Building a better virus trap

The concept of ecological 'traps' is based in theory from ecology and conservation biology that has now found application to infectious diseases with a study from Paul Turner's group. This study is important because it offers a mathematical model of ecological traps, applies this model to viruses, and tests the model in a bacteria-phage system. Although there will be technical hurdles to overcome, this concept might lead to benefits for both health and industry.     

Circle of healing: traditional storytelling, part three

Southcentral Foundation had to overcome several organizational and procedural hurdles when developing their Circle of Healing program. Among these hurdles was finding a way to credential Alaska Native healers so the Foundation could be reimbursed for their services and pay the healers, and so the healers could work in the hospital along with the staff delivering Western and alternative medical treatment. Southcentral Foundation chose to develop a process for certifying Alaska Native healers as tribal doctors. Rita Blumenstein is the first such person to be certified. Lisa Dolchok is the second. An important strength of Lisa’s presentation is that she helps us broaden our understanding of healing from an Alaska Native perspective. So often we equate healing with curing, and while it can have this dimension, Lisa reminds us there is much more to it. She echoes LouAnn Benson’s presentation in asserting that healing can address illness of the spirit or wounds to the soul.     

Recent advances in wheat transformation

Summary Since the first report of wheat transformation in the early 1990s, genetic engineering of wheat has evolved rapidly. Several laboratories worldwide have reported the production of fertile transgenic wheat plants using a variety of methods. While there are several innovative and promising approaches for wheat transformation using different explants as targets for transformation, different methods of transformation, and different selection schemes, the most common approach to wheat transformation is the bombardment of tissue derived from immature embryos followed by selection based on resistance to the bar gene. Even with all these successful reports, hurdles still exist for this recalcitrant crop. Of these hurdles, low transformation rates, tools for transgene expression, and transgene silencing in subsequent generations are probably the most critical. This review will provide an overview of wheat transformation in the past decade, addressing both positive and negative factors that effect transformation while highlighting the successes of the past and prospects for the future.     

Comparing Nonsynergistic Gamma Models with Interaction Models To Predict Growth of Emetic Bacillus cereus when Using Combinations of pH and Individual Undissociated Acids as Growth-Limiting Factors

A combination of multiple hurdles to limit microbial growth is frequently applied in foods to achieve an overall level of protection. Quantification of hurdle technology aims at identifying synergistic or multiplicative effects and is still being developed. The gamma hypothesis states that inhibitory environmental factors aiming at limiting microbial growth rates combine in a multiplicative manner rather than synergistically. Its validity was tested here with respect to the use of pH and various concentrations of undissociated acids, i.e., acetic, lactic, propionic, and formic acids, to control growth of Bacillus cereus in brain heart infusion broth. The key growth parameter considered was the maximum specific growth rate, μ_max, as observed by determination of optical density. A variety of models from the literature describing the effects of various pH values and undissociated acid concentrations on μ_max were fitted to experimental data sets and compared based on a predefined set of selection criteria, and the best models were selected. The cardinal model developed by Rosso (for pH dependency) and the model developed by Luong (for undissociated acid) were found to provide the best fit and were combined in a gamma model with good predictive performance. The introduction of synergy factors into the models was not able to improve the quality of the prediction. On the contrary, inclusion of synergy factors led to an overestimation of the growth boundary, with the inherent possibility of leading to underestimation of the risk under the conditions tested in this research.Consumers expect safe and sufficiently stable food within the given shelf life of a food product or component. Several growth-limiting factors, collectively referred to as hurdles, can be used to ensure food stability and safety. Examples of such hurdles are low pH, low water activity, or low temperature (12). Combining hurdles to achieve food stability and safety, known as hurdle technology, can be used to achieve an overall level of protection in food while minimizing impacts on food quality (20). When a combination of hurdles is used, generally the intensity of the hurdles may be lower, to exert a comparable preservative effect, than the intensity of those hurdles when used individually (20). Three classes of interaction can be defined when applying hurdle technology: “no interaction,” in which the effect of a combination is as expected from the response of the separate factors; “synergy,” in which the effect is greater than expected; and “antagonism,” in which the effect is less than expected (6).Though the concept of hurdle technology is rather well established, the quantification of the combined impact of hurdles on growth of microorganisms is still being developed. One significant problem is that there are two opposite views of how antimicrobial factors combine. One view states that there are interactive effects between hurdles; when they are applied together, they give a protection significantly greater than that expected on the basis of the application of the individual hurdles (synergy). The alternative view considers that the combined effect may be complex but that there are no interactive effects culminating in synergy. The latter view is called the gamma hypothesis (41) and states that inhibitory environmental factors combine in a multiplicative manner to produce the observed overall microbial inhibition. A major benefit of models based on the gamma hypothesis is a reduction in experimental work, since growth rates and, as a result, growth boundaries can be estimated upon evaluating single hurdles rather than their various combinations. This benefit can only be realized, however, when the gamma hypothesis is valid for the combination of hurdles considered. If the hypothesis is not valid and interactive effects are present, growth boundaries are estimated wrongly, which might result in fail-safe predictions.Over the years, the gamma hypothesis has been confirmed by several studies (16, 17, 26, 34, 38) that concluded that the combined effect of hurdles on growth rates is multiplicative rather than synergistic. Contrarily, Rödel and Scheuer (30) concluded that interaction occurs when various hurdles are combined, stressing the occurrence of synergy. Both Le Marc et al. (21) and Augustin and Carlier (5) developed a synergy model to take account of synergy occurring when hurdles are combined. It is prudent to conclude that the effect of combinations of hurdles is best evaluated on a case-by-case basis in order to ensure appropriate utility of hurdle technology approaches in establishing food designs that are stable and safe.This research aimed to validate or falsify the gamma hypothesis for two closely related hurdles often used in the food industry: the pH level and the undissociated acid concentration ([HA]). The approach chosen was to establish an overview of models for pH and undissociated acid from the literature. Based on predefined criteria, models were then selected to construct a new gamma model without synergy factors for the various hurdle combinations. The criteria were meant to enable evaluation of the fitting performance of all individual models to select the best-performing models for inclusion in the new gamma models. Finally, the validity of the gamma hypothesis was judged by comparing the predictive performance of the newly constructed gamma models with two gamma models, including a synergy factor reported in the literature. Bacillus cereus F4810/72, relevant for both food spoilage and poisoning (14, 19), was used as the model microorganism. Maximum specific growth rates were determined by optical density measurements combined with time to detection. This method was selected after thorough investigation of three different methods to obtain parameters for growth, as recently published (8).     

Silicon fingerprint sensors

The silicon fingerprint sensor is the first application of a technology where an integrated circuit needs to be touched to make the technology work. It should come as little surprise that there have been numerous technical barriers to overcome. Btt reviews how these hurdles are being tackled and follows the progress of a selection of leading companies and their products.     

Development of new RNAi therapeutics

RNAi-mediated gene inactivation has become a cornerstone of the present day gene function studies that are the foundation of mechanism and target based drug discovery and development, which could potentially shorten the otherwise long process of drug development. In particular, the coming of age of "RNAi drug" could provide new promising therapeutics bypassing traditional approaches. However, there are technological hurdles need to overcome and the biological limitations need to consider for achieving effective therapeutics. Major hurdles include the intrinsic poor pharmacokinetic property of siRNA and major biological restrictions include off-target effects, interferon response and the interference with endogenous miRNA. Recent innovations in nucleic acid chemistry, formulations and delivery methods have gradually rendered it possible to develop effective RNAi-based therapeutics. Careful design based on the newest RNAi/miRNA biology can also help to minimize the potential tissue toxicity. If successful with systemic application, RNAi drug will no doubt revolutionize the whole drug development process. This review attempts to describe the progress in this area, including applications in preclinical models and recent favorable experience in a number of human trials of local diseases, along with the discussion on the potential limitations of RNAi therapeutics.     

新一代抗结核分枝杆菌疫苗将会建立在现用卡介苗的基础上吗?

本文针对以卡介苗(bacillus Calmette-Guérin,BCG)为基础的结核分枝杆菌新疫苗本身的缺陷问题、临床前药效学评价面临的问题、临床研究可能面临的有效性评价问题及伦理问题等,对"新一代抗结核分枝杆菌疫苗将会建立在现用BCG的基础上"的观点进行评述。认为以BCG为基础的新疫苗保护力可能超过现用BCG,但要显著提高其对成人的保护效果尚有难度;新疫苗用于新生儿的临床研究因存在伦理问题而可能无法开展;针对潜伏结核感染人群的免疫预防是控制结核病的重要手段,以现用BCG为基础的新疫苗可能无法应用于此类人群。因此,新一代主流抗结核分枝杆菌疫苗将不会是建立在现用BCG基础之上的疫苗。     

A whole parasite vaccine to control the blood stages of Plasmodium: the case for lateral thinking

Now, 27 years following the cloning of malaria antigens with the promise of the rapid development of a malaria vaccine, we face significant obstacles that are belatedly being addressed. Poor immunogenicity of subunit vaccine antigens and significant antigenic diversity of target epitopes represent major hurdles for which there are no clear strategies for a way forward within the current paradigm. Thus, a different paradigm - a vaccine that uses the whole organism - is now being examined. Although most advances in this approach relate to a vaccine for the pre-erythrocytic stages (sporozoites, liver stages), this opinion paper will outline the possibilities of developing a whole parasite vaccine for the blood stage and address some of the challenges for this strategy, which are entirely different to the challenges for a subunit vaccine. It is the view of the author that both vaccine paradigms should be pursued, but that success will come more quickly using the paranormal approach of exposing individuals to ultra-low doses of whole attenuated or killed parasites.     

Prospects for nuclear gene phylogeography

In phylogeography, an empirical focus on gene lineages enables the history of population processes to be inferred from the simultaneous analysis of temporal and spatial patterns. Rapidly evolving cytoplasmic DNA has been the empirical workhorse propelling the success of this nascent field. Now, as more sophisticated historical models are being tested, there is a growing need for phylogeography to expand from a largely marker-specific discipline to a more general analytical approach that can be applied across independent loci. Recent results using nuclear haplotypes to study phylogeography indicate that the anticipated technical and biological hurdles can be overcome in many taxa to achieve phylogeographical comparisons across unlinked loci. Although many challenges remain, a more complete understanding of the historical, demographic and selective processes shaping phylogeographical patterns is emerging.     

B-cell depletion in SLE: clinical and trial experience with rituximab and ocrelizumaband implications for study design

B cells are believed to be central to the disease process in systemic lupuserythematosus (SLE), making them a target for new therapeutic intervention. In recentyears there have been many publications regarding the experience in SLE of B-celldepletion utilising rituximab, an anti-CD20 mAb that temporarily depletes B cells,reporting promising results in uncontrolled open studies and in routine clinical use.However, the two large randomised controlled trials in extra-renal lupus (EXPLORERstudy) and lupus nephritis (LUNAR study) failed to achieve their primary endpoints.Based on the clinical experience with rituximab this failure was somewhat unexpectedand raised a number of questions and concerns, not only into the true level ofbenefit of B-cell depletion in a broad population but also how to test the true levelof effectiveness of an investigational agent as we seek to improve the design oftherapeutic trials in SLE. A better understanding of what went wrong in these trialsis essential to elucidate the underlying reasons for the disparate observations notedin open studies and controlled trials. In this review, we focus on various factorsthat may affect the ability to accurately and confidently establish the level oftreatment effect of the investigational agent, in this case rituximab, in the twostudies and explore hurdles faced in the randomised controlled trials investigatingthe efficacy of ocrelizumab, the humanised anti-CD20 mAb, in SLE. Further, based onthe lessons learned from the clinical trials, we make suggestions that could beimplemented in future clinical trial design to overcome the hurdles faced.     

Feedback dynamics and cell function: Why systems biology is called Systems Biology

A new paradigm, like Systems Biology, should challenge the way research has been conducted previously. This Opinion article aims to present Systems Biology, not as the application of engineering principles to biology but as a merger of systems- and control theory with molecular- and cell biology. In our view, the central dogma of Systems Biology is that it is system dynamics that gives rise to the functioning and function of cells. The concepts of feedback regulation and control of pathways and the coordination of cell function are emphasized as an important area of Systems Biology research. The hurdles and risks for this area are discussed from the perspective of dynamic pathway modelling. Most of all, the aim of this article is to promote mathematical modelling and simulation as a part of molecular- and cell biology. Systems Biology is a success if it is widely accepted that there is nothing more practical than a good theory.     

Nuclear transfer: Progress and quandaries

Cloning mammals by nuclear transfer is a powerful technique that is quickly advancing the development of genetically defined animal models. However, the overall efficiency of nuclear transfer is still very low and several hurdles remain before the power of this technique will be fully harnessed. Among these hurdles include an incomplete understanding of biologic processes that control epigenetic reprogramming of the donor genome following nuclear transfer. Incomplete epigenetic reprogramming is considered the major cause of the developmental failure of cloned embryos and is frequently associated with the disregulation of specific genes. At present, little is known about the developmental mechanism of reconstructed embryos. Therefore, screening strategies to design nuclear transfer protocols that will mimic the epigenetic remodeling occurring in normal embryos and identifying molecular parameters that can assess the developmental potential of pre-implantation embryos are becoming increasingly important. A crucial need at present is to understand the molecular events required for efficient reprogramming of donor genomes after nuclear transfer. This knowledge will help to identify the molecular basis of developmental defects seen in cloned embryos and provide methods for circumventing such problems associated with cloning the future application of this technology.     

Clinical hurdles for the transplantation of cardiomyocytes derived from human embryonic stem cells: role of molecular imaging

Over the past few years, human embryonic stem cells (hESCs) have gained popularity as a potentially ideal cell candidate for tissue regeneration. In particular, hESCs are capable of cardiac lineage-specific differentiation and confer improvement of cardiac function following transplantation into animal models. Although such data are encouraging, there remain significant hurdles before safe and successful translation of hESC-based treatment into clinical therapy, including the ability to assess cells following transplant. To this end, molecular imaging has proven a reliable methodology for tracking the long-term fate of transplanted cells. Imaging reporter genes that are introduced into the cells before transplantation enable non-invasive and longitudinal studies of cell viability, location and behaviour in vivo. Therefore, molecular imaging is expected to play an increasing role in characterizing the biology and physiology of hESC-derived cardiac cells in living subjects.     

From nature to creation: Going around in circles,the art of peptide cyclization

Cyclic peptides and cyclotides are becoming common identities within the present efforts seen in peptide engineering – as we seek approaches to achieve potent biological activity, pharmacological selectivity, structurally stability and oral bioavailability. Yet this unique family of peptides has faced uncommon hurdles in their discovery, synthesis and bioengineering, retaining to characteristics that truly deviate these from their linear counterparts. In this mini-review we take a board spectrum approach to introduce this novel family of biomolecules and the troubles that they face in their sequence and disulfide connectivity assignment, together highlighting the present combined strategies involved in cyclic peptide/cyclotide synthesis and modification. These efforts have circumvented otherwise impossible hurdles in their manipulation and production that are only now advancing cyclic peptides/cyclotides as research probes and future pharmaceutical templates.     

Dairy propionibacteria as probiotics: recent evidences

Nowdays there is evidence that dairy propionibacteria display probiotic properties, which as yet have been underestimated. The aim of this paper is to review the recent highlights of data representing the probiotic potential of dairy propionibacteria, studied both by general selection criteria (useful for all probiotic potentials), and by more specific and innovative approach. Dairy propionibacteria show a robust nature, that makes them able to overcome technological hurdles, allowing their future use in various fermented probiotic foods. In addition to the general selection criteria for probiotics in areas such as food safety, technological and digestive stress tolerance, many potential health benefits have been recently described for dairy propionibacteria, including, production of several active molecules and adhesion capability, that can mean a steady action in modulation of microbiota and of metabolic activity in the gut; their impact on intestinal inflammation, modulation of the immune system, potential modulation of risk factors for cancer development modulation of intestinal absorption.     

Strengthening the Case for Epilepsy Drug Development: Bridging Experiences from the Alzheimer’s Disease Field—An Opinion

Given the sheer number of drugs (over 20!) available for treatment of seizures, epilepsy can be considered one of the most successful areas in pharmaceutical development and especially for neuroscience. However, despite the large number of drug treatment options available for managing patients with epilepsy, there remains considerable unmet need. For example, the overall impact on seizure control has not been substantial with approximately 30% of patients remaining refractory or their seizures not adequately controlled. Also there is need for epilepsy prevention and for certain sub-populations with severe intractable epilepsy. High unmet need often drives new industry investment into therapeutic market opportunities, however the profound success of antiepileptic drugs has contributed to the hurdles for industry investment in new therapies for epilepsy. Furthermore, the payor environment has also changed with new challenges for evidence generation and demonstration of additive value above existing standard of care treatments. Challenges in translational science, in the clinical trial environment including cost and operational technical difficulty, and in the commercial environment have resulted in the pharmaceutical industry directing investments away from epilepsy into other therapeutic areas such as oncology and immunology as opportunities for higher probabilities of success and returns of investment. The neuroscience area in general is perceived a high risk area and a notable exception has been the active industry involvement in Alzheimer’s disease (AD), especially for therapeutics that could modify the course or prevent AD. AD is a very high risk area with no successful efficacious treatments found to date despite recent failures, there remains promise that therapies are forthcoming. The promise is fueled by a number of innovative factors that reduced R&D challenges in the AD field and contributed to a high level of drug development activity and investment. This paper addresses hurdles facing epilepsy drug discovery and development and focuses on some key solutions that could be eased to facilitate industry interest. Similarities in drug development challenges provide opportunities that bridge experiences and learnings from AD to epilepsy. Overall, the epilepsy field is probably in a good position for advancing into the next generation therapeutics of antiepileptic drugs targeted for increased efficacy in refractory epilepsy and for antiepileptogenesis.

     

Advances in enteropathogen control in poultry production

Poultry meat has been associated frequently and consistently with the transmission of enteric pathogens, including Salmonella and Campylobacter. This association has resulted in the development of HACCP‐based intervention strategies. These strategies (hurdles) begin with elite breeder flocks and filter down the production pyramid. These hurdles include those already established, such as biosecurity, vaccination, competitive exclusion, pre‐ and probiotics, feed and water control, and those more experimental, such as bacteriophage or immunoglobulin therapy. The reduction in enteropathogens entering the processing plant, which employs critical control points, further reduce the exposure of consumers to these organisms. The synergistic application of hurdles will result in an environment that is restrictive and detrimental to enteropathogen colonization and contamination.     

RiboSubstrates: a web application addressing the cleavage specificities of ribozymes in designated genomes

Background  

RNA-dependent gene silencing is becoming a routine tool used in laboratories worldwide. One of the important remaining hurdles in the selection of the target sequence, if not the most important one, is the designing of tools that have minimal off-target effects (i.e. cleaves only the desired sequence). Increasingly, in the current dawn of the post-genomic era, there is a heavy reliance on tools that are suitable for high-throughput functional genomics, consequently more and more bioinformatic software is becoming available. However, to date none have been designed to satisfy the ever-increasing need for the accurate selection of targets for a specific silencing reagent.     

Nanoparticle Ligand Presentation for Targeting Solid Tumors

Among the many scientific advances to come from the study of nanoscience, the development of ligand-targeted nanoparticles to eliminate solid tumors is predicted to have a major impact on human health. There are many reports describing novel designs and testing of targeted nanoparticles to treat cancer. While the principles of the technology are well demonstrated in controlled lab experiments, there are still many hurdles to overcome for the science to mature into truly efficacious targeted nanoparticles that join the arsenal of agents currently used to treat cancer in humans. One of these hurdles is overcoming unwanted biodistribution to the liver while maximizing delivery to the tumor. This almost certainly requires advances in both nanoparticle stealth technology and targeting. Currently, it continues to be a challenge to control the loading of ligands onto polyethylene glycol (PEG) to achieve maximal targeting. Nanoparticle cellular uptake and subcellular targeting of genes and siRNA also remain a challenge. This review examines the types of ligands that have been most often used to target nanoparticles to solid tumors. As the science matures over the coming decade, careful control over ligand presentation on nanoparticles of precise size, shape, and charge will likely play a major role in achieving success.KEY WORDS: cancer, nanoparticle, targeted delivery     

Short AntiMicrobial Peptides (SAMPs) as a class of extraordinary promising therapeutic agents

The emergence of multidrug resistant bacteria has a direct impact on global public health because of the reduced potency of existing antibiotics against pathogens. Hence, there is a pressing need for new drugs with different modes of action that can kill microorganisms. Antimicrobial peptides (AMPs) can be regarded as an alternative tool for this purpose because they are proven to have therapeutic effects with broad‐spectrum activities. There are some hurdles in using AMPs as clinical candidates such as toxicity, lack of stability and high budgets required for manufacturing. This can be overcome by developing shorter and more easily accessible AMPs, the so‐called S hort A nti M icrobial P eptides (SAMPs) that contain between two and ten amino acid residues. These are emerging as an attractive class of therapeutic agents with high potential for clinical use and possessing multifunctional activities. In this review we attempted to compile those SAMPs that have exhibited biological properties which are believed to hold promise for the future. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.