Perception is everything.

Karting driver Scott Barnes heads into the SummerNationals – the final rounds of the Skusa Pro Tour – this weekend looking to wrap up the Shifter Masters title. Barnes, who will race at the New Castle Motorsports Park in Indianapolis in rounds five and six, is second in the overall points standings after a successful […]

Kreml dokáže využít opravdu jakýkoli možný způsob, který může oslabit Evropu zevnitř. Každý problém, s nímž se Evropa zrovna potýká, vnímá Moskva jako svoji potenciální příležitost. A jelikož Rusko dobře ví, že k hlavním výzvám Evropy patří ilegální migrace, snaží se ještě přisypávat sůl do krvácející rány a problém ještě více prohloubit.

Honor готовится выпустить новую модель смартфона Magic7 RSR Porsche Design, которая снова будет привлекать внимание своим дизайном, напоминающим стиль автомобилей Porsche.

1. Germany to hold snap election in February after government's coalition collapse  ABC News
2. The briefcase, the Porsche and the collapse of the German government – podcast  The Guardian
3. Germany set for snap election following collapse of Olaf Scholz’s coalition  The Conversation
4. President calls German early election plan 'realistic'  DW (English)

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ZombieGeisha says: "My guinea pig, Spooky, making a mess of his orange snack."

Now Spooky, who is going to take you seriously when you can't even bother to wipe your chin?

Do you have a squee pet that you want to share with the world? Send us your pet pictures and stories, and they could end up on Daily Squee!

Worldwide revenues will triple in 2022   April 11, 2022 (New York, NY) – TikTok’s worldwide ad revenues will triple this year and surpass that of two competitors combined, according […]

Dongmei Cheng
Jun 1, 2006; 5:1158-1170
Datasets

Jonathan C. Trinidad
Aug 1, 2012; 11:215-229
Research

Following its snap election, Japanese politics has entered uncharted waters Expert comment LToremark 5 November 2024

Prime Minister Ishiba’s election gamble has failed. Japan now faces another period of political uncertainty, which could affect its international standing.

In Japan’s snap election on 27 October, the ruling coalition of the Liberal Democratic Party (LDP) and New Komeito lost the overwhelming majority it had held since the 2012 general election. The ruling coalition now has 215 seats, leaving it 18 seats short of a majority. 

The largest opposition party is the Constitutional Democratic Party of Japan (CDP), which gained 50 seats to 148. The second largest opposition party is the Japan Innovation Party (Ishin), which lost six seats to 38, and the third largest opposition party is the National Democratic Party (NDP), which gained 21 seats to 28.

But the opposition is divided and there is no real appetite to form a coalition government. This will likely result in a hung parliament, which will further destabilize Japan’s government.

The election results reveal three key things  about the state of Japanese politics and what comes next.

First, that Prime Minister Ishiba’s snap election gamble has failed. The aim was for Ishiba, a non-mainstream member of the LDP, to strengthen the party base and stabilize his administration. But with the ruling coalition losing its majority, the party base has been further weakened and the Ishiba administration is now more likely to be short-lived. LDP voters as well as the public in general  had hoped that Ishiba, as the ‘opposition within the party’, would change the LDP’s structure and government policies, eliminate the uncertainty surrounding party funding and increase transparency on how MPs use public funds to finance political activities.

However, when Ishiba became LDP leader and prime minister, he abandoned his previously more critical stance and prioritized carrying on the policies of the mainstream LDP, leaving his supporters feeling betrayed.

Second, while the ruling coalition has been punished, the people of Japan still did not vote for a change of government. The opposition is divided and, despite its gains in this election, the CDP is not fully committed to take the lead and consolidate the opposition to form a coalition. The CDP also suffers from internal division. The left wing of the party would prefer a coalition with the Communist Party, while the right wing of the party does not want to form a coalition with the LDP or the Communist Party, preferring a partner such as the NDP.

Third, the NDP has become the key to future Japanese politics. By becoming the minority ruling party, the NDP is in a position to control the fate of Ishiba administration. While the CDP has no intention of cooperating with the LDP, the NDP is more willing to do so in order to implement its own policies. As the budget cannot be passed without the NDP’s cooperation, the ruling coalition will have no choice but to accept the NDP’s policy of substantial tax cuts through the expansion of tax credits. It will also likely have to accept an option for married couples to decide their family names, which requires a change of civil codes and is something it has been reluctant to do so far. 

If the NDP’s demands are rejected, a no-confidence motion will likely be submitted and passed, leaving the Ishiba cabinet with no choice but to resign or dissolve the House of Representatives (the lower house of Japan’s parliament).

But the NDP has chosen to not form a coalition with the ruling party and enter government. Why? From the NDP’s point of view, forming a coalition with the LDP, would mean getting involved in the LDP’s internal turmoil – something it wishes to avoid. In addition, elections to the House of Councillors (upper house of parliament) will be held in the summer of 2025. The NDP may have judged that it will have a better chance of implementing its policies by cooperating with the government on a case-by-case basis, rather than forming a coalition with a party that is losing public support and risk following suit.

The minority ruling system that has emerged after the election is extremely rare in Japan’s political history and is likely to make its politics even more unstable in the years ahead. The Ishiba administration will probably be able to survive until the budget is passed in March next year by cooperating with the NDP, but beyond that its prospects are unclear.

As the House of Councillors elections get closer, some in the LDP may say that they cannot fight the election with Ishiba as prime minister. If so, they may choose the option of a same-day election for the lower and the upper house. The cost of an election campaign is significant, and the LDP’s financial strength gives it an advantage in the case of a same-day election. There is also a strong possibility that the public will choose the LDP to regain stability in government. However, this election has shown that public distrust of the LDP is high, and if Ishiba continues to be pushed around by the NDP, his party’s chances of winning would be reduced.

Japanese politics has entered uncharted waters, where the patterns and customs of the past do not apply. There are now doubts both at home and abroad as to whether Ishiba, who has a weak party base, will be able to stay on and steer the government. Over the past decade, the Abe and Kishida administrations have provided Japan with political stability, which has in turn enhanced its international presence. An unstable political system, with frequent changes of government, will likely lead to a decline in Japan’s international influence.

There is also a risk that US–Japan relations  could become unstable. Although the NDP does not have a strong agenda to change the course of this relationship, Ishiba may struggle to keep the promise made by his predecessors to increase defence spending. Ishiba’s nationalist posture could also create a confrontational relationship with the United States, while his weak leadership means he may not seek to invest in strengthening the US–Japan alliance. 

Donald Trump’s win in the US presidential election could pose a further risk. Although Trump might be open to Ishiba’s demand for parity with the US, he could become irritated with Ishiba’s weak domestic position. Ishiba may not be able to make decisions – or a deal with Trump – unless the NDP agrees to it.

Highly engineered phytases, which sequentially hydrolyze the hexakisphosphate ester of inositol known as phytic acid, are routinely added to the feeds of monogastric animals to improve phosphate bioavailability. New phytases are sought as starting points to further optimize the rate and extent of dephosphorylation of phytate in the animal digestive tract. Multiple inositol polyphosphate phosphatases (MINPPs) are clade 2 histidine phosphatases (HP2P) able to carry out the stepwise hydrolysis of phytate. MINPPs are not restricted by a strong positional specificity making them attractive targets for development as feed enzymes. Here, we describe the characterization of a MINPP from the Gram-positive bacterium Bifidobacterium longum (BlMINPP). BlMINPP has a typical HP2P-fold but, unusually, possesses a large α-domain polypeptide insertion relative to other MINPPs. This insertion, termed the U-loop, spans the active site and contributes to substrate specificity pockets underpopulated in other HP2Ps. Mutagenesis of U-loop residues reveals its contribution to enzyme kinetics and thermostability. Moreover, four crystal structures of the protein along the catalytic cycle capture, for the first time in an HP2P, a large ligand-driven α-domain motion essential to allow substrate access to the active site. This motion recruits residues both downstream of a molecular hinge and on the U-loop to participate in specificity subsites, and mutagenesis identified a mobile lysine residue as a key determinant of positional specificity of the enzyme. Taken together, these data provide important new insights to the factors determining stability, substrate recognition, and the structural mechanism of hydrolysis in this industrially important group of enzymes.

Hideaki Kuge
Dec 1, 2020; 61:1747-1763
Research Articles

The plasma membrane of neurons consists of distinct domains, each of which carries specialized functions and a characteristic set of membrane proteins. While this compartmentalized membrane organization is essential for neuronal functions, it remains controversial how neurons establish these domains on the laterally fluid membrane. Here, using immunostaining, lipid-MS analysis and gene ablation with the CRISPR/Cas9 system, we report that the pancreatic lipase-related protein 2 (PLRP2), a phospholipase A1 (PLA1), is a key organizer of membrane protein localization at the neurite tips of PC12 cells. PLRP2 produced local distribution of 1-oleoyl-2-palmitoyl-PC at these sites through acyl-chain remodeling of membrane phospholipids. The resulting lipid domain assembled the syntaxin 4 (Stx4) protein within itself by selectively interacting with the transmembrane domain of Stx4. The localized Stx4, in turn, facilitated the fusion of transport vesicles that contained the dopamine transporter with the domain of the plasma membrane, which led to the localized distribution of the transporter to that domain. These results revealed the pivotal roles of PLA1, specifically PLRP2, in the formation of functional domains in the plasma membrane of neurons. In addition, our results suggest a mode of membrane organization in which the local acyl-chain remodeling of membrane phospholipids controls the selective localization of membrane proteins by regulating both lipid-protein interactions and the fusion of transport vesicles to the lipid domain.

The dominant role of CaV2 voltage-gated calcium channels for driving neurotransmitter release is broadly conserved. Given the overlapping functional properties of CaV2 and CaV1 channels, and less so CaV3 channels, it is unclear why there have not been major shifts toward dependence on other CaV channels for synaptic transmission. Here, we provide a structural and functional profile of the CaV2 channel cloned from the early-diverging animal Trichoplax adhaerens, which lacks a nervous system but possesses single gene homologues for CaV1–CaV3 channels. Remarkably, the highly divergent channel possesses similar features as human CaV2.1 and other CaV2 channels, including high voltage–activated currents that are larger in external Ba2+ than in Ca2+; voltage-dependent kinetics of activation, inactivation, and deactivation; and bimodal recovery from inactivation. Altogether, the functional profile of Trichoplax CaV2 suggests that the core features of presynaptic CaV2 channels were established early during animal evolution, after CaV1 and CaV2 channels emerged via proposed gene duplication from an ancestral CaV1/2 type channel. The Trichoplax channel was relatively insensitive to mammalian CaV2 channel blockers ω-agatoxin-IVA and ω-conotoxin-GVIA and to metal cation blockers Cd2+ and Ni2+. Also absent was the capacity for voltage-dependent G-protein inhibition by co-expressed Trichoplax Gβγ subunits, which nevertheless inhibited the human CaV2.1 channel, suggesting that this modulatory capacity evolved via changes in channel sequence/structure, and not G proteins. Last, the Trichoplax channel was immunolocalized in cells that express an endomorphin-like peptide implicated in cell signaling and locomotive behavior and other likely secretory cells, suggesting contributions to regulated exocytosis.

Thermal proteome profiling (TPP) allows for the unbiased detection of drug – target protein engagements in vivo. Traditionally, one cell type is used for TPP studies, with the risk of missing important differentially expressed target proteins. The use of whole organisms would circumvent this problem. Zebrafish embryos are amenable to such an approach. Here, we used TPP on whole zebrafish embryo lysate to identify protein targets of napabucasin, a compound that may affect Signal transducer and activator of transcription 3 (Stat3) signaling through an ill-understood mechanism. In zebrafish embryos, napabucasin induced developmental defects consistent with inhibition of Stat3 signaling. TPP profiling showed no distinct shift in Stat3 upon napabucasin treatment, but effects were detected on the oxidoreductase, Pora, which might explain effects on Stat3 signaling. Interestingly, thermal stability of several aldehyde dehydrogenases (Aldhs) was affected. Moreover, napabucasin activated ALDH enzymatic activity in vitro. Aldhs have crucial roles in retinoic acid metabolism and functionally we validated napabucasin-mediated activation of the retinoic acid pathway in zebrafish in vivo. We conclude that TPP profiling in whole zebrafish embryo lysate is feasible and facilitates direct correlation of in vivo effects of small molecule drugs with their protein targets.

Billy Napier will remain in place as head football coach at Florida, despite the Gators producing another lackluster campaign during his third season, athletic director Scott Stricklin announced Thursday.

Linebacker Quinton Bell and Miami Dolphins defenders deleted drives and put the Los Angeles Rams offense in quicksand, holding them without a touchdown to propel a primetime victory and snap a three-game losing streak.

Timo Meier scored the go-ahead goal late in the second period, Jacob Markstrom made 33 saves and the New Jersey Devils snapped Florida’s seven-game winning streak by beating the Panthers 4-1 on Tuesday night.

Guo-qiang Bi
Dec 15, 1998; 18:10464-10472
Articles

Robbert Havekes
Dec 12, 2012; 32:18137-18149
BehavioralSystemsCognitive

α-Neurexins are essential and highly expressed presynaptic cell-adhesion molecules that are frequently linked to neuropsychiatric and neurodevelopmental disorders. Despite their importance, how the elaborate extracellular sequences of α-neurexins contribute to synapse function is poorly understood. We recently characterized the presynaptic gain-of-function phenotype caused by a missense mutation in an evolutionarily conserved extracellular sequence of neurexin-3α (A687T) that we identified in a patient diagnosed with profound intellectual disability and epilepsy. The striking A687T gain-of-function mutation on neurexin-3α prompted us to systematically test using mutants whether the presynaptic gain-of-function phenotype is a consequence of the addition of side-chain bulk (i.e., A687V) or polar/hydrophilic properties (i.e., A687S). We used multidisciplinary approaches in mixed-sex primary hippocampal cultures to assess the impact of the neurexin-3α^A687 residue on synapse morphology, function and ligand binding. Unexpectedly, neither A687V nor A687S recapitulated the neurexin-3α A687T phenotype. Instead, distinct from A687T, molecular replacement with A687S significantly enhanced postsynaptic properties exclusively at excitatory synapses and selectively increased binding to neuroligin-1 and neuroligin-3 without changing binding to neuroligin-2 or LRRTM2. Importantly, we provide the first experimental evidence supporting the notion that the position A687 of neurexin-3α and the N-terminal sequences of neuroligins may contribute to the stability of α-neurexin–neuroligin-1 trans-synaptic interactions and that these interactions may specifically regulate the postsynaptic strength of excitatory synapses.

Injuries to the central nervous system (CNS) can cause severe neurological deficits. Axonal regrowth is a fundamental process for the reconstruction of compensatory neuronal networks after injury; however, it is extremely limited in the adult mammalian CNS. In this study, we conducted a loss-of-function genetic screen in cortical neurons, combined with a Web resource-based phenotypic screen, and identified synaptotagmin 4 (Syt4) as a novel regulator of axon elongation. Silencing Syt4 in primary cultured cortical neurons inhibits neurite elongation, with changes in gene expression involved in signaling pathways related to neuronal development. In a spinal cord injury model, inhibition of Syt4 expression in cortical neurons prevented axonal sprouting of the corticospinal tract, as well as neurological recovery after injury. These results provide a novel therapeutic approach to CNS injury by modulating Syt4 function.

Impaired inhibitory synapse development is suggested to drive neuronal hyperactivity in autism spectrum disorders (ASD) and epilepsy. We propose a novel mechanism by which astrocytes control the development of parvalbumin (PV)-specific inhibitory synapses in the hippocampus, implicating ephrin-B/EphB signaling. Here, we utilize genetic approaches to assess functional and structural connectivity between PV and pyramidal cells (PCs) through whole-cell patch–clamp electrophysiology, optogenetics, immunohistochemical analysis, and behaviors in male and female mice. While inhibitory synapse development is adversely affected by PV-specific expression of EphB2, a strong candidate ASD risk gene, astrocytic ephrin-B1 facilitates PV->PC connectivity through a mechanism involving EphB signaling in PV boutons. In contrast, the loss of astrocytic ephrin-B1 reduces PV->PC connectivity and inhibition, resulting in increased seizure susceptibility and an ASD-like phenotype. Our findings underscore the crucial role of astrocytes in regulating inhibitory circuit development and discover a new role of EphB2 receptors in PV-specific inhibitory synapse development.

Experience- and activity-dependent transcription is a candidate mechanism to mediate development and refinement of specific cortical circuits. Here, we demonstrate that the activity-dependent transcription factor myocyte enhancer factor 2C (MEF2C) is required in both presynaptic layer (L) 4 and postsynaptic L2/3 mouse (male and female) somatosensory (S1) cortical neurons for development of this specific synaptic connection. While postsynaptic deletion of Mef2c weakens L4 synaptic inputs, it has no effect on inputs from local L2/3, contralateral S1, or the ipsilateral frontal/motor cortex. Similarly, homozygous or heterozygous deletion of Mef2c in presynaptic L4 neurons weakens L4 to L2/3 excitatory synaptic inputs by decreasing presynaptic release probability. Postsynaptic MEF2C is specifically required during an early postnatal, experience-dependent, period for L4 to L2/3 synapse function, and expression of transcriptionally active MEF2C (MEF2C-VP16) rescues weak L4 to L2/3 synaptic strength in sensory-deprived mice. Together, these results suggest that experience- and/or activity-dependent transcriptional activation of MEF2C promotes development of L4 to L2/3 synapses. Additionally, MEF2C regulates the expression of many pre- and postsynaptic genes in postnatal cortical neurons. Interestingly, MEF2C was necessary for activity-dependent expression of many presynaptic genes, including those that function in transsynaptic adhesion and neurotransmitter release. This work provides mechanistic insight into the experience-dependent development of specific cortical circuits.

When the blaze in Moscow subsided on September 18, 1812, the French—who had traveled hundreds of miles into Russia—were left without vital resources as a brutal winter approached

Quebec provincial police have confirmed that the body found in a Montreal nature park on Oct. 30 was that of kidnapping victim and cryptocurrency influencer Kevin Mirshahi.

The Winnipeg Jets' reign as the only unbeaten NHL team ended with a 6-4 Toronto Maple Leafs' victory handed by John Tavares who scored three goals at the game Monday night at Canada Life Centre.

North American market leader speeds innovation and customization

Download the data from Education Week showing how over 900 school districts provided instruction on their first day of the school year.

About 80% of trophy home sales in Cape Town were along the Atlantic Seaboard, especially in Camps Bay, Clifton, Bantry Bay, Fresnaye and at the Waterfront.

Blue Ribbon and Snowflake owner Premier Foods is on the prowl for acquisitions, including the likes of JSE-listed food producers like Remgro-controlled RCL Foods, Libstar and RFG, if they ever become available.

iQOO Neo 10 series will be unveiled in China soon. Details about the upcoming lineup have been circulating in the rumour mill over the past few weeks, and now a senior company executive has confirmed its imminent launch, though the exact date remains unannounced. The series is expected to include a base iQOO Neo 10 and an iQOO Neo 10 Pro.

Google has announced the silent rollout of its Quick Share app for ARM-powered devices running Windows 11 or later. Users can now easily send and receive photos, documents, and more data between nearby Android devices and ARM-based Windows PCs including the new Snapdragon X Elite laptops.

Asus ROG Phone 9 will be officially launched later this week. Following Qualcomm's unveiling of the Snapdragon 8 Elite chipset last month, Asus confirmed that the ROG Phone 9 would use the flagship SoC. Now, ahead of the launch, the handset has been reportedly spotted in the Geekbench ML online database suggesting key specifications.

Avneet Kaur will also be seen in a groundbreaking India-Vietnam collaboration film Love in Vietnam

As a mark of respect for the victims of the senseless acts of violence perpetrated on April 15, 2021, in Indianapolis, Indiana, President Biden ordered flags at all U.S. government buildings and facilities to be flown at half-staff until sunset on April 20, 2021. In concurrence with the President’s order, Governor Carney has ordered both […]

NEW CASTLE (Jan. 10, 2022) – With Delaware facing the coldest temperatures of the winter Monday and Tuesday nights, Code Purple is being declared across the state by the nonprofit and volunteer organizations that operate the shelters to keep people who are homeless safe during dangerous winter weather. Because of the COVID-19 pandemic and the […]

Eligible SNAP Households Will Receive P-EBT Emergency Food Assistance on June 3 NEW CASTLE (June 1, 2022) – Delaware families receiving Supplemental Nutrition Assistance Program (SNAP) food benefits will get emergency food assistance through the Pandemic Electronic Benefit Transfer (P-EBT) program for children under the age of 6 living in their households. Eligible SNAP households […]

Los Hogares Elegibles Para SNAP Recibirán Asistencia de Emergencia Para Alimentos P-EBT el 3 de Junio NEW CASTLE (1 de Junio de 2022) – Las familias de Delaware que reciben beneficios de alimentos del Programa de Asistencia Nutricional Suplementaria (SNAP) obtendrán asistencia de emergencia de alimentos a través del programa de Transferencia Electrónica de Beneficios […]

NEW CASTLE (Oct. 26, 2022) – The Delaware Division of Social Services will issue emergency benefits for October to eligible households as part of the State’s ongoing response to the COVID-19 public health emergency. Benefits will be issued as part of the Supplemental Nutrition Assistance Program (SNAP) and two cash assistance programs – Temporary Assistance […]

NEW CASTLE (Dec. 21, 2022) – The Delaware Division of Social Services will issue emergency benefits for December to eligible households as part of the State’s ongoing response to the COVID-19 public health emergency.   Benefits will be issued as part of the Supplemental Nutrition Assistance Program (SNAP) and two cash assistance programs – Temporary Assistance […]

NEW CASTLE (20 de Diciembre de 2022) – La División de Servicios Sociales de Delaware emitirá beneficios de emergencia para Diciembre a los hogares elegibles como parte de la respuesta continua del Estado a la crisis de salud pública de COVID-19. Los beneficios se emitirán como parte del Programa de Asistencia Nutricional Suplementaria (SNAP) y […]

NEW CASTLE (Jan. 25, 2023) – The Delaware Division of Social Services (DSS) will issue emergency benefits for January to eligible households as part of the State’s ongoing response to the COVID-19 public health emergency. Benefits will be issued as part of the Supplemental Nutrition Assistance Program (SNAP) and two cash assistance programs – Temporary […]

Due to a recent change in federal law passed in the Consolidated Appropriations Act of 2023, this will be the final emergency benefits payment as part of the Supplemental Nutrition Assistance Program (SNAP). Emergency benefits paid as part of two cash assistance programs – Temporary Assistance for Needy Families (TANF) and General Assistance (GA) – will continue until the end of the federal Public Health Emergency in May.

WILMINGTON, Del. – Governor Carney and Lt. Governor Hall-Long on Wednesday announced a partnership with the Food Bank of Delaware to fill community food pantries statewide and hold food drives in each county for three months to help ease the transition from the ending of the federal Emergency benefits for Supplemental Nutrition Assistance Program (SNAP) households. The […]

NEW CASTLE (21 de Noviembre de 2022) – La División de Servicios Sociales de Delaware emitirá beneficios de emergencia para Noviembre a los hogares elegibles como parte de la respuesta continua del Estado a la crisis de salud pública de COVID-19. Los beneficios se emitirán como parte del Programa de Asistencia Nutricional Suplementaria (SNAP) y […]