Alternative signaling pathways: when, where and why?

Alternative cell signal transduction pathways have been demonstrated in some experimental systems. The importance of their existence has not been completely appreciated. In this review we present the cases of alternative pathways resulted from a survey of the available experimental data. The alternative pathways could show different relationships, i.e., synergistic, redundant, additive, opposite and competitive effects. They could have distinct time courses and cell, organ, sex or species specification. Further, they could happen during physiological or pathological situations, and display differentiated sensitivity. These case studies together imply that alternative signal pathways could be involved in the regulation of cell functions at the pathway level. In-depth understanding of the importance of the alternative pathways will rely on building and exploration of mathematical models.     

Avian sex determination: what, when and where?

Sex is determined genetically in all birds, but the underlying mechanism remains unknown. All species have a ZZ/ZW sex chromosome system characterised by female (ZW) heterogamety, but the chromosomes themselves can be heteromorphic (in most birds) or homomorphic (in the flightless ratites). Sex in birds might be determined by the dosage of a Z-linked gene (two in males, one in females) or by a dominant ovary-determining gene carried on the W sex chromosome, or both. Sex chromosome aneuploidy has not been conclusively documented in birds to differentiate between these possibilities. By definition, the sex chromosomes of birds must carry one or more sex-determining genes. In this review of avian sex determination, we ask what, when and where? What is the nature of the avian sex determinant? When should it be expressed in the developing embryo, and where is it expressed? The last two questions arise due to evidence suggesting that sex-determining genes in birds might be operating prior to overt sexual differentiation of the gonads into testes or ovaries, and in tissues other than the urogenital system.     

Homo erectus: Ancestor or evolutionary side branch?

Controversies in paleoanthropology wax and wane, but substantial interest is currently focused on Homo erectus. This species has traditionally been regarded as a member in good standing of the human family, where it is placed as an evolutionary intermediate between earlier Homo habilis and later Homo sapiens. Recently, however, some workers have questioned whether the species exists at all. If its populations have been transformed slowly toward the modern condition, and if continuity with living people can be demonstrated in many geographic regions, then any separation of Homo erectus from Homo sapiens must be largely arbitrary. In that case, only one species should be recognized and this slowly changing lineage would have to be called Homo sapiens. Other paleontologists adopt a different view, arguing that Homo erectus is not only anatomically distinctive but also restricted in its geographic distribution. They claim that the fossils from Java and China are so specialized in appearance that they cannot lie in the mainstream of human evolution. Homo erectus, strictly defined as limited to the Far East, probably went extinct without issue. If so, more modern populations must have evolved from another source, perhaps one outside of Asia altogether.     

Biofeedback in medicine: who,when, why and how?

Biofeedback is a mind-body technique in which individuals learn how to modify their physiology for the purpose of improving physical, mental, emotional and spiritual health. Much like physical therapy, biofeedback training requires active participation on the part of patients and often regular practice between training sessions. Clinical biofeedback may be used to manage disease symptoms as well as to improve overall health and wellness through stress management training. Research has shown that biofeedback interventions are efficacious in treating a variety of medical conditions, and many Americans are turning to biofeedback and other less traditional therapies for their routine healthcare.Clinical biofeedback training is growing increasingly popular in the USA, as many people are seeking out relatively new approaches to healthcare. This article provides an overview of clinical biofeedback training, outlines two models of training, details research which has established how effective biofeedback is in patients with a given disease, and describes who should be referred for biofeedback training.     

Breaching the basement membrane: who, when and how?

The basement membrane (BM), a specialized network of extracellular matrix macromolecules, surrounds epithelial, endothelial, muscle, fat and nerve cells. During development, immune surveillance and disease states ranging from cancer to fibrosis, host cells penetrate the BM by engaging tissue-invasive programs, the identity of which remain largely undefined. Although it is commonly assumed that all cells employ similar mechanisms to cross BM barriers, accumulating evidence indicates that cells might selectively mobilize protease-dependent or -independent invasion programs. New data indicate that protease-dependent transmigration is largely reliant on a group of membrane-anchored metalloenzymes, termed the membrane-type matrix metalloproteinases, which irreversibly remodel BM structure. By contrast, mechanisms that enable protease-independent transmigration remain undefined and potentially involve the reversible disassembly of the BM network. Further characterization of the molecular mechanisms underlying BM transmigration should provide important insights into pathophysiologic tissue remodeling events and also enable the development of novel therapeutics.     

Episodic memory in nonhumans: what, and where, is when?

Episodic memory is defined as the recollection of specific events in one's past, accompanied by the experience of having been there personally. This definition presents high hurdles to the investigation of episodic memory in nonhumans. Recent studies operationalize episodic memory as memory for when and where an event occurred, for the order in which events occurred, or for an animal's own behavior. None of these approaches has yet generalized across species, and each fails to capture features of human episodic memory. Nonetheless, the study of episodic memory in nonhumans seems less daunting than it did five years ago. To demonstrate a correspondence between human episodic memory and nonhuman memory, progress is needed in three areas. Putative episodic memories in nonhumans should be shown to be; first, represented in long-term memory, rather than short-term or working memory; second, explicit, or accessible to introspection; and third, distinct from semantic memory, or general knowledge about the world.     

Plant species radiations: where,when, why?

The spatial and temporal patterns of plant species radiations are largely unknown. I used a nonlinear regression to estimate speciation and extinction rates from all relevant dated clades. Both are surprisingly high. A high species richness can be the result of either little extinction, thus preserving the diversity that dates from older radiations (a 'mature radiation'), or a 'recent and rapid radiation'. The analysis of radiations from different regions (Andes, New Zealand, Australia, southwest Africa, tropics and Eurasia) revealed that the diversity of Australia may be largely the result of mature radiations. This is in sharp contrast to New Zealand, where the flora appears to be largely the result of recent and rapid radiations. Mature radiations are characteristic of regions that have been climatically and geologically stable throughout the Neogene, whereas recent and rapid radiations are more typical of younger (Pliocene) environments. The hyperdiverse Cape and Neotropical floras are the result of the combinations of mature as well as recent and rapid radiations. Both the areas contain stable environments (the Amazon basin and the Cape Fold Mountains) as well as dynamic landscapes (the Andes and the South African west coast). The evolution of diversity can only be understood in the context of the local environment.     

Protein quality control: the who’s who, the where’s and therapeutic escapes

In cells the quality of newly synthesized proteins is monitored in regard to proper folding and correct assembly in the early secretory pathway, the cytosol and the nucleoplasm. Proteins recognized as non-native in the ER will be removed and degraded by a process termed ERAD. ERAD of aberrant proteins is accompanied by various changes of cellular organelles and results in protein folding diseases. This review focuses on how the immunocytochemical labeling and electron microscopic analyses have helped to disclose the in situ subcellular distribution pattern of some of the key machinery proteins of the cellular protein quality control, the organelle changes due to the presence of misfolded proteins, and the efficiency of synthetic chaperones to rescue disease-causing trafficking defects of aberrant proteins.     

Biomarkers for early detection of breast cancer: what, when, and where?

Early detection of breast cancer reduces the suffering and cost to society associated with the disease. A sensitive assay to identify biomarkers that can accurately diagnose the onset of breast cancer using non-invasively collected clinical specimens is ideal for early detection. The earlier and more accurate the diagnostic biomarker can predict disease onset, the more valuable it becomes. Here, a brief review of existing and emerging approaches for breast cancer biomarker identification and analysis is presented. Those biomarkers found in biological fluids, blood in particular, apparently hold the best promise for fast development of screening assays. Autoantibodies and abnormal tumor-specific DNA methylation found in cell-free plasma DNA may provide the best opportunity for constructing multiplexed and highly redundant tests, which will be sufficiently specific and sensitive for early detection of breast cancer. It is expected that technologies developed for breast cancer detection will be useful for other types of cancer.     

Cranial growth in Homo erectus: how credible are the Ngandong juveniles?

Confusion exists regarding the developmental ages of numerous Asian and southeast Asian Homo erectus fossils because of Weidenreich's contention that Pithecanthropus fused its sutures prematurely relative to H. sapiens. I reevaluate the cranial developmental ages of the Ngandong “juveniles” (2, 5, 8, 9) based on a series of indicators of youth (superstructure development, suture development/fusion, and cranial thickness) and cranial contours. The Ngandong juveniles are compared with H. sapiens adults (n = 281) and subadults (n = 81) and with Ngandong and other H. erectus adults (n = 20) and subadults (n = 4). Cranial contours are assessed using bivariate plots of arc vs. chord measurements. All indicators suggest that Ngandong 5 and 9 are adults, whereas Ngandong 8 is an older juvenile or young adult and Ngandong 2 is a juvenile with a developmental age range of greater than 6 and less than 11 years. In addition, adult cranial contours and the pattern of contour development are similar between Ngandong adults and other H. erectus adults. There is nothing in the cranial contour data to suggest that Ngandong is, despite a relatively large brain, transitional in vault shape between H. erectus and H. sapiens. Am J Phys Anthropol 108:223–236, 1999. © 1999 Wiley-Liss, Inc.     

Homo floresiensis: microcephalic, pygmoid, Australopithecus, or Homo?

The remarkable partial adult skeleton (LB1) excavated from Liang Bua cave on the island of Flores, Indonesia, has been attributed to a new species, Homo floresiensis, based upon a unique mosaic of primitive and derived features compared to any other hominin. The announcement precipitated widespread interest, and attention quickly focused on its possible affinities. LB1 is a small-bodied hominin with an endocranial volume of 380-410 cm3, a stature of 1m, and an approximate geological age of 18,000 years. The describers [Brown, P., Sutikna, T., Morwood, M.J., Soejono, R.P., Jatmiko, Wayhu Saptomo, E., Awe Due, R., 2004. A new small-bodied hominin from the Late Pleistocene of Flores, Indonesia. Nature 431, 1055-1061] originally proposed that H. floresiensis was the end product of a long period of isolation of H. erectus or early Homo on a small island, a process known as insular dwarfism. More recently Morwood, Brown, and colleagues [Morwood, M.J., Brown, P., Jatmiko, Sutikna, T., Wahyu Saptomo, E., Westaway, K.E., Awe Due, R., Roberts, R.G., Maeda, T., Wasisto, S., Djubiantono, T., 2005. Further evidence for small-bodied hominins from the Late Pleistocene of Flores, Indonesia. Nature 437, 1012-1017] reviewed this assessment in light of new material from the site and concluded that H. floresiensis is not likely to be descended from H. erectus, with the genealogy of the species remaining uncertain. Other interpretations, namely that LB1 is a pygmy or afflicted with microcephaly, have also been put forward. We explore the affinities of LB1 using cranial and postcranial metric and non-metric analyses. LB1 is compared to early Homo, two microcephalic humans, a 'pygmoid' excavated from another cave on Flores, H. sapiens (including African pygmies and Andaman Islanders), Australopithecus, and Paranthropus. Based on these comparisons, we conclude that it is unlikely that LB1 is a microcephalic human, and it cannot be attributed to any known species. Its attribution to a new species, Homo floresiensis, is supported.     

Homo erectus found still further west: Reconstruction of the Kocabaş cranium (Denizli,Turkey)

Few human fossils are known in Turkey and no Homo erectus has been discovered until now. In this respect, the newly discovered partial skull from Kocaba? is very important: (1) to assess the pattern of the first settlements throughout the Old World; and (2) to document the extension of the species H. erectus to the west of continental Asia. Using CT data and 3D imaging techniques, this specimen was reconstructed and a more detailed analysis was done, including the inner anatomical features. The preliminary results of this study highlight that the fossil hominid from Kocaba? is close to the H. erectus species regarding the following cranial patterns: presence of a clear post-orbital constriction, strong development of the frontal brow-ridge with a depressed supratoral area in the lateral part, as well as endocranial patterns such as the development and orientation of the middle meningeal artery and the presence of a frontal bec. The Kocaba? skull is morphologically very close to the fossils from Zhoukoudian L-C. The partial Kocaba? skull is the oldest H. erectus known in Turkey and the only one from this species to have settled so far west in Asia.     

Human taxonomic diversity in the pleistocene: Does Homo erectus represent multiple hominid species?

Recently, nomina such as “Homo heidelbergensis” and “H. ergaster” have been resurrected to refer to fossil hominids that are perceived to be specifically distinct from Homo sapiens and Homo erectus. This results in a later human fossil record that is nearly as speciose as that documenting the earlier history of the family Hominidae. However, it is agreed that there remains only one extant hominid species: H. sapiens. Has human taxonomic diversity been significantly pruned over the last few hundred millennia, or have the number of taxa been seriously overestimated? To answer this question, the following null hypothesis is tested: polytypism was established relatively early and the species H. erectus can accommodate all spatio-temporal variation from ca. 1.7 to 0.5 Ma. A disproof of this hypothesis would suggest that modern human polytypism is a very recent phenomenon and that speciation throughout the course of human evolution was the norm and not the exception. Cranial variation in a taxonomically mixed sample of fossil hominids, and in a modern human sample, is analyzed with regard to the variation present in the fossils attributed to H. erectus. The data are examined using both univariate (coefficient of variation) and multivariate (determinant) analyses. Employing randomization methodology to offset the small size and non-normal distribution of the fossil samples, the CV and determinant results reveal a pattern and degree of variation in H. erectus that most closely approximates that of the single species H. sapiens. It is therefore concluded that the null hypothesis cannot be rejected. © 1993 Wiley-Liss, Inc.     

Physicians in health care management: 2. Managing performance: who,what, how and when?

Physicians are becoming more involved in performance management as hospitals restructure to increase effectiveness. Although physicians are not hospital employees, they are subject to performance appraisals because the hospitals are accountable to patients and the community for the quality of hospital services. The performance of a health care professional may be appraised by the appropriate departmental manager, by other professionals in a team or program or by peers, based on prior agreement on expectations. Appraisal approaches vary. They include behavioural approaches such as rating scales, peer rating, ranking or nomination and outcome approaches such as management by objectives and goal setting. Professionals should give and receive timely feedback on a flexible schedule. Feedback can be provided one-on-one, by a group assessing quality of care or through an anonymous survey.