Focal adhesions are controlled by microtubules through local contractility regulation.

Microtubules regulate cell polarity and migration via local activation of focal adhesion turnover, but the mechanism of this process is insufficiently understood. Molecular complexes containing KANK family proteins connect microtubules with talin, the major component of focal adhesions. Here, local optogenetic activation of KANK1-mediated microtubule/talin linkage promoted microtubule targeting to an individual focal adhesion and subsequent withdrawal, resulting in focal adhesion centripetal sliding and rapid disassembly. This sliding is preceded by a local increase of traction force due to accumulation of myosin-II and actin in the proximity of the focal adhesion. Knockdown of the Rho activator GEF-H1 prevented development of traction force and abolished sliding and disassembly of focal adhesions upon KANK1 activation. Other players participating in microtubule-driven, KANK-dependent focal adhesion disassembly include kinases ROCK, PAK, and FAK, as well as microtubules/focal adhesion-associated proteins kinesin-1, APC, and αTAT. Based on these data, we develop a mathematical model for a microtubule-driven focal adhesion disruption involving local GEF-H1/RhoA/ROCK-dependent activation of contractility, which is consistent with experimental data.

Symmetry and simplicity spontaneously emerge from the algorithmic nature of evolution.

SignificanceWhy does evolution favor symmetric structures when they only represent a minute subset of all possible forms? Just as monkeys randomly typing into a computer language will preferentially produce outputs that can be generated by shorter algorithms, so the coding theorem from algorithmic information theory predicts that random mutations, when decoded by the process of development, preferentially produce phenotypes with shorter algorithmic descriptions. Since symmetric structures need less information to encode, they are much more likely to appear as potential variation. Combined with an arrival-of-the-frequent mechanism, this algorithmic bias predicts a much higher prevalence of low-complexity (high-symmetry) phenotypes than follows from natural selection alone and also explains patterns observed in protein complexes, RNA secondary structures, and a gene regulatory network.

Increasing compliance with international pandemic law: international relations and new global health agreements.

Across multiple pandemics, global health governance institutions have struggled to secure the compliance of states with international legal and political commitments, ranging from data sharing to observing WHO guidance to sharing vaccines. In response, governments are negotiating a new pandemic treaty and revising the International Health Regulations. Achieving compliance remains challenging, but international relations and international law research in areas outside of health offers insights. This Health Policy analyses international relations research on the reasons why states comply with international law, even in the absence of sanctions. Drawing on human rights, trade, finance, tobacco, and environmental law, we categorise compliance mechanisms as police patrol, fire alarm, or community organiser models. We show that, to date, current and proposed global health law incorporates only a few of the mechanisms that have shown to be effective in other areas. We offer six specific, politically feasible mechanisms for new international agreements that, together, could create compliance pressures to shift state behaviour.

Benefits of living closer to kin vary by genealogical relationship in a territorial mammal.

While cooperative interactions among kin are a key building block in the societies of group-living species, their importance for species with more variable social environments is unclear. North American red squirrels (Tamiasciurus hudsonicus) defend individual territories in dynamic neighbourhoods and are known to benefit from living among familiar conspecifics, but not relatives. However, kin-directed behaviours may be restricted to specific genealogical relationships or strongly mediated by geographical distance, masking their influence at broader scales. Using distance between territories as a proxy for the ability of individuals to interact, we estimated the influence of primary kin (parents, offspring, siblings) on the annual survival and reproductive success of red squirrels. This approach revealed associations between fitness and access to kin, but only for certain genealogical relationships and fitness components. For example, females had enhanced annual survival when living closer to their daughters, though the reverse was not true. Most surprising was the finding that males had higher annual reproductive success when living closer to their father, suggesting possible recognition and cooperation among fathers and sons. Together, these findings point to unexpected nuance in the fitness consequences of kinship dynamics for a species that is territorial and largely solitary.

Identifying cellular cancer mechanisms through pathway-driven data integration.

MOTIVATION: Cancer is a genetic disease in which accumulated mutations of driver genes induce a functional reorganization of the cell by reprogramming cellular pathways. Current approaches identify cancer pathways as those most internally perturbed by gene expression changes. However, driver genes characteristically perform hub roles between pathways. Therefore, we hypothesize that cancer pathways should be identified by changes in their pathway-pathway relationships. RESULTS: To learn an embedding space that captures the relationships between pathways in a healthy cell, we propose pathway-driven non-negative matrix tri-factorization. In this space, we determine condition-specific (i.e. diseased and healthy) embeddings of pathways and genes. Based on these embeddings, we define our 'NMTF centrality' to measure a pathway's or gene's functional importance, and our 'moving distance', to measure the change in its functional relationships. We combine both measures to predict 15 genes and pathways involved in four major cancers, predicting 60 gene-cancer associations in total, covering 28 unique genes. To further exploit driver genes' tendency to perform hub roles, we model our network data using graphlet adjacency, which considers nodes adjacent if their interaction patterns form specific shapes (e.g. paths or triangles). We find that the predicted genes rewire pathway-pathway interactions in the immune system and provide literary evidence that many are druggable (15/28) and implicated in the associated cancers (47/60). We predict six druggable cancer-specific drug targets. AVAILABILITY AND IMPLEMENTATION: The code and data are available at: https://gitlab.bsc.es/swindels/pathway_driven_nmtf. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

CFTR Function Restoration upon Elexacaftor/Tezacaftor/Ivacaftor Treatment in Patient-Derived Intestinal Organoids with Rare CFTR Genotypes.

Cystic fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. The combination of the CFTR modulators elexacaftor, tezacaftor, and ivacaftor (ETI) enables the effective rescue of CFTR function in people with the most prevalent F508del mutation. However, the functional restoration of rare CFTR variants remains unclear. Here, we use patient-derived intestinal organoids (PDIOs) to identify rare CFTR variants and potentially individuals with CF that might benefit from ETI. First, steady-state lumen area (SLA) measurements were taken to assess CFTR function and compare it to the level observed in healthy controls. Secondly, the forskolin-induced swelling (FIS) assay was performed to measure CFTR rescue within a lower function range, and to further compare it to ETI-mediated CFTR rescue in CFTR genotypes that have received market approval. ETI responses in 30 PDIOs harboring the F508del mutation served as reference for ETI responses of 22 PDIOs with genotypes that are not currently eligible for CFTR modulator treatment, following European Medicine Agency (EMA) and/or U.S. Food and Drug Administration (FDA) regulations. Our data expand previous datasets showing a correlation between in vitro CFTR rescue in organoids and corresponding in vivo ppFEV1 improvement upon a CFTR modulator treatment in published clinical trials, and suggests that the majority of individuals with rare CFTR variants could benefit from ETI. CFTR restoration was further confirmed on protein levels using Western blot. Our data support that CFTR function measurements in PDIOs with rare CFTR genotypes can help to select potential responders to ETI, and suggest that regulatory authorities need to consider providing access to treatment based on the principle of equality for people with CF who do not have access to treatment.

Drug Repurposing for Cystic Fibrosis: Identification of Drugs That Induce CFTR-Independent Fluid Secretion in Nasal Organoids.

Individuals with cystic fibrosis (CF) suffer from severe respiratory disease due to a genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which impairs airway epithelial ion and fluid secretion. New CFTR modulators that restore mutant CFTR function have been recently approved for a large group of people with CF (pwCF), but ~19% of pwCF cannot benefit from CFTR modulators Restoration of epithelial fluid secretion through non-CFTR pathways might be an effective treatment for all pwCF. Here, we developed a medium-throughput 384-well screening assay using nasal CF airway epithelial organoids, with the aim to repurpose FDA-approved drugs as modulators of non-CFTR-dependent epithelial fluid secretion. From a ~1400 FDA-approved drug library, we identified and validated 12 FDA-approved drugs that induced CFTR-independent fluid secretion. Among the hits were several cAMP-mediating drugs, including ß2-adrenergic agonists. The hits displayed no effects on chloride conductance measured in the Ussing chamber, and fluid secretion was not affected by TMEM16A, as demonstrated by knockout (KO) experiments in primary nasal epithelial cells. Altogether, our results demonstrate the use of primary nasal airway cells for medium-scale drug screening, target validation with a highly efficient protocol for generating CRISPR-Cas9 KO cells and identification of compounds which induce fluid secretion in a CFTR- and TMEM16A-indepent manner.

A survey of International Health Regulations National Focal Points experiences in carrying out their functions.

BACKGROUND: The 2005 International Health Regulations (IHR (2005)) require States Parties to establish National Focal Points (NFPs) responsible for notifying the World Health Organization (WHO) of potential events that might constitute public health emergencies of international concern (PHEICs), such as outbreaks of novel infectious diseases. Given the critical role of NFPs in the global surveillance and response system supported by the IHR, we sought to assess their experiences in carrying out their functions. METHODS: In collaboration with WHO officials, we administered a voluntary online survey to all 196 States Parties to the IHR (2005) in Africa, Asia, Europe, and South and North America, from October to November 2019. The survey was available in six languages via a secure internet-based system. RESULTS: In total, 121 NFP representatives answered the 56-question survey; 105 in full, and an additional 16 in part, resulting in a response rate of 62% (121 responses to 196 invitations to participate). The majority of NFPs knew how to notify the WHO of a potential PHEIC, and believed they have the content expertise to carry out their functions. Respondents found training workshops organized by WHO Regional Offices helpful on how to report PHEICs. NFPs experienced challenges in four critical areas: 1) insufficient intersectoral collaboration within their countries, including limited access to, or a lack of cooperation from, key relevant ministries; 2) inadequate communications, such as deficient information technology systems in place to carry out their functions in a timely fashion; 3) lack of authority to report potential PHEICs; and 4) inadequacies in some resources made available by the WHO, including a key tool - the NFP Guide. Finally, many NFP representatives expressed concern about how WHO uses the information they receive from NFPs. CONCLUSION: Our study, conducted just prior to the COVID-19 pandemic, illustrates key challenges experienced by NFPs that can affect States Parties and WHO performance when outbreaks occur. In order for NFPs to be able to rapidly and successfully communicate potential PHEICs such as COVID-19 in the future, continued measures need to be taken by both WHO and States Parties to ensure NFPs have the necessary authority, capacity, training, and resources to effectively carry out their functions as described in the IHR.

TRIM46 Organizes Microtubule Fasciculation in the Axon Initial Segment.

Selective cargo transport into axons and dendrites over the microtubule network is essential for neuron polarization. The axon initial segment (AIS) separates the axon from the somatodendritic compartment and controls the microtubule-dependent transport into the axon. Interestingly, the AIS has a characteristic microtubule organization; it contains bundles of closely spaced microtubules with electron dense cross-bridges, referred to as microtubule fascicles. The microtubule binding protein TRIM46 localizes to the AIS and when overexpressed in non-neuronal cells forms microtubule arrays that closely resemble AIS fascicles in neurons. However, the precise role of TRIM46 in microtubule fasciculation in neurons has not been studied. Here we developed a novel correlative light and electron microscopy approach to study AIS microtubule organization. We show that in cultured rat hippocampal neurons of both sexes, TRIM46 levels steadily increase at the AIS during early neuronal differentiation and at the same time closely spaced microtubules form, whereas the fasciculated microtubules appear at later developmental stages. Moreover, we localized TRIM46 to the electron dense cross-bridges and show that depletion of TRIM46 causes loss of cross-bridges and increased microtubule spacing. These data indicate that TRIM46 has an essential role in organizing microtubule fascicles in the AIS.SIGNIFICANCE STATEMENT The axon initial segment (AIS) is a specialized region at the proximal axon where the action potential is initiated. In addition the AIS separates the axon from the somatodendritic compartment, where it controls protein transport to establish and maintain neuron polarity. Cargo vesicles destined for the axon recognize specialized microtubule tracks that enter the AIS. Interestingly the microtubules entering the AIS form crosslinked bundles, called microtubule fascicules. Recently we found that the microtubule-binding protein TRIM46 localizes to the AIS, where it may organize the AIS microtubules. In the present study we developed a novel correlative light and electron microscopy approach to study the AIS microtubules during neuron development and identified an essential role for TRIM46 in microtubule fasciculation.

Graphlet Laplacians for topology-function and topology-disease relationships.

MOTIVATION: Laplacian matrices capture the global structure of networks and are widely used to study biological networks. However, the local structure of the network around a node can also capture biological information. Local wiring patterns are typically quantified by counting how often a node touches different graphlets (small, connected, induced sub-graphs). Currently available graphlet-based methods do not consider whether nodes are in the same network neighbourhood. To combine graphlet-based topological information and membership of nodes to the same network neighbourhood, we generalize the Laplacian to the Graphlet Laplacian, by considering a pair of nodes to be 'adjacent' if they simultaneously touch a given graphlet. RESULTS: We utilize Graphlet Laplacians to generalize spectral embedding, spectral clustering and network diffusion. Applying Graphlet Laplacian-based spectral embedding, we visually demonstrate that Graphlet Laplacians capture biological functions. This result is quantified by applying Graphlet Laplacian-based spectral clustering, which uncovers clusters enriched in biological functions dependent on the underlying graphlet. We explain the complementarity of biological functions captured by different Graphlet Laplacians by showing that they capture different local topologies. Finally, diffusing pan-cancer gene mutation scores based on different Graphlet Laplacians, we find complementary sets of cancer-related genes. Hence, we demonstrate that Graphlet Laplacians capture topology-function and topology-disease relationships in biological networks. AVAILABILITY AND IMPLEMENTATION: http://www0.cs.ucl.ac.uk/staff/natasa/graphlet-laplacian/index.html. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Quantum dot interactions with and toxicity to Shewanella oneidensis MR-1.

Combining abiotic photosensitisers such as quantum dots (QDs) with non-photosynthetic bacteria presents an intriguing concept into the design of artificial photosynthetic organisms and solar-driven fuel production. Shewanella oneidensis MR-1 (MR-1) is a versatile bacterium concerning respiration, metabolism and biocatalysis, and is a promising organism for artificial photosynthesis as the bacterium's synthetic and catalytic ability provides a potential system for bacterial biohydrogen production. MR-1's hydrogenases are present in the periplasmatic space. It follows that for photoenergised electrons to reach these enzymes, QDs will need to be able to enter the periplasm, or electrons need to enter the periplasm via the Mtr pathway that is responsible for MR-1's extracellular electron transfer ability. As a step towards this goal, various QDs were tested for their photo-reducing potential, nanotoxicology and further for their interaction with MR-1. CdTe/CdS/TGA, CdTe/CdS/Cysteamine, a commercial, negatively charged CdTe and CuInS2/ZnS/PMAL QDs were examined. The photoreduction potential of the QDs was confirmed by measuring their ability to photoreduce methyl viologen with different sacrificial electron donors. The commercial CdTe and CuInS2/ZnS/PMAL QDs showed no toxicity towards MR-1 as evaluated by a colony-forming units method and a fluorescence viability assay. Only the commercial negatively charged CdTe QDs showed good interaction with MR-1. With transmission electron microscopy, QDs were observed both in the cytoplasm and periplasm. These results inform on the possibilities and bottlenecks when developing bionanotechnological systems for the photosynthetic production of biohydrogen by MR-1.

The Role of Exparel Plus Meloxicam for Postoperative Pain Management.

PURPOSE OF REVIEW: Acute postoperative pain reduction is a major target against the opioid crisis. While opioids have traditionally been the mainstay for postoperative analgesia, current practice has focused on a multimodal approach to pain control, including ultrasound-guided blocks with longer acting local anesthetic agents. RECENT FINDINGS: Non-steroidal anti-inflammatory drugs (NSAIDs), such as meloxicam, are an important class of medications utilized to manage pain in the perioperative period. An additional treatment used in perioperative or postoperative pain relief is Exparel, a bupivacaine (sodium channel blocker) liposomal injectable suspension with a 3-4-day duration of action. The long-acting mechanism and formulation of Exparel consistently has demonstrated decreased opioid use and pain scores in patients undergoing many different surgical procedures. A concern is that pH negatively alters the efficacy of bupivacaine, as in cases of inflamed tissue and acidic fluid pH. For this reason, a combination medication with both meloxicam and bupivacaine has been developed, which normalizes pH and has anti-inflammatory and anti-pain conduction properties. Clinical studies demonstrate that this combination agent can be extremely beneficial in treating postoperative pain. This manuscript summarizes the newest developments with regard to liposomal bupivacaine and the non-steroidal meloxicam, their roles in effective treatment of postoperative pain, contraindications, special considerations of using these medications, and future considerations. HTX-011 pairs up a new extended-release formulation of the local anesthetic bupivacaine with meloxicam, a well-established non-steroidal anti-inflammatory drug (NSAID).

Vocal sequences in narwhals (Monodon monoceros).

Sequences are indicative of signal complexity in vocal communication. While vocal sequences are well-described in birds and terrestrial mammals, the extent to which marine mammals use them is less well understood. This study documents the first known examples of sequence use in the narwhal (Monodon monoceros), a gregarious Arctic cetacean. Eight female narwhals were fitted with animal-borne recording devices, resulting in one of the largest datasets of narwhal acoustic behaviour to date. A combination of visual and quantitative classification procedures was used to test whether subjectively defined vocalization patterns were organized into sequences. Next, acoustic characteristics were analyzed to assess whether sequences could disclose group or individual identity. Finally, generalized linear models were used to investigate the behavioural context under which sequences were produced. Two types of sequences, consisting of "paired" patterns and "burst pulse series," were identified. Sequences of burst pulse series were typically produced in periods of high vocal activity, whereas the opposite was true for sequences of paired patterns, suggesting different functions for each. These findings extend the set of odontocetes which are known to use vocal sequences. Inquiry into vocal sequences in other understudied marine mammals may provide further insights into the evolution of vocal communication.

Repeated downsweep vocalizations of the Araguaian river dolphin, Inia araguaiaensis.

Araguaian botos (Inia araguaiaensis) are known to produce pulsed as well as tonal sounds. This study documents the first evidence for repetitive sequences of downsweep whistles in botos that appear to be shared between individuals, and the context of their occurrence is investigated. Boat surveys were conducted along the Tocantins River located in the Eastern Amazon over a period of 42 days between 2012 and 2018. Eighty-two groups of Araguaian botos were observed, and 43 h of sound recordings were acquired. 632 downsweep whistles were recorded in 10 encounters. Four of these encounters contained downsweep bouts (21 bouts with ≥2 whistles) with short inter-call intervals (bout criterion 50 s) and up to 161 whistles. A statistical relationship was not found between downsweep occurrence and any of the contextual parameters that were investigated, including socializing, travelling, feeding, group size, presence of calves, and socio-sexual displays. The rarity of these signals makes them unlikely candidates for individual or group identification. It is more likely that they are associated with very specific contexts, such as nursing or mating, both of which were rarely observed in this study. Further studies are required to investigate context specificity and elucidate the function of these signals.

Electron Accepting Units of the Diheme Cytochrome c TsdA, a Bifunctional Thiosulfate Dehydrogenase/Tetrathionate Reductase.

The enzymes of the thiosulfate dehydrogenase (TsdA) family are wide-spread diheme c-type cytochromes. Here, redox carriers were studied mediating the flow of electrons arising from thiosulfate oxidation into respiratory or photosynthetic electron chains. In a number of organisms, including Thiomonas intermedia and Sideroxydans lithotrophicus, the tsdA gene is immediately preceded by tsdB encoding for another diheme cytochrome. Spectrophotometric experiments in combination with enzymatic assays in solution showed that TsdB acts as an effective electron acceptor of TsdA in vitro when TsdA and TsdB originate from the same source organism. Although TsdA covers a range from -300 to +150 mV, TsdB is redox active between -100 and +300 mV, thus enabling electron transfer between these hemoproteins. The three-dimensional structure of the TsdB-TsdA fusion protein from the purple sulfur bacterium Marichromatium purpuratum was solved by X-ray crystallography to 2.75 Å resolution providing insights into internal electron transfer. In the oxidized state, this tetraheme cytochrome c contains three hemes with axial His/Met ligation, whereas heme 3 exhibits the His/Cys coordination typical for TsdA active sites. Interestingly, thiosulfate is covalently bound to Cys330 on heme 3. In several bacteria, including Allochromatium vinosum, TsdB is not present, precluding a general and essential role for electron flow. Both AvTsdA and the MpTsdBA fusion react efficiently in vitro with high potential iron-sulfur protein from A. vinosum (Em +350 mV). High potential iron-sulfur protein not only acts as direct electron donor to the reaction center in anoxygenic phototrophs but can also be involved in aerobic respiratory chains.

Multiplexing N-glycan analysis by DNA analyzer.

Analysis of N-glycan structures has been gaining attentions over the years due to their critical importance to biopharma-based applications and growing roles in biological research. Glycan profiling is also critical to the development of biosimilar drugs. The detailed characterization of N-glycosylation is mandatory because it is a nontemplate driven process and that significantly influences critical properties such as bio-safety and bio-activity. The ability to comprehensively characterize highly complex mixtures of N-glycans has been analytically challenging and stimulating because of the difficulties in both the structure complexity and time-consuming sample pretreatment procedures. CE-LIF is one of the typical techniques for N-glycan analysis due to its high separation efficiency. In this paper, a 16-capillary DNA analyzer was coupled with a magnetic bead glycan purification method to accelerate the sample preparation procedure and therefore increase N-glycan assay throughput. Routinely, the labeling dye used for CE-LIF is 8-aminopyrene-1,3,6-trisulfonic acid, while the typical identification method involves matching migration times with database entries. Two new fluorescent dyes were used to either cross-validate and increase the glycan identification precision or simplify sample preparation steps. Exoglycosidase studies were carried out using neuramididase, galactosidase, and fucosidase to confirm the results of three dye cross-validation. The optimized method combines the parallel separation capacity of multiple-capillary separation with three labeling dyes, magnetic bead assisted preparation, and exoglycosidase treatment to allow rapid and accurate analysis of N-glycans. These new methods provided enough useful structural information to permit N-glycan structure elucidation with only one sample injection.

Genetic Correlations Greatly Increase Mutational Robustness and Can Both Reduce and Enhance Evolvability.

Mutational neighbourhoods in genotype-phenotype (GP) maps are widely believed to be more likely to share characteristics than expected from random chance. Such genetic correlations should strongly influence evolutionary dynamics. We explore and quantify these intuitions by comparing three GP maps-a model for RNA secondary structure, the HP model for protein tertiary structure, and the Polyomino model for protein quaternary structure-to a simple random null model that maintains the number of genotypes mapping to each phenotype, but assigns genotypes randomly. The mutational neighbourhood of a genotype in these GP maps is much more likely to contain genotypes mapping to the same phenotype than in the random null model. Such neutral correlations can be quantified by the robustness to mutations, which can be many orders of magnitude larger than that of the null model, and crucially, above the critical threshold for the formation of large neutral networks of mutationally connected genotypes which enhance the capacity for the exploration of phenotypic novelty. Thus neutral correlations increase evolvability. We also study non-neutral correlations: Compared to the null model, i) If a particular (non-neutral) phenotype is found once in the 1-mutation neighbourhood of a genotype, then the chance of finding that phenotype multiple times in this neighbourhood is larger than expected; ii) If two genotypes are connected by a single neutral mutation, then their respective non-neutral 1-mutation neighbourhoods are more likely to be similar; iii) If a genotype maps to a folding or self-assembling phenotype, then its non-neutral neighbours are less likely to be a potentially deleterious non-folding or non-assembling phenotype. Non-neutral correlations of type i) and ii) reduce the rate at which new phenotypes can be found by neutral exploration, and so may diminish evolvability, while non-neutral correlations of type iii) may instead facilitate evolutionary exploration and so increase evolvability.

Prostate cancer progression and mortality: a review of diet and lifestyle factors.

PURPOSE: To review and summarize evidence on the role of diet and lifestyle factors and prostate cancer progression, with a specific focus on habits after diagnosis and the risk of subsequent disease recurrence, progression, or death. METHODS: Given the well-documented heterogeneity of prostate cancer and the long survivorship of the majority of diagnoses, our goal was to summarize and describe modifiable risk factors for clinically relevant prostate cancer. We focused where possible on epidemiologic studies of post-diagnostic habits and prostate cancer progression, defined as recurrence (e.g., PSA risk, secondary treatment), metastasis, or death. Where data were limited, we also describe evidence on risk factors and indicators of prostate cancer aggressiveness at diagnosis. RESULTS: A variety of dietary and lifestyle factors appear to affect prostate cancer progression. Several generally widely recommended lifestyle factors such as not smoking, maintaining a healthy body weight, and regular vigorous physical exercise also appear to affect prostate cancer progression. Several dietary factors, such as tomato sauce/lycopene, cruciferous vegetables, healthy sources of vegetable fats, and coffee, may also have a role in reducing risk of prostate cancer progression. CONCLUSION: Diet and lifestyle factors, in particular exercise and smoking cessation, may reduce the risk of prostate cancer progression and death. These promising findings warrant further investigation, as their overall impact might be large.

Assessing the Relative Influence and Efficacy of Public and Private Food Safety Regulation Regimes: Comparing Codex and Global G.A.P. Standards.

An extensive global system of private food regulation is under construction, one that exceeds conventional regulation thought of as being driven by public authorities like FDA and USDA in the U.S. or the Food Standards Agency in the UK. Agrifood and grocer organizations, in concert with some farming groups, have been the primary designers of this new food regulatory regime. These groups have established alliances that compete with national regulators in complex ways. This article analyzes the relationship between public and private sources of food safety regulation by examining standards adopted by the Codex Alimentarius Commission, a food safety organization jointly run by the Food and Agricultural Organization and the World Health Organization and GlobalG.A.P., a farm assurance program created in the late 1990s by supermarket chains and their major suppliers which has now expanded into a global certifying coalition. While Codex standards are adopted, often as written, by national food safety regulators who are principal drivers of the standard setting process, customers for agricultural products in many countries now demand evidence of GlobalG.A.P. certification as a prerequisite for doing business This article tests not only the durability and strength of private sector standard setting in the food safety system, but also the desirability of that system as an alternative to formal, governmental processes embodied, for our purposes, in the standards adopted by Codex. In many cases, official standards and GlobalG.A.P. standards clash in ways that implicate not only food safety but the flow of agricultural products in the global trading system. The article analyzes current weaknesses in both regimes and possibilities for change that will better reconcile the two competing systems.