From Product to Promise - Advancing Rectal Microbicide Research and Advocacy

There is increasing recognition that gay men and other men who have sex with men (MSM) throughout the world -- in developed and developing countries alike -- have very high, disproportionate rates of HIV.Gay men and other MSM in developing countries remain largely under-represented and often completely invisible in national HIV and AIDS strategies, epidemiology, surveillance, and research; and they are woefully under-served by prevention, care, support, and treatment programmes.Anal sex between men and women is under-recognised, under-researched and undercharacterised, resulting in a pressing need to address the attendant HIV prevention issues.While rectal microbicide research efforts continue, other viable options should be pursued aggressively to prevent transmission of HIV and other sexually transmitted infections through anal intercourse and to promote better anal health. For example: provision of male and female condoms, water-based lubricants, and human papillomavirus (HPV) vaccination

Less Silence, More Science: Advocacy to Make Rectal Microbicides a Reality

Since its creation in 2005, International Rectal Microbicide Advocates (IRMA) has seen significant growth and success. From a handful of advocates, IRMA has built a network of well over 500 advocates, researchers, and policy makers from 40 countries on six continents.New name, new look, same goals Originally founded as the International Rectal Microbicides Working Group (IRMWG), the group re-branded our name at the end of 2007, created a new logo, and launched a new website (www.rectalmicrobicides.org). Amidst all this change, IRMA remains committed to the same goals we developed from our inception: To advocate for accelerated research, development and access to safe, effective and acceptable rectal microbicides;To promote rectal safety studies on all viable vaginal microbicide candidates;To support, where appropriate, the research of other new prevention technologies, such as male circumcision, vaccines and oral prevention (prep), and to promote existing prevention methods such as male and female condoms as part of a range of prevention options;To serve as a central forum for exchange, debate, and networking on rectal microbicides; and,To convene diverse perspectives and scientific disciplines to improve understanding and action around rectal microbicide research and development.Focus on safety - In these very early stages of rectal microbicide development, the primary focus of research is safety: examining the rectal safety of sexual lubricants (section 2.12), urging the collection of rectal safety data from late stage vaginal microbicide trials (section 3.1), determining the measures for assessing basic rectal safety (section 2.3), and of course, evaluating the safety of potential rectal-specific microbicides (sections 2.1 and 2.2).We hope this document will:Serve as an authoritative reference on recent developments and current efforts in rectal microbicide research;Illustrate key advocacy goals and strategies;Provide a description of the resources and activities of IRMA; and, Inspire people working in hiv prevention, whether in advocacy, research, policy or funding, to become involved in rectal microbicide advocacy and research

High Precision AFM-Based SMFS of Mechanically Labile Type III Secretion System Effectors

Pathogenic bacteria have developed a wide range of tools for circumventing or overcoming the host’s defenses. Over time, these tools have become increasingly complex, allowing bacteria to live and thrive within a wide variety of host environments. One such tool is the Type III Secretion System (T3SS), a needle-like complex that allows bacteria to directly inject proteins, known as effectors, from their cytoplasm into host cells. Once inside host cells, effector proteins have a wide range of effects, from shutting down the host immune response to rearranging the host cytoskeleton to accommodate invading bacteria. Because the T3SS needle presents a narrow channel (< 2 nm), effector proteins must be mechanically unfolded before passing through. Proteins are unfolded by a molecular motor that associates with the base of needle and pulls protein into the channel. While this motor can unfold and secrete many proteins, it is unable to unfold proteins that have high mechanical stability. This indicates a need for effectors to be mechanically labile no matter their function. This may be one of the reasons effectors have very low sequence and structural similarity to other members of their protein super-families. This spurred our investigation into how effectors respond to mechanical force. To investigate effector protein stability, I used atomic force microscopy (AFM) to mechanically unfold the proteins. Here I show that effector proteins of the T3SS unfold at very low force, despite containing a wide variety folds and functions. This supports our hypothesis that to facilitate efficient secretion, effectors evolved to be mechanically labile. Because effector proteins unfold at such low force, it was critical for me to utilize site-specific attachment to both the AFM tip and surface, increasing both the amount of data I could collect and the quality of collected data. Site-specific attachment resulted in a 70-fold improvement in the yield of high quality data, allowing rapid characterization of mechanically labile α-helical proteins.Combining site-specific attachment with modified cantilevers allowed the collection of unfolding data for 5 effector proteins, finding they all unfold at low force (<20 pN), making them some of the most mechanically labile proteins studied to date by AFM-SMFS. Comparing the mechanical stability of effector proteins to their in vivo secretion rates, showed that unfolding force does not always correlate with in vivo secretion rate. However, the distance to the transition state does correlate with in vivo secretion rate. To elucidate how effector proteins have evolved to be efficiently secreted, the mechanical stability of an effector protein, NleC, was compared with a non-secreted homologue, protealysin. While the initial unfolding event of NleC occurs below the detection limit of our AFM platform, the unfolding of an intermediate along the unfolding pathway was measured. When compared to the unfolding of protealysin, the unfolding intermediate of NleC was shown to be significantly less stable, supporting our hypothesis that effector proteins have evolved to unfold at low force to facilitate efficient secretion. We now have an array of tools that allow for the efficient mechanical characterization of diverse proteins with high-precision

Anticancer, Biophysical and Computational Investigations of Half-Sandwich Ruthenium(II) Thiosemicarbazone Complexes: The Effect of Arene \u3ci\u3eVersus\u3c/i\u3e Thiacrown Face-Cap

A series of half-sandwich ruthenium complexes, two containing an arene face-cap and the other a thiacrown ether face-cap were synthesized to investigate the necessity of the arene for anticancer activity in this class of compounds. The complexes are formulated as [(h6-p-cymene)Ru(dmabTSC)Cl]PF6, [(h6-benzene)Ru(dmabTSC)Cl]PF6 (arene complexes), and [([9]aneS3(dmabTSC)Cl]PF6 (dmabTSC = dimethylaminobenzaldehye thiosemicarbazone). It was observed that none of the complexes showed good anticancer activity in vitro against HCT-116 and Caco-2 (colon adenocarcinoma) cells. All three complexes can bind strongly to calf-thymus DNA with binding constants on the order of 105 M-1. In addition they all bind strongly to human serum albumin with binding constants between 105 and 106 M-1. There appears to be a single binding site on the protein for these complexes. A computational investigation of these complexes and their hydrolysis products was carried out by molecular docking with DNA and topoisomerase II. From this analysis it is noted that the type of face-capping ligand had different effects on the two macromolecules. It is therefore noted that the knowledge gained from this study will be useful in identifying the type of complexes in this class that show useful metallodrug potential

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Cardiopoietic cell therapy for advanced ischemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial

Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort