Dual-barrel conductance micropipet as a new approach to the study of ionic crystal dissolution kinetics

A new approach to the study of ionic crystal dissolution kinetics is described, based on the use of a dual-barrel theta conductance micropipet. The solution in the pipet is undersaturated with respect to the crystal of interest, and when the meniscus at the end of the micropipet makes contact with a selected region of the crystal surface, dissolution occurs causing the solution composition to change. This is observed, with better than 1 ms time resolution, as a change in the ion conductance current, measured across a potential bias between an electrode in each barrel of the pipet. Key attributes of this new technique are: (i) dissolution can be targeted at a single crystal surface; (ii) multiple measurements can be made quickly and easily by moving the pipet to a new location on the surface; (iii) materials with a wide range of kinetics and solubilities are open to study because the duration of dissolution is controlled by the meniscus contact time; (iv) fast kinetics are readily amenable to study because of the intrinsically high mass transport rates within tapered micropipets; (v) the experimental geometry is well-defined, permitting finite element method modeling to allow quantitative analysis of experimental data. Herein, we study the dissolution of NaCl as an example system, with dissolution induced for just a few milliseconds, and estimate a first-order heterogeneous rate constant of 7.5 (±2.5) × 10–5 cm s–1 (equivalent surface dissolution flux ca. 0.5 μmol cm–2 s–1 into a completely undersaturated solution). Ionic crystals form a huge class of materials whose dissolution properties are of considerable interest, and we thus anticipate that this new localized microscale surface approach will have considerable applicability in the future

Nitric oxide sensing in plants is mediated by proteolytic control of group VII ERF transcription factors

Nitric oxide (NO) is an important signaling compound in prokaryotes and eukaryotes. In plants, NO regulates critical developmental transitions and stress responses. Here, we identify a mechanism for NO sensing that coordinates responses throughout development based on targeted degradation of plant-specific transcriptional regulators, the group VII ethylene response factors (ERFs). We show that the N-end rule pathway of targeted proteolysis targets these proteins for destruction in the presence of NO, and we establish them as critical regulators of diverse NO-regulated processes, including seed germination, stomatal closure, and hypocotyl elongation. Furthermore, we define the molecular mechanism for NO control of germination and crosstalk with abscisic acid (ABA) signaling through ERF-regulated expression of ABSCISIC ACID INSENSITIVE5 (ABI5). Our work demonstrates how NO sensing is integrated across multiple physiological processes by direct modulation of transcription factor stability and identifies group VII ERFs as central hubs for the perception of gaseous signals in plants

Framing the Drivers of Antimicrobial Resistance in Tanzania.

Despite global awareness of the key factors surrounding antimicrobial resistance (AMR), designing and implementing policies to address the critical issues around the drivers of AMR remains complex to put into practice. We identified prevalent narratives and framing used by epistemological communities involved in the response to AMR in Tanzania, interrogated how this framing may inform policymaking, and identified interventions that could be tailored to the groups believed responsible for AMR. We interviewed 114 key informants from three districts and analysed transcripts line by line. Our results suggest that many different groups help drive the spread of AMR in Tanzania and need to be involved in any effective response. Human health is currently perceived as driving the response, while other domains lag behind in their efforts. For AMR programmes to be successful, all sectors need to be involved, including civil society groups, community representatives, and those working in communities (e.g., primary care physicians). However, current plans and programmes largely fail to include these viewpoints. The perceived presence of political will in Tanzania is a significant step towards such a response. Any strategies to tackle AMR need to be tailored to the context-specific realities, taking into account constraints, beliefs, and power dynamics within countries

Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice

The lymph node (LN) is the primary site of alloimmunity activation and regulation during transplantation. Here, we investigated how fibroblastic reticular cells (FRCs) facilitate the tolerance induced by anti-CD40L in a murine model of heart transplantation. We found that both the absence of LNs and FRC depletion abrogated the effect of anti-CD40L in prolonging murine heart allograft survival. Depletion of FRCs impaired homing of T cells across the high endothelial venules (HEVs) and promoted formation of alloreactive T cells in the LNs in heart-transplanted mice treated with anti-CD40L. Single-cell RNA sequencing of the LNs showed that anti-CD40L promotes a Madcam1+ FRC subset. FRCs also promoted the formation of regulatory T cells (Tregs) in vitro. Nanoparticles (NPs) containing anti-CD40L were selectively delivered to the LNs by coating them with MECA-79, which binds to peripheral node addressin (PNAd) glycoproteins expressed exclusively by HEVs. Treatment with these MECA-79-anti-CD40L-NPs markedly delayed the onset of heart allograft rejection and increased the presence of Tregs. Finally, combined MECA-79-anti-CD40L-NPs and rapamycin treatment resulted in markedly longer allograft survival than soluble anti-CD40L and rapamycin. These data demonstrate that FRCs are critical to facilitating costimulatory blockade. LN-targeted nanodelivery of anti-CD40L could effectively promote heart allograft acceptance

Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition

Practices and Challenges of Veterinary Paraprofessionals in Regards to Antimicrobial Use and Resistance in Animals in Dar Es Salaam, Tanzania.

We conducted a qualitative study to explore the practices and challenges of veterinary paraprofessionals (paravets) on antimicrobial use and resistance in domestic animals. METHODS: This was a qualitative study, which involved semi-structured interviews with paravets from the Ilala, Ubungo, Kigamboni, Kinondoni, and Temeke districts in Dar es Salaam, Tanzania. RESULTS: A total of 40 paravets participated in this study. The majority (72.5%) admitted to having not undergone any formal training on antimicrobial use and/or resistance. Paravets face several challenges, including poor working conditions and having no access to laboratory services to advise on antimicrobial choice and selection. They also face challenges from livestock farmers such as the inability to afford the recommended medicines, the self-prescription of antimicrobials, and poor record keeping. The presence of sub-standard medicine and the lack of guidelines on the appropriate disposal of medicines were also identified as affecting their services. CONCLUSION: Paravets should be trained in the judicious use of antimicrobials, and the same training should be used to refresh their knowledge on the diagnosis and prevention of infections. The Veterinary Council of Tanzania and other regulatory agencies should assist in addressing the challenges facing paravets that are related to animal health services and the quality of medicines

Exploring the meaning in meaningful coincidences: an interpretative phenomenological analysis of synchronicity in therapy

Synchronicity experiences (SEs) are defined as psychologically meaningful connections between inner events (e.g. thought, dream or vision) and one or more external events occurring simultaneously or at a future point in time. There has been limited systematic research that has investigated the phenomenology of SEs in therapy. This study aimed to redress this by exploring the process and nature of such experiences from the perspective of the practitioner. Semi-structured face-to-face interviews were conducted with a purposive sample of nine practitioners who reported SEs in their therapeutic sessions (three counsellors, three psychologists and three psychotherapists), and focused on how participants make sense of their experiences of synchronicity in therapy. Interpretative phenomenological analysis was used to identify three superordinate themes: sense of connectedness, therapeutic process, and professional issues. Findings suggest that SEs can serve to strengthen the therapeutic relationship and are perceived as useful harbingers of information about the therapeutic process, as well as being a means of overcoming communication difficulties, as they are seen to provide insights into the client’s experiencing of themselves and others, regardless of whether or not the SE is acknowledged by the client or disclosed by the therapist

The Governance and Implementation of the National Action Plan on Antimicrobial Resistance in Tanzania: A Qualitative Study.

Tanzania launched its first National Action Plan (NAP) on antimicrobial resistance (AMR) in 2017 to reduce the burden of AMR in the country and contribute to the global response. We aimed to analyze the implementation of the NAP on AMR in Tanzania using the governance framework. In-depth interviews were conducted with human and animal health practitioners and national-level policy actors. We adapted Chua's AMR governance framework to analyze the development and implementation of the NAP in Tanzania. Implementation of the NAP has realized several achievements, including: (i) the establishment of a functioning Multi-Sectoral Coordinating Committee for coordinating the implementation of AMR activities; (ii) existence of governance structure; (iii) establishment of human and animal surveillance sites; (iv) creation of AMR awareness in the community and (v) availability of guidelines at the health facility level to ensure AMR stewardship. However, some dimensions of the governance areas, including reporting and feedback mechanisms, accountability, transparency and sustainability of AMR plans, are not effectively implemented. Addressing these challenges should involve strengthening the collaboration of the different sectors involved at different NAP implementation levels by careful planning and coordination, and provision of adequate resources to ensure sustainability

Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting