Engineered phage-based therapeutic materials inhibit Chlamydia trachomatis intracellular infection

Developing materials that are effective against sexually transmitted pathogens such as Chlamydia trachomatis (Ct) and HIV-1 is challenging both in terms of material selection and improving bio-membrane and cellular permeability at desired mucosal sites. Here, we engineered the prokaryotic bacterial virus (M13 phage) carrying two functional peptides, integrin binding peptide (RGD) and a segment of the polymorphic membrane protein D (PmpD) from Ct, as a phage-based material that can ameliorate Ct infection. Ct is a globally prevalent human pathogen for which there are no effective vaccines or microbicides. We show that engineered phage stably express both RGD motifs and Ct peptides and traffic intracellularly and into the lumen of the inclusion in which the organism resides within the host cell. Engineered phage were able to significantly reduce Ct infection in both HeLa and primary endocervical cells compared with Ct infection alone. Polyclonal antibodies raised against PmpD and co-incubated with constructs prior to infection did not alter the course of infection, indicating that PmpD is responsible for the observed decrease in Ct infection. Our results suggest that phage-based design approaches to vector delivery that overcome mucosal cellular barriers may be effective in preventing Ct and other sexually transmitted pathogens

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Debt Begets Debt: Examining Negative Credit Card Behaviors and Other Forms of Consumer Debt

The effect of negative credit card behaviors is examined for association with other forms of consumer debt (automobile debt, installment debt, and personal loan debt). Data were collected using a combination of random digit dialing and convenience sampling from two cities. Respondents\u27 median age is 48 years old, ranging from 20-87. Results indicate that despite controlling for income, not paying off the monthly balance and reaching the maximum limit on credit cards are associated with a variety of other debts. Although consumers can increase lifetime utility by borrowing, less educated consumers are more vulnerable to less favorable sources of credit. Negative credit card behaviors can be easily identifiable signals of larger lurking issues related to consumer behavior or lack of financial literacy. Controlling for income, younger adults accrue significantly more installment debt, possibly suggesting that younger generations perceive a larger number of required appliances and electronics as being necessary to run the household than previous generations

Search for CP violation in the phase space of D0 → π+π−π+π−decays

A search for time-integrated CP violation in the Cabibbo-suppressed decay D 0 → π + π − π + π − is performed using an unbinned, model-independent technique known as the energy test. This is the first application of the energy test in four-body decays. The search is performed for P-even CP asymmetries and, for the first time, is extended to probe the P-odd case. Using proton–proton collision data corresponding to an integrated luminosity of 3.0 fb-1 collected by the LHCb detector at centre-of-mass energies of √S = 7 TeV and 8 TeV, the world's best sensitivity to CP violation in this decay is obtained. The data are found to be consistent with the hypothesis of CP symmetry with a p-value of 4.6 +-0.5 % in the P-even case, and marginally consistent with a p-value of 0.6+-0.2 % in the P-odd case, corresponding to a significance for CP non-conservation of 2.7 standard deviations

LMTK3 confers chemo-resistance in breast cancer

Lemur tyrosine kinase 3 (LMTK3) is an oncogenic kinase that is involved in different types of cancer (breast, lung, gastric, colorectal) and biological processes including proliferation, invasion, migration, chromatin remodeling as well as innate and acquired endocrine resistance. However, the role of LMTK3 in response to cytotoxic chemotherapy has not been investigated thus far. Using both 2D and 3D tissue culture models, we found that overexpression of LMTK3 decreased the sensitivity of breast cancer cell lines to cytotoxic (doxorubicin) treatment. In a mouse model we showed that ectopic overexpression of LMTK3 decreases the efficacy of doxorubicin in reducing tumor growth. Interestingly, breast cancer cells overexpressing LMTK3 delayed the generation of double strand breaks (DSBs) after exposure to doxorubicin, as measured by the formation of γH2AX foci. This effect was at least partly mediated by decreased activity of ataxia-telangiectasia mutated kinase (ATM) as indicated by its reduced phosphorylation levels. In addition, our RNA-seq analyses showed that doxorubicin differentially regulated the expression of over 700 genes depending on LMTK3 protein expression levels. Furthermore, these genes were found to promote DNA repair, cell viability and tumorigenesis processes / pathways in LMTK3-overexpressing MCF7 cells. In human cancers, immunohistochemistry staining of LMTK3 in pre- and postchemotherapy breast tumor pairs from four separate clinical cohorts revealed a significant increase of LMTK3 following both doxorubicin and docetaxel based chemotherapy. In aggregate, our findings show for the first time a contribution of LMTK3 in cytotoxic drug resistance in breast cancer

Brainformers: Trading Simplicity for Efficiency

Transformers are central to recent successes in natural language processing and computer vision. Transformers have a mostly uniform backbone where layers alternate between feed-forward and self-attention in order to build a deep network. Here we investigate this design choice and find that more complex blocks that have different permutations of layer primitives can be more efficient. Using this insight, we develop a complex block, named Brainformer, that consists of a diverse sets of layers such as sparsely gated feed-forward layers, dense feed-forward layers, attention layers, and various forms of layer normalization and activation functions. Brainformer consistently outperforms the state-of-the-art dense and sparse Transformers, in terms of both quality and efficiency. A Brainformer model with 8 billion activated parameters per token demonstrates 2x faster training convergence and 5x faster step time compared to its GLaM counterpart. In downstream task evaluation, Brainformer also demonstrates a 3% higher SuperGLUE score with fine-tuning compared to GLaM with a similar number of activated parameters. Finally, Brainformer largely outperforms a Primer dense model derived with NAS with similar computation per token on fewshot evaluations

Long-Term Efficacy and Safety of Cardiac Genome Editing for Catecholaminergic Polymorphic Ventricular Tachycardia

INTRODUCTION: Heterozygous autosomal-dominant single nucleotide variants in RYR2 account for 60% of cases of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmia disorder associated with high mortality rates. CRISPR/Cas9-mediated genome editing is a promising therapeutic approach that can permanently cure the disease by removing the mutant RYR2 allele. However, the safety and long-term efficacy of this strategy have not been established in a relevant disease model. AIM: The purpose of this study was to assess whether adeno-associated virus type-9 (AAV9)-mediated somatic genome editing could prevent ventricular arrhythmias by removal of the mutant allele in mice that are heterozygous for METHODS AND RESULTS: Guide RNA and SaCas9 were delivered using AAV9 vectors injected subcutaneously in 10-day-old mice. At 6 weeks after injection, R176Q/+ mice had a 100% reduction in ventricular arrhythmias compared to controls. When aged to 12 months, injected R176Q/+ mice maintained a 100% reduction in arrhythmia induction. Deep RNA sequencing revealed the formation of insertions/deletions at the target site with minimal off-target editing on the wild-type allele. Consequently, CRISPR/SaCas9 editing resulted in a 45% reduction of total CONCLUSION: Taken together, AAV9-mediated CRISPR/Cas9 genome editing could efficiently disrupt the mutant Ryr2 allele, preventing lethal arrhythmias while preserving normal cardiac function in the R176Q/+ mouse model of CPVT

Lack of Effect of Sleep Apnea on Oxidative Stress in Obstructive Sleep Apnea Syndrome (OSAS) Patients

PURPOSE: The aim of this study was to evaluate markers of systemic oxidative stress and antioxidant capacity in subjects with and without OSAS in order to investigate the most important factors that determine the oxidant-antioxidant status. METHODS: A total of 66 subjects referred to our Sleep laboratory were examined by full polysomnography. Oxidative stress and antioxidant activity were assessed by measurement of the derivatives of reactive oxygen metabolites (d-ROMs) and the biological antioxidant capacity (BAP) in blood samples taken in the morning after the sleep study. Known risk factors for oxidative stress, such as age, sex, obesity, smoking, hypelipidemia, and hypertension, were investigated as possible confounding factors. RESULTS: 42 patients with OSAS (Apnea-Hypopnea index >15 events/hour) were compared with 24 controls (AHI<5). The levels of d-ROMS were significantly higher (p = 0.005) in the control group but the levels of antioxidant capacity were significantly lower (p = 0.004) in OSAS patients. The most important factors predicting the variance of oxidative stress were obesity, smoking habit, and sex. Parameters of sleep apnea severity were not associated with oxidative stress. Minimal oxygen desaturation and smoking habit were the most important predicting factors of BAP levels. CONCLUSION: Obesity, smoking, and sex are the most important determinants of oxidative stress in OSAS subjects. Sleep apnea might enhance oxidative stress by the reduction of antioxidant capacity of blood due to nocturnal hypoxia