Insulin receptor substrate 2 (IRS2) is an essential adaptor that mediates signaling downstream of the insulin receptor and other receptor tyrosine kinases. Transduction through IRS2-dependent pathways is important for coordinating metabolic homeostasis, and dysregulation of IRS2 causes systemic insulin signaling defects. Despite the importance of maintaining proper IRS2 abundance, little is known about what factors mediate its protein stability. We conducted an unbiased proteomic screen to uncover novel substrates of the Anaphase Promoting Complex/Cyclosome (APC/C), a ubiquitin ligase that controls the abundance of key cell cycle regulators. We found that IRS2 levels are regulated by APC/C activity and that IRS2 is a direct APC/C target in G₁. Consistent with the APC/C's role in degrading cell cycle regulators, quantitative proteomic analysis of IRS2-null cells revealed a deficiency in proteins involved in cell cycle progression. We further show that cells lacking IRS2 display a weakened spindle assembly checkpoint in cells treated with microtubule inhibitors. Together, these findings reveal a new pathway for IRS2 turnover and indicate that IRS2 is a component of the cell cycle control system in addition to acting as an essential metabolic regulator.

Natural compounds that can stimulate salivary secretion are of interest in developing treatments for xerostomia, the perception of a dry mouth, that affects between 10 and 30% of the adult and elderly population. Chemesthetic transient receptor potential (TRP) channels are expressed in the surface of the oral mucosa. The TRPV1 agonists capsaicin and piperine have been shown to increase salivary flow when introduced into the oral cavity but the sialogogic properties of other TRP channel agonists have not been investigated. In this study we have determined the influence of different TRP channel agonists on the flow and protein composition of saliva. Mouth rinsing with the TRPV1 agonist nonivamide or menthol, a TRPM8 agonist, increased whole mouth saliva (WMS) flow and total protein secretion compared with unstimulated saliva, the vehicle control mouth rinse or cinnamaldehyde, a TRPA1 agonist. Nonivamide also increased the flow of labial minor gland saliva but parotid saliva flow rate was not increased. The influence of TRP channel agonists on the composition and function of the salivary proteome was investigated using a multi-batch quantitative MS method novel to salivary proteomics. Inter-personal and inter-mouth rinse variation was observed in the secreted proteomes and, using a novel bioinformatics method, inter-day variation was identified with some of the mouth rinses. Significant changes in specific salivary proteins were identified after all mouth rinses. In the case of nonivamide, these changes were attributed to functional shifts in the WMS secreted, primarily the over representation of salivary and nonsalivary cystatins which was confirmed by immunoassay. This study provides new evidence of the impact of TRP channel agonists on the salivary proteome and the stimulation of salivary secretion by a TRPM8 channel agonist, which suggests that TRP channel agonists are potential candidates for developing treatments for sufferers of xerostomia.

This article has been withdrawn by the authors. We discovered an error after this manuscript was published as a Paper in Press. Specifically, we learned that the structures of glycans presented for the PD-L1 peptide were drawn and labeled incorrectly. We wish to withdraw this article and submit a corrected version for review.

The histopathological subtype of lung adenocarcinoma (LUAD) is closely associated with prognosis. Micropapillary or solid predominant LUAD tends to relapse after surgery at an early stage, whereas lepidic pattern shows a favorable outcome. However, the molecular mechanism underlying this phenomenon remains unknown. Here, we recruited 31 lepidic predominant LUADs (LR: low-risk subtype group) and 28 micropapillary or solid predominant LUADs (HR: high-risk subtype group). Tissues of these cases were obtained and label-free quantitative proteomic and bioinformatic analyses were performed. Additionally, prognostic impact of targeted proteins was validated using The Cancer Genome Atlas databases (n=492) and tissue microarrays composed of early-stage LUADs (n=228). A total of 192 differentially expressed proteins were identified between tumor tissues of LR and HR and three clusters were identified via hierarchical clustering excluding eight proteins. Cluster 1 (65 proteins) showed a sequential decrease in expression from normal tissues to tumor tissues of LR and then to HR and was predominantly enriched in pathways such as tyrosine metabolism and ECM-receptor interaction, and increased matched mRNA expression of 18 proteins from this cluster predicted favorable prognosis. Cluster 2 (70 proteins) demonstrated a sequential increase in expression from normal tissues to tumor tissues of LR and then to HR and was mainly enriched in pathways such as extracellular organization, DNA replication and cell cycle, and high matched mRNA expression of 25 proteins indicated poor prognosis. Cluster 3 (49 proteins) showed high expression only in LR, with high matched mRNA expression of 20 proteins in this cluster indicating favorable prognosis. Furthermore, high expression of ERO1A and FEN1 at protein level predicted poor prognosis in early-stage LUAD, supporting the mRNA results. In conclusion, we discovered key differentially expressed proteins and pathways between low-risk and high-risk subtypes of early-stage LUAD. Some of these proteins could serve as potential biomarkers in prognostic evaluation.

VOLUME 279 (2004) PAGES 33438–33446For Fig. 1B, the second, third, and fifth panels were mistakenly duplicated during article preparation as no yeast colonies were observed in these conditions. The corrected images are presented in the revised Fig. 1B. This correction does not affect the results or conclusions of the work. The authors apologize for the error.jbc;295/50/17382/F1F1F1Figure 1B.

Systemic study of pathogenic pathways and interrelationships underlying genes associated with Alzheimer's disease (AD) facilitates the identification of new targets for effective treatments. Recently available large-scale multiomics datasets provide opportunities to use computational approaches for such studies. Here, we devised a novel disease gene identification (digID) computational framework that consists of a semi-supervised deep learning classifier to predict AD-associated genes and a protein–protein interaction (PPI) network-based analysis to prioritize the importance of these predicted genes in AD. digID predicted 1,529 AD-associated genes and revealed potentially new AD molecular mechanisms and therapeutic targets including GNAI1 and GNB1, two G-protein subunits that regulate cell signaling, and KNG1, an upstream modulator of CDC42 small G-protein signaling and mediator of inflammation and candidate coregulator of amyloid precursor protein (APP). Analysis of mRNA expression validated their dysregulation in AD brains but further revealed the significant spatial patterns in different brain regions as well as among different subregions of the frontal cortex and hippocampi. Super-resolution STochastic Optical Reconstruction Microscopy (STORM) further demonstrated their subcellular colocalization and molecular interactions with APP in a transgenic mouse model of both sexes with AD-like mutations. These studies support the predictions made by digID while highlighting the importance of concurrent biological validation of computationally identified gene clusters as potential new AD therapeutic targets.

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.

The wild canines have the same muscles used by domestic dogs to create the wide-eyed, pleading look that captures humans' hearts

Hospice Northwest Services is inviting people to visit its third annual photography exhibit, "A Personal Lens on Grief." Here's what the project in Thunder Bay, Ont., entails, and why staff say it's important to find creative ways to express loss.

Shraddha dropped a string of sweaty face and head slamming emojis

DOVER, DE (OCT. 28, 2022) – The Delaware Division of Public Health (DPH) is concerned about increases in respiratory viruses in the state, particularly influenza (flu) and respiratory syncytial virus (RSV). For the week of Oct. 16, 2022, through Oct. 22, 2022, there were 44 laboratory-confirmed cases of the flu, compared to 19 cases the week […]

At least five people were killed this morning after their speeding car rammed a truck that had broken down and was parked on the roadside in Noida.

Hi,

I have a question about printing noise summary via maestro output expressions.

How can I print noise data using output expressions, for multiple levels of the hierarchy?

I have found this article which describe the procedure using ocnGenNoiseSummary() function: https://support.cadence.com/apex/ArticleAttachmentPortal?id=a1Od0000007MViHEAW&pageName=ArticleContent

I see also Andrew Beckett referring to the above mentioned article as a solution to a similar question: community.cadence.com/.../noise-summary-per-instance

However, this seems to work only if I'm to extract noise data from a single level of hierarchy.

If I have the output expression "ocnGenNoiseSummary(2 ?result 'hbnoise)", it will generate a "noisesummary" directory under results directory for a hierarchy level of 2.

If I am to extract data from various hierarchy levels, I should be able to generate multiple noise summary directories, such as noisesummary1, noisesummary2 where they correspond to "ocnGenNoiseSummary(1 ?result 'hbnoise)" & "ocnGenNoiseSummary(2 ?result 'hbnoise)", respectively. However this does not seem to be possible.

Can you please advice? Thanks.

My Cadence version: IC23.1-64b.ISR7.27

BR,

Denizhan Karaca

Hi,

My Virtuoso and Spectre Version: ICADVM20.1-64b.NYISR30.2

I have an expression where the EvalType is "sweeps". Here is the expression (I also attached the snapshot):

(peakToPeak(leafValue(swapSweep(delay(?wf1 clip((VT("/clk0") - VT("/clk180")) (VAR("mt_stop") - (4.0 / VAR("datarate"))) VAR("mt_stop")) ?value1 0 ?edge1 "rising" ?nth1 1 ?td1 0 ?tol1 nil ?wf2 clip((VT("/tx_padp") - VT("/tx_padn")) (VAR("mt_stop") - (4.0 / VAR("datarate"))) VAR("mt_stop")) ?value2 0 ?edge2 "rising" ?nth2 1 ?tol2 nil ?td2 nil ?stop nil ?multiple nil) "VDD_FIXED_NOISE") "VREGLN_cmode" 0.85 "VREGDRV_novn" 0.4 "datarate" 1.658e+10) ?overall t) / 10.0)

What this expression does is that it compares the delay between the output data with respect to a reference clock. I then get this information for two conditions (VDD_FIXED_NOISE = 0 or 10mV) to get the effect of the supply-induced jitter. In the expression, I need to give the value of each parameter in different modes to distinguish them from each other. Now I want to sweep the base supply values and see the supply variation effects. For example, I want to change VREGLN_cmode from 0.85 to 0.81 and see how my supply-induced jitter changes. For that, the hard way is to copy the expression and change that value accordingly (e.g. "VREGLN_cmode" 0.81). I'm looking for an easier way to use a variable in the expression. Something like VAR("VREGLN_Sweep"). But I see it doesn't work in my expression and it gives an eVal error. I tested this before in other expressions (not sweep type) and it always worked. I have only one test and these variables are all Design Variables and not Global variables.
I want to know what mistake am I doing here and is there a way to make this work. Sorry that if I could not explain better my inquiry. Thank you.

Starting at noon ET on Nov. 11, Walmart+ members can buy a Keurig K-Express Essentials single-serve coffee maker for just $29.88.

Check here each week to keep up with the latest from John MacArthur's pulpit at Grace Community Church.

Following the keenly contested war of ballots in the recent presidential election between the incumbent President Goodluck Ebele Jonathan — who represented the ruling People’s Democratic Party (PDP) and retired General Muhammadu Buhari of the All Progressives Congress (APC) — which ended in favour of the retired General, Nigerians have barred their minds on their expectations from the incoming administration as they say, “to whom much is given, much more is expected.” Foremost amongst the challenges Nigerians are confronted with are economic instability, insecurity and terrorism, provision of shelter, social and infrastructural amenities, qualitative education, employment generation, and more. Proffering […]

We often skim quickly over the introductory parts of Paul’s epistles, but they are usually pregnant with meaning—and in the case of his letter to Titus, profoundly so. In his seemingly simple salutation, Paul gives us some vivid insight into how the plan of redemption started.

Ariana Grande praises her ‘adorable’ beau Ethan SlaterAriana Grande has recently expressed her admiration for beau and adorable Wicked co-star Ethan Slater.Speaking to Entertainment Tonight at Wicked press tour in Los Angeles over the weekend, the pop star praised Ethan for his...

Animal germline development and fertility rely on paralogs of general transcription factors that recruit RNA polymerase II to ensure cell type-specific gene expression. It remains unclear whether gene expression processes downstream from such paralog-based transcription is distinct from that of canonical RNA polymerase II genes. In Drosophila, the testis-specific TBP-associated factors (tTAFs) activate over a thousand spermatocyte-specific gene promoters to enable meiosis and germ cell differentiation. Here, we show that efficient termination of tTAF-activated transcription relies on testis-specific paralogs of canonical polymerase-associated factor 1 complex (PAF1C) proteins, which form a testis-specific PAF1C (tPAF). Consequently, tPAF mutants show aberrant expression of hundreds of downstream genes due to read-in transcription. Furthermore, tPAF facilitates expression of Y-linked male fertility factor genes and thus serves to maintain spermatocyte-specific gene expression. Consistently, tPAF is required for the segregation of meiotic chromosomes and male fertility. Supported by comparative in vivo protein interaction assays, we provide a mechanistic model for the functional divergence of tPAF and the PAF1C and identify transcription termination as a developmentally regulated process required for germline-specific gene expression.

Chronic hypertension leads to injury and fibrosis in major organs. Fibroblast activation protein (FAP) is one of key molecules in tissue fibrosis, and ⁶⁸Ga-labeled FAP inhibitor-46 (FAPI46) PET is a recently developed method for evaluating FAP. The aim of this study was to evaluate FAP expression and fibrosis in a hypertension model and to test the feasibility of ⁶⁸Ga-FAPI46 PET in hypertension. Methods: Hypertension was induced in mice by angiotensin II infusion for 4 wk. ⁶⁸Ga-FAPI46 biodistribution studies and PET scanning were conducted at 1, 2, and 4 wk after hypertension modeling, and uptake in the major organs was measured. The FAP expression and fibrosis formation of the heart and kidney tissues were analyzed and compared with ⁶⁸Ga-FAPI46 uptake. Subgroups of the hypertension model underwent angiotensin receptor blocker administration and high-dose FAPI46 blocking, for comparison. As a preliminary human study, ⁶⁸Ga-FAPI46 PET images of lung cancer patients were analyzed and compared between hypertension and control groups. Results: Uptake of ⁶⁸Ga-FAPI46 in the heart and kidneys was significantly higher in the hypertension group than in the sham group as early as week 1 and decreased after week 2. The uptake was specifically blocked in the high-dose blocking study. Immunohistochemistry also revealed FAP expression in both heart and kidney tissues. However, overt fibrosis was observed in the heart, whereas it was absent from the kidneys. The angiotensin receptor blocker–treated group showed lower uptake in the heart and kidneys than did the hypertension group. In the pilot human study, renal uptake of ⁶⁸Ga-FAPI46 significantly differed between the hypertension and control groups. Conclusion: In hypertension, FAP expression is increased in the heart and kidneys from the early phases and decreases over time. FAP expression appears to represent fibrosis activity preceding or underlying fibrotic tissue formation. ⁶⁸Ga-FAPI46 PET has potential as an effective imaging method for evaluating FAP expression in progressive fibrosis by hypertension.

This is not a joke, the subscription to ExpressVPN is at an unprecedented price. We'll tell you everything you need to know so you don't miss out on its Black Friday offer.

Around half of Wales’ community pharmacies have expressed interest to health boards in providing COVID-19 vaccinations as part of the national programme.

Actor/comedian Rob Riggle announces his next breakfast move as the Holiday Inn Express brand�s Creative Director � BREAKFA-mojis!

With a Keurig� in every room at Holiday Inn Express� hotels, smart travelers � like actor/comedian Rob Riggle � can get a great cup of coffee with just the push of a button.

The attacks by Hamas on Israel led to widespread trauma, affecting not just the immediate victims but also the larger community. Many individuals experienced

Acclaimed thespian and actor Manoj Mitra, admired by critics for innovative theatrical productions and his innate acting style, passed away in Kolkata on Tuesday morning.

1. Chennai and surrounding districts get light to moderate rain, holiday for schools  The New Indian Express
2. Tamil Nadu weather: Schools shut in Chennai, IMD puts 17 districts in state on heavy rainfall alert  Business Today
3. Chennai rain: IMD predicts heavy rainfall for Tamil Nadu. Are schools, colleges closed today?  Hindustan Times
4. Tamil Nadu rains: Schools, colleges closed in several districts amid heavy rain  The Hindu
5. Tamil Nadu weather: Schools shut in few districts, yellow alert in place  India Today

Vande Bharat Express Train: আরও প্রযুক্তি নির্ভর হচ্ছে বন্দে ভারত এক্সপ্রেস! চলন্ত ট্রেনের সমস্ত আপডেট এবার নজরবন্দি থাকবে নয়া প্রযুক্তিতে। শুধু তাই নয়, ভারতীয় রেল ট্র্যাকে ছোটার সময়েও প্রতি মুহূর্তের নজর রাখা হবে। আর এজন্য বসানো হবে বিশেষ এক যন্ত্র! আর

Train Derailed: സെക്കന്തരാബാദ്-ഷാലിമർ സൂപ്പർഫാസ്റ്റ് എക്‌സ്പ്രസ് പാളം തെറ്റി. സാന്ത്രാഗച്ചി, ഖരഗ്പൂർ എന്നിവിടങ്ങളിൽ നിന്നും മെഡിക്കൽ റിലീഫ് ട്രെയിനുകളും അപകട സ്ഥലത്തെത്തി.

Vande Bharat Express: रेलवे यात्रियों के लिए बड़ी खबर आ गई है। उत्तर रेलवे की ओर से बनारस वालों को एक और नई वंदे भारत ट्रेन की सौगात मिलने जा रही है। लोगों की मांग और सुविधा को देखते हुए बनारस

Travelers using the Vande Bharat Express should be aware that cancelling tickets can result in charges. The cancellation fee depends on when the ticket is cancelled and the class of service. For example, if a ticket is cancelled more than 48

Seventeen artists have displayed 40 art works at the group show at Dys Art Gallery in Visakhapatnam

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The accident on Mumbai-Pune Expressway took place around 4 am on November 9, police said.

The council wants to expand the effective screening network of anaemia among different age populations across India

'We are the kids from the '90s who have grown up watching Shah Rukh Khan and Kajol romancing on Suraj Hua Maddham.' 'At the same time, we are also the same people who text our partner and tell them, 'I am breaking up with you'.'

Distinct dance forms exploring the rich tapestry of traditions marked the “Saare Jahan Se Accha” festival in New Delhi.

Apart from a few flashes of brilliance, Bharatanatyam dancer Jyotsna Jagannathan could not match the standards set by her guru at the Uttaradhikar festival of classical arts.

Former FBI agent and body language expert Joe Navarro is back, this time to breaks down the non-verbal ways we communicate using facial expressions. What does it mean when we scrunch up our noses or show tension in the glabella? Joe also goes deep into chirality, and equates this concept with some of the most quizzical of human expressions. Check out Joe's book "The Dictionary of Body Language" https://www.jnforensics.com/

Four people were killed and around 100 others injured after the North East Express train derailed in Bihar on Wednesday. An official said that the incident took place close to Raghunathpur station near Buxar around 9.35 pm. The train, which started from Anand Vihar Terminus in Delhi, was on its way to Kamakhya near Guwahati […]

The post North-East Express train derails in Bihar – Four dead and hundreds injured appeared first on TIMES OF ASSAM by S Kumar Deka.

F. W. Murnau’s Nosferatu, far and away the most influential early vampire movie, came out 102 years ago. For about ten of those years, Robert Eggers has been trying to remake it. He wouldn’t be the first: Werner Herzog cast Klaus Kinski as the blood-sucking aristocrat at the center of his own version in 1979, and, though […]