Miracle Mechanical has successfully transformed the lives of families facing financial and health-related challenges with no-cost HVAC and plumbing services.

Bob Kepford discusses Decoupled CMS. Many CMS practitioners are adopting a decoupled approach to improve scale, allow for more specialized roles, and to separate data collection from delivery. Host Jeff Doolittle spoke with Kepford about what makes a Decoupled CMS different.

dklaughman has added a photo to the pool:

The woman liked the music by Sticky Situations (live band) so much that she wanted to dance even though the guy was eating a sandwich.
Georgetown, during Return Day.
More info at this website: www.returnday.com/

www.facebook.com/p/Sticky-Situation-Band-100057364341837/

Retired couple escape death as Russian rocket hits their home in Kherson

Aerospace Quick Disconnects And Couplings Market Global Outlook And Forecast 2023–2035

Bonnie and Michael Quinn started Rockin’ 4 Heroes four years ago, to honor the men and women who helped their son, Michael Patrick Joseph “P.J.” Quinn, in his fight with cancer…

After a month-long vacation, Russ Collins made his return to the WEMU studio for Cinema Chat! Along with a few travel stories, Russ shared what's coming to the silver screen in the coming days with WEMU's David Fair.

It originated in Tibet. Then made its way onto a yacht. Then took over Canada. How the classic board game of Yahtzee came to be.

SPEED golf is a sport where you run between holes, trying to finish as quickly as possible yet shoot a low score. Wahroonga couple Roddy Main and Carole Whitehouse competed in the World Championships.

Dear Eric: I am newly in love and engaged. My fiancé and I are both in our early 70s. Quite a few of my friends (not my close friends but others) have responded to the news with: how cute! Somehow the fact that we have fallen in love and plan to marry is "cute."

Look back at celebrity couples who have walked the BET Awards red carpet, including Will and Jada Pinkett Smith, Alicia Keys and Swizz Beatz, Dwyane Wade and Gabrielle Union, and more.

They can’t criticize the cops who arrested them.

The gaming world is more broad and diverse today than it has ever been before. Games nowadays can be played on all sorts of devices, online and offline, alone or with large groups of people, on a tabletop or... Tagged as:

We’ve all been there – the frustration of searching high and low for that elusive piece of furniture to turn our home decorating vision into reality. For Sabrina, her search was for the ideal console table. “Unfortunately, I could not find the perfect console, so my husband had to believe in it again and build one himself!” she shared on her Instagram post. After realizing that the perfect entryway console was nowhere to be found, the couple decided to take […]

The post Failed Furniture Hunt Inspires Couple’s Fabulous Entryway Console Hack appeared first on IKEA Hackers.

Independent Thinking: Myanmar, the coup two years on Audio NCapeling 2 February 2023

Episode 13 of our weekly podcast focuses on the ongoing crisis in Myanmar, marking the two-year anniversary of the coup there by the Tatmadaw armed forces.

In February 2021 the Tatmadaw overthrew the democratically-elected government of Aung San Suu Kyi in Myanmar and, since then, the country has descended into a brutal and complex civil war.

Our panel analyses the state of the country and its people two years on. Can Myanmar hold together, can democracy ever be restored? And is the world ignoring a major humanitarian crisis in the making?

With Bronwen Maddox to discuss the issues are two journalists who have both covered Myanmar extensively. Sebastian Strangio is an author and the Southeast Asia editor at The Diplomat, and Ali Fowle is a freelance journalist with Al Jazeera and the BBC.

Joining them in the studio from Chatham House are Ben Bland, director of our Asia-Pacific programme, and Rashmin Sagoo, director of our International Law programme.

About Independent Thinking

A weekly podcast hosted by Chatham House director Bronwen Maddox, in conversation with leading policymakers, journalists, and Chatham House experts providing insight on the latest international issues.

The functional mechanisms of multidomain proteins often exploit interdomain interactions, or “cross-talk.” An example is human Pin1, an essential mitotic regulator consisting of a Trp–Trp (WW) domain flexibly tethered to a peptidyl-prolyl isomerase (PPIase) domain, resulting in interdomain interactions important for Pin1 function. Substrate binding to the WW domain alters its transient contacts with the PPIase domain via means that are only partially understood. Accordingly, we have investigated Pin1 interdomain interactions using NMR paramagnetic relaxation enhancement (PRE) and molecular dynamics (MD) simulations. The PREs show that apo-Pin1 samples interdomain contacts beyond the range suggested by previous structural studies. They further show that substrate binding to the WW domain simultaneously alters interdomain separation and the internal conformation of the WW domain. A 4.5-μs all-atom MD simulation of apo-Pin1 suggests that the fluctuations of interdomain distances are correlated with fluctuations of WW domain interresidue contacts involved in substrate binding. Thus, the interdomain/WW domain conformations sampled by apo-Pin1 may already include a range of conformations appropriate for binding Pin1's numerous substrates. The proposed coupling between intra-/interdomain conformational fluctuations is a consequence of the dynamic modular architecture of Pin1. Such modular architecture is common among cell-cycle proteins; thus, the WW–PPIase domain cross-talk mechanisms of Pin1 may be relevant for their mechanisms as well.

20 August 2020

The development of a chronic, low-grade inflammation originating from adipose tissue in obese subjects is widely recognized to induce insulin resistance, leading to the development of type 2 diabetes. The adipose tissue microenvironment drives specific metabolic reprogramming of adipose tissue macrophages, contributing to the induction of tissue inflammation. Uncoupling protein 2 (UCP2), a mitochondrial anion carrier, is thought to separately modulate inflammatory and metabolic processes in macrophages and is up-regulated in macrophages in the context of obesity and diabetes. Here, we investigate the role of UCP2 in macrophage activation in the context of obesity-induced adipose tissue inflammation and insulin resistance. Using a myeloid-specific knockout of UCP2 (Ucp2ΔLysM), we found that UCP2 deficiency significantly increases glycolysis and oxidative respiration, both unstimulated and after inflammatory conditions. Strikingly, fatty acid loading abolished the metabolic differences between Ucp2ΔLysM macrophages and their floxed controls. Furthermore, Ucp2ΔLysM macrophages show attenuated pro-inflammatory responses toward Toll-like receptor-2 and -4 stimulation. To test the relevance of macrophage-specific Ucp2 deletion in vivo, Ucp2ΔLysM and Ucp2fl/fl mice were rendered obese and insulin resistant through high-fat feeding. Although no differences in adipose tissue inflammation or insulin resistance was found between the two genotypes, adipose tissue macrophages isolated from diet-induced obese Ucp2ΔLysM mice showed decreased TNFα secretion after ex vivo lipopolysaccharide stimulation compared with their Ucp2fl/fl littermates. Together, these results demonstrate that although UCP2 regulates both metabolism and the inflammatory response of macrophages, its activity is not crucial in shaping macrophage activation in the adipose tissue during obesity-induced insulin resistance.

Post-transcriptional modifications of pre-mRNAs expand the diversity of proteomes in higher eukaryotes. In the brain, these modifications diversify the functional output of many critical neuronal signal molecules. In this study, we identified a brain-specific A-to-I RNA editing that changed glutamine to arginine (Q/R) at exon 20 and an alternative splicing of exon 4 in Tmem63b, which encodes a ubiquitously expressed osmosensitive cation channel. The channel isoforms lacking exon 4 occurred in ∼80% of Tmem63b mRNAs in the brain but were not detected in other tissues, suggesting a brain-specific splicing. We found that the Q/R editing was catalyzed by Adar2 (Adarb1) and required an editing site complementary sequence located in the proximal 5' end of intron 20. Moreover, the Q/R editing was almost exclusively identified in the splicing isoform lacking exon 4, indicating a coupling between the editing and the splicing. Elimination of the Q/R editing in brain-specific Adar2 knockout mice did not affect the splicing efficiency of exon 4. Furthermore, transfection with the splicing isoform containing exon 4 suppressed the Q/R editing in primary cultured cerebellar granule neurons. Thus, our study revealed a coupling between an RNA editing and a distant alternative splicing in the Tmem63b pre-mRNA, in which the splicing plays a dominant role. Finally, physiological analysis showed that the splicing and the editing coordinately regulate Ca2+ permeability and osmosensitivity of channel proteins, which may contribute to their functions in the brain.

Driven by the energy of a photon, the visual pigments in rod and cone photoreceptor cells isomerize 11-cis-retinal to the all-trans configuration. This photochemical reaction initiates the signal transduction pathway that eventually leads to the transmission of a visual signal to the brain and leaves the opsins insensitive to further light stimulation. For the eye to restore light sensitivity, opsins require recharging with 11-cis-retinal. This trans–cis back conversion is achieved through a series of enzymatic reactions composing the retinoid (visual) cycle. Although it is evident that the classical retinoid cycle is critical for vision, the existence of an adjunct pathway for 11-cis-retinal regeneration has been debated for many years. Retinal pigment epithelium (RPE)–retinal G protein-coupled receptor (RGR) has been identified previously as a mammalian retinaldehyde photoisomerase homologous to retinochrome found in invertebrates. Using pharmacological, genetic, and biochemical approaches, researchers have now established the physiological relevance of the RGR in 11-cis-retinal regeneration. The photoisomerase activity of RGR in the RPE and Müller glia explains how the eye can remain responsive in daylight. In this review, we will focus on retinoid metabolism in the eye and visual chromophore regeneration mediated by RGR.  

Adaptive thermogenesis is highly dependent on uncoupling protein 1 (UCP1), a protein expressed by thermogenic adipocytes present in brown adipose tissue (BAT) and white adipose tissue (WAT). Thermogenic capacity of human and mouse BAT can be measured by positron emission tomography-computed tomography quantifying the uptake of ¹⁸F-fluodeoxyglucose or lipid tracers. BAT activation is typically studied in response to cold exposure or treatment with β-3-adrenergic receptor agonists such as CL316,243 (CL). Currently, it is unknown whether cold-stimulated uptake of glucose or lipid tracers is a good surrogate marker of UCP1-mediated thermogenesis. In metabolic studies using radiolabeled tracers, we found that glucose uptake is increased in mildly cold-activated BAT of Ucp1^–/– versus WT mice kept at subthermoneutral temperature. Conversely, lower glucose disposal was detected after full thermogenic activation achieved by sustained cold exposure or CL treatment. In contrast, uptake of lipoprotein-derived fatty acids into chronically activated thermogenic adipose tissues was substantially increased in UCP1-deficient mice. This effect is linked to higher sympathetic tone in adipose tissues of Ucp1^–/– mice, as indicated by elevated levels of thermogenic genes in BAT and WAT. Thus, glucose and lipoprotein handling does not necessarily reflect UCP1-dependent thermogenic activity, but especially lipid uptake rather mirrors sympathetic activation of adipose tissues.

In nucleotide excision repair, bulky DNA lesions such as UV-induced cyclobutane pyrimidine dimers are removed from the genome by concerted dual incisions bracketing the lesion, followed by gap filling and ligation. So far, two dual-incision patterns have been discovered: the prokaryotic type, which removes the damage in 11–13-nucleotide-long oligomers, and the eukaryotic type, which removes the damage in 24–32-nucleotide-long oligomers. However, a recent study reported that the UvrC protein of Mycobacterium tuberculosis removes damage in a manner analogous to yeast and humans in a 25-mer oligonucleotide arising from incisions at 15 nt from the 3´ end and 9 nt from the 5´ end flanking the damage. To test this model, we used the in vivo excision assay and the excision repair sequencing genome-wide repair mapping method developed in our laboratory to determine the repair pattern and genome-wide repair map of Mycobacterium smegmatis. We find that M. smegmatis, which possesses homologs of the Escherichia coli uvrA, uvrB, and uvrC genes, removes cyclobutane pyrimidine dimers from the genome in a manner identical to the prokaryotic pattern by incising 7 nt 5´ and 3 or 4 nt 3´ to the photoproduct, and performs transcription-coupled repair in a manner similar to E. coli.

Researchers once faced death threats for asking women what gives them pleasure. Now they’re helping individuals and couples figure it out themselves.

Sleep is known to drive the consolidation of motor memories. During nonrapid eye movement (NREM) sleep, the close temporal proximity between slow oscillations (SOs) and spindles ("nesting" of SO-spindles) is known to be essential for consolidation, likely because it is closely associated with the reactivation of awake task activity. Interestingly, recent work has found that spindles can occur in temporal clusters or "trains." However, it remains unclear how spindle trains are related to the nesting phenomenon. Here, we hypothesized that spindle trains are more likely when SOs co-occur in the prefrontal and motor cortex. We conducted simultaneous neural recordings in the medial prefrontal cortex (mPFC) and primary motor cortex (M1) of male rats training on the reach-to-grasp motor task. We found that intracortically recorded M1 spindles are organized into distinct temporal clusters. Notably, the occurrence of temporally precise SOs between mPFC and M1 was a strong predictor of spindle trains. Moreover, reactivation of awake task patterns is much more persistent during spindle trains in comparison with that during isolated spindles. Together, our work suggests that the precise coupling of SOs across mPFC and M1 may be a potential driver of spindle trains and persistent reactivation of motor memory during NREM sleep.

In demanding listening situations, a listener's motivational state may affect their cognitive investment. Here, we aim to delineate how domain-specific sensory processing, domain-general neural alpha power, and pupil size as a proxy for cognitive investment encode influences of motivational state under demanding listening. Participants (male and female) performed an auditory gap-detection task while the pupil size and the magnetoencephalogram were simultaneously recorded. Task demand and a listener's motivational state were orthogonally manipulated through changes in gap duration and monetary-reward prospect, respectively. Whereas task difficulty impaired performance, reward prospect enhanced it. The pupil size reliably indicated the modulatory impact of an individual's motivational state. At the neural level, the motivational state did not affect auditory sensory processing directly but impacted attentional postprocessing of an auditory event as reflected in the late evoked-response field and alpha-power change. Both pregap pupil dilation and higher parietal alpha power predicted better performance at the single-trial level. The current data support a framework wherein the motivational state acts as an attentional top–down neural means of postprocessing the auditory input in challenging listening situations.

The 1898 Wilmington massacre left dozens of Black North Carolinians dead. Conspirators also forced the city's multiracial government to resign at gunpoint

OM Sweden's newest team members - a van and a trailer - bring new opportunities for sharing and recruiting.

Veterans face unique health challenges, and Penn State Health is committed to providing care respecting their experiences. Veterans/employees Mark and Julie Chesney advocate for awareness of those health needs.

A woman was left shocked when she was offered food at a BBQ only after there were some leftovers.

DOVER, Del. – Governor John Carney on Wednesday issued the following statement on the Senate’s vote to confirm the Governor’s nominations of Josette Manning to serve as Cabinet Secretary of the Delaware Department of Health and Social Services; Steven Yeatman to serve as Cabinet Secretary of the Delaware Department of Children, Youth, and Their Families; and Robert […]

DOVER, DEL. (August 20, 2024) – The Division of Public Health (DPH) Office of Animal Welfare’s (OAW) Delaware Animal Services (DAS) announces the arrest of a man and woman after 20 dogs were rescued from a home in Bridgeville. Ray Anderson, age 42, and Melissa Layton, age 40, of Bridgeville were arraigned Aug. 15. DAS […]

A Bengaluru couple found themselves in legal trouble after they posted videos of their balcony garden on Facebook. The posts included images of plants later identified as ganja.

Hello,

A mybe silly question came to my mind: When routing sense lines, is it better to hav them as close as possible to DUT or afer the decoupling capacitors ?

Force in red, sense in purple.

Best way is 1 or 2 ?

Thanks in advance and Merry Christmas to everybody !

Hello everyone,

For my cross-coupled oscillator design, I have a problem with stability analysis. Based on my achieved results which are attached, where is my design problem?

Best,

https://ibb.co/bgKFP4N

https://ibb.co/3FGRLmV

https://ibb.co/pwSZDSF

Could Putin be vulnerable to a coup or uprising? All of the grievances that traditionally motivate a coup against a dictator are in place.

A British business person is keeping the skeleton of the dilapidated R20 million Upper Constantia house, but has to replace the roof and the interior

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Antifolates are important for chemotherapy in non–small cell lung cancer (NSCLC). They mainly rely on reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT) to enter cells. PCFT is supposed to be the dominant transporter of the two in tumors, as it operates optimally at acidic pH and has limited transport activity at physiological pH, whereas RFC operates optimally at neutral pH. In this study, we found RFC showed a slightly pH-dependent uptake of antifolates, with similar affinity values at pH 7.4 and 6.5. PCFT showed a highly pH-dependent uptake of antifolates, with an optimum pH of 6.0 for pemetrexed and 5.5 for methotrexate. The Michaelis-Menten constant (K_m) value of PCFT for pemetrexed at pH 7.4 was more than 10 times higher than that at pH 6.5. Interestingly, we found that antifolate accumulations mediated by PCFT at acidic pH were significantly affected by the efflux transporter, breast cancer resistance protein (BCRP). The highest pemetrexed concentration was observed at pH 7.0–7.4 after a 60-minute accumulation in PCFT-expressing cells, which was further evidenced by the cytotoxicity of pemetrexed, with the IC₅₀ value of pemetrexed at pH 7.4 being one-third of that at pH 6.5. In addition, the in vivo study indicated that increasing PCFT and RFC expression significantly enhanced the antitumor efficacy of pemetrexed despite the high expression of BCRP. These results suggest that both RFC and PCFT are important for antifolates accumulation in NSCLC, although there is an acidic microenvironment and high BCRP expression in tumors.

The class F of G protein-coupled receptors (GPCRs) consists of 10 Frizzleds (FZD_1–10) and Smoothened (SMO). FZDs bind and are activated by secreted lipoglycoproteins of the Wingless/Int-1 (WNT) family, and SMO is indirectly activated by the Hedgehog (Hh) family of morphogens acting on the transmembrane protein Patched. The advance of our understanding of FZDs and SMO as dynamic transmembrane receptors and molecular machines, which emerged during the past 14 years since the first-class F GPCR IUPHAR nomenclature report, justifies an update. This article focuses on the advances in molecular pharmacology and structural biology providing new mechanistic insight into ligand recognition, receptor activation mechanisms, signal initiation, and signal specification. Furthermore, class F GPCRs continue to develop as drug targets, and novel technologies and tools such as genetically encoded biosensors and CRISP/Cas9 edited cell systems have contributed to refined functional analysis of these receptors. Also, advances in crystal structure analysis and cryogenic electron microscopy contribute to the rapid development of our knowledge about structure-function relationships, providing a great starting point for drug development. Despite the progress, questions and challenges remain to fully understand the complexity of the WNT/FZD and Hh/SMO signaling systems.

The appointment of a political outsider like Musk could help Trump cut regulations and rein in government bureaucracy, even if the moves are unpopular

Ajai Kesavan’s The Odd Couple attempts to bring laughter and nostalgia to Bengaluru with a fresh take on Neil Simon’s beloved comedy about unlikely roommates