Synaptic dysfunction provoking dysregulated cortical neural circuits is currently hypothesized as a key pathophysiological process underlying clinical manifestations in Alzheimer's disease and related neurodegenerative tauopathies. Here, we conducted PET along with postmortem assays to investigate time course changes of excitatory and inhibitory synaptic constituents in an rTg4510 mouse model of tauopathy, which develops tau pathologies leading to noticeable brain atrophy at 5-6 months of age. Both male and female mice were analyzed in this study. We observed that radiosignals derived from [¹¹C]flumazenil, a tracer for benzodiazepine receptor, in rTg4510 mice were significantly lower than the levels in nontransgenic littermates at 2-3 months of age. In contrast, retentions of (E)-[¹¹C]ABP688, a tracer for mGluR5, were unaltered relative to controls at 2 months of age but then gradually declined with aging in parallel with progressive brain atrophy. Biochemical and immunohistochemical assessment of postmortem brain tissues demonstrated that inhibitory, but not excitatory, synaptic constituents selectively diminished without overt loss of somas of GABAergic interneurons in the neocortex and hippocampus of rTg4510 mice at 2 months of age, which was concurrent with enhanced immunoreactivity of cFos, a well-characterized immediate early gene, suggesting that impaired inhibitory neurotransmission may cause hyperexcitability of cortical circuits. Our findings indicate that tau-induced disruption of the inhibitory synapse may be a critical trigger of progressive neurodegeneration, resulting in massive neuronal loss, and PET assessments of inhibitory versus excitatory synapses potentially offer in vivo indices for hyperexcitability and excitotoxicity early in the etiologic pathway of neurodegenerative tauopathies.

SIGNIFICANCE STATEMENT In this study, we examined the in vivo status of excitatory and inhibitory synapses in the brain of the rTg4510 tauopathy mouse model by PET imaging with (E)-[¹¹C]ABP688 and [¹¹C]flumazenil, respectively. We identified inhibitory synapse as being significantly dysregulated before brain atrophy at 2 months of age, while excitatory synapse stayed relatively intact at this stage. In line with this observation, postmortem assessment of brain tissues demonstrated selective attenuation of inhibitory synaptic constituents accompanied by the upregulation of cFos before the formation of tau pathology in the forebrain at young ages. Our findings indicate that selective degeneration of inhibitory synapse with hyperexcitability in the cortical circuit constitutes the critical early pathophysiology of tauopathy.

The septo-hippocampal cholinergic system is critical for hippocampal learning and memory. However, a quantitative description of the in vivo firing patterns and physiological function of medial septal (MS) cholinergic neurons is still missing. In this study, we combined optogenetics with multichannel in vivo recording and recorded MS cholinergic neuron firings in freely behaving male mice for 5.5–72 h. We found that their firing activities were highly correlated with hippocampal theta states. MS cholinergic neurons were highly active during theta-dominant epochs, such as active exploration and rapid eye movement sleep, but almost silent during non-theta epochs, such as slow-wave sleep (SWS). Interestingly, optogenetic activation of these MS cholinergic neurons during SWS suppressed CA1 ripple oscillations. This suppression could be rescued by muscarinic M₂ or M₄ receptor antagonists. These results suggest the following important physiological function of MS cholinergic neurons: maintaining high hippocampal acetylcholine level by persistent firing during theta epochs, consequently suppressing ripples and allowing theta oscillations to dominate.

SIGNIFICANCE STATEMENT The major source of acetylcholine in the hippocampus comes from the medial septum. Early experiments found that lesions to the MS result in the disappearance of hippocampal theta oscillation, which leads to speculation that the septo-hippocampal cholinergic projection contributing to theta oscillation. In this article, by long-term recording of MS cholinergic neurons, we found that they show a theta state-related firing pattern. However, optogenetically activating these neurons shows little effect on theta rhythm in the hippocampus. Instead, we found that activating MS cholinergic neurons during slow-wave sleep could suppress hippocampal ripple oscillations. This suppression is mediated by muscarinic M₂ and M₄ receptors.

Plague, war and politics have altered the yearly pilgrimage to Mecca throughout history

Where is the truly disruptive software? Are we stuck with Microsoft Word until the end of eternity? For now, promising companies are usually just gobbled up by their bigger rivals.

Poor health in children is associated with exposure to family violence and disruption. Telomere length has been hypothesized to be a lasting biological indicator of exposure to early adversity and potentially predictive of negative health outcomes throughout the life course.

Telomere length reflects exposure to family violence and disruption and may be an early indicator of the biological impact of early adversity. Children exposed to interpersonal violence and family disruptions had significantly shorter telomeres. Gender moderated these associations. (Read the full article)

Research firm IHS Markit expects the display panel factories in Wuhan, China, to struggle to resume full production when the Chinese New Year holiday ends on Feb. 2. As a result, supplies for panels for TVs and PCs are expected to be tight in the ensuing months.

The champion of disruptive innovation in business and education passed away this month. One of Christensen's co-authors of "Disrupting Class," Michael B. Horn, assesses the impact his late colleague had on schools.

While four of the MPC members voted in favour of the eventual 75-basis point (bps) cut, external members Chetan Ghate and Pami Dua argued for a 50-bps cut, the minutes, released on Monday, showed.

The need of the hour is to promote remote working and expand gig economy, speakers at a Niti Aaayog-organised Webinar said.

Join us today, May 5 — Coronavirus and Supply Chains Disruption Panel Broadcast at: 7:45 am PCT, 10:45 am EST, 3:45 pm BST and 4:45 pm CET COVID-19 has caused severe supply chain disruptions and has affected almost every facet of our daily lives. What will the landscape look like after this disease passes and […]

Professional pyrotechnician Zack James is lighting his next fuse under the tractor market. The founder of Rabbit Tractors develops autonomous farm robots intended for multiple tasks and to be scaled up in number as needed, challenging traditional tractors. Based in northwest Indiana, Rabbit Tractors is a so-called swarm farming startup among a field of like-minded Read article >

The post Field Day: AI Startup Cultivates Robo Tractors for ‘Swarm Farming’ Disruption appeared first on The Official NVIDIA Blog.

By Boy Lüthje HONOLULU (6 April 2020)—The development of electric and self-driving vehicles is bringing on a massive restructuring of the global automotive industry. Emerging forms of new and shared mobility undermine the very model of private car ownership that has underpinned the automotive industry since the days of Henry Ford.

This is a summary only. Click the title for the full article, or visit www.EastWestCenter.org/Research-Wire for more.

The European guide to strikes and other industrial action has been created by Eversheds Sutherland to provide you with a quickand easy reference when responding to threats of industrial action in 15 European countries. Click here to download the pub...

Introduction In the wake of the Coronavirus outbreak, and the restrictions imposed to curb its spread, there has been significant market disruption.  As has been seen in some real estate funds, there may therefore be difficulties for fund manag...

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  This week’s industrial action by University lecturers and other members of staff brings back into focus the risk of disruption on campus from students and others who are affected by the strike action. Disruption on campus can arise...

The latest round of industrial action by University lecturers and other members of staff brings back into focus the risk of disruption on campus from students and others who are affected by the strike action. Disruption on campus can arise and ...

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China’s military may have been spared any coronavirus infections, but the global health crisis has slowed the progress of Chinese President Xi Jinping’s plan to transform the People’s Liberation Army into a modern fighting force capable of long-range power-projecting operations, experts say.According to China’s defence ministry, the world’s largest armed force – with about 2.3 million personnel – has had zero confirmed cases of Covid-19. In contrast, the US and Russian militaries, ranked second…

STAMFORD, CT – May 5, 2016 – Today, HARMAN International Industries, Incorporated (NYSE:HAR), the premier connected technologies company for automotive, consumer and enterprise markets, announced it will showcase the industry’s first  developer-ready ...

HARMAN Hacks TechCrunch Disrupt NY As one of the year’s premier tech events, TechCrunch Disrupt NY continues to attract the industry’s top innovators, startups and developers – this year was no exception. Today, developers can personalize everything...

STAMFORD, CT – September 14, 2016 –HARMAN International Industries, Incorporated (NYSE:HAR), the premier connected technologies company for automotive, consumer and enterprise markets, announced it will showcase additional sensor functionality for the...

There's no doubt China's tech sector is heating up, but not all opportunities are made equal. 500 Startups' China partner Rui Ma tells Reuters' Jon Gordon where she sees the most promise

Companies across the globe are focused on delivering voice-enabled products to their customers. However, voice technology is a nascent, complicated one that few companies can develop internally, without any collaboration. Enter, HARMAN Embedded Audio. A...

Membrane-bound proteins have been proposed to mediate the transport of long-chain FA (LCFA) transport through the plasma membrane (PM). These proposals are based largely on reports that PM transport of LCFAs can be blocked by a number of enzymes and purported inhibitors of LCFA transport. Here, using the ratiometric pH indicator (2',7'-bis-(2-carboxyethyl)-5-(and-6-)-carboxyfluorescein and acrylodated intestinal FA-binding protein-based dual fluorescence assays, we investigated the effects of nine inhibitors of the putative FA transporter protein CD36 on the binding and transmembrane movement of LCFAs. We particularly focused on sulfosuccinimidyl oleate (SSO), reported to be a competitive inhibitor of CD36-mediated LCFA transport. Using these assays in adipocytes and inhibitor-treated protein-free lipid vesicles, we demonstrate that rapid LCFA transport across model and biological membranes remains unchanged in the presence of these purported inhibitors. We have previously shown in live cells that CD36 does not accelerate the transport of unesterified LCFAs across the PM. Our present experiments indicated disruption of LCFA metabolism inside the cell within minutes upon treatment with many of the "inhibitors" previously assumed to inhibit LCFA transport across the PM. Furthermore, using confocal microscopy and a specific anti-SSO antibody, we found that numerous intracellular and PM-bound proteins are SSO-modified in addition to CD36. Our results support the hypothesis that LCFAs diffuse rapidly across biological membranes and do not require an active protein transporter for their transmembrane movement.

Antibiotics revolutionized the treatment of infectious diseases; however, it is now clear that broad-spectrum antibiotics alter the composition and function of the host’s microbiome. The microbiome plays a key role in human health, and its perturbation is increasingly recognized as contributing to many human diseases. Widespread broad-spectrum antibiotic use has also resulted in the emergence of multidrug-resistant pathogens, spurring the development of pathogen-specific strategies such as monoclonal antibodies (MAbs) to combat bacterial infection. Not only are pathogen-specific approaches not expected to induce resistance in nontargeted bacteria, but they are hypothesized to have minimal impact on the gut microbiome. Here, we compare the effects of antibiotics, pathogen-specific MAbs, and their controls (saline or control IgG [c-IgG]) on the gut microbiome of 7-week-old, female, C57BL/6 mice. The magnitude of change in taxonomic abundance, bacterial diversity, and bacterial metabolites, including short-chain fatty acids (SCFA) and bile acids in the fecal pellets from mice treated with pathogen-specific MAbs, was no different from that with animals treated with saline or an IgG control. Conversely, dramatic changes were observed in the relative abundance, as well as alpha and beta diversity, of the fecal microbiome and bacterial metabolites in the feces of all antibiotic-treated mice. Taken together, these results indicate that pathogen-specific MAbs do not alter the fecal microbiome like broad-spectrum antibiotics and may represent a safer, more-targeted approach to antibacterial therapy.

In our atmosphere, strange dense patches of charged air sometimes bounce radio waves around and disrupt radar – and now they have been spotted on Mars

Disruptor Beam, the mobile gaming startup behind Star Trek Timelines, has a new name and a new business. It’s now calling itself Beamable, and it’s selling a set of tools to help game developers add commerce and social functionality to their titles. The company’s direction became clear earlier this year when it sold Timelines to […]

In many fish species body size plays an important role in sexual selection. Large individuals are preferred mating partners because they can enhance offspring survival by providing better quality resources than small individuals. While large females and males are often favored by sexual selection, fishing targets and removes these reproductively superior individuals.

Disruptive social distancing measures are expected to remain in place to combat coronavirus in the UK until a vaccine or effective treatment is available, England's chief medical officer has said.

The Canadian Institutes of Health Research (CIHR) put off its regular $275-million competition this spring to focus on delivering federal grants related to the novel coronavirus.

Pablo Mari insists his future remains with Arsenal and is determined to secure a permanent move to the north London club.

Amid the coronavirus lockdown, Prince Harry and Meghan have kept a fairly low profile since their recent move to California, but a Hollywood insider says they're already being shopped around for projects.

In many fish species body size plays an important role in sexual selection. Large individuals are preferred mating partners because they can enhance offspring survival by providing better quality resources than small individuals. While large females and males are often favored by sexual selection, fishing targets and removes these reproductively superior individuals. Academy Research Fellow Silva Uusi-Heikkilä discusses in her recent literature review the implications fisheries selection might have on sexual selection, individual reproductive success and population viability.

Driving the need for strategic positioning is not a marketing game - it’s a game-changing CEO-level initiative.

Keep on reading: Differentiate or Die: 5 Keys to Disruptive Positioning

Will home infusion growth be a long-overdue correction for the buy -and-bill channel or a temporary blip that will soon vanish?

For some time, I have been tracking the evolution of the buy-and-bill system for provider-administered drugs. The data have shown that hospital outpatient departments have been displacing physician offices. Amid this shift, home infusion providers have accounted for a minority of commercial medical benefit spending and a tiny share of Medicare Part B spending.

However, the coronavirus pandemic is triggering new growth in home infusion for buy-and-bill products. Below, I highlight the early signs of a marketplace change. I believe that some of these short-term shifts in the buy-and-bill market will persist even after we have recovered from COVID-19. They may even slow the runaway growth of the 340B Drug Pricing Program.

If not, then I suppose we'll just keep living in a world with limited home infusion over and over.

In early May, Drug Channels Institute will host two live video webinars: Industry Update and COVID-19 Impact: Retail & Specialty Pharmacies (May 1) and Industry Update and COVID-19 Impact: PBMs & Payers (May 8). CLICK HERE TO LEARN MORE AND SIGN UP. DCI will donate 20% of all profits from these events to The Center for Disaster Philanthropy’s COVID-19 Response Fund. Watch my video invitation below.

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This week, I’m rerunning some popular posts while I prepare for this Friday’s video webinar: Industry Update and COVID-19 Impact: PBMs & Payers.

Life was very different when I originally published today’s article. 2020 is not turning out to be quite what any of us expected. However, the pandemic has exposed some intriguing pros and cons of vertical consolidation. Click here to see the original post and comments from December 2019.

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The largest insurers, PBMs, and specialty pharmacies have now combined into vertically-integrated organizations. As I explain below, these companies have also been rapidly integrating with healthcare providers.

I also provide an updated look at these companies and highlight strategies that they are using—or could use—to control the channel. I believe that these insurer / PBM / specialty pharmacy / provider organizations are poised to restructure U.S. drug channels by exerting greater control over patient access, sites of care/dispensing, and pricing.

If they can effectively coordinate their sprawling business operations, they will pose a substantial threat of disruption to the existing commercial strategies of pharma companies.

Will they succeed by better managing care and costs, or merely by extracting higher profits from our convoluted system?
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Today the Department of Justice and the FBI, along with international law enforcement partners, announced the indictment of two individuals from Latvia and the seizure of more than 40 computers, servers and bank accounts as part of Operation Trident Tribunal, an ongoing, coordinated enforcement action targeting international cybercrime.

The Justice Department today filed a status report with the United States District Court for the Western District of Pennsylvania updating the court on the progress in disrupting the Gameover Zeus botnet and the malicious software known as Cryptolocker

Business leaders from around the Asia-Pacific met in Sydney last week to discuss the year ahead

The COVID-19 pandemic—in addition to posing a severe threat to public health—has disrupted the economy and financial markets, and prompted a strong desire among investors for safe and liquid securities. In that environment, one might expect U.S. Treasury securities to be the investment of choice, but for a while in March, the $18 trillion market…

The COVID-19 pandemic—in addition to posing a severe threat to public health—has disrupted the economy and financial markets, and prompted a strong desire among investors for safe and liquid securities. In that environment, one might expect U.S. Treasury securities to be the investment of choice, but for a while in March, the $18 trillion market…