Hepatocyte nuclear factor-1β (HNF-1β) is a tissue-specific transcription factor that is required for normal kidney development and renal epithelial differentiation. Mutations of HNF-1β produce congenital kidney abnormalities and inherited renal tubulopathies. Here, we show that ablation of HNF-1β in mIMCD3 renal epithelial cells results in activation of β-catenin and increased expression of lymphoid enhancer–binding factor 1 (LEF1), a downstream effector in the canonical Wnt signaling pathway. Increased expression and nuclear localization of LEF1 are also observed in cystic kidneys from Hnf1b mutant mice. Expression of dominant-negative mutant HNF-1β in mIMCD3 cells produces hyperresponsiveness to exogenous Wnt ligands, which is inhibited by siRNA-mediated knockdown of Lef1. WT HNF-1β binds to two evolutionarily conserved sites located 94 and 30 kb from the mouse Lef1 promoter. Ablation of HNF-1β decreases H3K27 trimethylation repressive marks and increases β-catenin occupancy at a site 4 kb upstream to Lef1. Mechanistically, WT HNF-1β recruits the polycomb-repressive complex 2 that catalyzes H3K27 trimethylation. Deletion of the β-catenin–binding domain of LEF1 in HNF-1β–deficient cells abolishes the increase in Lef1 transcription and decreases the expression of downstream Wnt target genes. The canonical Wnt target gene, Axin2, is also a direct transcriptional target of HNF-1β through binding to negative regulatory elements in the gene promoter. These findings demonstrate that HNF-1β regulates canonical Wnt target genes through long-range effects on histone methylation at Wnt enhancers and reveal a new mode of active transcriptional repression by HNF-1β.

A. V. Silantyev
Trans. Moscow Math. Soc. 83 (), 75-149.
Abstract, references and article information

A. P. Starovoitov and N. V. Ryabchenko
Trans. Moscow Math. Soc. 83 (), 15-31.
Abstract, references and article information

High-throughput sequencing of hematologic malignancies and other cancers has revealed recurrent mis-sense mutations of genes encoding pre-mRNA splicing factors. The essential splicing factor U2AF2 recognizes a polypyrimidine-tract splice-site signal and initiates spliceosome assembly. Here, we investigate representative, acquired U2AF2 mutations, namely N196K or G301D amino acid substitutions associated with leukemia or solid tumors, respectively. We determined crystal structures of the wild-type (WT) compared with N196K- or G301D-substituted U2AF2 proteins, each bound to a prototypical AdML polypyrimidine tract, at 1.5, 1.4, or 1.7 Å resolutions. The N196K residue appears to stabilize the open conformation of U2AF2 with an inter-RNA recognition motif hydrogen bond, in agreement with an increased apparent RNA-binding affinity of the N196K-substituted protein. The G301D residue remains in a similar position as the WT residue, where unfavorable proximity to the RNA phosphodiester could explain the decreased RNA-binding affinity of the G301D-substituted protein. We found that expression of the G301D-substituted U2AF2 protein reduces splicing of a minigene transcript carrying prototypical splice sites. We further show that expression of either N196K- or G301D-substituted U2AF2 can subtly alter splicing of representative endogenous transcripts, despite the presence of endogenous, WT U2AF2 such as would be present in cancer cells. Altogether, our results demonstrate that acquired U2AF2 mutations such as N196K and G301D are capable of dysregulating gene expression for neoplastic transformation.

10 September 2020

Large regions in tumor tissues, particularly pancreatic cancer, are hypoxic and nutrient-deprived because of unregulated cell growth and insufficient vascular supply. Certain cancer cells, such as those inside a tumor, can tolerate these severe conditions and survive for prolonged periods. We hypothesized that small molecular agents, which can preferentially reduce cancer cell survival under nutrient-deprived conditions, could function as anticancer drugs. In this study, we constructed a high-throughput screening system to identify such small molecules and screened chemical libraries and microbial culture extracts. We were able to determine that some small molecular compounds, such as penicillic acid, papyracillic acid, and auranofin, exhibit preferential cytotoxicity to human pancreatic cancer cells under nutrient-deprived compared with nutrient-sufficient conditions. Further analysis revealed that these compounds target to redox systems such as GSH and thioredoxin and induce accumulation of reactive oxygen species in nutrient-deprived cancer cells, potentially contributing to apoptosis under nutrient-deprived conditions. Nutrient-deficient cancer cells are often deficient in GSH; thus, they are susceptible to redox system inhibitors. Targeting redox systems might be an attractive therapeutic strategy under nutrient-deprived conditions of the tumor microenvironment.

The neuronal basis of complex social behavior is still poorly understood. In honeybees, reproductive investment decisions are made at the colony-level. Queens develop from female-destined larvae that receive alloparental care from nurse bees in the form of ad-libitum royal jelly (RJ) secretions. Typically, the number of raised new queens is limited but genetic breeding of "royal jelly bees" (RJBs) for enhanced RJ production over decades has led to a dramatic increase of reproductive investment in queens. Here, we compare RJBs to unselected Italian bees (ITBs) to investigate how their cognitive processing of larval signals in the mushroom bodies (MBs) and antennal lobes (ALs) may contribute to their behavioral differences. A cross-fostering experiment confirms that the RJB syndrome is mainly due to a shift in nurse bee alloparental care behavior. Using olfactory conditioning of the proboscis extension reflex, we show that the RJB nurses spontaneously respond more often to larval odors compared with ITB nurses but their subsequent learning occurs at similar rates. These phenotypic findings are corroborated by our demonstration that the proteome of the brain, particularly of the ALs differs between RJBs and ITBs. Notably, in the ALs of RJB newly emerged bees and nurses compared with ITBs, processes of energy and nutrient metabolism, signal transduction are up-regulated, priming the ALs for receiving and processing the brood signals from the antennae. Moreover, highly abundant major royal jelly proteins and hexamerins in RJBs compared with ITBs during early life when the nervous system still develops suggest crucial new neurobiological roles for these well-characterized proteins. Altogether, our findings reveal that RJBs have evolved a strong olfactory response to larvae, enabled by numerous neurophysiological adaptations that increase the nurse bees' alloparental care behavior.

The faithful segregation, or “partition,” of many low-copy number bacterial plasmids is driven by plasmid-encoded ATPases that are represented by the P1 plasmid ParA protein. ParA binds to the bacterial nucleoid via an ATP-dependent nonspecific DNA (nsDNA)-binding activity, which is essential for partition. ParA also has a site-specific DNA-binding activity to the par operator (parOP), which requires either ATP or ADP, and which is essential for it to act as a transcriptional repressor but is dispensable for partition. Here we examine how DNA binding by ParA contributes to the relative distribution of its plasmid partition and repressor activities, using a ParA with an alanine substitution at Arg351, a residue previously predicted to participate in site-specific DNA binding. In vivo, the parAR351A allele is compromised for partition, but its repressor activity is dramatically improved so that it behaves as a “super-repressor.” In vitro, ParAR351A binds and hydrolyzes ATP, and undergoes a specific conformational change required for nsDNA binding, but its nsDNA-binding activity is significantly damaged. This defect in turn significantly reduces the assembly and stability of partition complexes formed by the interaction of ParA with ParB, the centromere-binding protein, and DNA. In contrast, the R351A change shows only a mild defect in site-specific DNA binding. We conclude that the partition defect is due to altered nsDNA binding kinetics and affinity for the bacterial chromosome. Furthermore, the super-repressor phenotype is explained by an increased pool of non-nucleoid bound ParA that is competent to bind parOP and repress transcription.

Business Development in Madagascar: How to Enable Entrepreneurialism 15 November 2017 — 12:00PM TO 1:00PM Anonymous (not verified) 9 November 2017 Chatham House, London

Tumor hypoxia, an integral biomarker to guide radiotherapy, can be imaged with ¹⁸F-fluoromisonidazole (¹⁸F-FMISO) hypoxia PET. One major obstacle to its broader application is the lack of standardized interpretation criteria. We sought to develop and validate practical interpretation criteria and a dedicated training protocol for nuclear medicine physicians to interpret ¹⁸F-FMISO hypoxia PET. Methods: We randomly selected 123 patients with human papillomavirus–positive oropharyngeal cancer enrolled in a phase II trial who underwent 123 ¹⁸F-FDG PET/CT and 134 ¹⁸F-FMISO PET/CT scans. Four independent nuclear medicine physicians with no ¹⁸F-FMISO experience read the scans. Interpretation by a fifth nuclear medicine physician with over 2 decades of ¹⁸F-FMISO experience was the reference standard. Performance was evaluated after initial instruction and subsequent dedicated training. Scans were considered positive for hypoxia by visual assessment if ¹⁸F-FMISO uptake was greater than floor-of-mouth uptake. Additionally, SUV_max was determined to evaluate whether quantitative assessment using tumor-to-background ratios could be helpful to define hypoxia positivity. Results: Visual assessment produced a mean sensitivity and specificity of 77.3% and 80.9%, with fair interreader agreement ( = 0.34), after initial instruction. After dedicated training, mean sensitivity and specificity improved to 97.6% and 86.9%, with almost perfect agreement ( = 0.86). Quantitative assessment with an estimated best SUV_max ratio threshold of more than 1.2 to define hypoxia positivity produced a mean sensitivity and specificity of 56.8% and 95.9%, respectively, with substantial interreader agreement ( = 0.66), after initial instruction. After dedicated training, mean sensitivity improved to 89.6% whereas mean specificity remained high at 95.3%, with near-perfect interreader agreement ( = 0.86). Conclusion: Nuclear medicine physicians without ¹⁸F-FMISO hypoxia PET reading experience demonstrate much improved interreader agreement with dedicated training using specific interpretation criteria.

The bias may make it harder for depressed and anxious people to take a risk on a new relationship, job or other career opportunity.

The therapy helps the brain work more efficiently and lifts depression.

It is linked to higher risk of self-harm and suicidal thoughts.

Although common ‘disorders’ (e.g., eating disorders, anxiety, and depression) look different on the surface, there are some common underlying mechanisms. One of these is checking. I’m going to go explain the role of checking in a selection of common mental health problems. Checking in Health Anxiety Examples: – Person goes to the Dr for blood […]

The post CBT: How Checking Contributes to Mental Health Problems (Eating Disorders, Depression, Anxiety) appeared first on Dr Alice Boyes.

The justices declined to take up a major challenge to exclusive-bargaining arrangements for teachers' unions and other public employee labor organizations.

Umut Güçlü
Jul 8, 2015; 35:10005-10014
BehavioralSystemsCognitive

Abnormal neuronal morphological features, such as dendrite branching, axonal branching, and spine density, are thought to contribute to the symptoms of depression and anxiety. However, the role and molecular mechanisms of aberrant neuronal morphology in the regulation of mood disorders remain poorly characterized. Here, we show that neuritin, an activity-dependent protein, regulates the axonal morphology of serotonin neurons. Male neuritin knock-out (KO) mice harbored impaired axonal branches of serotonin neurons in the medial prefrontal cortex and basolateral region of the amygdala (BLA), and male neuritin KO mice exhibited depressive and anxiety-like behaviors. We also observed that the expression of neuritin was decreased by unpredictable chronic stress in the male mouse brain and that decreased expression of neuritin was associated with reduced axonal branching of serotonin neurons in the brain and with depressive and anxiety behaviors in mice. Furthermore, the stress-mediated impairments in axonal branching and depressive behaviors were reversed by the overexpression of neuritin in the BLA. The ability of neuritin to increase axonal branching in serotonin neurons involves fibroblast growth factor (FGF) signaling, and neuritin contributes to FGF-2-mediated axonal branching regulation in vitro. Finally, the oral administration of an FGF inhibitor reduced the axonal branching of serotonin neurons in the brain and caused depressive and anxiety behaviors in male mice. Our results support the involvement of neuritin in models of stress-induced depression and suggest that neuronal morphological plasticity may play a role in controlling animal behavior.

Neural responses are naturally variable from one moment to the next, even when the stimulus is held constant. What factors might underlie this variability in neural population activity? We hypothesized that spontaneous fluctuations in cortical stimulus representations are created by changes in arousal state. We tested the hypothesis using a combination of fMRI, probabilistic decoding methods, and pupillometry. Human participants (20 female, 12 male) were presented with gratings of random orientation. Shortly after viewing the grating, participants reported its orientation and gave their level of confidence in this judgment. Using a probabilistic fMRI decoding technique, we quantified the precision of the stimulus representation in the visual cortex on a trial-by-trial basis. Pupil size was recorded and analyzed to index the observer's arousal state. We found that the precision of the cortical stimulus representation, reported confidence, and variability in the behavioral orientation judgments varied from trial to trial. Interestingly, these trial-by-trial changes in cortical and behavioral precision and confidence were linked to pupil size and its temporal rate of change. Specifically, when the cortical stimulus representation was more precise, the pupil dilated more strongly prior to stimulus onset and remained larger during stimulus presentation. Similarly, stronger pupil dilation during stimulus presentation was associated with higher levels of subjective confidence, a secondary measure of sensory precision, as well as improved behavioral performance. Taken together, our findings support the hypothesis that spontaneous fluctuations in arousal state modulate the fidelity of the stimulus representation in the human visual cortex, with clear consequences for behavior.

Different people listening to the same story may converge upon a largely shared interpretation while still developing idiosyncratic experiences atop that shared foundation. What linguistic properties support this individualized experience of natural language? Here, we investigate how the "concrete–abstract" axis—the extent to which a word is grounded in sensory experience—relates to within- and across-subject variability in the neural representations of language. Leveraging a dataset of human participants of both sexes who each listened to four auditory stories while undergoing functional magnetic resonance imaging, we demonstrate that neural representations of "concreteness" are both reliable across stories and relatively unique to individuals, while neural representations of "abstractness" are variable both within individuals and across the population. Using natural language processing tools, we show that concrete words exhibit similar neural representations despite spanning larger distances within a high-dimensional semantic space, which potentially reflects an underlying representational signature of sensory experience—namely, imageability—shared by concrete words but absent from abstract words. Our findings situate the concrete–abstract axis as a core dimension that supports both shared and individualized representations of natural language.

Santiago, Chile- The declaration of the XXI Specialized Meeting on Family Farming of MERCOSUR (REAF, in Spanish) held last week in Argentina, acknowledged the advances promoted by FAO’s Director General, [...]

Vientiane.- A delegation of seven Permanent Representatives to the Rome-based Food and Agriculture Organization of the U.N (FAO) concluded a week-long visit to Lao PDR, during which they held meetings [...]

The Galeón Andalucía, which is now making its way to London, was designed to resemble the armed merchant vessels manufactured by Spain and Portugal between the 16th and 18th centuries

Scientists used EEG headsets, MRI machines and eye trackers to study volunteers' responses to five paintings housed at the Mauritshuis museum in the Netherlands

A man from Queens County has been sentenced to five years and nine months in federal prison for charges including making and transmitting child pornography, voyeurism and intercepting private communications.

The entrepreneur and financial adviser defeated Adam Bassett for the party nomination in Egmont after two days of voting last week. 

Charlottetown-born curler Brett Gallant says competing in the Olympics will be a dream come true for him and his fiancée, Jocelyn Peterman, even if COVID-19 protocols will make it difficult for them to see each other.

It’s official — Team Galusha will be representing the N.W.T. at the 2022 Scotties Tournament of Hearts in Thunder Bay later this month.

Curling Canada, with the assistance of Own the Podium and the Canadian Olympic Committee, announced Rachel Homan and John Morris as the mixed doubles team for Canada competing at the Beijing Olympics.

ioSafe Uses SolidWorks to Design Disaster-Proof Computer Hardware; Company Saves $15,000 and Three Months

People who experience depression and concussions simultaneously have significantly worse symptoms for both conditions and disruptions to brain connectivity, according to a study by researchers at Penn State.

The U.S. Supreme Court declined to take up a case that held the potential to deal a further blow to public-employee unions after last year's "Janus" decision.

Rudy Gay's Flight 22 Foundation is partnering with ed-tech company EverFi to teach students how to create a successful business.

Jeffrey Goldberg and Matthew Vogt contribute a significant portion of the sales of their company, Sky Devil Wines, to veterans and veteran-specific causes. In 2018 they established a fund that is now named the Sky Devil Veteran's Entrepreneur Fund. The first two recipients of proceeds from that fund were recently named.

Khamila Barnes successfully took the leap from the corporate world to entrepreneurship thanks for her vibrant personality, innate drive, and the skills she developed at Penn State Abington. 

Penn State Berks will host a variety of events during Global Entrepreneurship Week 2024, set for Monday, Nov. 18, to Friday, Nov. 22. Events are sponsored by the college’s Flemming Creativity, Entrepreneurship, and Economic Development Center and the Berks LaunchBox in downtown Reading.

Penn State has been ranked as the No. 28 school for undergraduate entrepreneurship studies by the Princeton Review and Entrepreneurship magazine in the partnership's annual ratings released Nov. 12, moving up five spots from the previous year. Among schools in the Mid-Atlantic region, Penn State came in at No. 4.

Some of Pakistan cricket's legends have criticised the Indian team's refusal to travel across the border for ICC Champions Trophy next year.

Wilmington, Del. (March 10, 2022) – From a field of ten Delaware high school students, Natalie Kim Ramos, a senior from Saint Mark’s High School, earned the title of 2022 Poetry Out Loud Delaware State Champion at the virtual state finals held on March 10. The first runner-up was Kai Schmiedel from Delaware Valley Classical […]

Wilmington, Del. (March 3, 2023) – From a field of twelve Delaware high school students, Maiss Hussein, a junior from Paul M. Hodgson Vocational Technical High School, earned the title of 2023 Poetry Out Loud Delaware State Champion at the state finals held on March 2 at the Smyrna Opera House. The first runner-up was […]

Washington, DC and Chicago, IL — After two years of virtual competitions, the Poetry Out Loud® National Finals are returning to Washington, DC, this Spring, May 9–10, 2023, and will be streamed live at Arts.gov/Poetry-Out-Loud. This annual event brings together high school students from across the country who memorize and recite classic and contemporary poems, […]

Hussein named Delaware’s finalist for second consecutive year   Wilmington, Del. (March 7, 2024) – Following a spirited competition featuring eleven talented high school students from Delaware, Maiss Hussein, a senior from Paul M. Hodgson Vocational Technical High School, emerged as the 2024 Poetry Out Loud Delaware State Champion. The exhilarating state finals took place […]

DOJ-CLASI agreement covers most disputes with community owners Attorney General Kathy Jennings announced Monday that manufactured home owners in disputes with their community owners will be eligible for free legal representation by the non-profit Delaware Community Legal Aid Society, Inc. (CLASI), under a contract it entered with the Delaware Department of Justice. “Constituents in all three counties have […]

Federal judge ensures mifepristone access in Delaware Attorney General Kathy Jennings announced Friday that Judge Thomas O. Rice of the U.S. District Court for the Eastern District of Washington has issued an order reiterating that his injunction protecting access to mifepristone in 17 states — including Delaware — and the District of Columbia remains in […]

The legal debacle over mifepristone underscores how easily a small group of extremist plaintiffs can abuse the judicial system to force draconian, unscientific, and undemocratic laws on the nation. These questions should not even be up for debate: mifepristone has a safer track record than Viagra. But we live in an era where women once […]

A Bengaluru-based entrepreneur recently took to social media to jokingly explain how his daily commute on bike taxes in the city doubles as an unexpected fitness routine.