Ebola virus VP30 and nucleoprotein interactions modulate viral RNA synthesis

AbstractEbola virus (EBOV) is an enveloped negative-sense RNA virus that causes sporadic outbreaks with high case fatality rates. Ebola viral protein 30 (eVP30) plays a critical role in EBOV transcription initiation at the nucleoprotein (eNP) gene, with additional roles in the replication cycle such as viral assembly. However, the mechanistic basis for how eVP30 functions during the virus replication cycle is currently unclear. Here we define a key interaction between eVP30 and a peptide derived from eNP that is important to facilitate interactions leading to the recognition of the RNA template. We present crystal structures of the eVP30 C-terminus in complex with this eNP peptide. Functional analyses of the eVP30–eNP interface identify residues that are critical for viral RNA synthesis. Altogether, these results support a model where the eVP30–eNP interaction plays a critical role in transcription initiation and provides a novel target for the development of antiviral therapy.</jats:p

Preventing human immunodeficiency virus infection among sexual assault survivors in Cape Town, South Africa: an observational study.

We describe 131 South African sexual assault survivors offered HIV post-exposure prophylaxis (PEP). While the median days completed was 27 (IQR 27, 28), 34% stopped PEP or missed doses. Controlling for baseline symptoms, PEP was not associated with symptoms (OR = 1.30, 95% CI = 0.66, 2.64). Factors associated with unprotected sex included prior unprotected sex (OR = 6.46, 95% CI = 3.04, 13.74), time since the assault (OR = 1.33, 95% CI = 1.12, 1.57) and age (OR = 1.30, 95% CI = 1.08, 1.57). Trauma counseling was protective (OR = 0.18, 95% CI = 0.05, 0.58). Four instances of seroconversion were observed by 6 months (risk = 3.7%, 95% CI = 1.0, 9.1). Proactive follow-up is necessary to increase the likelihood of PEP completion and address the mental health and HIV risk needs of survivors. Adherence interventions and targeted risk reduction counseling should be provided to minimize HIV acquisition

Experimental localisation of quantum entanglement through monitored classical mediator

Quantum entanglement is a form of correlation between quantum particles that cannot be increased via local operations and classical communication. It has therefore been proposed that an increment of quantum entanglement between probes that are interacting solely via a mediator implies non-classicality of the mediator. Indeed, under certain assumptions regarding the initial state, entanglement gain between the probes indicates quantum coherence in the mediator. Going beyond such assumptions, there exist other initial states which produce entanglement between the probes via only local interactions with a classical mediator. In this process the initial entanglement between any probe and the rest of the system ``flows through'' the classical mediator and gets localised between the probes. Here we theoretically characterise maximal entanglement gain via classical mediator and experimentally demonstrate, using liquid-state NMR spectroscopy, the optimal growth of quantum correlations between two nuclear spin qubits interacting through a mediator qubit in a classical state. We additionally monitor, i.e., dephase, the mediator in order to emphasise its classical character. Our results indicate the necessity of verifying features of the initial state if entanglement gain between the probes is used as a figure of merit for witnessing non-classical mediator. Such methods were proposed to have exemplary applications in quantum optomechanics, quantum biology and quantum gravity.Comment: 5 pages, 2 figure

Utilisation and outcomes of cervical cancer prevention services among HIV-infected women in Cape Town

Objective. An audit of outcomes of cervical cancer screening and prevention services for HIV-positive women in Cape Town, South Africa. Design. Retrospective review of clinic registers, patient records and pathology databases at three HIV primary health clinics and a tertiary colposcopy referral centre. Subjects. Women recently diagnosed with HIV at three primary health clinics between 2006 and 2008 (N=2 240); new patients seen for colposcopy at a tertiary referral centre between 2006 and 2009 (N=2 031). Outcome measures. The proportion of women undergoing cervical cancer screening after HIV diagnosis at primary health clinics, demographic characteristics of women referred for colposcopy at a tertiary centre, and outcomes of therapy for precancerous lesions of the cervix. Results. The proportion of women undergoing at least one Pap smear at HIV primary health clinics after HIV diagnosis was low (13.1%). Women referred for colposcopy tended to be HIV-positive and over the age of 30 years, and in most (70.2%) cytological examination revealed high-grade cervical dysplasia. HIV-positive women treated with excision for precancerous lesions of the cervix were significantly more likely than their HIV-negative counterparts to undergo incomplete excision, experience persistent cervical disease after treatment, and be lost to follow-up. Conclusion. Cervical cancer screening efforts must be scaled up for women with HIV. Treatment and surveillance guidelines for cervical intraepithelial neoplasia in HIV-positive women may need to be revised and new interventions developed to reduce incomplete treatment and patient default

Myco-Biocontrol of Insect Pests: Factors Involved, Mechanism, and Regulation

The growing demand for reducing chemical inputs in agriculture and increased resistance to insecticides have provided great impetus to the development of alternative forms of insect-pest control. Myco-biocontrol offers an attractive alternative to the use of chemical pesticides. Myco-biocontrol agents are naturally occurring organisms which are perceived as less damaging to the environment. Their mode of action appears little complex which makes it highly unlikely that resistance could be developed to a biopesticide. Past research has shown some promise of the use of fungi as a selective pesticide. The current paper updates us about the recent progress in the field of myco-biocontrol of insect pests and their possible mechanism of action to further enhance our understanding about the biological control of insect pests

MUC4 overexpression augments cell migration and metastasis through EGFR family proteins in triple negative breast cancer cells.

INTRODUCTION: Current studies indicate that triple negative breast cancer (TNBC), an aggressive breast cancer subtype, is associated with poor prognosis and an early pattern of metastasis. Emerging evidence suggests that MUC4 mucin is associated with metastasis of various cancers, including breast cancer. However, the functional role of MUC4 remains unclear in breast cancers, especially in TNBCs. METHOD: In the present study, we investigated the functional and mechanistic roles of MUC4 in potentiating pathogenic signals including EGFR family proteins to promote TNBC aggressiveness using in vitro and in vivo studies. Further, we studied the expression of MUC4 in invasive TNBC tissue and normal breast tissue by immunostaining. RESULTS: MUC4 promotes proliferation, anchorage-dependent and-independent growth of TNBC cells, augments TNBC cell migratory and invasive potential in vitro, and enhances tumorigenicity and metastasis in vivo. In addition, our studies demonstrated that MUC4 up-regulates the EGFR family of proteins, and augments downstream Erk1/2, PKC-γ, and FAK mediated oncogenic signaling. Moreover, our studies also showed that knockdown of MUC4 in TNBC cells induced molecular changes suggestive of mesenchymal to epithelial transition. We also demonstrated in this study, for the first time, that knockdown of MUC4 was associated with reduced expression of EGFR and ErbB3 (EGFR family proteins) in TNBC cells, suggesting that MUC4 uses an alternative to ErbB2 mechanism to promote aggressiveness. We further demonstrate that MUC4 is differentially over-expressed in invasive TNBC tissues compared to normal breast tissue. CONCLUSIONS: MUC4 mucin expression is associated with TNBC pathobiology, and its knockdown reduced aggressiveness in vitro, and tumorigenesis and metastasis in vivo. Overall, our findings suggest that MUC4 mucin promotes invasive activities of TNBC cells by altering the expression of EGFR, ErbB2, and ErbB3 molecules and their downstream signaling

Depletion of Transmembrane Mucin 4 (Muc4) Alters Intestinal Homeostasis in a Genetically Engineered Mouse Model of Colorectal Cancer

Mucins are components of the mucus layer overlying the intestinal epithelial cells, which maintains physiological homeostasis. Altered mucin expression is associated with disease progression. Expression of MUC4 decreases in colorectal cancer (CRC); however, its functional role and implications in the intestinal pathology in CRC are not studied well. Therefore, we generated a genetically engineered Muc4 knockout (Muc4-/-) CRC mouse model by crossing with Muc4-/- and Apcflox/flox mice in the presence of colon-specific inducible Cre. We observed that deficiency of Muc4 results in an increased number of macroscopic tumors in the colon and rectal region and leads to poor survival. Further, the absence of Muc4 was associated with goblet cell dysfunction where the expression of intestinal homeostasis molecules (Muc2 and Fam3D) was downregulated. Next, we also observed that loss of Muc4 showed reduced thickness of mucus layer, leading to infiltration of bacteria, reduction in anti-microbial peptides, and upregulation of pro-inflammatory cytokines. Further, Apc gene mutation results in activation of the Wnt/β-catenin signaling pathway that corroborated with an increased nuclear accumulation of β-catenin and activation of its target genes: cyclin D1 and c-Myc in Muc4-/- mice was observed. We conclude that the presence of Muc4 is essential for intestinal homeostasis, reduces tumor burden, and improves overall survival