Modulation of oestrone sulphate formation and hydrolysis in breast cancer cells by breast cyst fluid from British and Hungarian women

Women with gross cystic breast disease may have an increased risk of breast cancer. In this study the ability of breast cyst fluid (BCF), obtained from British or Hungarian women, to modulate oestrone sulphate (E1S) formation or hydrolysis, has been examined. For this, oestrogen receptor-positive (ER+) MCF-7 or MDA-MB-231 (ER–) breast cancer cells were employed. The formation and hydrolysis of E1S was measured using radiometric techniques. BCF from British and Hungarian women mainly inhibited E1S hydrolysis in MCF-7 cells while stimulating hydrolysis in MDA-MB-231 cells. The extent of inhibition or stimulation of E1S hydrolysis in these cells was related to the Na+/K+ratio of the BCF. There was a significant inverse relationship between the extent to which BCF samples inhibited hydrolysis in MCF-7 cells and stimulated it in MDA-MB-231 cells. BCF stimulated E1S formation in MCF-7 cells while inhibiting formation in MDA-MB-231 cells. No difference in the ability of BCF from British or Hungarian women to inhibit or stimulate E1S hydrolysis was detected in ER+ or ER– breast cancer cells. In contrast, BCF from British women stimulated E1S formation in ER+ cells (median 82%) to a significantly greater extent (P< 0.01) than BCF from Hungarian women (median 33%). The role that E1S has in breast cancer development remains unclear. The greater stimulation of E1S formation by BCF from British women, who have a higher risk of breast cancer than Hungarian women, suggests that it may act as a storage form of oestrogen within cells that can be activated by oestrone sulphatase. © 2000 Cancer Research Campaig

A Transcript Cleavage Factor of Mycobacterium tuberculosis Important for Its Survival

After initiation of transcription, a number of proteins participate during elongation and termination modifying the properties of the RNA polymerase (RNAP). Gre factors are one such group conserved across bacteria. They regulate transcription by projecting their N-terminal coiled-coil domain into the active center of RNAP through the secondary channel and stimulating hydrolysis of the newly synthesized RNA in backtracked elongation complexes. Rv1080c is a putative gre factor (MtbGre) in the genome of Mycobacterium tuberculosis. The protein enhanced the efficiency of promoter clearance by lowering abortive transcription and also rescued arrested and paused elongation complexes on the GC rich mycobacterial template. Although MtbGre is similar in domain organization and shares key residues for catalysis and RNAP interaction with the Gre factors of Escherichia coli, it could not complement an E. coli gre deficient strain. Moreover, MtbGre failed to rescue E. coli RNAP stalled elongation complexes, indicating the importance of specific protein-protein interactions for transcript cleavage. Decrease in the level of MtbGre reduced the bacterial survival by several fold indicating its essential role in mycobacteria. Another Gre homolog, Rv3788 was not functional in transcript cleavage activity indicating that a single Gre is sufficient for efficient transcription of the M. tuberculosis genome

Integrated syphilis/HIV screening in China: a qualitative analysis

<p>Abstract</p> <p>Background</p> <p>The last decade has seen enormous advances in HIV treatment and care, but how to implement scaled up HIV testing, prevention, and treatment in low-income areas still presents a formidable public health challenge. South China faces expanding syphilis and sexually transmitted HIV epidemics, but health systems characteristics important for scaling up syphilis and HIV testing have not been defined.</p> <p>Methods</p> <p>A purposive sample to ensure public, private, and public-private hybrid STI clinic inclusion was selected in a South China city. Eight key informant interviews were conducted with the STI clinic manager, followed by eight focus group discussions with physicians. Data collection relied on a semi-structured format that included questions in each of the following domains: 1) clinical facilities; 2) laboratory capacity with a focus on syphilis/HIV diagnosis; 3) clinic personnel; 4) physical space with a focus on locations to disclose confidential results; 5) financial support.</p> <p>Results</p> <p>Public STI clinics had free syphilis testing/treatment and laboratory facilities to perform essential syphilis and HIV tests. However, despite serving a large number of STI patients, private STI clinics lacked nontreponemal syphilis testing, HIV testing, and had fewer connections to the public health infrastructure. Formally trained assistant physicians were 2.5 times as common as physicians at STI clinics. Only one of the 8 sites had onsite voluntary counseling and testing (VCT) services available.</p> <p>Conclusion</p> <p>These STI case studies reveal the potential for expanding integrated syphilis/HIV services at public STI clinics in China. More health services research is needed to guide scale-up of syphilis/HIV testing in China.</p

Transcranial Alternating Current Stimulation Enhances Individual Alpha Activity in Human EEG

Non-invasive electrical stimulation of the human cortex by means of transcranial direct current stimulation (tDCS) has been instrumental in a number of important discoveries in the field of human cortical function and has become a well-established method for evaluating brain function in healthy human participants. Recently, transcranial alternating current stimulation (tACS) has been introduced to directly modulate the ongoing rhythmic brain activity by the application of oscillatory currents on the human scalp. Until now the efficiency of tACS in modulating rhythmic brain activity has been indicated only by inference from perceptual and behavioural consequences of electrical stimulation. No direct electrophysiological evidence of tACS has been reported. We delivered tACS over the occipital cortex of 10 healthy participants to entrain the neuronal oscillatory activity in their individual alpha frequency range and compared results with those from a separate group of participants receiving sham stimulation. The tACS but not the sham stimulation elevated the endogenous alpha power in parieto-central electrodes of the electroencephalogram. Additionally, in a network of spiking neurons, we simulated how tACS can be affected even after the end of stimulation. The results show that spike-timing-dependent plasticity (STDP) selectively modulates synapses depending on the resonance frequencies of the neural circuits that they belong to. Thus, tACS influences STDP which in turn results in aftereffects upon neural activity

Immunological Tolerance to Muscle Autoantigens Involves Peripheral Deletion of Autoreactive CD8+ T Cells

Muscle potentially represents the most abundant source of autoantigens of the body and can be targeted by a variety of severe autoimmune diseases. Yet, the mechanisms of immunological tolerance toward muscle autoantigens remain mostly unknown. We investigated this issue in transgenic SM-Ova mice that express an ovalbumin (Ova) neo-autoantigen specifically in skeletal muscle. We previously reported that antigen specific CD4+ T cell are immunologically ignorant to endogenous Ova in this model but can be stimulated upon immunization. In contrast, Ova-specific CD8+ T cells were suspected to be either unresponsive to Ova challenge or functionally defective. We now extend our investigations on the mechanisms governing CD8+ tolerance in SM-Ova mice. We show herein that Ova-specific CD8+ T cells are not detected upon challenge with strongly immunogenic Ova vaccines even after depletion of regulatory T cells. Ova-specific CD8+ T cells from OT-I mice adoptively transferred to SM-Ova mice started to proliferate in vivo, acquired CD69 and PD-1 but subsequently down-regulated Bcl-2 and disappeared from the periphery, suggesting a mechanism of peripheral deletion. Peripheral deletion of endogenous Ova-specific cells was formally demonstrated in chimeric SM-Ova mice engrafted with bone marrow cells containing T cell precursors from OT-I TCR-transgenic mice. Thus, the present findings demonstrate that immunological tolerance to muscle autoantigens involves peripheral deletion of autoreactive CD8+ T cells

Theiler's Murine Encephalomyelitis Virus as a Vaccine Candidate for Immunotherapy

The induction of sterilizing T-cell responses to tumors is a major goal in the development of T-cell vaccines for treating cancer. Although specific components of anti-viral CD8+ immunity are well characterized, we still lack the ability to mimic viral CD8+ T-cell responses in therapeutic settings for treating cancers. Infection with the picornavirus Theiler's murine encephalomyelitis virus (TMEV) induces a strong sterilizing CD8+ T-cell response. In the absence of sterilizing immunity, the virus causes a persistent infection. We capitalized on the ability of TMEV to induce strong cellular immunity even under conditions of immune deficiency by modifying the virus to evaluate its potential as a T-cell vaccine. The introduction of defined CD8+ T-cell epitopes into the leader sequence of the TMEV genome generates an attenuated vaccine strain that can efficiently drive CD8+ T-cell responses to the targeted antigen. This virus activates T-cells in a manner that is capable of inducing targeted tissue damage and glucose dysregulation in an adoptive T-cell transfer model of diabetes mellitus. As a therapeutic vaccine for the treatment of established melanoma, epitope-modified TMEV can induce strong cytotoxic T-cell responses and promote infiltration of the T-cells into established tumors, ultimately leading to a delay in tumor growth and improved survival of vaccinated animals. We propose that epitope-modified TMEV is an excellent candidate for further development as a human T-cell vaccine for use in immunotherapy

Face recognition and visual search strategies in autism spectrum disorders: Amending and extending a recent review by Weigelt et al.

The purpose of this review was to build upon a recent review by Weigelt et al. which examined visual search strategies and face identification between individuals with autism spectrum disorders (ASD) and typically developing peers. Seven databases, CINAHL Plus, EMBASE, ERIC, Medline, Proquest, PsychInfo and PubMed were used to locate published scientific studies matching our inclusion criteria. A total of 28 articles not included in Weigelt et al. met criteria for inclusion into this systematic review. Of these 28 studies, 16 were available and met criteria at the time of the previous review, but were mistakenly excluded; and twelve were recently published. Weigelt et al. found quantitative, but not qualitative, differences in face identification in individuals with ASD. In contrast, the current systematic review found both qualitative and quantitative differences in face identification between individuals with and without ASD. There is a large inconsistency in findings across the eye tracking and neurobiological studies reviewed. Recommendations for future research in face recognition in ASD were discussed

Attentional learning helps language acquisition take shape for atypically developing children, not just children with Autism Spectrum Disorders

The shape bias-generalising labels to same shaped objects-has been linked to attentional learning or referential intent. We explore these origins in children with typical development (TD), autism spectrum disorders (ASD) and other developmental disorders (DD). In two conditions, a novel object was presented and either named or described. Children selected another from a shape, colour or texture match. TD children choose the shape match in both conditions, children with DD and 'high-verbal mental age' (VMA) children with ASD (language age > 4.6) did so in the name condition and 'low-VMA' children with ASD never showed the heuristic. Thus, the shape bias arises from attentional learning in atypically developing children and is delayed in ASD

Appropriate DevR (DosR)-Mediated Signaling Determines Transcriptional Response, Hypoxic Viability and Virulence of Mycobacterium tuberculosis

Background: The DevR(DosR) regulon is implicated in hypoxic adaptation and virulence of Mycobacterium tuberculosis. The present study was designed to decipher the impact of perturbation in DevR-mediated signaling on these properties. Methodology/Principal Findings: M. tb complemented (Comp) strains expressing different levels of DevR were constructed in Mut1 * background (expressing DevR N-terminal domain in fusion with AphI (DevRN-Kan) and in Mut2DdevR background (deletion mutant). They were compared for their hypoxia adaptation and virulence properties. Diverse phenotypes were noted; basal level expression (,5.362.3 mM) when induced to levels equivalent to WT levels (,25.869.3 mM) was associated with robust DevR regulon induction and hypoxic adaptation (Comp 9 * and 10*), whereas low-level expression (detectable at transcript level) as in Comp 11 * and Comp15 was associated with an adaptation defect. Intermediate-level expression (,3.361.2 mM) partially restored hypoxic adaptation functions in Comp2, but not in Comp1 * bacteria that coexpressed DevRN-Kan. Comp * strains in Mut1 * background also exhibited diverse virulence phenotypes; high/very low-level DevR expression was associated with virulence whereas intermediate-level expression was associated with low virulence. Transcription profiling and gene expression analysis revealed up-regulation of the phosphate starvation response (PSR) in Mut1 * and Comp11 * bacteria, but not in WT/Mut2DdevR/other Comp strains, indicating a plasticity in expression pathways that is determined by the magnitude of signaling perturbation through DevRN-Kan