PTEN Regulation of Local and Long-Range Connections in Mouse Auditory Cortex

Autism spectrum disorders (ASDs) are highly heritable developmental disorders caused by a heterogeneous collection of genetic lesions. Here we use a mouse model to study the effect on cortical connectivity of disrupting the ASD candidate gene PTEN (phosphatase and tensin homolog deleted on chromosome 10). Through Cre-mediated recombination, we conditionally knocked out PTEN expression in a subset of auditory cortical neurons. Analysis of long-range connectivity using channelrhodopsin-2 revealed that the strength of synaptic inputs from both the contralateral auditory cortex and from the thalamus onto PTEN-cko neurons was enhanced compared with nearby neurons with normal PTEN expression. Laser-scanning photostimulation showed that local inputs onto PTEN-cko neurons in the auditory cortex were similarly enhanced. The hyperconnectivity caused by PTEN-cko could be blocked by rapamycin, a specific inhibitor of the PTEN downstream molecule mammalian target of rapamycin complex 1. Together, our results suggest that local and long-range hyperconnectivity may constitute a physiological basis for the effects of mutations in PTEN and possibly other ASD candidate genes

The effects of lip revision surgery on nasolabial esthetics in patients with cleft lip

1) To determine the concordance among surgeons on subjective assessments of nasolabial esthetics in children with repaired cleft lip; and 2) to evaluate longitudinal changes in nasolabial esthetics in relation to cleft lip revision surgery.School of Dentistry at University of North Carolina, Chapel Hill. Children with repaired unilateral cleft lip: 32 had lip revision surgery and 27 did not have surgery.Retrospective observational study from a non-randomized clinical trial. Ratings of nasolabial esthetics performed by six surgeons using the Asher-McDade scale at baseline and 12-month follow-up.Concordance among surgeons ranged from poor to acceptable. Nasolabial ratings at follow-up were better in the Revision group than in the Non-Revision group, although differences were small. The most prevalent change in the Revision Group was improvement in one or more units on the scale, while ‘no change’ was most prevalent in the Non-Revision group. Participants in the Revision group were more likely to receive a ‘no’ in relation to the need for lip or nose revision at the follow-up visit.There were mild esthetic improvements observed in relation to lip revision surgery, which should be interpreted with caution given the subjectivity of the rating method used

Effects of Lip Revision Surgery in Cleft Lip/Palate Patients

The decision for lip revision surgery in patients with repaired cleft lip/palate is based on surgeons’ subjective evaluation of lip disability. An objective evaluation would be highly beneficial for the assessment of surgical outcomes. In this study, the effects of lip revision on circumoral movements were objectively quantified. The hypothesis was that lip revision increases scarring and impairment. The study was a non-randomized clinical trial that included patients with cleft lip who had revision, patients with cleft lip who did not, and non-cleft control individuals. Three-dimensional facial movements were measured. Revision patients were measured before and after surgery. Other individuals were measured at similar intervals. Regression models were fit to summary measurements, and changes were modeled. Patients with repaired cleft lip/palate had fewer mean movements than control individuals. Lip revision did not worsen mean movements; however, individual patients’ movements varied from ‘improvement’ to ‘no change’ to ‘worse’ relative to those of control individuals

Within-Document Term-Based Index Pruning with Statistical Hypothesis Testing

Abstract. Document-centric static index pruning methods provide smaller indexes and faster query times by dropping some within-document term information from inverted lists. We present a method of pruning in-verted lists derived from the formulation of unigram language models for retrieval. Our method is based on the statistical significance of term frequency ratios: using the two-sample two-proportion (2P2N) test, we statistically compare the frequency of occurrence of a word within a given document to the frequency of its occurrence in the collection to de-cide whether to prune it. Experimental results show that this technique can be used to significantly decrease the size of the index and querying speed with less compromise to retrieval effectiveness than similar heuris-tic methods. Furthermore, we give a formal statistical justification for such methods.

Pleckstrin homology domain leucine-rich repeat protein phosphatases set the amplitude of receptor tyrosine kinase output

Growth factor receptor levels are aberrantly high in diverse cancers, driving the proliferation and survival of tumor cells. Understanding the molecular basis for this aberrant elevation has profound clinical implications. Here we show that the pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) suppresses receptor tyrosine kinase (RTK) signaling output by a previously unidentified epigenetic mechanism unrelated to its previously described function as the hydrophobic motif phosphatase for the protein kinase AKT, protein kinase C, and S6 kinase. Specifically, we show that nuclear-localized PHLPP suppresses histone phosphorylation and acetylation, in turn suppressing the transcription of diverse growth factor receptors, including the EGF receptor. These data uncover a much broader role for PHLPP in regulation of growth factor signaling beyond its direct inactivation of AKT: By suppressing RTK levels, PHLPP dampens the downstream signaling output of two major oncogenic pathways, the PI3 kinase/AKT and the Rat sarcoma (RAS)/ERK pathways. Our data are consistent with a model in which PHLPP modifies the histone code to control the transcription of RTKs

Projective Hilbert space structures at exceptional points

A non-Hermitian complex symmetric 2x2 matrix toy model is used to study projective Hilbert space structures in the vicinity of exceptional points (EPs). The bi-orthogonal eigenvectors of a diagonalizable matrix are Puiseux-expanded in terms of the root vectors at the EP. It is shown that the apparent contradiction between the two incompatible normalization conditions with finite and singular behavior in the EP-limit can be resolved by projectively extending the original Hilbert space. The complementary normalization conditions correspond then to two different affine charts of this enlarged projective Hilbert space. Geometric phase and phase jump behavior are analyzed and the usefulness of the phase rigidity as measure for the distance to EP configurations is demonstrated. Finally, EP-related aspects of PT-symmetrically extended Quantum Mechanics are discussed and a conjecture concerning the quantum brachistochrone problem is formulated.Comment: 20 pages; discussion extended, refs added; bug correcte

Full automation of total metabolic tumor volume from FDG-PET/CT in DLBCL for baseline risk assessments

BACKGROUND: Current radiological assessments of (18)fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging data in diffuse large B-cell lymphoma (DLBCL) can be time consuming, do not yield real-time information regarding disease burden and organ involvement, and hinder the use of FDG-PET to potentially limit the reliance on invasive procedures (e.g. bone marrow biopsy) for risk assessment. METHODS: Our aim is to enable real-time assessment of imaging-based risk factors at a large scale and we propose a fully automatic artificial intelligence (AI)-based tool to rapidly extract FDG-PET imaging metrics in DLBCL. On availability of a scan, in combination with clinical data, our approach generates clinically informative risk scores with minimal resource requirements. Overall, 1268 patients with previously untreated DLBCL from the phase III GOYA trial (NCT01287741) were included in the analysis (training: n = 846; hold-out: n = 422). RESULTS: Our AI-based model comprising imaging and clinical variables yielded a tangible prognostic improvement compared to clinical models without imaging metrics. We observed a risk increase for progression-free survival (PFS) with hazard ratios [HR] of 1.87 (95% CI: 1.31–2.67) vs 1.38 (95% CI: 0.98–1.96) (C-index: 0.59 vs 0.55), and a risk increase for overall survival (OS) (HR: 2.16 (95% CI: 1.37–3.40) vs 1.40 (95% CI: 0.90–2.17); C-index: 0.59 vs 0.55). The combined model defined a high-risk population with 35% and 42% increased odds of a 4-year PFS and OS event, respectively, versus the International Prognostic Index components alone. The method also identified a subpopulation with a 2-year Central Nervous System (CNS)-relapse probability of 17.1%. CONCLUSION: Our tool enables an enhanced risk stratification compared with IPI, and the results indicate that imaging can be used to improve the prediction of central nervous system relapse in DLBCL. These findings support integration of clinically informative AI-generated imaging metrics into clinical workflows to improve identification of high-risk DLBCL patients. TRIAL REGISTRATION: Registered clinicaltrials.gov number: NCT01287741. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40644-022-00476-0

Mix 'n Match: Integrating Text Matching and Product Substitutability within Product Search

Two products are substitutes if both can satisfy the same consumer need. Intrinsic incorporation of product substitutability - where substitutability is integrated within latent vector space models - is in contrast to the extrinsic re-ranking of result lists. The fusion of text matching and product substitutability objectives allows latent vector space models to mix and match regularities contained within text descriptions and substitution relations. We introduce a method for intrinsically incorporating product substitutability within latent vector space models for product search that are estimated using gradient descent; it integrates flawlessly with state-of-the-art vector space models. We compare our method to existing methods for incorporating structural entity relations, where product substitutability is incorporated extrinsically by re-ranking. Our method outperforms the best extrinsic method on four benchmarks. We investigate the effect of different levels of text matching and product similarity objectives, and provide an analysis of the effect of incorporating product substitutability on product search ranking diversity. Incorporating product substitutability information improves search relevance at the cost of diversity

Ubiquitination regulates PTEN nuclear import and tumor suppression

The PTEN tumor suppressor is frequently affected in cancer cells, and inherited PTEN mutation causes cancer-susceptibility conditions such as Cowden syndrome. PTEN acts as a plasma-membrane lipid-phosphatase antagonizing the phosphoinositide 3-kinase/AKT cell survival pathway. However, PTEN is also found in cell nuclei, but mechanism, function, and relevance of nuclear localization remain unclear. We show that nuclear PTEN is essential for tumor suppression and that PTEN nuclear import is mediated by its monoubiquitination. A lysine mutant of PTEN, K289E associated with Cowden syndrome, retains catalytic activity but fails to accumulate in nuclei of patient tissue due to an import defect. We identify this and another lysine residue as major monoubiquitination sites essential for PTEN import. While nuclear PTEN is stable, polyubiquitination leads to its degradation in the cytoplasm. Thus, we identify cancer-associated mutations of PTEN that target its posttranslational modification and demonstrate how a discrete molecular mechanism dictates tumor progression by differentiating between degradation and protection of PTEN

Patients with treated indolent lymphomas immunized with BNT162b2 have reduced anti-spike neutralizing IgG to SARS-CoV-2 variants, but preserved antigen-specific T cell responses

Patients with indolent lymphoma undertaking recurrent or continuous B cell suppression are at risk of severe COVID-19. Patients and healthy controls (HC; N = 13) received two doses of BNT162b2: follicular lymphoma (FL; N = 35) who were treatment naïve (TN; N = 11) or received immunochemotherapy (ICT; N = 23) and Waldenström's macroglobulinemia (WM; N = 37) including TN (N = 9), ICT (N = 14), or treated with Bruton's tyrosine kinase inhibitors (BTKi; N = 12). Anti-spike immunoglobulin G (IgG) was determined by a high-sensitivity flow-cytometric assay, in addition to live-virus neutralization. Antigen-specific T cells were identified by coexpression of CD69/CD137 and CD25/CD134 on T cells. A subgroup (N = 29) were assessed for third mRNA vaccine response, including omicron neutralization. One month after second BNT162b2, median anti-spike IgG mean fluorescence intensity (MFI) in FL ICT patients (9977) was 25-fold lower than TN (245 898) and HC (228 255, p =.0002 for both). Anti-spike IgG correlated with lymphocyte count (r =.63; p =.002), and time from treatment (r =.56; p =.007), on univariate analysis, but only with lymphocyte count on multivariate analysis (p =.03). In the WM cohort, median anti-spike IgG MFI in BTKi patients (39 039) was reduced compared to TN (220 645, p =.0008) and HC (p <.0001). Anti-spike IgG correlated with neutralization of the delta variant (r =.62, p <.0001). Median neutralization titer for WM BTKi (0) was lower than HC (40, p <.0001) for early-clade and delta. All cohorts had functional T cell responses. Median anti-spike IgG decreased 4-fold from second to third dose (p =.004). Only 5 of 29 poor initial responders assessed after third vaccination demonstrated seroconversion and improvement in neutralization activity, including to the omicron variant