London, [29 January 1994]

Karim Fifel
Jan 24, 2018; 38:784-786
Journal Club

Erin E. Hecht
Sep 25, 2019; 39:7748-7758
BehavioralSystemsCognitive

In today's evolving business environment, every operational decision is critical -- and that includes best practices for managing the customer journey. The CRM platform is an integral part of the process. In fact, 91 percent of companies with more than 11 employees use a CRM system. Because of the time it saves and the structure CRM delivers, it can seem daunting for businesses to make a switch.

The Drosophila nervous system is ensheathed by a layer of outer glial cells, the perineurial glia, and a specialized extracellular matrix, the neural lamella. The function of perineurial glial cells and how they interact with the extracellular matrix are just beginning to be elucidated. Integrin-based focal adhesion complexes link the glial membrane to the extracellular matrix, but little is known about integrin's regulators in the glia. The transmembrane Ig domain protein Basigin/CD147/EMMPRIN is highly expressed in the perineurial glia surrounding the Drosophila larval nervous system. Here we show that Basigin associates with integrin at the focal adhesions to uphold the structure of the glia-extracellular matrix sheath. Knockdown of Basigin in perineurial glia using RNAi results in significant shortening of the ventral nerve cord, compression of the glia and extracellular matrix in the peripheral nerves, and reduction in larval locomotion. We determined that Basigin is expressed in close proximity to integrin at the glial membrane, and that expression of the extracellular integrin-binding domain of Basigin is sufficient to rescue peripheral glial compression. We also found that a reduction in expression of integrin at the membrane rescues the ventral nerve cord shortening, peripheral glial compression, and locomotor phenotypes, and that reduction in the integrin-binding protein Talin can partially rescue glial compression. These results identify Basigin as a potential negative regulator of integrin in the glia, supporting proper glial and extracellular matrix ensheathment of the nervous system.

SIGNIFICANCE STATEMENT The glial cells and extracellular matrix play important roles in supporting and protecting the nervous system, but the interactions between these components have not been well characterized. Our study identified expression of a conserved Ig superfamily protein, Basigin, at the glial membrane of Drosophila where it associates with the integrin-based focal adhesion complexes to ensure proper ensheathment of the CNS and PNS. Loss of Basigin in the glia results in an overall compression of the nervous system due to integrin dysregulation, which causes locomotor defects in the animals. This underlies the importance of glia-matrix communication for structural and functional support of the nervous system.

Nitric oxide (NO) is an important signaling molecule that fulfills diverse functional roles as a neurotransmitter or diffusible second messenger in the developing and adult CNS. Although the impact of NO on different behaviors such as movement, sleep, learning, and memory has been well documented, the identity of its molecular and cellular targets is still an area of ongoing investigation. Here, we identify a novel role for NO in strengthening inhibitory GABA_A receptor-mediated transmission in molecular layer interneurons of the mouse cerebellum. NO levels are elevated by the activity of neuronal NO synthase (nNOS) following Ca²⁺ entry through extrasynaptic NMDA-type ionotropic glutamate receptors (NMDARs). NO activates protein kinase G with the subsequent production of cGMP, which prompts the stimulation of NADPH oxidase and protein kinase C (PKC). The activation of PKC promotes the selective strengthening of α3-containing GABA_ARs synapses through a GABA receptor-associated protein-dependent mechanism. Given the widespread but cell type-specific expression of the NMDAR/nNOS complex in the mammalian brain, our data suggest that NMDARs may uniquely strengthen inhibitory GABAergic transmission in these cells through a novel NO-mediated pathway.

SIGNIFICANCE STATEMENT Long-term changes in the efficacy of GABAergic transmission is mediated by multiple presynaptic and postsynaptic mechanisms. A prominent pathway involves crosstalk between excitatory and inhibitory synapses whereby Ca²⁺-entering through postsynaptic NMDARs promotes the recruitment and strengthening of GABA_A receptor synapses via Ca²⁺/calmodulin-dependent protein kinase II. Although Ca²⁺ transport by NMDARs is also tightly coupled to nNOS activity and NO production, it has yet to be determined whether this pathway affects inhibitory synapses. Here, we show that activation of NMDARs trigger a NO-dependent pathway that strengthens inhibitory GABAergic synapses of cerebellar molecular layer interneurons. Given the widespread expression of NMDARs and nNOS in the mammalian brain, we speculate that NO control of GABAergic synapse efficacy may be more widespread than has been appreciated.

Behavior can be guided by neuronal activity in visual, auditory, or somatosensory cerebral cortex, depending on task requirements. In contrast to this flexible access of cortical signals, several observations suggest that behaviors depend more on neurons in later areas of visual cortex than those in earlier areas, although neurons in earlier areas would provide more reliable signals for many tasks. We recorded from neurons in different levels of visual cortex of 2 male rhesus monkeys while the animals did a visual discrimination task and examined trial-to-trial correlations between neuronal and behavioral responses. These correlations became stronger in primary visual cortex as neuronal signals in that area became more reliable relative to the other areas. The results suggest that the mechanisms that read signals from cortex might access any cortical area depending on the relative value of those signals for the task at hand.

SIGNIFICANCE STATEMENT Information is encoded by the action potentials of neurons in various cortical areas in a hierarchical manner such that increasingly complex stimulus features are encoded in successive stages. The brain must extract information from the response of appropriate neurons to drive optimal behavior. A widely held view of this decoding process is that the brain relies on the output of later cortical areas to make decisions, although neurons in earlier areas can provide more reliable signals. We examined correlations between perceptual decisions and the responses of neurons in different levels of monkey visual cortex. The results suggest that the brain may access signals in any cortical area depending on the relative value of those signals for the task at hand.

Structural plasticity of dendritic spines is a key component of the refinement of synaptic connections during learning. Recent studies highlight a novel role for the NMDA receptor (NMDAR), independent of ion flow, in driving spine shrinkage and LTD. Yet little is known about the molecular mechanisms that link conformational changes in the NMDAR to changes in spine size and synaptic strength. Here, using two-photon glutamate uncaging to induce plasticity at individual dendritic spines on hippocampal CA1 neurons from mice and rats of both sexes, we demonstrate that p38 MAPK is generally required downstream of non-ionotropic NMDAR signaling to drive both spine shrinkage and LTD. In a series of pharmacological and molecular genetic experiments, we identify key components of the non-ionotropic NMDAR signaling pathway driving dendritic spine shrinkage, including the interaction between NOS1AP (nitric oxide synthase 1 adaptor protein) and neuronal nitric oxide synthase (nNOS), nNOS enzymatic activity, activation of MK2 (MAPK-activated protein kinase 2) and cofilin, and signaling through CaMKII. Our results represent a large step forward in delineating the molecular mechanisms of non-ionotropic NMDAR signaling that can drive shrinkage and elimination of dendritic spines during synaptic plasticity.

SIGNIFICANCE STATEMENT Signaling through the NMDA receptor (NMDAR) is vitally important for the synaptic plasticity that underlies learning. Recent studies highlight a novel role for the NMDAR, independent of ion flow, in driving synaptic weakening and dendritic spine shrinkage during synaptic plasticity. Here, we delineate several key components of the molecular pathway that links conformational signaling through the NMDAR to dendritic spine shrinkage during synaptic plasticity.

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"This could be the oldest and longest-lived team ball game in the world," says one archaeologist

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Bayern Munich has secured Canadian soccer star Alphonso Davies for another two years through June 2025, with club officials and the teenager donning surgical masks to ink the deal during the global pandemic.

Former CFL kicker Lirim Hajrullahu signed with the NFL's Los Angeles Rams on Monday to potentially replace veteran Greg Zuerlein.

New England head coach Bill Belichick said not taking a quarterback in the Patriots' first post-Tom Brady draft "wasn't by design."

Andy Dalton is coming home to Texas as Dak Prescott's backup with the Dallas Cowboys.

Kevin Khungay played high school basketball. His friend's older brother Sunny Basran was his coach. Years later, their unique designs are worn by some of the sports biggest stars.

Boston Bruins goaltender Jaroslav Halak signed a one-year contract worth $2.25 million US, the team announced Friday. He was playing in the final season of a two-year contract.

The Toronto Maple Leafs have signed Finnish defenceman Mikko Lehtonen to a one-year, entry-level contract for the 2020-21 season, the club announced Monday.

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Washington, D.C. Newsroom, May 7, 2020 / 07:55 am (CNA).- Pope Francis has accepted the resignation of Bishop Joseph Binzer, Cincinnati's auxiliary bishop, who was accused in August of failing to act on allegations made against a priest. 

A statement from the Holy See press office May 7 said the pope had accepted the 65-year-old bishop’s resignation but gave no reason for the decision. 

In a statement released by the Archdiocese of Cincinnati, Archbishop Dennis Schnurr said the pope accepted Binzer’s resignation after conversations between the bishop and the Holy See. 

The archdiocese also included a brief statement from Binzer in which he said he was “deeply sorry for my role in addressing the concerns raised about Father Drew, which has had a negative impact on the trust and faith of the people of the Archdiocese of Cincinnati.”  

“In April, having studied this matter since last summer, the Holy See informed me that it agreed with this assessment. As a result, and after much prayer and reflection, I offered my resignation from the Office of Auxiliary Bishop of the Archdiocese of Cincinnati,” said Binzer. ”I believe this to be in the best interest of the archdiocese.”

Archbishop Schnurr said that although retired, Binzer will continue to serve in the archdiocese with the title of “Auxiliary Bishop Emeritus.” 

“What exactly that ministry will look like will be determined after discussions between Bishop Binzer, the Priest Personnel Board, and me,” Schnurr said. “In this difficult and unfortunate time, please keep Bishop Binzer and all the people of the archdiocese in your prayers.”

Archbishop Schnurr removed Binzer from his position as head of priest personnel in August, after CNA presented officials with its investigation into claims that Binzer failed to pass on reports that a priest had engaged in inappropriate behavior with teenage boys.

In August last year, Schnurr told CNA that “We obviously made serious mistakes in our handling of this matter, for which we are very sorry.”

While Schnurr’s public comments did not address Binzer’s role directly, senior sources in the archdiocese told CNA in August that Schnurr had “gone nuclear” when he discovered the situation.

“The archbishop was as mad as I have ever seen him. When he was told that Bishop Binzer had withheld information, well, he used words I have never heard him use before,” one senior source told CNA, saying Schnurr called Binzer’s actions a “firestorm” for the archdiocese.

In September, 2019, an archdiocesan spokesperson told CNA that Schnurr had sent a "full report to Rome on the whole case and he is waiting for the Vatican’s response,” and he expected "a full investigation” to be conducted by the Vatican.

Binzer later resigned as a member of the U.S. bishops’ conference committee for the protection of children and young people, on which he represented Region VI.

CNA reported in August last year that Binzer was told in 2013 about allegations concerning a recently suspended priest, Fr. Geoff Drew, and failed to disclose them to Cincinnati Archbishop Dennis Schnurr and other archdiocesan officials.

While the archdiocesan victims’ assistance coordinator, who reported to Binzer, was aware of the allegation, the information was not made known to the diocesan priest personnel board or Archbishop Schnurr. 

In 2015, similar allegations were again made against Drew. The matter was forwarded to Butler County officials, who determined that the activity was not criminal. Again, Binzer reported neither the complaints nor the investigation to the archbishop or informed the priest personnel board.

Sources in the archdiocesan chancery told CNA in August that Binzer met with Drew twice, was assured by him that he would reform his conduct, and considered this sufficient.

In early 2018, Drew applied for a transfer to St. Ignatius of Loyola Parish in Green Township, which is attached to the largest Catholic school in the archdiocese.

As head of priest personnel, Binzer was in charge of the process that considers requests and proposals for reassignment, in conjunction with the priest personnel board.

Neither the board nor the archbishop were made aware of the multiple complaints against Drew, and the transfer was approved.

The allegations were also reportedly not recorded by Binzer in the priest’s personnel file that would have been available to the archdiocesan personnel board as part of the process.

A month after Drew’s arrival at St. Ignatius, a parishioner at Drew’s former parish resubmitted the 2015 complaints about the priest, but this time it was also brought to the attention of Archbishop Schnurr.

Also in 2018, Binzer received an additional complaint of similarly inappropriate contact by Drew, dating to his time as a high school music teacher, before his ordination as a priest. 

Following a diocesan investigation, Drew was ordered to attend counselling with a psychologist.

On July 23, Drew was removed from ministry, when it emerged that he had sent a series of inappropriate text messages to a 17-year-old. 

Chancery sources told CNA in August that it was only after the recent incident at St. Ignatius that archdiocesan officials discovered that the otherwise undisclosed complaints about Drew had been made to Binzer, and that the auxiliary bishop had failed to report them to other diocesan officials, or raise them during the decision to approve his transfer in 2018.

Purifying and culturing cells from the central nervous system (CNS) has proved to be an incredibly powerful tool for dissecting fundamental neuron and glial properties, and especially powerful in understanding neuronal–glial interactions. In a series of detailed protocols, we have provided step-by-step instructions for purifying and culturing specific types of neurons, glia, and vascular cells from the CNS by immunopanning. This article discusses common pitfalls and errors as well as important design considerations for the immunopanning procedure.

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