Fisheries policies for a new era

This Guidance Note presents a simple approach to analyzing the governance context for development of aquatic agricultural systems; it is intended as an aid to action research, and a contribution to effective program planning and evaluation. It provides a brief introduction to the value of assessing governance collaboratively, summarizes an analytical framework, and offers practical guidance on three stages of the process: identifying obstacles and opportunities, debating strategies for influence, and planning collaborative actions

The peacebuilding potential of healthcare training programs.

Global health professionals regularly conduct healthcare trainings, such as first aid courses, in disadvantaged communities across the world. Many of these communities lack healthcare infrastructure because of war and political conflict. The authors draw on their experience conducting a first aid course in South Sudan to provide a perspective on how healthcare trainings for people with no medical background can be used to bridge ethnic, political, and religious differences. They argue that a necessary step for turning a healthcare training into a vehicle for peacebuilding is to bring people from different communities to the same physical space to learn the course material together. Importantly, simply encouraging contact between communities is unlikely to improve intergroup relations and could be detrimental if the following features are not incorporated. Buy-in from respected community leaders is essential to ensure that training participants trust that their safety during the training sessions is not at risk. Trainers should also create a supportive environment by conferring equal status and respect on all trainees. Finally, hands-on training exercises allow for positive interactions between trainees from different groups, which in turn can challenge stereotypes and facilitate cross-group friendships. These features map onto social psychological principles that have been shown to improve intergroup relations and are consistent with lessons learned from peace through health initiatives in public health and medicine. By adopting peacebuilding features, healthcare trainings can serve their primary goal of medical education and provide the added benefit of strengthening social relations

Splicing factor 3B subunit 1 interacts with HIV Tat and plays a role in viral transcription and reactivation from latency

ABSTRACT The main obstacle to an HIV cure is the transcriptionally inert proviruses that persist in resting CD4 T cells and other reservoirs. None of the current approaches has significantly reduced the size of the viral reservoir. Hence, alternative approaches, such as permanent blocking of viral transcription, to achieve a sustained remission, need urgent attention. To identify cellular factors that may be important for this approach, we sought for host targets that when altered could block HIV transcription and reactivation. Here, we identified splicing factor 3B subunit 1 (SF3B1) as a critical HIV dependency factor required for viral replication. SF3B1 is a splicing factor involved in directing chromatin and nascent gene transcripts to appropriate splice sites. Inhibitors of SF3B1 are currently in development for cancer and have been found to be nontoxic to normal cells compared to malignant cells. Knockdown of SF3B1 abrogated HIV replication in all cell types tested. SF3B1 interacted with viral protein Tat in vitro and in vivo. Genetic or pharmacologic inhibition of SF3B1 prevented Tat-mediated HIV transcription and RNA polymerase II association with the HIV promoter. In addition, an inhibitor of SF3B1 prevented HIV reactivation from latency irrespective of the latency-reversing agent used. The data show that SF3B1 is involved in viral transcription and reactivation from latency and may serve as a therapeutic target in the HIV cure efforts. IMPORTANCE The reason why HIV cannot be cured by current therapy is because of viral persistence in resting T cells. One approach to permanent HIV remission that has received less attention is the so-called “block and lock” approach. The idea behind this approach is that the virus could be permanently disabled in patients if viral genome or surrounding chromatin could be altered to silence the virus, thus enabling patients to stop therapy. In this work, we have identified splicing factor 3B subunit 1 (SF3B1) as a potential target for this approach. SF3B1 interacts with the viral protein Tat, which is critical for viral transcription. Inhibition of SF3B1 prevents HIV transcription and reactivation from latency. Since there are preclinical inhibitors for this protein, our findings could pave the way to silence HIV transcription, potentially leading to prolonged or permanent remission

AFM pulling and the folding of donor-acceptor oligorotaxanes: phenomenology and interpretation

The thermodynamic driving force in the self-assembly of the secondary structure of a class of donor-acceptor oligorotaxanes is elucidated by means of molecular dynamics simulations of equilibrium isometric single-molecule force spectroscopy AFM experiments. The oligorotaxanes consist of cyclobis(paraquat-\emph{p}-phenylene) rings threaded onto an oligomer of 1,5-dioxynaphthalenes linked by polyethers. The simulations are performed in a high dielectric medium using MM3 as the force field. The resulting force vs. extension isotherms show a mechanically unstable region in which the molecule unfolds and, for selected extensions, blinks in the force measurements between a high-force and a low-force regime. From the force vs. extension data the molecular potential of mean force is reconstructed using the weighted histogram analysis method and decomposed into energetic and entropic contributions. The simulations indicate that the folding of the oligorotaxanes is energetically favored but entropically penalized, with the energetic contributions overcoming the entropy penalty and effectively driving the self-assembly. In addition, an analogy between the single-molecule folding/unfolding events driven by the AFM tip and the thermodynamic theory of first-order phase transitions is discussed and general conditions, on the molecule and the cantilever, for the emergence of mechanical instabilities and blinks in the force measurements in equilibrium isometric pulling experiments are presented. In particular, it is shown that the mechanical stability properties observed during the extension are intimately related to the fluctuations in the force measurements.Comment: 42 pages, 17 figures, accepted to the Journal of Chemical Physic

Design of a fault tolerant airborne digital computer. Volume 2: Computational requirements and technology

This final report summarizes the work on the design of a fault tolerant digital computer for aircraft. Volume 2 is composed of two parts. Part 1 is concerned with the computational requirements associated with an advanced commercial aircraft. Part 2 reviews the technology that will be available for the implementation of the computer in the 1975-1985 period. With regard to the computation task 26 computations have been categorized according to computational load, memory requirements, criticality, permitted down-time, and the need to save data in order to effect a roll-back. The technology part stresses the impact of large scale integration (LSI) on the realization of logic and memory. Also considered was module interconnection possibilities so as to minimize fault propagation

Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation

AbstractCurrent antiretroviral therapy (ART) for HIV/AIDS slows disease progression by reducing viral loads and increasing CD4 counts. Yet ART is not curative due to the persistence of CD4+ T-cell proviral reservoirs that chronically resupply active virus. Elimination of these reservoirs through the administration of synergistic combinations of latency reversing agents (LRAs), such as histone deacetylase (HDAC) inhibitors and protein kinase C (PKC) modulators, provides a promising strategy to reduce if not eradicate the viral reservoir. Here, we demonstrate that largazole and its analogues are isoform-targeted histone deacetylase inhibitors and potent LRAs. Significantly, these isoform-targeted HDAC inhibitors synergize with PKC modulators, namely bryostatin-1 analogues (bryologs). Implementation of this unprecedented LRA combination induces HIV-1 reactivation to unparalleled levels and avoids global T-cell activation within resting CD4+ T-cells.</jats:p

The dual-specificity kinase DYRK1A modulates the levels of cyclin L2 to control HIV replication in macrophages

HIV replication in macrophages contributes to the latent viral reservoirs, which are considered the main barrier to HIV eradication. Few cellular factors that facilitate HIV replication in latently infected cells are known. We previously identified cyclin L2 as a critical factor required by HIV-1 and found that depletion of cyclin L2 attenuates HIV-1 replication in macrophages. Here we demonstrate that cyclin L2 promotes HIV-1 replication through interactions with the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Cyclin L2 and DYRK1A were colocalized in the nucleus and were found together in immunoprecipitation experiments. Knockdown or inhibition of DYRK1A increased HIV-1 replication in macrophages, while depletion of cyclin L2 decreased HIV-1 replication. Furthermore, depletion of DYRK1A increased expression levels of cyclin L2. DYRK1A is a proline-directed kinase that phosphorylates cyclin L2 at serine residues. Mutations of cyclin L2 at serine residues preceding proline significantly stabilized cyclin L2 and increased HIV-1 replication in macrophages. Thus, we propose that DYRK1A controls cyclin L2 expression, leading to restriction of HIV replication in macrophages

Nod1 signaling overcomes resistance of S. pneumoniae to opsonophagocytic killing

Airway infection by the Gram-positive pathogen Streptococcus pneumoniae (Sp) leads to recruitment of neutrophils but limited bacterial killing by these cells. Co-colonization by Sp and a Gram-negative species, Haemophilus influenzae (Hi), provides sufficient stimulus to induce neutrophil and complement-mediated clearance of Sp from the mucosal surface in a murine model. Products from Hi, but not Sp, also promote killing of Sp by ex vivo neutrophil-enriched peritoneal exudate cells. Here we identify the stimulus from Hi as its peptidoglycan. Enhancement of opsonophagocytic killing was facilitated by signaling through nucleotide-binding oligomerization domain-1 (Nod1), which is involved in recognition of γ-D-glutamyl-meso-diaminopimelic acid (meso-DAP) contained in cell walls of Hi but not Sp. Neutrophils from mice treated with Hi or compounds containing meso-DAP, including synthetic peptidoglycan fragments, showed increased Sp killing in a Nod1-dependent manner. Moreover, Nod1-/- mice showed reduced Hi-induced clearance of Sp during co-colonization. These observations offer insight into mechanisms of microbial competition and demonstrate the importance of Nod1 in neutrophil-mediated clearance of bacteria in vivo

Exposure to negative stereotypes influences representations of monetary incentives in the nucleus accumbens

Contemporary society is saturated with negative representations of racial and ethnic minorities. Social science research finds that exposure to such negative stereotypes creates stress above and beyond pre-existing effects of income inequality and structural racism. Neuroscience studies in animals and humans show that life stress modulates brain responses to rewards. However, it is not known whether contending with negative representations of one's social group spills overs to influence reward processing. We used functional magnetic resonance imaging to examine the effects of stigmatizing negative stereotypes on neural responding to the anticipation and consumption of monetary gains and losses in a Mexican American sample. Machine learning analyses indicated that incentive-related patterns of brain activity within the nucleus accumbens differed between Mexican Americans subjected to negative stereotypes and those who were not. This effect occurred for anticipating both gains and losses. Our work suggests that rhetoric stigmatizing Latinos and other minorities could alter how members of such groups process incentives in their environment. These findings contribute to our understanding of the linkage between stigmatizing experiences and motivated behavior, with implications for well-being and health

Ion and polymer dynamics in polymer electrolytes PPO-LiClO4: II. 2H and 7Li NMR stimulated-echo experiment

We use 2H NMR stimulated-echo spectroscopy to measure two-time correlation functions characterizing the polymer segmental motion in polymer electrolytes PPO-LiClO4 near the glass transition temperature Tg. To investigate effects of the salt on the polymer dynamics, we compare results for different ether oxygen to lithium ratios, namely, 6:1, 15:1, 30:1 and infinity. For all compositions, we find nonexponential correlation functions, which can be described by a Kohlrausch function. The mean correlation times show quantitatively that an increase of the salt concentration results in a strong slowing down of the segmental motion. Consistently, for the high 6:1 salt concentration, a high apparent activation energy E_a=4.1eV characterizes the temperature dependence of the mean correlation times at Tg < T< 1.1T_g, while smaller values E_a=2.5eV are observed for moderate salt contents. The correlation functions are most nonexponential for 15:1 PPO-LiClO4, whereas the stretching is reduced for higher and lower salt concentrations. A similar dependence of the correlation functions on the evolution time in the presence and in the absence of ions indicates that addition of salt hardly affects the reorientational mechanism. For all compositions, mean jump angles of about 15 degree characterize the segmental reorientation. In addition, comparison of results from 2H and 7Li NMR stimulated-echo experiments suggests a coupling of ion and polymer dynamics in 15:1 PPO-LiClO4.Comment: 14 pages, 12 figure