Online Health Social Networks and Patient Health Decision Behavior: A Research Agenda

Patients and health care practitioners alike are using the Internet and specifically online health social networks to gain access to knowledge and social support that they could not obtain as quickly or efficiently from their traditional face-to-face social networks. Given concerns about the quality of information available on the Internet and the differences between social interaction online and offline, it is important to determine whether this new phenomenon influences health decision behavior. We propose a framework for investigating the influence online health social networks may have on the health decisions that patients and their physicians make. We also propose a number of research questions that flow from this framework

The Polycomb protein, Bmi1, regulates insulin sensitivity

Objective: The Polycomb Repressive Complexes (PRC) 1 and 2 function to epigenetically repress target genes. The PRC1 component, Bmi1, plays a crucial role in maintenance of glucose homeostasis and beta cell mass through repression of the Ink4a/Arf locus. Here we have explored the role of Bmi1 in regulating glucose homeostasis in the adult animal, which had not been previously reported due to poor postnatal survival of Bmi1−/− mice. Methods: The metabolic phenotype of Bmi1+/− mice was characterized, both in vivo and ex vivo. Glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps were performed. The insulin signaling pathway was assessed at the protein and transcript level. Results: Here we report a negative correlation between Bmi1 levels and insulin sensitivity in two models of insulin resistance, aging and liver-specific insulin receptor deficiency. Further, heterozygous loss of Bmi1 results in increased insulin sensitivity in adult mice, with no impact on body weight or composition. Hyperinsulinemic-euglycemic clamp reveals increased suppression of hepatic glucose production and increased glucose disposal rate, indicating elevated glucose uptake to peripheral tissues, in Bmi1+/− mice. Enhancement of insulin signaling, specifically an increase in Akt phosphorylation, in liver and, to a lesser extent, in muscle appears to contribute to this phenotype. Conclusions: Together, these data define a new role for Bmi1 in regulating insulin sensitivity via enhancement of Akt phosphorylation

Using the IBM Analog In-Memory Hardware Acceleration Kit for Neural Network Training and Inference

Analog In-Memory Computing (AIMC) is a promising approach to reduce the latency and energy consumption of Deep Neural Network (DNN) inference and training. However, the noisy and non-linear device characteristics, and the non-ideal peripheral circuitry in AIMC chips, require adapting DNNs to be deployed on such hardware to achieve equivalent accuracy to digital computing. In this tutorial, we provide a deep dive into how such adaptations can be achieved and evaluated using the recently released IBM Analog Hardware Acceleration Kit (AIHWKit), freely available at https://github.com/IBM/aihwkit. The AIHWKit is a Python library that simulates inference and training of DNNs using AIMC. We present an in-depth description of the AIHWKit design, functionality, and best practices to properly perform inference and training. We also present an overview of the Analog AI Cloud Composer, that provides the benefits of using the AIHWKit simulation platform in a fully managed cloud setting. Finally, we show examples on how users can expand and customize AIHWKit for their own needs. This tutorial is accompanied by comprehensive Jupyter Notebook code examples that can be run using AIHWKit, which can be downloaded from https://github.com/IBM/aihwkit/tree/master/notebooks/tutorial

Practical First Total Synthesis of the Potent Phytotoxic (±)-Naphthotectone, Isolated from Tectona grandis

Naphthotectone is a quinone isolated recently from teak extracts of Tectona grandis. It has been shown to be one of the most abundant compounds and the most active compound isolated form teak. Thus, it has been proposed that naphthotectone is one of the compounds responsible for the allelophathic activity of this plant. An efficient total synthesis of (±) -naphthotectone was achieved in seven steps and 31% overall yield. The best results were obtained by using an aqueous Wittig reaction as a key step. Other reactions used were the formation of an epoxide ring by the Corey– Chaykovsky method, and an innovative one-pot anodic electrooxidation and demethylation

Topoisomerase 1 Inhibition in MYC-Driven Cancer Promotes Aberrant R-Loop Accumulation to Induce Synthetic Lethality

CRISPR screening reveals topoisomerase 1 as an immediately actionable vulnerability in cancers harboring MYC as a driver oncoprotein that can be targeted with clinically approved inhibitors. MYC is a central regulator of gene transcription and is frequently dysregulated in human cancers. As targeting MYC directly is challenging, an alternative strategy is to identify specific proteins or processes required for MYC to function as a potent cancer driver that can be targeted to result in synthetic lethality. To identify potential targets in MYC-driven cancers, we performed a genome-wide CRISPR knockout screen using an isogenic pair of breast cancer cell lines in which MYC dysregulation is the switch from benign to transformed tumor growth. Proteins that regulate R-loops were identified as a potential class of synthetic lethal targets. Dysregulated MYC elevated global transcription and coincident R-loop accumulation. Topoisomerase 1 (TOP1), a regulator of R-loops by DNA topology, was validated to be a vulnerability in cells with high MYC activity. Genetic knockdown of TOP1 in MYC-transformed cells resulted in reduced colony formation compared with control cells, demonstrating synthetic lethality. Overexpression of RNaseH1, a riboendonuclease that specifically degrades R-loops, rescued the reduction in clonogenicity induced by TOP1 deficiency, demonstrating that this vulnerability is driven by aberrant R-loop accumulation. Genetic and pharmacologic TOP1 inhibition selectively reduced the fitness of MYC-transformed tumors in vivo. Finally, drug response to TOP1 inhibitors (i.e., topotecan) significantly correlated with MYC levels and activity across panels of breast cancer cell lines and patient-derived organoids. Together, these results highlight TOP1 as a promising target for MYC-driven cancers.Significance: CRISPR screening reveals topoisomerase 1 as an immediately actionable vulnerability in cancers harboring MYC as a driver oncoprotein that can be targeted with clinically approved inhibitors

Chemical Architecture and Applications of Nucleic Acid Derivatives Containing 1,2,3-Triazole Functionalities Synthesized via Click Chemistry

There is considerable attention directed at chemically modifying nucleic acids with robust functional groups in order to alter their properties. Since the breakthrough of copper-assisted azide-alkyne cycloadditions (CuAAC), there have been several reports describing the synthesis and properties of novel triazole-modified nucleic acid derivatives for potential downstream DNA- and RNA-based applications. This review will focus on highlighting representative novel nucleic acid molecular structures that have been synthesized via the “click” azide-alkyne cycloaddition. Many of these derivatives show compatibility for various applications that involve enzymatic transformation, nucleic acid hybridization, molecular tagging and purification, and gene silencing. The details of these applications are discussed. In conclusion, the future of nucleic acid analogues functionalized with triazoles is promising

Computational design of syntheses leading to compound libraries or isotopically labelled targets

Although computer programs for retrosynthetic planning have shown improved and in some cases quite satisfactory performance in designing routes leading to specific, individual targets, no algorithms capable of planning syntheses of entire target libraries - important in modern drug discovery - have yet been reported. This study describes how network-search routines underlying existing retrosynthetic programs can be adapted and extended to multi-target design operating on one common search graph, benefitting from the use of common intermediates and reducing the overall synthetic cost. Implementation in the Chematica platform illustrates the usefulness of such algorithms in the syntheses of either (i) all members of a user-defined library, or (ii) the most synthetically accessible members of this library. In the latter case, algorithms are also readily adapted to the identification of the most facile syntheses of isotopically labelled targets. These examples are industrially relevant in the context of hitto-lead optimization and syntheses of isotopomers of various bioactive molecules

Understanding how, why, for whom, and under what circumstances opt-out blood-borne virus testing programmes work to increase test engagement and uptake within prison: a rapid-realist review.

BACKGROUND: Prisons represent a unique opportunity to diagnose blood-borne viruses. Opt-out testing is receiving increasing interest, as a result of mounting evidence to suggest that the manner in which a test offer is delivered, affects test uptake. Although the effectiveness of opt-out testing within the prison setting has been established, robust explanations are required for the variation in outcomes reported. METHODS: Rapid-realist review methodology was used to synthesise the literature on prison-based opt-out testing. The review was carried out in three phases. Phase one: An expert panel provided literature relevant to the implementation of opt-out testing within the English prison estate. Unstructured searches were also conducted to identify other social programmes where "opt-out" had been used to increase uptake. Phase two: a systematic search of six peer-review and five grey literature databases was carried out to identify empirical data on opt-out testing within the prison setting. Phase three: Additional non-exhaustive searches were carried out to identify literature that reinforced emergent concepts. The development of programme theory took place with each iteration and was validated in consultation with stakeholders. RESULTS: Programme theory was constructed for two outcomes: the proportion of intake offered a test and the proportion offered that accepted testing. The proportion of intake offered testing was influenced by the timing of the test offer, which was often delayed due to barriers to prisoner access. The decision to accept testing was influenced by concerns about confidentiality, fear of a positive diagnosis, a prisoner's personal interpretation of risk, discomfort with invasive procedures, trust in healthcare, and the fidelity of the opt-out offer. CONCLUSIONS: This review identified important implementation considerations that moderate the effectiveness of opt-out testing programmes. It also highlighted a lack of appreciation for the theoretical underpinnings of opt-out programmes and tension around how to implement testing in a manner that adheres to both default theory and informed consent. It is anticipated that results will be used to inform the design and implementation of subsequent versions of these programmes, as well as catalyse further in-depth analysis into their operation within the unique context of prison. REVIEW REGISTRATION: CRD42017068342

Genital Herpes Has Played a More Important Role than Any Other Sexually Transmitted Infection in Driving HIV Prevalence in Africa

Extensive evidence from observational studies suggests a role for genital herpes in the HIV epidemic. A number of herpes vaccines are under development and several trials of the efficacy of HSV-2 treatment with acyclovir in reducing HIV acquisition, transmission, and disease progression have just reported their results or will report their results in the next year. The potential impact of these interventions requires a quantitative assessment of the magnitude of the synergy between HIV and HSV-2 at the population level.A deterministic compartmental model of HIV and HSV-2 dynamics and interactions was constructed. The nature of the epidemiologic synergy was explored qualitatively and quantitatively and compared to other sexually transmitted infections (STIs). The results suggest a more substantial role for HSV-2 in fueling HIV spread in sub-Saharan Africa than other STIs. We estimate that in settings of high HSV-2 prevalence, such as Kisumu, Kenya, more than a quarter of incident HIV infections may have been attributed directly to HSV-2. HSV-2 has also contributed considerably to the onward transmission of HIV by increasing the pool of HIV positive persons in the population and may explain one-third of the differential HIV prevalence among the cities of the Four City study. Conversely, we estimate that HIV had only a small net impact on HSV-2 prevalence.HSV-2 role as a biological cofactor in HIV acquisition and transmission may have contributed substantially to HIV particularly by facilitating HIV spread among the low-risk population with stable long-term sexual partnerships. This finding suggests that prevention of HSV-2 infection through a prophylactic vaccine may be an effective intervention both in nascent epidemics with high HIV incidence in the high risk groups, and in established epidemics where a large portion of HIV transmission occurs in stable partnerships