Conditional Image-Text Embedding Networks

This paper presents an approach for grounding phrases in images which jointly learns multiple text-conditioned embeddings in a single end-to-end model. In order to differentiate text phrases into semantically distinct subspaces, we propose a concept weight branch that automatically assigns phrases to embeddings, whereas prior works predefine such assignments. Our proposed solution simplifies the representation requirements for individual embeddings and allows the underrepresented concepts to take advantage of the shared representations before feeding them into concept-specific layers. Comprehensive experiments verify the effectiveness of our approach across three phrase grounding datasets, Flickr30K Entities, ReferIt Game, and Visual Genome, where we obtain a (resp.) 4%, 3%, and 4% improvement in grounding performance over a strong region-phrase embedding baseline.Comment: ECCV 2018 accepted pape

Toxicity to immune checkpoint inhibitors presenting as pulmonary arterial vasculopathy and rapidly progressing right ventricular dysfunction

Introduction: Immune Checkpoint Inhibitors (ICIs) are antitumor drugs associated with a number of serious immune-related adverse events (IRAEs). ICIs enhance anti-tumor immunity, thereby  energized  patient's immune system to fight cancer. IRAEs may affect functions of various organs, including heart, and may lead to morbidity and, to some  extent  mortality. Left ventricle (LV) myocarditis with dysfunction is a known side effect of this class of drugs. However, right ventricle (RV) myocarditis and pulmonary vasculitis are an unknown entity and has not been previously reported.  Here, we present the first case of  IRAEs causing selective RV involvement with dysfunctions, attributed to immune checkpoint inhibitors described till date in medical literature.Presentation of Case: A 58-year male presented  with history of low-grade fever and  weight loss. On palpation, he had diffuse cervical lymphadenopathy. Histopathology evaluation of  lymph node revealed  metastatic lesions of Renal Cell Carcinoma (RCC).Conclusion: Fatal cardiovascular adverse events can occur as a side effect of ICI. The combination of RV myocarditis with progressive pulmonary hypertension is fatal. Treatment with high dose corticosteroids and immunomodulators may help in patient survival. Physicians treating patients with ICIs should be aware of their lethal cardiotoxic side effects  to reduce adverse cardiac outcomes. Because the number of patients exposed to this new immune therapy is expected to increase remarkably in the near future, our study encourages further work to define guidelines for cardiovascular monitoring and management

Transient activation of human cytomegalovirus lytic gene expression during latency allows cytotoxic T cell killing of latently infected cells.

Human cytomegalovirus (HCMV) latency in the myeloid lineage is maintained by repressive histone modifications around the major immediate early promoter (MIEP), which results in inhibition of the lytic viral life cycle. We now show that pharmacological inhibition of histone deacetylases (HDACs) relieves this repression of the MIEP and induces transient expression of the viral lytic immediate early (IE) antigens but, importantly, not full virus reactivation. In turn, these latently infected cells now become targets for IE-specific cytotoxic T cells (CTLs) which are present at high frequency in all normal healthy HCMV positive carriers but would normally be unable to target latent (lytic antigen-negative) cells. This approach of transiently inducing viral lytic gene expression by HDAC inhibition, in otherwise latently infected cells, offers a window of opportunity to target and purge the latent myeloid cell reservoir by making these normally immunologically undetectable cells visible to pre-existing host immune responses to viral lytic antigens.This work was funded by a British Medical Research programme grant, grant number G0701279 and Wellcome Research Grant, grant number RG68483. This research was supported by the Cambridge NIHR BRC Cell Phenotyping Hub.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/srep2467

Transient activation of human cytomegalovirus lytic gene expression during latency allows cytotoxic T cell killing of latently infected cells

Human cytomegalovirus (HCMV) latency in the myeloid lineage is maintained by repressive histone modifications around the major immediate early promoter (MIEP), which results in inhibition of the lytic viral life cycle. We now show that pharmacological inhibition of histone deacetylases (HDACs) relieves this repression of the MIEP and induces transient expression of the viral lytic immediate early (IE) antigens but, importantly, not full virus reactivation. In turn, these latently infected cells now become targets for IE-specific cytotoxic T cells (CTLs) which are present at high frequency in all normal healthy HCMV positive carriers but would normally be unable to target latent (lytic antigen-negative) cells. This approach of transiently inducing viral lytic gene expression by HDAC inhibition, in otherwise latently infected cells, offers a window of opportunity to target and purge the latent myeloid cell reservoir by making these normally immunologically undetectable cells visible to pre-existing host immune responses to viral lytic antigens.This work was funded by a British Medical Research programme grant, grant number G0701279 and Wellcome Research Grant, grant number RG68483. This research was supported by the Cambridge NIHR BRC Cell Phenotyping Hub.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/srep2467

Targeting the latent cytomegalovirus reservoir with an antiviral fusion toxin protein.

Reactivation of human cytomegalovirus (HCMV) in transplant recipients can cause life-threatening disease. Consequently, for transplant recipients, killing latently infected cells could have far-reaching clinical benefits. In vivo, myeloid cells and their progenitors are an important site of HCMV latency, and one viral gene expressed by latently infected myeloid cells is US28. This viral gene encodes a cell surface G protein-coupled receptor (GPCR) that binds chemokines, triggering its endocytosis. We show that the expression of US28 on the surface of latently infected cells allows monocytes and their progenitor CD34+ cells to be targeted and killed by F49A-FTP, a highly specific fusion toxin protein that binds this viral GPCR. As expected, this specific targeting of latently infected cells by F49A-FTP also robustly reduces virus reactivation in vitro. Consequently, such specific fusion toxin proteins could form the basis of a therapeutic strategy for eliminating latently infected cells before haematopoietic stem cell transplantation

Artesunate potentiates antibiotics by inactivating heme-harbouring bacterial nitric oxide synthase and catalase

<p>Abstract</p> <p>Background</p> <p>A current challenge of coping with bacterial infection is that bacterial pathogens are becoming less susceptible to or more tolerant of commonly used antibiotics. It is urgent to work out a practical solution to combat the multidrug resistant bacterial pathogens.</p> <p>Findings</p> <p>Oxidative stress-acclimatized bacteria thrive in rifampicin by generating antibiotic-detoxifying nitric oxide (NO), which can be repressed by artesunate or an inhibitor of nitric oxide synthase (NOS). Suppressed bacterial proliferation correlates with mitigated NO production upon the combined treatment of bacteria by artesunate with antibiotics. Detection of the heme-artesunate conjugate and accordingly declined activities of heme-harbouring bacterial NOS and catalase indicates that artesunate renders bacteria susceptible to antibiotics by alkylating the prosthetic heme group of hemo-enzymes.</p> <p>Conclusions</p> <p>By compromising NO-mediated protection from antibiotics and triggering harmful hydrogen peroxide burst, artesunate may serve as a promising antibiotic synergist for killing the multidrug resistant pathogenic bacteria.</p

Babies of South Asian and European Ancestry Show Similar Associations With Genetic Risk Score for Birth Weight Despite the Smaller Size of South Asian Newborns.

Size at birth is known to be influenced by various fetal and maternal factors, including genetic effects. South Asians have a high burden of low birth weight and cardiometabolic diseases, yet studies of common genetic variations underpinning these phenotypes are lacking. We generated independent, weighted fetal genetic scores (fGSs) and maternal genetic scores (mGSs) from 196 birth weight-associated variants identified in Europeans and conducted an association analysis with various fetal birth parameters and anthropometric and cardiometabolic traits measured at different follow-up stages (5-6-year intervals) from seven Indian and Bangladeshi cohorts of South Asian ancestry. The results from these cohorts were compared with South Asians in UK Biobank and the Exeter Family Study of Childhood Health, a European ancestry cohort. Birth weight increased by 50.7 g and 33.6 g per SD of fGS (P = 9.1 × 10-11) and mGS (P = 0.003), respectively, in South Asians. A relatively weaker mGS effect compared with Europeans indicates possible different intrauterine exposures between Europeans and South Asians. Birth weight was strongly associated with body size in both childhood and adolescence (P = 3 × 10-5 to 1.9 × 10-51); however, fGS was associated with body size in childhood only (P < 0.01) and with head circumference, fasting glucose, and triglycerides in adults (P < 0.01). The substantially smaller newborn size in South Asians with comparable fetal genetic effect to Europeans on birth weight suggests a significant role of factors related to fetal growth that were not captured by the present genetic scores. These factors may include different environmental exposures, maternal body size, health and nutritional status, etc. Persistent influence of genetic loci on size at birth and adult metabolic syndrome in our study supports a common genetic mechanism that partly explains associations between early development and later cardiometabolic health in various populations, despite marked differences in phenotypic and environmental factors in South Asians

Three dimensional first-pass myocardial perfusion imaging at 3T: feasibility study

<p>Abstract</p> <p>Background</p> <p>In patients with ischemic heart disease, accurate assessment of the extent of myocardial perfusion deficit may be important in predicting prognosis of clinical cardiac outcomes. The aim of this study was to compare the ability of three dimensional (3D) and of two dimensional (2D) multi-slice myocardial perfusion imaging (MPI) using cardiovascular magnetic resonance (CMR) in determining the size of defects, and to demonstrate the feasibility of 3D MPI in healthy volunteers at 3 Tesla.</p> <p>Methods</p> <p>A heart phantom was used to compare the accuracy of 3D and 2D multi-slice MPI in estimating the volume fraction of seven rubber insets which simulated transmural myocardial perfusion defects. Three sets of cross-sectional planes were acquired for 2D multi-slice imaging, where each set was shifted along the partition encoding direction by ± 10 mm. 3D first-pass contrast-enhanced (0.1 mmol/kg Gd-DTPA) MPI was performed in three volunteers with sensitivity encoding for six-fold acceleration. The upslope of the myocardial time-intensity-curve and peak SNR/CNR values were calculated.</p> <p>Results</p> <p>Mean/standard deviation of errors in estimating the volume fraction across the seven defects were -0.44/1.49%, 2.23/2.97%, and 2.59/3.18% in 3D, 2D 4-slice, and 2D 3-slice imaging, respectively. 3D MPI performed in healthy volunteers produced excellent quality images with whole left ventricular (LV) coverage. Peak SNR/CNR was 57.6 ± 22.0/37.5 ± 19.7 over all segments in the first eight slices.</p> <p>Conclusion</p> <p>3D performed better than 2D multi-slice MPI in estimating the size of perfusion defects in phantoms. Highly accelerated 3D MPI at 3T was feasible in volunteers, allowing whole LV coverage with excellent image quality and high SNR/CNR.</p

Central engine afterglow of Gamma-ray Bursts

Before 2004, nearly all GRB afterglow data could be understood in the context of the external shocks model. This situation has changed in the past two years, when it became clear that some afterglow components should be attributed to the activity of the central engine; i.e., the {\it central engine afterglow}. We review here the afterglow emission that is directly related to the GRB central engine. Such an interpretation proposed by Katz, Piran & Sari, peculiar in pre-{\it Swift} era, has become generally accepted now.Comment: 4 pages including 1 figure. Presented at the conference "Astrophysics of Compact Objects" (July 1-7, 2007; Huangshan, China