Trypanosomal immune evasion, chronicity and transmission: an elegant balancing act

During their life cycle, trypanosomes must overcome conflicting demands to ensure their survival and transmission. First, they must evade immunity without overwhelming the host. Second, they must generate and maintain transmission stages at sufficient levels to allow passage into their tsetse vector. Finally, they must rapidly commit to onward development when they enter the tsetse fly. On the basis of recent quantification and modelling of Trypanosoma brucei infection dynamics, we propose that the interplay between immune evasion and development achieves both infection chronicity and transmissibility. Moreover, we suggest that a novel form of bistable regulation ensures developmental commitment on entry into the tsetse fly midgut.     

极化上皮细胞中转运蛋白的分选

上皮组织细胞必须极化其表面区域以执行其转运生理功能。不同膜转运蛋白定位于细胞膜的不同区域,而细胞与细胞之间则须通过紧密连接复合体紧密连接成极化区域,并调节旁细胞途径的通透性。精密的机体要求上皮细胞具备一个筛选装置,用于将新合成的转运蛋白定位于合适的表面区域;转运蛋白本身也必须内含规定其功能位置的分选信号。目前上皮细胞蛋白分选和蛋白质之间相互作用已被逐渐阐明。上皮细胞通过细胞信号转导途径形成极化初始状态,将自己定位于特定位置,调节细胞与细胞之间、细胞与基质之问的相互作用。最近研究发现其信号转导通路的一个成员是一种AMP激活的蛋白激酶（AMP-stimulated protein kinase．AMPK）,它也是细胞能量感受器。     

Informed consent and nudging

In order to avoid patient abuse, under normal situations before performing a medical intervention on a patient, a physician must obtain informed consent from that patient, where to give genuine informed consent a patient must be competent, understand her condition, her options and their expected risks and benefits, and must expressly consent to one of those options. However, many patients refrain from the option that their physician believes to be best, and many physicians worry that their patients make irrational healthcare decisions, hindering their ability to provide efficient healthcare for their patients. Some philosophers have proposed a solution to this problem: they advocate that physicians nudge their patients to steer them towards their physician's preferred option. A nudge is any influence designed to predictably alter a person's behavior without limiting their options or giving them reasons to act. Proponents of nudging contend that nudges are consistent with obtaining informed consent. Here I argue that nudging is incompatible with genuine informed consent, as it violates a physician's obligation to tell their patients the truth, the whole truth, and nothing but the truth during adequate disclosure.     

Protein import into chloroplasts

The structural complexity of chloroplasts is reflected in their intriguing protein-targeting system. Not only must nucleus-encoded proteins be targeted to the chloroplast, but also, once inside the chloroplast, these polypeptides must be directed to their final destination in one of six intrachloroplastic compartments. Although the details of this process remain elusive, many recent advances have improved our vantage point for examining this system.     

Active sensation: insights from the rodent vibrissa sensorimotor system

Rats sweep their vibrissae through space to locate objects in their immediate environment. In essence, their view of the proximal world is generated through pliable hairs that tap and palpate objects. The texture and shape of those objects must be discerned for the rat to assess the value of the object. Furthermore, the location of those objects must be specified with reference to the position of the rat's head for the rat to plan its movements. Recent in vivo and in vitro electrophysiological measurements provide insight into the algorithms and mechanisms that underlie these behavioral-based computations.     

Organellar genes: why do they end up in the nucleus?

Many mitochondrial and plastid proteins are derived from their bacterial endosymbiotic ancestors, but their genes now reside on nuclear chromosomes instead of remaining within the organelle. To become an active nuclear gene and return to the organelle as a functional protein, an organellar gene must first be assimilated into the nuclear genome. The gene must then be transcribed and acquire a transit sequence for targeting the protein back to the organelle. On reaching the organelle, the protein must be properly folded and modified, and in many cases assembled in an orderly manner into a larger protein complex. Finally, the nuclear copy must be properly regulated to achieve a fitness level comparable with the organellar gene. Given the complexity in establishing a nuclear copy, why do organellar genes end up in the nucleus? Recent data suggest that these genes are worse off than their nuclear and free-living counterparts because of a reduction in the efficiency of natural selection, but do these population-genetic processes drive the movement of genes to the nucleus? We are now at a stage where we can begin to discriminate between competing hypotheses using a combination of experimental, natural population, bioinformatic and theoretical approaches.     

Lay concepts in informed consent to biomedical research: the capacity to understand and appreciate risk

Persons generally must give their informed consent to participate in research. To provide informed consent persons must be given information regarding the study in simple, lay language. Consent must be voluntary, and persons giving consent must be legally competent to consent and possess the capacity to understand and appreciate the information. This paper examines the relationship between the obligation to disclose information regarding risks and the requirement that persons have the capacity to understand and appreciate the information. There has been insufficient attention to the extent to which persons must be able to understand and appreciate study information in order to have their consent deemed valid when the information is provided in simple, lay language. This paper argues that (1) the capacity to understand and appreciate information that should be deemed necessary to give valid consent should be defined by the capacity of the typical, cognitively normal adult and (2) the capacity of the typical, cognitively normal adult to understand and appreciate the concept of risk is limited. Therefore, (3) all things being equal, potential subjects must possess a limited capacity to understand and appreciate risk to be deemed competent to consent to research participation. (4) In some cases investigators ought to require that persons possess a greater than typical capacity to understand and appreciate risk.     

Health policy and ethnic diversity in older Americans. Dissonance or harmony?

The rapid growth and diversity of the older population have long-term implications for health care policies in the United States. Current policies designed for a homogeneous population are increasingly obsolete. To ameliorate obstacles that handicap many ethnic minority elders and to provide equal access to adequate and acceptable health care, several factors need to be considered. Enhanced data collection and analytic techniques are needed. The effects of race or ethnicity must be separated from other biologic, environmental, socioeconomic, cultural, and temporal factors on health status and behavior. Health care professionals and organizations serving minority elders must continue to expand their advocacy efforts to articulate the findings and their concerns to policymakers. Policymakers must understand and acknowledge the implications of an increasingly diverse society and determine what will constitute adequate, accessible, and acceptable health care within continuing fiscal constrains. Program planning, implementation, and evaluation methods must be revised to meet future health care needs effectively and efficiently.     

Justifying Community Benefit Requirements in International Research

It is widely agreed that foreign sponsors of research in low‐ and middle‐income countries (LMICs) are morally required to ensure that their research benefits the broader host community. There is no agreement, however, about how much benefit or what type of benefit research sponsors must provide, nor is there agreement about what group of people is entitled to benefit. To settle these questions, it is necessary to examine why research sponsors have an obligation to benefit the broader host community, not only their subjects. Justifying this claim is not straightforward. There are three justifications for an obligation to benefit host communities that each apply to some research, but not to all. Each requires a different amount of benefit, and each requires benefit to be directed toward a different group. If research involves significant net risk to LMIC subjects, research must provide adequate benefit to people in LMICs to avoid an unjustified appeal to subjects’ altruism. If research places significant burdens on public resources, research must provide fair compensation to the community whose public resources are burdened. If research is for profit, research sponsors must contribute adequately to the upkeep of public goods from which they benefit in order to avoid the wrong of free‐riding, even if their use of these public goods is not burdensome.     

Review of the morbidity of 300 free-flap donor sites

Donor-site morbidity in 300 consecutive free flaps was reviewed to identify their etiologies and potentially prevent their recurrence in future cases. An overall morbidity rate of 20 percent was seen in this series. Secondary surgical procedures specific for donor-site problems were required in 7.7 percent of patients. Major complications occurred in 2.3 percent of the donor sites. From this review it is apparent that major donor-site morbidity is uncommon and most donor-site problems could probably have been avoided. Our recommendations are as follows: closure of the donor site to avoid excessive tension must be carefully planned preoperatively, donor-site anatomy and flap elevation techniques must be precisely understood, surgical retractors must be carefully placed to avoid injury to nearby structures, the donor site should be closed immediately following pedicle division, thus minimizing wound exposures, and complete surgical hemostasis is mandatory.     

Glycosyltransferases and glycan structures contributing to the adhesive activities of L-, E- and P-selectin counter-receptors

In mammals, leucocytes of the adaptive and innate immune systems must move from their sites of origin to sites of maturation, or to where they are deployed against the invasion of pathogens. The vascular tree serves as the primary throughfare by which leucocytes move to these various destinations. Adhesion must be established between the leucocyte and the endothelial cells that line the vascular tree to enable leucocytes to escape the vascular compartment and then contribute to extravascular immune processes. A major fraction of these leucocyte-endothelial-cell adhesive events initiate with, and require interactions between, the selectin family of cell adhesion molecules and their glycoconjugate counter-receptors. This article will review the structures of the glycan components of these counter-receptors, and the glycosyltransferases that control their expression.     

Methods, equipment and techniques for rural health care and their evaluation

It is obvious that any strategy for village health care must involve the people actively--something that is more easily said than done. There is hardly any technology for rural health that does not have a significant software component. Why is it that so much that is known cannot be applied? What factors may be important in the diffusion of technology in a rural society? Technology must address itself to the needs as perceived by the people (in addition to what is perceived as their needs by the health care system). It must be compatible with the knowledge and skill levels of the community. Benefits must be visible to the community through appropriate assessment and feedback procedures so as to secure greater and greater involvement.     

Beyond the ABCs: ternary complex formation in the control of floral organ identity

The production of a flower requires several events to occur. A floral meristem must form, boundaries must be set to enable discrete primordia to arise and the primordia must adopt the correct organ identity. Homeotic mutants, whose organs adopt inappropriate identities for their position within the flower, have helped the construction of a simple combinatorial model to explain how floral organ identity is defined. However, recent experiments suggest that the regulation of floral organ identity is more complex than was previously apparent. The simple interactions are becoming more complex and the universal applicability of the model less clear.     

Reanimation of the long-standing partial facial paralysis

Those unfortunate people who suffer from permanent partial facial paralysis have great difficulty finding surgeons who can offer corrective operations. Improving their function is a most delicate procedure. Great care must be exercised to avoid injuring nerves and muscles which are still operating, although in a greatly diminished state. The pathogenesis must be understood before attempting any corrective procedure. Adequate time must elapse from the moment of injury to surgical intervention, thus allowing for maximal nerve and muscle regeneration. This paper describes techniques that could improve facial movements. The most frequently used procedure is shortening of the levator and/or the zygomatic muscles that are partially atrophied. It must be understood that total reanimation is impossible as of this time.     

Mechanisms of stage-regulated gene expression in kinetoplastida

During their life cycle, trypanosomatid parasites of mammals encounter substantially different environments in their hosts and insect vectors, to which they must adapt by undergoing a series of differentiation processes. At the molecular level, these processes must be the direct result of an elaborate series of changes in stage-regulated expression of a wide range of gene products. How are these changes accomplished? In this review, Sheila Graham discusses some recent advances in understanding the mechanisms of gene expression in trypanosomatids, and examines some clues to some intriguingly complex means of regulating life cycle stage-specific gene expression.     

Equilibrium theory and paleoecology

Although several paleontologists have recently attempted to apply MacArthur & Wilson's equilibrium theory to the fossil record, their efforts have not met with overwhelming success. The major difficulties have involved the use of questionable methodologies and the application of a fundamentally inappropriate theoretical base. In the first category it appears as if previous methods of data collection and their subsequent analyses must be critically reviewed in order to adequately test the equilibrium theory. Thus detailed species lists that include population numbers must be compiled for spatially restricted habitats. Sampling of local stratigraphic sections must be carried out on a centimeter by centimeter basis rather than at meter intervals. It appears most likely that the use of colonization curves, coupled with a determination of species saturation levels, will provide a rigorous, quantitative technique for the analysis of equilibrium states. It has become obvious over the past ten years that paleoecologists need to be more critical in their application of ecological theories to the fossil record and in substantiation of this claim, and contrary to earlier reports, it seems as if a valid test of the equilibrium theory in the fossil record has yet to be made.     

Bioethics for clinicians: 10. Research ethics

Medical research involving human subjects raises complex ethical, legal and social issues. Investigators sometimes find that their obligations with respect to a research project come into conflict with their obligations to individual patients. The ethical conduct of research rests on 3 guiding principles: respect for persons, beneficience, and justice. Respect for persons underlies the duty to obtain informed consent from study participants. Beneficence demands a favourable balance between the potential benefits and harms of participation. Justice requires that vulnerable people not be exploited and that eligible candidates who may benefit from participation not be excluded without good cause. Studies must be designed in a way that ensures the validity of findings and must address questions of sufficient importance to justify the risks of participation. In any clinical trial there must be genuine uncertainty as to which treatment arm offers the most benefit, and placebo controls should not be used if effective standard therapies exist. Researchers have a responsibility to inform themselves about the ethical, legal and policy standards that govern their activities. When difficulties arise, they should consult the existing literature and seek the advice of experts in research ethics.     

Higher alcohol and acetoin production by Zygosaccharomyces wine yeasts

Seventy strains of Zygosaccharomyces isolated from grape musts were investigated for their ability to produce higher alcohols and acetoin in synthetic medium and grape must. The Zygosaccharomyces strains produced generally low amounts of higher alcohols. Within this genus, Z. fermentati behaved differently from Z. bailii producing less isobutanol in synthetic medium and more amyl alcohols and isobutanol in grape must. Zygosaccharomyces fermentati did not form detectable amounts of acetoin in any conditions whereas Z. bailii produced it both in synthetic medium and in grape must. These strains were found to contribute to aroma and taste of wine.     

The tail,locomotion and balance in mice

The locomotor patterns of normal and tailless mice were studied. Two modes of locomotion were observed suggesting that when deprived of their tails, mice must alter their locomotor patterns to assure good balance.     

Visualizing protein movement on DNA at the single-molecule level using DNA curtains

A fundamental feature of many nucleic-acid binding proteins is their ability to move along DNA either by diffusion-based mechanisms or by ATP-hydrolysis driven translocation. For example, most site-specific DNA-binding proteins must diffuse to some extent along DNA to either find their target sites, or to otherwise fulfill their biological roles. Similarly, nucleic-acid translocases such as helicases and polymerases must move along DNA to fulfill their functions. In both instances, the proteins must also be capable of moving in crowded environments while navigating through DNA-bound obstacles. These types of behaviors can be challenging to analyze by bulk biochemical methods because of the transient nature of the interactions, and/or heterogeneity of the reaction intermediates. The advent of single-molecule methodologies has overcome some of these problems, and has led to many new insights into the mechanisms that contribute to protein motion along DNA. We have developed DNA curtains as a tool to facilitate single molecule observations of protein-nucleic acid interactions, and we have applied these new research tools to systems involving both diffusive-based motion as well as ATP directed translocation. Here we highlight these studies by first discussing how diffusion contributes to target searches by proteins involved in post-replicative mismatch repair. We then discuss DNA curtain assays of two different DNA translocases, RecBCD and FtsK, which participate in homologous DNA recombination and site-specific DNA recombination, respectively.