e.g. WTO, WorldBank, WEF) and others might be available for fees (Bloomberg, Amazon, eBay).
  • Connect the tool to virtual production resources and capabilities, where UK SMEs will be able to rent and use production resources from international providers, charged per use or per time unit.
  • Target mass consumers on social media, and manage marketing accounts over media streams like Facebook, Twitter, and Instagram. This will enable firms to better understand market and customer needs, analyse feedback from customers, and manage promotions.
  • Internet of Things (IoT)-based APIs capture data from physical smart objects in real time to support decision-making capabilities toward realisation of sophisticated cyber-physical systems. The IoTs can be both industrial and consumer. Industrial IoT APIs will help in monitoring and managing production machines in international facilities while consumer IoT APIs will help  improve the products and after-sales services.
  • Check the business partner or supplier background, where companies who would like to trade globally must ensure their details are published on a distributed ledger or third-party trade managing unit, thus, local SMEs will be able to check the partner certifications, quality standards, audit, and any crucial information.
  • Smart micro-contracts based on blockchain technology will be embedded within the tool to allow quick and secure agreements between parties.
  • Evaluate, match jurisdictional policies and regulations and highlight relevant terms that need extra attention. Therefore, SMEs will be aware of how best to resolve disputes in case the contract breached.
  • APIs for IP monitoring and copyright control, based on blockchain to manage and control protected products or services worldwide.
  •  


    Auditory sensory memory span for duration is severely curtailed in females with Rett syndrome | killexams.com real questions and Pass4sure dumps

    The current data show that participants with RTT produce the MMN response for the shortest 450 ms SOA condition, albeit attenuated and delayed, indicating that they have somewhat preserved ability to build an auditory sensory memory representation for duration and to discriminate duration deviance when a sequence of auditory signals is presented at a fast stimulation rate. However, these sensory memory traces for tone duration appear to have a substantially foreshortened temporal span in RTT, as evident by the highly atypical absence of a detectable MMN at longer SOAs of 900 and 1800ms.

    The presence of an MMN to auditory duration deviance in the current study corresponds with our previous findings using a pitch deviance paradigm, where the presence of an MMN pointed to the neural ability to represent frequency deviations in RTT albeit that the pitch-evoked MMN was morphologically atypical and substantially delayed in that study9. The presence of a duration-evoked MMN here similarly suggests the neural capacity to present duration deviants. On the other hand, the fact that the duration MMN is absent at slower presentation rates might also suggest that sensory memory for this fundamental auditory feature is more impacted in RTT than is frequency representation. It is worth noting, however, that in our prior study, only a single frequency manipulation was used to generate the MMN, and that the difference between the standard and deviant (503 versus 996 Hz) was very large and therefore highly detectable. Unlike the current study, we did not parametrically vary the strength of the memory trace, either by changing the presentation rate or by narrowing the frequency difference. Taken together, the two studies suggest that while MMN is relatively preserved in RTT when the stimulation parameters are such that the deviation, be it in duration or pitch, is large and highly detectable, once the system is taxed to any degree, significant deficits begin to reveal themselves. Clearly, it will be important to follow up with parametric studies to assess the limits of the auditory sensory memory system in RTT for these and other fundamental auditory features (i.e., frequency, duration, location, and loudness).

    It is also worth pointing out that the specificity of impaired MMN to the longer SOA conditions indicates that the MMN reduction was unlikely caused by factors such as attention or motivation, which under certain limited circumstances are known to modulate MMN amplitude32. The intact MMN in the fastest condition, and the fact that the blocks with different SOAs were equally distributed within experimental session clearly show that it is the ability to sustain sensory memory representations of duration over longer periods that is reduced in RTT.

    Our study also showed an increase in MMN amplitude with age in the TD group, consistent with previous findings33. Noteworthy, the rate of MMN maturation was similar across SOAs, indicating that while duration discrimination ability is still developing from childhood into adulthood, the ability to sustain auditory sensory memory representations is already above 2 s within the age range of the participants in this study (6–26 years old). This result is in line with prior work showing that auditory sensory memory for frequency can last for at least 3 s in 6-year-old children34. In typical development, there is a gradual increase in the duration of sensory memory with development, such that no MMN is observed in children younger than 2 years old when SOAs are longer than 1 s, in 4-year-old children when SOAs are longer than 2 s, or in 6-year-old children with SOAs longer than 3 s. However, the MMN is prominent in each of these groups with faster presentation rates34,35,36.

    One possible implication of the fact that patients with RTT showed no reliable MMN at 900 ms, is that their sensory memory systems may have stagnated at a developmental stage compatible with that of a 1–2-year-old TD child. It is in this age range that patients with RTT usually experience developmental arrest that affects cognitive and motor functions, including language skills. Another measure of basic auditory function previously examined in RTT is the brainstem frequency following response, which measures responses that are phase-locked to the frequency of a periodic stimulus. Galbraith and colleagues, working with adults with RTT, found that the ability to entrain external high-frequency modulation was at a level more consistent with infant maturation levels seen in TDs37. Thus, it might be suggested that auditory system maturation is also halted at an early developmental stage.

    One might argue that the decay in sensory memory could be specific to duration representation, since previous studies have suggested that memory representation for duration decays more rapidly with aging and cognitive decline than does frequency representation38,39,40. In our previous study of RTT patients, MMN data suggested that the lifetime of frequency representation is at least 900 ms, longer than observed here for duration, but as mentioned, that was the only SOA employed in that study9. Nonetheless, it is a distinct possibility that the duration system is more vulnerable than the frequency representation system, and this may relate to the separable cortical circuits responsible for generating these two varieties of the MMN26. Whereas the major generators of the frequency MMN are found in hierarchically early primary auditory cortex as well as fronto-parietal regions, a more complex set of regions was involved in generating the duration MMN, including secondary auditory cortex and a more extended set of fronto-parietal generators. It is plausible that higher-order cortical regions are more impacted by the disease than are early regions, and that it follows that processes reliant on these higher-order regions might be more vulnerable. However, that we have not yet parametrically varied the presentation rates for frequency deviations within the same cohort, leaves this an open question for now.

    The MMN measures in our study were not related to RTT severity as measured by the RSSS. While the RSSS accumulates all aspects of RTT symptomatology and is based on observational and clinical symptoms, the MMN is an objective measure of auditory sensory memory. The absence of correlation between the two measures suggests that cognitive and perceptual deficits, which are difficult to assess via behavioral methods, may be independent from core motor symptoms. Thus, our neurophysiological measure provides critical additional information about auditory perceptual and cognitive brain function in patients with RTT that is not directly related to the currently used clinical measures of RTT severity. Importantly, it also has implications for speech and language comprehension.

    The attenuated memory span, as measured by MMN to stimulation with different SOAs is characteristic of several neurological conditions. MMN generation is crucially dependent on the proper functioning of NMDA receptors, as shown by animal studies as well as pharmacological studies in healthy adults and patients with schizophrenia41,42. NMDA abnormalities have also been implicated in RTT. In a small post-mortem study that included nine independent RTT samples from prefrontal cortex, Blue and colleagues reported that NMDA receptor density was increased in samples from younger girls (2–8 years old), while it was decreased in samples from older girls (up to 30 years of age)43. Similar biphasic shifts in the direction of this NMDA effect with age were confirmed in prefrontal brain regions of a RTT animal model44. While there was no age-related difference in MMN changes across condition in our RTT patients, most of them were older than 8 years. NMDA receptor dysfunction has also been reported in healthy elderly subjects and those with Alzheimer’s disease45, which have both also been shown to exhibit shortened sensory memory39,46,47,48. Therefore, the absence of MMN in RTT for longer SOAs and the apparent reduction of MMN for the shortest SOA could, in theory, be linked to decreased NMDA receptor binding. Similar to what we see here, patients with schizophrenia show reduced MMN even with short SOAs of 450–500 ms49,50. Nevertheless, understanding the role of NMDA receptors in modulating the span of sensory memory traces in different neurological disorders needs further investigation.

    The oddball paradigm with varied SOAs can be easily implemented in animals. The animal model of RTT, either with total Mecp2 knockout or deficient Mecp2 in specific neuronal subtypes11,51, is a potentially very valuable tool to track down the neurophysiological and molecular mechanisms underlying the drastic decay in auditory sensory memory representation over longer periods that we report in this study, as well as to investigate its response to treatment. Taking into account that such profound deficits in sensory memory might be of crucial importance for language acquisition, the index of MMN attenuation with increasing SOA can be a very promising biomarker not only for RTT subjects, but also for other neurodevelopmental disorders.

    Study limitations

    A limitation of the current study is the wide age-range of the participants, given that auditory responses continue to mature with typical development across the age-range tested33,52. Although age was correlated with MMN amplitude in the TD group, it was not associated with manipulations of stimulus rate. This suggests that group differences seen as a function of presentation rate were not affected by age, but rather, represent frank differences in brain function in RTT. A second limitation is that mutation subtype could not be effectively examined here due to the relatively restricted sample size. Neither were we able to consider potential differences as a function of classic versus atypical Rett phenotype. Both of these distinctions will be of great interest as this work progresses. We must also acknowledge that hearing testing was not conducted at the time of EEG acquisition in patients with RTT due to difficulties in assessing it in this population. However, the presence of an MMN for the shortest SOA in the RTT group, clearly indicates that they could detect and decode auditory information. Lastly, non-invasive recordings such as those conducted here cannot shed light on the mechanisms by which MECP2 protein loss leads to auditory cortical processing deficits. Work using similar paradigms in murine models of RTT will be highly instructive in this regard11,53.



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    SOA S90-01A Exam (Fundamental SOA & Service-Oriented Computing) Detailed Information



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