Hydrocephalus is a pathologic condition associated with various brain diseases, including Alzheimer's disease (AD). Dysfunctional ependymal cells (EpCs) are believed to contribute to the development of hydrocephalus. It is thus of interest to investigate EpCs' development and function. Here, we report that vacuolar protein sorting-associated protein 35 (VPS35) is critical for EpC differentiation, ciliogenesis, and survival, and thus preventing neonatal hydrocephalus. VPS35 is abundantly expressed in EpCs. Mice with conditional knock-out (cKO) of Vps35 in embryonic (Vps35^GFAP-Cre and Vps35^Emx1-Cre) or postnatal (Vps35^Foxj1-CreER) EpC progenitors exhibit enlarged lateral ventricles (LVs) and hydrocephalus-like pathology. Further studies reveal marked reductions in EpCs and their cilia in both Vps35^GFAP-Cre and Vps35^Foxj1-CreER mutant mice. The reduced EpCs appear to be due to impairments in EpC differentiation and survival. Additionally, both Vps35^GFAP-Cre and Vps35^Foxj1-CreER neonatal pups exhibit increased cell proliferation and death largely in a region close to LV-EpCs. Many microglia close to the mutant LV-EpC region become activated. Depletion of the microglia by PLX3397, an antagonist of colony-stimulating factor 1 receptor (CSF1R), restores LV-EpCs and diminishes the pathology of neonatal hydrocephalus in Vps35^Foxj1-CreER mice. Taken together, these observations suggest unrecognized functions of Vps35 in EpC differentiation, ciliogenesis, and survival in neonatal LV, and reveal pathologic roles of locally activated microglia in EpC homeostasis and hydrocephalus development.

SIGNIFICANCE STATEMENT This study reports critical functions of vacuolar protein sorting-associated protein 35 (VPS35) not only in promoting ependymal cell (EpC) differentiation, ciliogenesis, and survival, but also in preventing local microglial activation. The dysfunctional EpCs and activated microglia are likely to induce hydrocephalus.

Calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine, are widely used as standard immunosuppressants in organ transplantation recipients. However, these drugs can cause severe pain in patients, commonly referred to as calcineurin inhibitor-induced pain syndrome (CIPS). Although calcineurin inhibition increases NMDAR activity in the spinal cord, the underlying mechanism remains enigmatic. Using an animal model of CIPS, we found that systemic administration of FK506 in male and female mice significantly increased the amount of α2-1–GluN1 complexes in the spinal cord and the level of α2-1–bound GluN1 proteins in spinal synaptosomes. Treatment with FK506 significantly increased the frequency of mEPSCs and the amplitudes of monosynaptic EPSCs evoked from the dorsal root and puff NMDAR currents in spinal dorsal horn neurons. Inhibiting α2-1 with gabapentin or disrupting the α2-1–NMDAR interaction with α2-1Tat peptide completely reversed the effects of FK506. In α2-1 gene KO mice, treatment with FK506 failed to increase the frequency of NMDAR-mediated mEPSCs and the amplitudes of evoked EPSCs and puff NMDAR currents in spinal dorsal horn neurons. Furthermore, systemic administration of gabapentin or intrathecal injection of α2-1Tat peptide reversed thermal and mechanical hypersensitivity in FK506-treated mice. In addition, genetically deleting GluN1 in dorsal root ganglion neurons or α2-1 genetic KO similarly attenuated FK506-induced thermal and mechanical hypersensitivity. Together, our findings indicate that α2-1–bound NMDARs mediate calcineurin inhibitor-induced tonic activation of presynaptic and postsynaptic NMDARs at the spinal cord level and that presynaptic NMDARs play a prominent role in the development of CIPS.

SIGNIFICANCE STATEMENT Calcineurin inhibitors are immunosuppressants used to prevent rejection of transplanted organs and tissues. However, these drugs can cause severe, unexplained pain. We showed that calcineurin inhibition enhances physical interaction between α2-1 and NMDARs and their synaptic trafficking in the spinal cord. α2-1 is essential for calcineurin inhibitor-induced aberrant activation of presynaptic and postsynaptic NMDARs in the spinal cord. Furthermore, inhibiting α2-1 or disrupting α2-1–NMDAR interaction reduces calcineurin inhibitor-induced pain hypersensitivity. Eliminating NMDARs in primary sensory neurons or α2-1 KO also attenuates calcineurin inhibitor-induced pain hypersensitivity. This new information extends our mechanistic understanding of the role of endogenous calcineurin in regulating synaptic plasticity and nociceptive transmission and suggests new strategies for treating this painful condition.

The pint-sized institution, which opened last year, is filled with 1,000 feline-themed knickknacks that journeyed with their owners from Ukraine

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Arrival Day brought teens, Service Team members, coaches and thunderstorms. As another incredible TeenStreet began, teens shared what they are most looking forward to in the week ahead.

In a new twist on oral history, University of Alberta paleontologists have discovered that an Argentinian reptile from 95 million years ago developed a type of tooth enamel that is common in humans and other mammals but rare among reptiles.

Our ongoing celebration of the Library of Congress National Book Festival continues with Poets Laureate Tracy K. Smith and Robert Hass discussing the making of poetry, the position of Poet Laureate and their new books, "American Journal: Fifty Poems for Our Time" (edited by Smith) and "A Little Book on Form: An Exploration into the Formal Imagination of Poetry" (Hass), on the Poetry & Prose stage at the 2018 Festival.

Our ongoing celebration of the Library of Congress National Book Festival continues with presidential scholar Annette Gordon-Reed discussing "The Hemingses of Monticello: An American Family" on the Special Programs stage at the 2015 Festival.

Our ongoing celebration of the Library of Congress National Book Festival continues with crime writer Patricia Cornwell discussing "Red Mist,” her 19th Kay Scarpetta novel, on the Fiction & Mystery stage at the 2012 Festival.

Our ongoing celebration of the Library of Congress National Book Festival continues with young adult and fantasy author Leigh Bardugo discussing "Crooked Kingdom" on the Genre Fiction stage at the 2018 Festival. This post includes prompts for writing and thinking that young readers, families and teachers can use to explore the author and the author’s work—recommended for ages 13+.

Our ongoing celebration of the Library of Congress National Book Festival continues with former Secretary of State Condoleezza Rice discussing "Democracy: Stories from the Long Road to Freedom" on the Main Stage at the 2017 Festival.

Our ongoing celebration of the Library of Congress National Book Festival continues with two-time Pulitzer Prize-winning novelist Colson Whitehead discussing "Zone One" on the Poetry & Prose stage at the 2012 Festival.

Our ongoing celebration of the Library of Congress National Book Festival continues with historian Michael Beschloss discussing “Presidents of War” on the Main Stage at the 2019 Festival.

Our ongoing celebration of the Library of Congress National Book Festival continues with crime and mystery writer Karin Slaughter discussing "Broken," part of her Will Trent series, on the Fiction & Mystery stage at the 2010 Festival.

Our ongoing celebration of the Library of Congress National Book Festival continues with actor and author Neil Patrick Harris discussing "The Magic Misfits: The Minor Third." The event, part of the new year-long National Book Festival Presents series, took place in the Library’s Coolidge Auditorium. This post includes prompts for writing and thinking that young readers, families and teachers can use to explore the author and the author’s work—recommended for ages 8+.

BCBS Press release "Basel Committee and IOSCO announce deferral of final implementation phases of the margin requirements for non-centrally cleared derivatives", 3 April 2020

Rutgers' RUCDR Infinite Biologics received an amended emergency use authorization from the FDA late Thursday for the first SARS-CoV-2 coronavirus test that will allow people to collect their own saliva at home and send to a lab for results.

Notional amounts of OTC derivatives rose to $640 trillion at end-June 2019. This is up from $544 trillion at end-2018 and the highest level since 2014. It marks a continuation of the trend increase evident since end-2016. The gross market value of OTC derivatives, summing positive and negative values, also rose, from $9.7 trillion to $12.1 trillion, led by increases in euro interest rate derivative contracts. The lastest semiannual data benefit from the addition of more comprehensive information for smaller dealers collected as part of the BIS Triennial Survey. Dealers in emerging market economies (EMEs) accounted for 9% of the outstanding notional amounts of foreign exchange and commodity derivatives globally at end-June 2019, up from 7% at end-June 2016.

The exchange-traded derivatives statistics provide monthly data on the turnover, and quarterly data on the open interest, of foreign exchange and interest rate futures and options. They refer to notional amounts, which enables comparisons of levels and trends in activity across different markets.

The National Capital Commission has reversed its decision and will now allow passersby to take photos at this year's Canadian Tulip Festival.

The National Capital Commission (NCC) says tulip admirers can "feel free" to take photos of the colourful flowers while visiting the Canadian Tulip Festival after placing signs saying photography wasn't allowed in tulip beds earlier this week.

Hate crimes against Vancouver's Asian communities have increased since the early days of the outbreak and the #Elimin8hate campaign is an effort to combat that and comfort victims.

Justin Young and Justine Manuel in Kamloops, B.C., shaved off their eyebrows as extra incentive to stay home and avoid socializing.

Advanced preliminary release for Q4 2019 quarterly data on debt service ratios (DSRs) for the private non-financial sector (PNFS) for 32 countries have been updated. DSRs for PNFS breakdown sectors, ie for households and for non-financial corporations are also available for 17 countries.

Notional amounts of OTC derivatives rose from $544 trillion at end-December 2018 to $559 trillion at end-December 2019. This, however, corresponds to a significant fall over the last six months, which could be at least partly attributed to seasonal factors. The seasonal pattern in the data, whereby end-June values tend typically to be larger than end-of-year values, appears strongest in positions vis-à-vis central counterparties. Such end-of-year contractions can occur if dealer banks and/or their clients shrink their outstanding notional derivative positions for regulatory and financial reporting purposes. Contracts denominated in non-G4 currencies (ie excluding USD, EUR, JPY and GBP) have grown in size for both interest rate and foreign exchange derivatives, even though those denominated in US dollars remain the largest segment.

The semiannual OTC derivatives statistics provide data on notional amounts outstanding and gross market values for all types of over-the-counter derivatives contracts. They are reported by large dealers in 12 countries on a worldwide consolidated basis.

The Kangaroo Privacy Camera is an affordable indoor home security camera that delivers sharp daytime footage and is equipped with a built-in privacy shield, but some features require a paid subscription and its nighttime video quality could be better.

Penn State Mont Alto recognizes and honors winners during awards ceremony

CNA Staff, May 7, 2020 / 11:50 am (CNA).- Bishop Kevin Rhoades of Fort Wayne-South Bend said Thursday that the alleged visions and revelations known as “Our Lady of America” cannot be said to be of supernatural origin, and that public devotion to “Our Lady of America” is not permitted for Catholics.

Sister Mary Ephrem Neuzil of the Congregation of the Sisters of the Most Precious Blood of Jesus began having what seemed like mystical experiences, including inner locutions and visions of the spirit, around 1938. She revealed these to her confessor in 1948, and they became a devotion to Mary as “Our Lady of America” in 1954.

Sr. Neuzil said the Blessed Virgin began appearing to her in 1956 in Rome City, Ind., about 40 miles northwest of Fort Wayne.

The alleged visions and messages from Mary and from St. Joseph continued through 1959, in a number of locations. After 1959, she said Our Lady communicated with her primarily by locutions, until her death in 2000.

Bishop Rhoades agreed in 2017 to conduct an investigation into the alleged apparitions. The bishop issued to other U.S. bishops a statement May 7 on the investigation, which was obtained by CNA, along with a July 2019 decree on the matter.

In the statement, Rhoades said that Sr. Neuzil “was honest, morally upright, psychologically balanced, devoted to religious life and without guile.” He added that she had “signs of imperfection, but no evidence that she was the perpetrator of a hoax or the victim of delusion.”

“What she communicated about her alleged experiences, she believed to be true, and her communication of those experiences are filled with humility and forthrightness,” he added.

The bishop noted there are numerous reports of conversions, spiritual refreshments and consolations, and even some physical healings related to the alleged apparition. He added, though, that “we cannot conclude that any of these events are conclusive enough to warrant certification as miracles. It seems likely that in such personal contexts of faith and prayer, God's graces were received.”

While “much of what is expressed” in the alleged revelations “does not contain any doctrinal error,” Bishop Rhoades wrote that there is a claim of St. Joseph as “'co-redeemer' with Christ for the salvation of the world … which has never been expressed as Catholic doctrine and must be seen as an error.”

He reported that Sr. Neuzil's spiritual director, Archbishop Paul Leibold, wrote in 1970 that he was unable to make a judgement on the supernatural nature of her visions, and that while he had helped her in promoting them as a “private devotion,” he had never acted “to promote her devotion publicly.”

“Looking at the nature and quality of the experiences themselves, we find that they are more to be described as subjective inner religious experiences rather than objective external visions and revelations,” Bishop Rhoades wrote.

“Thus, while it may be said that there is possibly an authenticity to Sister Neuzil's subjective religious experience, we do not find evidence pointing to her experience as being in the category of objective private revelation.”

The bishop and his investigatory commission found that “her experiences were of a type where her own imagination and intellect were involved in the formation of the events. It seems that these were authentically graced moments, even perhaps of a spiritual quality beyond what most people experience, but subjective ones in which her own imagination and intellect were constitutively engaged, putting form to inner spiritual movements. However, we do not find evidence that these were objective visions and revelations of the type seen at Guadalupe, Fatima and Lourdes.”

Bishop Rhoades' judgement was issued in the July 29, 2019 decree, which was signed also by Fr. Mark Gurtner, then-chancellor of the Diocese of Fort Wayne-South Bend.

The five other bishops where the purported visions were said to have occurred – Archbishop Dennis Schnurr of Cincinnati, Archbishop Allen Vigneron of Detroit, Bishop Timothy Doherty of Lafayette in Indiana, Bishop Thomas Olmsted of Phoenix, and Bishop Daneil Thomas of Toledo in Ohio – each concur with Bishop Rhoades' findings and conclusions.

The six bishops had in 2017 asked the US bishops' conference to investigate the alleged apparitions, considering that inquiries were being received about the alleged apparition and its purported request for a procession of the nation's bishops and that a statue of Our Lady of America be placed in the Basilica of the National Shrine of the Immaculate Conception.

The Congregation for the Doctrine of the Faith advised that it be conducted by one of the bishops, and Bishop Rhoades agreed to do so.

He received documentation of Sr. Neuzil's correspondence the following year, and he conducted the evaluation with a commission of theological and canonical experts. They also gathered personal interviews with witnesses who knew Sr. Neuzil.

The procedure for the investigation was carried out in accordance with the Congregation for the Doctrine of the Faith's 1978 "Norms regarding the manner of proceeding in the discernment of presumed apparitions or revelations."

Some bishops have permitted the public display of statues of Our Lady of America, and then-Msgr. Liebold had given an imprimatur to a prayer attached to the devotion in 1963.

The six bishops wrote May 7 that “given this history of prayers and religious articles being given approval by competent ecclesiastical authority, the use of such prayers religious articles may continue as a matter of private devotion, but not as a public devotion of the Church.”

“Indeed, such private devotion would be consistent with the history of the United States of America being dedicated to Our Lady,” they added.

However, “such private devotion should in no way imply approval or acceptance of purported revelations, visions, or locutions attributed to Sister Mary Ephrem (Mildred) Neuzil other than as her own subjective inner religious experiences.”

A spokesperson for the Diocese of Fort Wayne-South Bend told CNA that “the conclusion of Bishop Rhoades and the other five bishops pertains to the entire Church. The same would have been true if the decision were in the affirmative.”

 

This is the first blog post regarding the SOLIDWORKS activation error message. I will briefly try to go through the four most common activation error messages when using a standalone license. I will in a later blog post cover the

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Working with SOLIDWORKS on an SNL server, you can sometimes experience an Activation error message. Often these messages are not the same as the activation error messages you recieve when performing standalone activation What is SNL? SNL is short for

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“Looking around that pub at the various people enjoying their tea, I started really thinking about what he’d said,” Hannah remembers. “Praying for revival…In a country that many have come to learn is spiritually dark, have we given up on praying for the people? Has the belief in revival died, or are we still trusting that God can move in a mighty way?”

Historically returns are high.

Partners of OM EAST distribute copies of My First Bible to Nenets children on the Yamal Peninsula in northern Arctic Russia.

Find out about the festival of football that has proceeded the UEFA Champions League final every year since 2006.

More than 800 children were impacted by the Festival of Smiles 2011 that took place in the indigenous community of Talamanca, Costa Rica.

OM Costa Rica team members and volunteers share in the joy of giving more than 1,000 indigenous children a dream Christmas.

SCOTLAND'S capital is coming to terms with the "heart-breaking" news that its summer festivals will not go ahead this year - costing the city hundreds of millions of pounds.

Football players and coaches of all levels from across Latvia have been invited by the Latvian Football Federation to take part in football-based activities for UEFA Grassroots Day.

Celtic Connections

From Thursday 16 January to Sunday 2 February 2020, musicians from across the world will take part in over 300 events in venues throughout Glasgow for the UK's premier celebration of celtic music.

IF you’re anything like me, these weird alcohol-free January fads are to be avoided so let's raise a glass to a guilt-free month and kick it off with a look at something clean and refreshing to wash the season of excess away.

THE UK Government is “actively looking at” quarantining people arriving from abroad as criticism mounts over the country dragging its feet compared to other parts of the world.

Glasgow's Summer Nights at the Bandstand festival has become the latest major music event to be cancelled due to the Covid-19 pandemic.

Many state and local education agency websites aren't disclosing the presence of third-party tracking services, which can use information about users' browsing.

Teachers can feel pressured to use education technology products without knowing how to protect their own and their students' privacy, according to a new online survey by privacy advocacy groups.

The pandemic has boosted appreciation for public schools; the next step is greater funding, argues education historian and activist Diane Ravitch.

New guidance from the U.S. Department of Education says all private school students are entitled to "equitable services" under federal coronavirus emergency relief. Let's explore what that means.

In this lesson, 7th grade English/language arts teacher Emily Park-Friend takes her students through a three-step interview activity.