Krabbe's disease is an infantile neurodegenerative disease, which is affected by mutations in the lysosomal enzyme galactocerebrosidase, leading to the accumulation of its metabolite psychosine. We have shown previously that the S1P receptor agonist fingolimod (FTY720) attenuates psychosine-induced glial cell death and demyelination both in vitro and ex vivo models. These data, together with a lack of therapies for Krabbe's disease, prompted the current preclinical study examining the effects of fingolimod in twitcher mice, a murine model of Krabbe's disease. Twitcher mice, both male and female, carrying a natural mutation in the galc gene were given fingolimod via drinking water (1 mg/kg/d). The direct impact of fingolimod administration was assessed via histochemical and biochemical analysis using markers of myelin, astrocytes, microglia, neurons, globoid cells, and immune cells. The effects of fingolimod on twitching behavior and life span were also demonstrated. Our results show that treatment of twitcher mice with fingolimod significantly rescued myelin levels compared with vehicle-treated animals and also regulated astrocyte and microglial reactivity. Furthermore, nonphosphorylated neurofilament levels were decreased, indicating neuroprotective and neurorestorative processes. These protective effects of fingolimod on twitcher mice brain pathology was reflected by an increased life span of fingolimod-treated twitcher mice. These in vivo findings corroborate initial in vitro studies and highlight the potential use of S1P receptors as drug targets for treatment of Krabbe's disease.

SIGNIFICANCE STATEMENT This study demonstrates that the administration of the therapy known as fingolimod in a mouse model of Krabbe's disease (namely, the twitcher mouse model) significantly rescues myelin levels. Further, the drug fingolimod also regulates the reactivity of glial cells, astrocytes and microglia, in this mouse model. These protective effects of fingolimod result in an increased life span of twitcher mice.

Hepatocyte growth factor (HGF) is a multifunctional protein that signals through the MET receptor. HGF stimulates cell proliferation, cell dispersion, neuronal survival, and wound healing. In the inner ear, levels of HGF must be fine-tuned for normal hearing. In mice, a deficiency of HGF expression limited to the auditory system, or an overexpression of HGF, causes neurosensory deafness. In humans, noncoding variants in HGF are associated with nonsyndromic deafness DFNB39. However, the mechanism by which these noncoding variants causes deafness was unknown. Here, we reveal the cause of this deafness using a mouse model engineered with a noncoding intronic 10 bp deletion (del10) in Hgf. Male and female mice homozygous for del10 exhibit moderate-to-profound hearing loss at 4 weeks of age as measured by tone burst auditory brainstem responses. The wild type (WT) 80 mV endocochlear potential was significantly reduced in homozygous del10 mice compared with WT littermates. In normal cochlea, endocochlear potentials are dependent on ion homeostasis mediated by the stria vascularis (SV). Previous studies showed that developmental incorporation of neural crest cells into the SV depends on signaling from HGF/MET. We show by immunohistochemistry that, in del10 homozygotes, neural crest cells fail to infiltrate the developing SV intermediate layer. Phenotyping and RNAseq analyses reveal no other significant abnormalities in other tissues. We conclude that, in the inner ear, the noncoding del10 mutation in Hgf leads to developmental defects of the SV and consequently dysfunctional ion homeostasis and a reduction in the EP, recapitulating human DFNB39 nonsyndromic deafness.

SIGNIFICANCE STATEMENT Hereditary deafness is a common, clinically and genetically heterogeneous neurosensory disorder. Previously, we reported that human deafness DFNB39 is associated with noncoding variants in the 3'UTR of a short isoform of HGF encoding hepatocyte growth factor. For normal hearing, HGF levels must be fine-tuned as an excess or deficiency of HGF cause deafness in mouse. Using a Hgf mutant mouse with a small 10 bp deletion recapitulating a human DFNB39 noncoding variant, we demonstrate that neural crest cells fail to migrate into the stria vascularis intermediate layer, resulting in a significantly reduced endocochlear potential, the driving force for sound transduction by inner ear hair cells. HGF-associated deafness is a neurocristopathy but, unlike many other neurocristopathies, it is not syndromic.

Although the etiology of schizophrenia is still unknown, it is accepted to be a neurodevelopmental disorder that results from the interaction of genetic vulnerabilities and environmental insults. Although schizophrenia's pathophysiology is still unclear, postmortem studies point toward a dysfunction of cortical interneurons as a central element. It has been suggested that alterations in parvalbumin-positive interneurons in schizophrenia are the consequence of a deficient signaling through NMDARs. Animal studies demonstrated that early postnatal ablation of the NMDAR in corticolimbic interneurons induces neurobiochemical, physiological, behavioral, and epidemiological phenotypes related to schizophrenia. Notably, the behavioral abnormalities emerge only after animals complete their maturation during adolescence and are absent if the NMDAR is deleted during adulthood. This suggests that interneuron dysfunction must interact with development to impact on behavior. Here, we assess in vivo how an early NMDAR ablation in corticolimbic interneurons impacts on mPFC and ventral hippocampus functional connectivity before and after adolescence. In juvenile male mice, NMDAR ablation results in several pathophysiological traits, including increased cortical activity and decreased entrainment to local gamma and distal hippocampal theta rhythms. In addition, adult male KO mice showed reduced ventral hippocampus-mPFC-evoked potentials and an augmented low-frequency stimulation LTD of the pathway, suggesting that there is a functional disconnection between both structures in adult KO mice. Our results demonstrate that early genetic abnormalities in interneurons can interact with postnatal development during adolescence, triggering pathophysiological mechanisms related to schizophrenia that exceed those caused by NMDAR interneuron hypofunction alone.

SIGNIFICANCE STATEMENT NMDAR hypofunction in cortical interneurons has been linked to schizophrenia pathophysiology. How a dysfunction of GABAergic cortical interneurons interacts with maturation during adolescence has not been clarified yet. Here, we demonstrate in vivo that early postnatal ablation of the NMDAR in corticolimbic interneurons results in an overactive but desynchronized PFC before adolescence. Final postnatal maturation during this stage outspreads the impact of the genetic manipulation toward a functional disconnection of the ventral hippocampal-prefrontal pathway, probably as a consequence of an exacerbated propensity toward hippocampal-evoked depotentiation plasticity. Our results demonstrate a complex interaction between genetic and developmental factors affecting cortical interneurons and PFC function.

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.

Microglial cells are considered as sensors of brain pathology by detecting any sign of brain lesions, infections, or dysfunction and can influence the onset and progression of neurological diseases. They are capable of sensing their neuronal environment via many different signaling molecules, such as neurotransmitters, neurohormones and neuropeptides. The neuropeptide VGF has been associated with many metabolic and neurological disorders. TLQP21 is a VGF-derived peptide and has been shown to signal via C3aR1 and C1qBP receptors. The effect of TLQP21 on microglial functions in health or disease is not known. Studying microglial cells in acute brain slices, we found that TLQP21 impaired metabotropic purinergic signaling. Specifically, it attenuated the ATP-induced activation of a K⁺ conductance, the UDP-stimulated phagocytic activity, and the ATP-dependent laser lesion-induced process outgrowth. These impairments were reversed by blocking C1qBP, but not C3aR1 receptors. While microglia in brain slices from male mice lack C3aR1 receptors, both receptors are expressed in primary cultured microglia. In addition to the negative impact on purinergic signaling, we found stimulating effects of TLQP21 in cultured microglia, which were mediated by C3aR1 receptors: it directly evoked membrane currents, stimulated basal phagocytic activity, evoked intracellular Ca²⁺ transient elevations, and served as a chemotactic signal. We conclude that TLQP21 has differential effects on microglia depending on C3aR1 activation or C1qBP-dependent attenuation of purinergic signaling. Thus, TLQP21 can modulate the functional phenotype of microglia, which may have an impact on their function in health and disease.

SIGNIFICANCE STATEMENT The neuropeptide VGF and its peptides have been associated with many metabolic and neurological disorders. TLQP21 is a VGF-derived peptide that activates C1qBP receptors, which are expressed by microglia. We show here, for the first time, that TLQP21 impairs P2Y-mediated purinergic signaling and related functions. These include modulation of phagocytic activity and responses to injury. As purinergic signaling is central for microglial actions in the brain, this TLQP21-mediated mechanism might regulate microglial activity in health and disease. We furthermore show that, in addition to C1qBP, functional C3aR1 responses contribute to TLQP21 action on microglia. However, C3aR1 responses were only present in primary cultures but not in situ, suggesting that the expression of these receptors might vary between different microglial activation states.

The superior colliculus (SC) is arguably the most important visual structure in the mouse brain and is well known for its involvement in innate responses to visual threats and prey items. In other species, the SC plays a central role in voluntary as well as innate visual functions, including crucial contributions to selective attention and perceptual decision-making. In the mouse, the possible role of the SC in voluntary visual choice behaviors has not been established. Here, we demonstrate that the mouse SC of both sexes plays a causal role in visual perceptual decision-making by transiently inhibiting SC activity during an orientation change detection task. First, unilateral SC inhibition-induced spatially specific deficits in detection. Hit rates were reduced, and reaction times increased for orientation changes in the contralateral but not ipsilateral visual field. Second, the deficits caused by SC inhibition were specific to a temporal epoch coincident with early visual burst responses in the SC. Inhibiting SC during this 100-ms period caused a contralateral detection deficit, whereas inhibition immediately before or after did not. Third, SC inhibition reduced visual detection sensitivity. Psychometric analysis revealed that inhibiting SC visual activity significantly increased detection thresholds for contralateral orientation changes. In addition, effects on detection thresholds and lapse rates caused by SC inhibition were larger in the presence of a competing visual stimulus, indicating a role for the mouse SC in visual target selection. Together, our results demonstrate that the mouse SC is necessary for the normal performance of voluntary visual choice behaviors.

SIGNIFICANCE STATEMENT The mouse superior colliculus (SC) has become a popular model for studying the circuit organization and development of the visual system. Although the SC is a fundamental component of the visual pathways in mice, its role in visual perceptual decision-making is not clear. By investigating how temporally precise SC inhibition influenced behavioral performance during a visually guided orientation change detection task, we identified a 100-ms temporal epoch of SC visual activity that is crucial for the ability of mice to detect behaviorally relevant visual changes. In addition, we found that SC inhibition also caused deficits in visual target selection. Thus, our findings highlight the importance of the SC for visual perceptual choice behavior in the mouse.

Mountains provide freshwater and biodiversity, and are a major source of food. By definition, they dominate their surroundings with towering height and protect valleys and their inhabitants. They play a critical part in moving the world towards sustainable economic growth and have a leading role as indicators of climate change. As we celebrate the International Mountain Day, see how much you [...]

In some countries, mountains are considered deities. In others, mountains are peaks to climb. In others still, mountains, like volcanoes, are spirits that can be angered. In countries around the world though, mountains provide life-sustaining water, energy and food for over half the world’s population.

A firefly mating ritual turns into a synchronized light show

The British Navy knew it couldn't completely disguise a ship to protect it from attack during WWI. So they turned to 'Dazzle Painting'

The Getty Museum hopes its social media challenge will spark inspiration amid the COVID-19 pandemic

The planet's temperatures spike around the latitudes where auroras show up

The 72-year-old animal was the third oldest in the North American population

When the full moon rises, dark skies shine with bright fire, and the stars go to the dance, as if greeting it. Kazakhstan

A large destination resort in Minnesota, just a few hours south of Thunder Bay, Ont., has some big expansion plans.

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Newfoundland and Labrador's already fragile economy suffered another gut-punch in April, with Statistics Canada reporting Friday that 29,000 jobs were lost in April alone.

Mar del Plata, Argentina :: Crewmembers visit a Christian rehabilitation centre and remind women of their value in God's eyes.

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.

Some school travel groups in Cape Breton that had trips cancelled in March due to COVID-19 are still waiting to get their money back.

Discover the real George Washington through his restored home and gardens, over 1,000 artifacts, and an immersive Revolutionary War "snow" experience

Ottawa police have arrested a 15-year-old boy in connection with January's shooting. He's charged with first-degree murder and attempted murder.

Grit and red wine: Famous war photographer beats virus at 97  WSET

A team of Canadian balloon twisters earned five awards at the World Balloon Convention in California this month for their Mickey and Minnie Mouse as Romeo and Juliet design.

The Royal Canadian Mint's newest offering features Manitoba's most famous UFO encounter, which happened in 1967 when Stefan Michalak went looking for precious metals near Falcon Lake.

The Coldwater band is calling for federal intervention after Trans Mountain announced it was changing the way it would study the aquifer the First Nation relies on for its drinking water.

Some residents of Canmore, Alta., are mourning the death of an unusual elk that went by the name of Marvin. He was known to frequent backyards and hang out with pets.

Three people living in the mountains of Western Canada tell us about the beauty, the lifestyle and the danger of calling them home.

The post Solving Mounting Problems Using xDesign appeared first on SOLIDWORKS Education Blog.

This is a SOLIDWORKS Tutorial for a drop out bowl mold. The mold is designed to create a slip cast ceramic bowl. The tutorial focuses on the combine tool, and the use of undercut analysis, which evaluates the design of the bowl for possible issues for molding. It is essential to test a model in this way before molding to avoid the model getting trapped in the mold.

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The post Drop Out Bowl Mould appeared first on SOLIDWORKS Tech Blog.

Nirmal Purja, mountaineer

An OM worker and local team of believers visit indigenous Cabecar communities in the mountains of Talamanca, Costa Rica.

STYLE AND SUBSTANCE

Castilla y León made an impressive start to their bid for a second UEFA Regions' Cup title as two goals from Roberto García Puente set them on course for a 4-1 victory.

Aleksei Lomovtsev struck nine minutes after half-time as Russia's South Region kept themselves in contention going into the last group games; Olomouc are out.

Eoin Hayes struck either side of half-time as Region 2 accelerated away from Olomouc, a 4-1 victory enough to take them into Sunday's UEFA Regions' Cup final as Group B winners.

Six teacher-authors discuss what they learned over the past year and a half as they wrote books that are set to be published in the coming weeks.

A couple launches a monthly class for children and their parents despite low numbers. Through prayer and free advertising, more begin to come.

Source: www.brooklynpaper.com - Saturday, May 09, 2020
The owner of the iconic Park Slope events venue Grand Prospect Hall, Michael Halkias, died from COVID-19 on Wednesday. He was 82. Halkias’ death sent shockwaves throughout Brooklyn, where community leaders and friends remember him as a passionate, generous figure. “ He was a Brooklyn character for sure in the best sort of way,” said Randy Peers, president and CEO of the Brooklyn Chamber of Commerce. “He was larger than life.” Halkias and his wife Alice bought Grand Prospect Hall in 1984 and turned the extravagant Prospect Avenue building into an opulent catering hall. The space became a New York icon because of the its long-running, popular commercials, where Alice Halkias declares in a Greek accent, “We make your dreams come true!” Saturday Night Live spoofed the famous commercial in February of 2019, and the pair appeared on Jimmy Kimmel Live in October to remake the ad with Mets player Pete Alonso. Grand Prospect Hall, a Victorian banquet hall built in 1892, attracted big names such as dancer Fred Astaire and mafioso Al Capone during its heyday in the early 20th century — and boasted some of the borough’s oldest treasures, such as Brooklyn’s first reported elevator, which functions to this day. But by the 1980s, the landmarked building had fallen into disrepair: its walls had been painted black, molding had been stripped off the walls, and the chandeliers were gone, Halkias told Brooklyn Paper in 2004. The couple spent 20 yea

United Kingdom and European Union negotiators were working through Sunday as the outcome of Brexit talks hung in the balance.

Penn State and the Palmer Museum of Art mourn the loss of dear friend, generous donor, and loyal champion John P. Driscoll, who died from complications due to COVID-19 on Friday, April 10. Driscoll, owner of Driscoll Babcock Galleries in New York, was a longtime friend and supporter of the Palmer Museum and will be remembered for his role as a leader, gracious mentor and trusted adviser, as well as for the expansive gifts he made to the collection and to his alma mater, Penn State.

Telacebec (Q203) is a new anti-tubercular drug with extremely potent activity against Mycobacterium ulcerans. Here, we explored the treatment-shortening potential of Q203 alone or in combination with rifampin (RIF) in a mouse footpad infection model. The first study compared Q203 at 5 and 10 mg/kg doses alone and with rifampin. Q203 alone rendered most mouse footpads culture-negative in 2 weeks. Combining Q203 with rifampin resulted in relapse-free cure 24 weeks after completing 2 weeks of treatment, compared to a 25% relapse rate in mice receiving RIF+clarithromycin, the current standard of care, for 4 weeks.

The second study explored the dose-ranging activity of Q203 alone and with RIF, including the extended activity of Q203 after treatment discontinuation. The bactericidal activity of Q203 persisted for ≥ 4 weeks beyond the last dose. All mice receiving just 1 week of Q203 at 2-10 mg/kg were culture-negative 4 weeks after stopping treatment. Mice receiving 2 weeks of Q203 at 0.5, 2 and 10 mg/kg were culture-negative 4 weeks after treatment. RIF did not increase the efficacy of Q203. A pharmacokinetics sub-study revealed that Q203 doses of 2-10 mg/kg in mice produce plasma concentrations similar to those produced by 100-300 mg doses in humans, with no adverse effect of RIF on Q203 concentrations.

These results indicate the extraordinary potential of Q203 to reduce the duration of treatment necessary for cure to ≤ 1 week (or 5 doses of 2-10 mg/kg) in our mouse footpad infection model and warrant further evaluation of Q203 in clinical trials.

Source: www.businessinsider.com - Friday, May 08, 2020
Los Angeles' food truck population of over 800 trucks faces a downturn in profits during the coronavirus pandemic, which threatens the livelihood of dozens of vendors. Trucks, many of which are family-owned, are losing up to 60% to 70% of their business. The disintegration of Los Angeles' food truck scene is creating ripple effects as truck owners, employees, and commissaries take financial hits. California recently allowed food trucks to obtain a permit to sell at rest stops, giving vendors the chance to sell to truckers outside the LA proper. Visit Business Insider's homepage for more stories . Los Angeles' food truck scene of over 800 operational trucks is facing a difficult time as business essentially grinds to a halt during the coronavirus pandemic. Food trucks, which are often run as small family businesses, cost on average $29,000 to run in LA, according to a report by the US Chambers of Commerce . But as the lifeblood of food trucks — foot traffic, social gathering, and events — disappears in the wake of the coronavirus, families and small businesses are suffering. "Food trucks rely on people to gather. That model went away pretty quickly," Ross Resnick, founder of food-truck-booking company Roaming Hunger, told the Orange County Register in March. "Pre-corona, it's events, it's workplaces, it's nighttime gatherings in markets. When you close your eyes and imagine a food truck, you imagine a group of people." There are

Europe's most famous footballing families are supporting a new TV campaign by UEFA which calls on dads to encourage their daughters to play football.

A record number of student startups from across Penn State campuses are getting ready for the 2020 Summer Founders program, a 13-week entrepreneurial bootcamp offering mentoring, networking, resources and $15,000 in funding to teams of Penn State student entrepreneurs from all campus locations and the World Campus.

Workers in Tajikistan long for the people of the country to replace superstition with trust in their Saviour.

After years of living among a remote unreached people group, OMers see God draw the first local believers to Himself.