The Coevolution of Virulence: Tolerance in Perspective

Coevolutionary interactions, such as those between host and parasite, predator and prey, or plant and pollinator, evolve subject to the genes of both interactors. It is clear, for example, that the evolution of pollination strategies can only be understood with knowledge of both the pollinator and the pollinated. Studies of the evolution of virulence, the reduction in host fitness due to infection, have nonetheless tended to focus on parasite evolution. Host-centric approaches have also been proposed—for example, under the rubric of “tolerance”, the ability of hosts to minimize virulence without necessarily minimizing parasite density. Within the tolerance framework, however, there is room for more comprehensive measures of host fitness traits, and for fuller consideration of the consequences of coevolution. For example, the evolution of tolerance can result in changed selection on parasite populations, which should provoke parasite evolution despite the fact that tolerance is not directly antagonistic to parasite fitness. As a result, consideration of the potential for parasite counter-adaptation to host tolerance—whether evolved or medially manipulated—is essential to the emergence of a cohesive theory of biotic partnerships and robust disease control strategies.     

Placebo Trends across the Border: US versus Canada

Background

Physicians around the world report to using placebos in a variety of situations and with varying degrees of frequency. Inconsistent methodologies, however, complicate interpretation and prevent direct comparisons across studies. While US- and Canada-based physicians share similar professional standards, Canada harbours a less-litigious universal healthcare model with no formal placebo-related policy—factors that may impact how physicians view and use placebos.

Methods

To compare American and Canadian data, we circulated an online survey to academic physicians practicing in Canada, collected anonymous responses, and extracted those of internists and rheumatologists for comparison to US data obtained through parallel methodologies.

Results

Whereas our data show overall concordance across the border—from definitions to ethical limitations and therapeutic potential—differences between American- and Canadian-based placebo practices merit acknowledgement. For example, compared to 45%-80% among US-based respondents, only 23±7% of Canada-based respondents reported using placebos in clinical practice. However, 79±7% of Canada-respondents—a figure comparable to US data—professed to prescribing at least one form of treatment without proven or expected efficacy. Placebo interventions including unwarranted vitamins and herbal supplements (impure placebos) as well as sugar pills and saline injections (pure placebos) appear more common in Canada, where more doctors described placebos as “placebos” (rather than “medications”) and used them as a “diagnostic” tool (rather than a means of placating patient demands for treatment).

Interpretation

Cross-border variation in the use of clinical placebos appears minor despite substantial differences in health care delivery system, malpractice climate, and placebo-related policy. The prevalence of impure placebos in both Canadian and US clinics raises ethical and practical questions currently unaddressed by policy and warranting investigation.     

Physicians' Own Health—Some Advice for the Advisors

Information about physicians'' health and health practices is sparse and scattered. With a few exceptions, however—notably suicide and substance abuse—it appears that physicians'' health and health-promotion activities are at least similar to those of the general public. In some areas, such as smoking cessation, physicians have far outstripped the general public. As physicians gain more insight into their own health and health habits, advice to patients can be realistic and effective. Indeed, several personal health activities, including immunization, have direct, salutary impacts on patient care. Physicians should analyze and change their own health practices as indicated and pay special attention to “high yield” health habits, such as seat-belt use.     

Prevalence and Correlates of HIV Testing among Young People Enrolled in Non-Formal Education Centers in Urban Chiang Mai,Thailand: A Cross-Sectional Study

BackgroundHIV testing is the gateway to HIV prevention, treatment, and care. Despite the established vulnerability of young Thai people to HIV infection, studies examining the prevalence and correlates of HIV testing among the general population of Thai youth are still very limited. This study investigates socio-demographic, behavioral, and psychosocial factors associated with HIV testing among young Thai people enrolled in Non-formal Education Centers (NFEC) in urban Chiang Mai, Northern Thailand.MethodsThis was a cross-sectional quantitative study conducted among young unmarried Thai youth—between the ages of 15 and 24—who were enrolled in NFEC in urban Chiang Mai. Multiple logistic regressions were used to identify correlates of “ever tested for HIV” among the sexually active participants.FindingsOf the 295 sexually active participants, 27.3% reported “ever tested for HIV;” 65.4% “did not consistently use condom;” and 61.7% “had at least 2 lifetime partners.” We found that “self-efficacy” (AOR, 4.92; CI, 1.22–19.73); “perception that it is easy to find a location nearby to test for HIV” (AOR, 4.67; CI, 1.21–18.06); “having at least 2 lifetime sexual partners” (AOR, 2.05; CI, 1.09–3.85); and “ever been pregnant or made someone pregnant” (AOR, 4.06; CI, 2.69–9.15); were associated with increased odds of having ever been tested. On the other hand, “fear of HIV test results” (AOR, 0.21; CI, 0.08–0.57) was associated with lower odds of ever having been tested for HIV.ConclusionThe main finding is that a substantially high proportion of Thai youth is engaged in risky sexual behaviors—yet reports low rates of ever having been tested for HIV. This highlights an urgent need to develop appropriate interventions—based on the identified correlates of HIV testing. There is also an urgent need to enhance HIV testing and to promote safer sexual behaviors among young Thai people—particularly those who are out-of-school.     

Use of artificial genomes in assessing methods for atypical gene detection

Parametric methods for identifying laterally transferred genes exploit the directional mutational biases unique to each genome. Yet the development of new, more robust methods—as well as the evaluation and proper implementation of existing methods—relies on an arbitrary assessment of performance using real genomes, where the evolutionary histories of genes are not known. We have used the framework of a generalized hidden Markov model to create artificial genomes modeled after genuine genomes. To model a genome, “core” genes—those displaying patterns of mutational biases shared among large numbers of genes—are identified by a novel gene clustering approach based on the Akaike information criterion. Gene models derived from multiple “core” gene clusters are used to generate an artificial genome that models the properties of a genuine genome. Chimeric artificial genomes—representing those having experienced lateral gene transfer—were created by combining genes from multiple artificial genomes, and the performance of the parametric methods for identifying “atypical” genes was assessed directly. We found that a hidden Markov model that included multiple gene models, each trained on sets of genes representing the range of genotypic variability within a genome, could produce artificial genomes that mimicked the properties of genuine genomes. Moreover, different methods for detecting foreign genes performed differently—i.e., they had different sets of strengths and weaknesses—when identifying atypical genes within chimeric artificial genomes.     

A dynamic formin-dependent deep F-actin network in axons

Although actin at neuronal growth cones is well-studied, much less is known about actin organization and dynamics along axon shafts and presynaptic boutons. Using probes that selectively label filamentous-actin (F-actin), we found focal “actin hotspots” along axons—spaced ∼3–4 µm apart—where actin undergoes continuous assembly/disassembly. These foci are a nidus for vigorous actin polymerization, generating long filaments spurting bidirectionally along axons—a phenomenon we call “actin trails.” Super-resolution microscopy reveals intra-axonal deep actin filaments in addition to the subplasmalemmal “actin rings” described recently. F-actin hotspots colocalize with stationary axonal endosomes, and blocking vesicle transport diminishes the actin trails, suggesting mechanistic links between vesicles and F-actin kinetics. Actin trails are formin—but not Arp2/3—dependent and help enrich actin at presynaptic boutons. Finally, formin inhibition dramatically disrupts synaptic recycling. Collectively, available data suggest a two-tier F-actin organization in axons, with stable “actin rings” providing mechanical support to the plasma membrane and dynamic "actin trails" generating a flexible cytoskeletal network with putative physiological roles.     

Androgen Function in “Psychogenic” and “Constitutional” Types of Impotence

Androgen function was studied in twenty-five physically healthy “primarily” impotent males classified on clinical criteria into “psychogenic” or “constitutional” groups. The mean urinary testosterone level in the former was significantly higher than in the latter group (P<0·005). Important variables associated significantly with higher urinary testosterone levels (P<0·05) were (a) “late onset” impotence, (b) shorter duration than two years, (c) stronger “sex drive,” and (d) an alternative sexual outlet to orgasm and ejaculation in the three months preceding referral; the last-mentioned appeared to be the single most important discriminatory feature.It is suggested that testosterone excretion patterns—namely, high, average, and low—may be one method of classifying impotence.     

Autophagosomes,phagosomes, autolysosomes,phagolysosomes, autophagolysosomes… Wait,I’m confused

When an autophagosome or an amphisome fuse with a lysosome, the resulting compartment is referred to as an autolysosome. Some people writing papers on the topic of autophagy use the terms “autolysosome” and “autophagolysosome” interchangeably. We contend that these words should be used to denote 2 different compartments, and that it is worthwhile maintaining this distinction—the autophagolysosome has a particular origin in the process of xenophagy that makes it distinct from an autolysosome.     

The Hospital Medical Advisory Committee—The Cabinet of the Medical Staff

Before a hospital medical staff can realistically accept responsibility for the professional practices of its members, a principle initially fostered by the American College of Surgeons and adopted by both the Canadian and American accreditation programs, it must have an effectively functioning medical staff organization. The medical advisory committee is the most important committee of the medical staff organization. A representative composition, adherence to sound administrative principles, and recognition of its prime functions of co-ordination, supervision and jurisdiction will permit this committee—and the total medical staff organization—to discharge adequately the very important responsibilities delegated to them by the governing board of the hospital. Properly structured medical staff bylaws with clearly defined terms of reference assist the smooth functioning of the “cabinet” of the medical staff and safeguard the prerogatives of the individual members of the staff.     

THE THORNY CHILD

Too many physicians—and parents—hide behind the overworked excuse that “Johnny is just going through a stage.” If the remark is inaccurate a great disservice can be done to both mother and child, and ultimately to society. The well oriented physician would no more permit a young mother to unwittingly feel “guilty” because her two-year-old “little stinker” behaves like a two-year-old little stinker than he would casually reassure when a ten-year-old behaves as though he were two.Actually much of the unpleasant behavior of children is quite normal. If physicians would help all young mothers to recognize this without dismissing abnormal behavior, it would do much to avert the overwhelming sense of inadequacy that so many modern young mothers feel—especially with their first baby. If they can be made comfortable with their first the others usually come easily. Many physicians who care for children are not trained in the rudiments of developmental behavior. By means of a simple outline and drawing of “the thorny child” even the least of the experts can better understand some of the chronologic variations in developmental behavior.     

Epithelial cell plasticity: breaking boundaries and changing landscapes

Epithelial tissues respond to a wide variety of environmental and genotoxic stresses. As an adaptive mechanism, cells can deviate from their natural paths to acquire new identities, both within and across lineages. Under extreme conditions, epithelial tissues can utilize “shape‐shifting” mechanisms whereby they alter their form and function at a tissue‐wide scale. Mounting evidence suggests that in order to acquire these alternate tissue identities, cells follow a core set of “tissue logic” principles based on developmental paradigms. Here, we review the terminology and the concepts that have been put forward to describe cell plasticity. We also provide insights into various cell intrinsic and extrinsic factors, including genetic mutations, inflammation, microbiota, and therapeutic agents that contribute to cell plasticity. Additionally, we discuss recent studies that have sought to decode the “syntax” of plasticity—i.e., the cellular and molecular principles through which cells acquire new identities in both homeostatic and malignant epithelial tissues—and how these processes can be manipulated for developing novel cancer therapeutics.     

“HIDDEN” ALCOHOLICS—Medical Implications of Undiscovered Addiction

“Hidden alcoholics”—those who drink surreptitiously to keep their addiction secret—far out-number the overt habitues of skid rows. The former rather than the latter should be considered “typical” alcoholics. Even though they have severe problems, they maintain fairly good employment stability and stability in marriage. Yet they steadily deteriorate.Often “hidden” alcoholics go to physicians because of symptoms referable to alcoholism but contrive to conceal their addiction and so make diagnosis difficult. Hence, physicians observing certain kinds of symptoms that cannot be attributed to a readily observable or demonstrable pathologic change should make searching inquiry as to the patient''s drinking habits. For not until the proper diagnosis is made in such cases can there be hope of effective treatment.     

Inferring Social Status and Rich Club Effects in Enterprise Communication Networks

Social status, defined as the relative rank or position that an individual holds in a social hierarchy, is known to be among the most important motivating forces in social behaviors. In this paper, we consider the notion of status from the perspective of a position or title held by a person in an enterprise. We study the intersection of social status and social networks in an enterprise. We study whether enterprise communication logs can help reveal how social interactions and individual status manifest themselves in social networks. To that end, we use two enterprise datasets with three communication channels — voice call, short message, and email — to demonstrate the social-behavioral differences among individuals with different status. We have several interesting findings and based on these findings we also develop a model to predict social status. On the individual level, high-status individuals are more likely to be spanned as structural holes by linking to people in parts of the enterprise networks that are otherwise not well connected to one another. On the community level, the principle of homophily, social balance and clique theory generally indicate a “rich club” maintained by high-status individuals, in the sense that this community is much more connected, balanced and dense. Our model can predict social status of individuals with 93% accuracy.     

The Grand Convergence: Closing the Divide between Public Health Funding and Global Health Needs

The Global Health 2035 report notes that the “grand convergence”—closure of the infectious, maternal, and child mortality gap between rich and poor countries—is dependent on research and development (R&D) of new drugs, vaccines, diagnostics, and other health tools. However, this convergence (and the R&D underpinning it) will first require an even more fundamental convergence of the different worlds of public health and innovation, where a largely historical gap between global health experts and innovation experts is hindering achievement of the grand convergence in health.The Global Health 2035 report notes that the “grand convergence”—closure of the infectious, maternal, and child mortality gap between rich and poor countries—is dependent on research and development (R&D) of new drugs, vaccines, diagnostics, and other health tools. New tools alone are estimated to deliver a 2% decline each year in the under-5 mortality rate, maternal mortality ratio, and deaths from HIV/AIDS and tuberculosis (TB) [1].However, this convergence (and the R&D underpinning it) is unlikely unless we first have an even more fundamental convergence of the parallel worlds of public health and innovation. At the moment, these worlds are often disconnected, with major gaps to be bridged at both the intellectual and practical levels before we can truly reach a grand convergence in health.     

PSYCHIATRY AND THE LAW

In Rex vs. Arnold (1724) it was held that to avail himself of the defense of insanity “a man must be totally deprived of his understanding and memory, so as not to know what he is doing, no more than an infant, a brute, or a wild beast.” Although there has been some modification of this formula in most jurisdictions, the courts still operate under the McNaghten Rule (1843) which is no more logical and actually is more difficult to apply. That such a situation exists in 1956 is a reflection on the indifference of society—and particularly the courts which it elects—as well as on the failure of modern psychiatry to communicate its viewpoint to society. If we are to correct the sad formulae of the “right and wrong” and “policeman at the elbow” tests, we must have more study and better methods of communication in this area.A similar state of confusion exists in the methods of commitment of mentally ill people to psychiatric hospitals. The methods prescribed by law are archaic and cruel—and again reflect the failure of modern psychiatry to communicate its understanding to the legislatures and courts.There are many other areas of conflict between law (which looks to the past for its insights) and psychiatry (which seeks for its concepts in the current scientific advances).     

CRANIOCEREBRAL INJURIES

The postconcussion syndrome is a definite entity, and the patient''s complaints are due to legitimate injury. The following three factors contribute to the symptomatology:1. Headaches, caused by the associated sprain of the cervical spine with resultant radiculitis—giving rise to muscle spasm and suboccipital headaches.2. Vertigo, due to trauma of the vestibular and labyrinthine apparatus.3. A vasomotor imbalance and instability resulting from the reaction to “stress.”In treatment of an unconscious patient great care must be taken to prevent anoxia and to balance the fluids and electrolytes.If coma develops following brain injury, hemorrhage into the cerebellar fossa as well as above the tentorium must be considered.     

What Is Stochastic Resonance? Definitions, Misconceptions, Debates, and Its Relevance to Biology

Stochastic resonance is said to be observed when increases in levels of unpredictable fluctuations—e.g., random noise—cause an increase in a metric of the quality of signal transmission or detection performance, rather than a decrease. This counterintuitive effect relies on system nonlinearities and on some parameter ranges being “suboptimal”. Stochastic resonance has been observed, quantified, and described in a plethora of physical and biological systems, including neurons. Being a topic of widespread multidisciplinary interest, the definition of stochastic resonance has evolved significantly over the last decade or so, leading to a number of debates, misunderstandings, and controversies. Perhaps the most important debate is whether the brain has evolved to utilize random noise in vivo, as part of the “neural code”. Surprisingly, this debate has been for the most part ignored by neuroscientists, despite much indirect evidence of a positive role for noise in the brain. We explore some of the reasons for this and argue why it would be more surprising if the brain did not exploit randomness provided by noise—via stochastic resonance or otherwise—than if it did. We also challenge neuroscientists and biologists, both computational and experimental, to embrace a very broad definition of stochastic resonance in terms of signal-processing “noise benefits”, and to devise experiments aimed at verifying that random variability can play a functional role in the brain, nervous system, or other areas of biology.     

Cephalic and Limb Anatomy of a New Isoxyid from the Burgess Shale and the Role of “Stem Bivalved Arthropods” in the Disparity of the Frontalmost Appendage

We herein describe Surusicaris elegans gen. et sp. nov. (in Isoxyidae, amended), a middle (Series 3, Stage 5) Cambrian bivalved arthropod from the new Burgess Shale deposit of Marble Canyon (Kootenay National Park, British Columbia). Surusicaris exhibits 12 simple, partly undivided biramous trunk limbs with long tripartite caeca, which may illustrate a plesiomorphic “fused” condition of exopod and endopod. We construe also that the head is made of five somites (= four segments), including two eyes, one pair of anomalocaridid-like frontalmost appendages, and three pairs of poorly sclerotized uniramous limbs. This fossil may therefore be a candidate for illustrating the origin of the plesiomorphic head condition in euarthropods, and questions the significance of the “two-segmented head” in, e.g., fuxianhuiids. The frontalmost appendage in isoxyids is intriguingly disparate, bearing similarities with both dinocaridids and euarthropods. In order to evaluate the relative importance of bivalved arthropods, such as Surusicaris, in the hypothetical structuro-functional transition between the dinocaridid frontal appendage and the pre-oral—arguably deutocerebral—appendage of euarthropods, we chose a phenetic approach and computed morphospace occupancy for the frontalmost appendages of 36 stem and crown taxa. Results show different levels of evolutionary decoupling between frontalmost appendage disparity and body plans. Variance is greatest in dinocaridids and “stem bivalved” arthropods, but these groups do not occupy the morphospace homogeneously. Rather, the diversity of frontalmost appendages in “stem bivalved” arthropods, distinct in its absence of clear clustering, is found to link the morphologies of “short great appendages,” chelicerae and antennules. This find fits the hypothesis of an increase in disparity of the deutocerebral appendage prior to its diversification in euarthropods, and possibly corresponds to its original time of development. The analysis of this pattern, however, is sensitive to the—still unclear—extent of polyphyly of the “stem bivalved” taxa.     

Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism,the field effect and genomic instability in cancer cells

Loss of stromal fibroblast caveolin-1 (Cav-1) is a powerful single independent predictor of poor prognosis in human breast cancer patients, and is associated with early tumor recurrence, lymph node metastasis and tamoxifen-resistance. We developed a novel co-culture system to understand the mechanism(s) by which a loss of stromal fibroblast Cav-1 induces a “lethal tumor microenvironment.” Here, we propose a new paradigm to explain the powerful prognostic value of stromal Cav-1. In this model, cancer cells induce oxidative stress in cancer-associated fibroblasts, which then acts as a “metabolic” and “mutagenic” motor to drive tumor-stroma co-evolution, DNA damage and aneuploidy in cancer cells. More specifically, we show that an acute loss of Cav-1 expression leads to mitochondrial dysfunction, oxidative stress and aerobic glycolysis in cancer associated fibroblasts. Also, we propose that defective mitochondria are removed from cancer-associated fibroblasts by autophagy/mitophagy that is induced by oxidative stress. As a consequence, cancer associated fibroblasts provide nutrients (such as lactate) to stimulate mitochondrial biogenesis and oxidative metabolism in adjacent cancer cells (the “Reverse Warburg effect”). We provide evidence that oxidative stress in cancer-associated fibroblasts is sufficient to induce genomic instability in adjacent cancer cells, via a bystander effect, potentially increasing their aggressive behavior. Finally, we directly demonstrate that nitric oxide (NO) over-production, secondary to Cav-1 loss, is the root cause for mitochondrial dysfunction in cancer associated fibroblasts. In support of this notion, treatment with anti-oxidants (such as N-acetyl-cysteine, metformin and quercetin) or NO inhibitors (L-NAME) was sufficient to reverse many of the cancer-associated fibroblast phenotypes that we describe. Thus, cancer cells use “oxidative stress” in adjacent fibroblasts (1) as an “engine” to fuel their own survival via the stromal production of nutrients and (ii) to drive their own mutagenic evolution towards a more aggressive phenotype, by promoting genomic instability. We also present evidence that the “field effect” in cancer biology could also be related to the stromal production of ROS and NO species. eNOS-expressing fibroblasts have the ability to downregulate Cav-1 and induce mitochondrial dysfunction in adjacent fibroblasts that do not express eNOS. As such, the effects of stromal oxidative stress can be laterally propagated, amplified and are effectively “contagious”—spread from cell-to-cell like a virus—creating an “oncogenic/mutagenic” field promoting widespread DNA damage.Key words: caveolin-1, cancer associated fibroblasts, oxidative stress, reactive oxygen species (ROS), mitochondrial dysfunction, autophagy, nitric oxide (NO), DNA damage, aneuploidy, genomic instability, anti-oxidant cancer therapy, the “field effect” in cancer biology