A novel machine learning-based approach for the computational functional assessment of pharmacogenomic variants

Background: The field of pharmacogenomics focuses on the way a person’s genome affects his or her response to a certain dose of a specified medication. The main aim is to utilize this information to guide and personalize the treatment in a way that maximizes the clinical benefits and minimizes the risks for the patients, thus fulfilling the promises of personalized medicine. Technological advances in genome sequencing, combined with the development of improved computational methods for the efficient analysis of the huge amount of generated data, have allowed the fast and inexpensive sequencing of a patient’s genome, hence rendering its incorporation into clinical routine practice a realistic possibility. Results: The potential availability of a vast number of identified genetic variants in a clinical setting highlights the necessity of developing a method to evaluate and prioritize this information towards its exploitation in guiding medication or dosing scheme systematically and effectively. In this direction, the present study examines the development of a computational model that can classify new variants according to their possible effects on protein function, which in turn affects drug response, by using as a training set a dataset of functionally validated single nucleotide variants (SNVs) located in pharmacogenes. Conclusion: Overall, the proposed model holds promise to lead to an extremely useful variant prioritization and scoring tool with interesting clinical applications in pharmacogenomics.

Deep Sea Mining Partnerships with Developing States: Favourable Collaborations or Opportunistic Endeavours?

In order to engage in deep sea mining activities on the international seabed (otherwise known as ‘the Area’), non-State actors must be sponsored by a State, which bears the responsibility to ensure that the sponsored entity complies with the applicable rules. Not only the State of nationality, but also the State which exercises ‘effective control’ might be required to serve as a sponsoring State, depending on the circumstances. However, it is not completely clear how ‘effective control’ should be interpreted. Forum shopping seems a realistic possibility, and the recent trend of partnerships between private deep sea mining companies and developing States can produce similar effects. These collaborations might be beneficial to both parties, but given the privileges awarded to developing States, it should be scrutinised as to whether such partnerships undermine the principle of the common heritage of mankind and the objective to realise benefits for mankind as a whole.

Advances and Perspectives in Dental Pulp Stem Cell Based Neuroregeneration Therapies

Human dental pulp stem cells (hDPSCs) are some of the most promising stem cell types for regenerative therapies given their ability to grow in the absence of serum and their realistic possibility to be used in autologous grafts. In this review, we describe the particular advantages of hDPSCs for neuroregenerative cell therapies. We thoroughly discuss the knowledge about their embryonic origin and characteristics of their postnatal niche, as well as the current status of cell culture protocols to maximize their multilineage differentiation potential, highlighting some common issues when assessing neuronal differentiation fates of hDPSCs. We also review the recent progress on neuroprotective and immunomodulatory capacity of hDPSCs and their secreted extracellular vesicles, as well as their combination with scaffold materials to improve their functional integration on the injured central nervous system (CNS) and peripheral nervous system (PNS). Finally, we offer some perspectives on the current and possible future applications of hDPSCs in neuroregenerative cell therapies.

Head Wounds Received During Force-on-Force Training With Non-lethal Ammunition

ABSTRACT Close quarters combat training is designed to replicate the mental and physiological stressors of firing upon an adversary while in close proximity. One method to replicate combat stressors is to use non-lethal training ammunition specifically designed for force-on-force exercises. These rounds can be fired from slightly modified service-issued weapons and provide a pain sensation upon striking the opponent. The current investigation presents a case study of several injuries when these rounds impacted the head directly, which is a primary area of concern for safety issues. Most impacts produced initial swelling that reduced substantially within the first few hours. Approximately 24 hours later, the swelling disappeared entirely with a visible contusion near the impact center. Bruising would typically clear within a few days. However, another example produced sufficient bleeding to require intervention before continuing with the training exercises and sanguineous crust or scabbing rather than the typical contusion. Pain was minimal for all wounds after only several days, which aligns with previous research on pain from non-lethal training ammunition wounds. Based on the head wounds observed here, loss of eyesight is a realistic possibility. Eye protection should be a requisite across all force-on-force training exercises without exception. This case study documents some potential hazards of force-on-force training, but more importantly, it further highlights the need for medically informed training standards about engagement distances and personal protective equipment.

Cell Transplantation to Restore Lost Auditory Nerve Function is a Realistic Clinical Opportunity

Hearing is one of our most important means of communication. Disabling hearing loss (DHL) is a long-standing, unmet problem in medicine, and in many elderly people, it leads to social isolation, depression, and even dementia. Traditionally, major efforts to cure DHL have focused on hair cells (HCs). However, the auditory nerve is also important because it transmits electrical signals generated by HCs to the brainstem. Its function is critical for the success of cochlear implants as well as for future therapies for HC regeneration. Over the past two decades, cell transplantation has emerged as a promising therapeutic option for restoring lost auditory nerve function, and two independent studies on animal models show that cell transplantation can lead to functional recovery. In this article, we consider the approaches most likely to achieve success in the clinic. We conclude that the structure and biochemical integrity of the auditory nerve is critical and that it is important to preserve the remaining neural scaffold, and in particular the glial scar, for the functional integration of donor cells. To exploit the natural, autologous cell scaffold and to minimize the deleterious effects of surgery, donor cells can be placed relatively easily on the surface of the nerve endoscopically. In this context, the selection of donor cells is a critical issue. Nevertheless, there is now a very realistic possibility for clinical application of cell transplantation for several different types of hearing loss.

Understanding the unimodal distributions of cancer occurrence rates: it takes two factors for a cancer to occur

Data from the SEER reports reveal that the occurrence rate of a cancer type generally follows a unimodal distribution over age, peaking at an age that is cancer-type specific and ranges from 30+ through 70+. Previous studies attribute such bell-shaped distributions to the reduced proliferative potential in senior years but fail to explain why some cancers have their occurrence peak at 30+ or 40+. We present a computational model to offer a new explanation to such distributions. The model uses two factors to explain the observed age-dependent cancer occurrence rates: cancer risk of an organ and the availability level of the growth signals in circulation needed by a cancer type, with the former increasing and the latter decreasing with age. Regression analyses were conducted of known occurrence rates against such factors for triple negative breast cancer, testicular cancer and cervical cancer; and all achieved highly tight fitting results, which were also consistent with clinical, gene-expression and cancer-drug data. These reveal a fundamentally important relationship: while cancer is driven by endogenous stressors, it requires sufficient levels of exogenous growth signals to happen, hence suggesting the realistic possibility for treating cancer via cleaning out the growth signals in circulation needed by a cancer.

PHOTOGRAMMETRIC SOLUTIONS FOR 3D MODELING OF CULTURAL HERITAGE SITES IN REMOTE AREAS

The realistic possibility of using non-metric digital cameras to achieve reliable 3D models has eased the application of photogrammetry in different domains. Documentation, conservation and dissemination of the Cultural Heritage (CH) can be obtained and implemented through virtual copies and replicas. Structure-from-Motion (SfM) photogrammetry has widely proven its impressive potential for image-based 3D reconstruction resulting in great 3D point clouds’ acquisitions but at minimal cost. Images from Unmanned Aerial Vehicles (UAVs) can be also processed within SfM pipeline to obtain point cloud of Cultural Heritage sites in remote regions. Both aerial and terrestrial images can be integrated to obtain a more complete 3D. In this paper, the application of SfM photogrammetry for surveying of the Ziggurat Chogha Zanbil in Iran is presented. Here point clouds have been derived from oblique and nadir photos captured from UAV as well as terrestrial photos. The obtained four point clouds have been compared on the basis of different techniques to highlight differences among them.

Technologies for the Production of Fertilizable Mammalian Oocytes

Women affected by ovarian pathologies or with cancer can usually preserve fertility by egg/embryo freezing. When oocyte retrieval is not feasible, the only option available is ovarian tissue cryopreservation and transplantation. The culture of follicles isolated from fresh or cryopreserved ovaries is considered still experimental, although this procedure is considered safer, because the risk of unintentional spreading of cancer cells eventually present in cryopreserved tissue is avoided. Animal and human small follicles can be cultured in vitro, but standardized protocols able to produce in vitro grown oocytes with the same developmental capacity of in vivo grown oocytes are not available yet. In fact, the different sizes of follicles and oocytes, the hormonal differences existing between mono- (e.g., human, goat, cow, and sheep) and poly-ovulatory (rodents and pig) species, and the incomplete identification of the mechanisms regulating the oocyte–follicle and follicle–ovary interrelationships affect the outcome of in vitro culture. From all these attempts, however, new ideas arise, and the goal of assuring the preservation of female reproductive potential appears a more realistic possibility. This review surveys and discusses advances and challenges of these technologies that, starting from a simple attempt, are now approaching the biosynthesis of a functional engineered ovary.

Anarchism

Anarchism is the view that a society without the state, or government, is both possible and desirable. Although there have been intimations of the anarchist outlook throughout history, anarchist ideas emerged in their modern form in the late eighteenth and early nineteenth centuries in the wake of the French and Industrial Revolutions. All anarchists support some version of each of the following broad claims: (1) people have no general obligation to obey the commands of the state; (2) the state ought to be abolished; (3) some kind of stateless society is possible and desirable; (4) the transition from state to anarchy is a realistic prospect Within this broad framework there is a rich variety of anarchist thought. The main political division is between the ‘classical’ or socialist school, which tends to reject or restrict private property, and the ‘individualist’ or libertarian tradition, which defends private acquisition and looks to free market exchange as a model for the desirable society. Philosophical differences follow this division to some extent, the classical school appealing principally to natural law and perfectionist ethics, and the individualists to natural rights and egoism. Another possible distinction is between the ‘old’ anarchism of the nineteenth century (including both the classical and individualist traditions) and the ‘new’ anarchist thought that has developed since the Second World War, which applies the insights of such recent ethical currents as feminism, ecology and postmodernism. Anarchists have produced powerful arguments denying any general obligation to obey the state and pointing out the ill effects of state power. More open to question are their claims that states ought to be abolished, that social order is possible without the state and that a transition to anarchy is a realistic possibility.