One axon, many kinesins: What's the logic?

A large number of membrane-bounded organelles, protein complexes, and mRNAs are transported along microtubules to different locations within the neuronal axon. Axonal transport in the anterograde direction is carried out by members of a superfamily of specialized motor proteins, the kinesins. All kinesins contain a conserved motor domain that hydrolyses ATP to generate movement along microtubules. Regions outside the motor domain are responsible for cargo binding and regulation of motor activity. Present in a soluble, inactive form in the cytoplasm, kinesins are activated upon cargo binding. Selective targeting of different types of kinesin motors to specific cargoes is directed by amino acid sequences situated in their variable tails. Cargo proteins with specific function at their destination, bind directly to specific kinesins for transport. Whereas most kinesins move to microtubule plus-ends, a small number of them move to microtubule minus-ends, and may participate in retrograde axonal transport. Axonal transport by kinesins has a logic: Fully assembled, multisubunit, functional complexes (e.g., ion channel complexes, signaling complexes, RNA-protein complexes) are transported to their destination by kinesin motors that interact transiently (i.e., during transport only) with one of the complexes' subunits.     

Development and selection of T cells: how many subsets? How many rules?

Since the discovery indicating that thymus-derived lymphocytes (T cells) can be divided into two subpopulations: CD8+ (killer) and CD4+ (helper) cells, subsequent studies revealed a bewildering heterogeneity of T cells. In the present review an attempt is made to present the current picture of T cell heterogeneity, introduce some order into the nomenclature, and summarize the rules behind the development and selection of different currently recognized T cell subsets.     

The many lives of IL-9: a question of survival?

Although the cytokine interleukin 9 (IL-9) was discovered decades ago, it remains one of the most enigmatic cytokines identified so far, in particular because its functional activities remain far from clear. Breakthroughs made through the use of IL-9 reporter mice have allowed the identification of cell types that produce IL-9 in vivo and, contrary to expectations based on previous results obtained in vitro, it is not T cells but instead a previously unknown type of innate lymphoid cell, called the 'ILC2 cell', that is the main cell type that expresses IL-9 in vivo. In this perspective, we put forward a hypothesis about the potential biological functions of IL-9 in the immune system and beyond.     

Inverted duplications: how many of them are mosaic?

The best-known situation indissolubly linked to mosaicism is the uniparental disomy where a trisomic or monosomic zygote develops at least one cell line with 46 chromosomes. The mosaicism normal/abnormal cell lines may remain confined to placenta or persist in the embryo. Here, we describe a second situation that might also be indissolubly linked to a mosaic condition or at least to a confined placental mosaicism. We analysed the case of a mosaicism del(8p)/inv dup(8p) found in prenatal diagnosis. We had already demonstrated that the first product of the abnormal meiotic recombination at the basis of the inv dup rearrangements is a dicentric chromosome. Its breakage leads to the formation of a deleted and an inv dup chromosome. Although we had previously assumed that the dicentric underwent a breakage at meiosis II so that the zygote inherited the inv dup chromosome, our findings and those of others indeed indicate that the dicentric may be inherited in the zygote and that it might persist as such in early postzygotic stages, then undergoing different breakages in different cells leading to different abnormal chromosomes, either deleted or duplicated. Selection versus the most viable cell line(s) results either in a confined placental mosaicism with the inv dup cell line as the only one present in the embryo or in children with both the deleted and the inv dup cell lines. Phenotype/karyotype relationships in inv dup rearrangements must also take into account the influence of the other abnormal cell line during embryogenesis.     

Polydactyly: how many disorders and how many genes?

Disorders that include polydactyly as a manifestation are diverse and numerous. Cataloging these disorders by phenotype and genotype demonstrates numerous overlapping phenotypes, genetic heterogeneity of phenotypes, and distinct phenotypes generated from mutations in single genes. To assess these issues, a list of disorders with polydactyly has been compiled from several sources. Among 119 disorders, 39 disorders are associated with mutations in genes, and among these, genotypic and phenotypic overlap is demonstrated. These issues highlight the need for a diagnostic system that catalogs both genotype and phenotype. Published 2002 Wiley-Liss, Inc.     

Polydactyly: How many disorders and how many genes?

Disorders that include polydactyly as a manifestation are diverse and numerous. Cataloging these disorders by phenotype and genotype demonstrates numerous overlapping phenotypes, genetic heterogeneity of phenotypes, and distinct phenotypes generated from mutations in single genes. To assess these issues, a list of disorders with polydactyly has been compiled from several sources. Among 119 disorders, 39 disorders are associated with mutations in genes, and among these, genotypic and phenotypic overlap is demonstrated. These issues highlight the need for a diagnostic system that catalogs both genotype and phenotype. Published 2002 Wiley‐Liss, Inc.     

A definition of drowsiness: One purpose for sleep?

While significant research has been done into the physiological mechanisms that underlie sleep and the sleep/wake cycle, the available data regarding the nature of drowsiness is far more limited. An objective measurement of drowsiness would have clinical utility, and a precise definition of the drowsy state could offer insights into the nature and purpose of sleep. Studies utilizing fMRI have demonstrated increased area of central nervous system involvement with tasks of increasing complexity. Preliminary data from studies of magnetoencephalography (MEG) with a receptive language task have demonstrated a progressive increase in global coherence of activity between MEG sensors with increasing drowsiness. The relationship between global coherence and the level of drowsiness suggests that the former may serve as an objective measurement of the latter. If true, the relationship suggests the hypothesis that drowsiness may be defined as a progressive loss of cortical network processing efficiency, requiring the recruitment of greater amounts of cortical tissue to perform the same task.     

Evolution of vertebrate forebrain development: how many different mechanisms?

Over the past 50 years and more, many models have been proposed to explain how the nervous system is initially induced and how it becomes subdivided into gross regions such as forebrain, midbrain, hindbrain and spinal cord. Among these models is the 2-signal model of Nieuwkoop & Nigtevecht (1954), who suggested that an initial signal ('activation') from the organiser both neuralises and specifies the forebrain, while later signals ('transformation') from the same region progressively caudalise portions of this initial territory. An opposing idea emerged from the work of Otto Mangold (1933) and other members of the Spemann laboratory: 2 or more distinct organisers, emitting different signals, were proposed to be responsible for inducing the head, trunk and tail regions. Since then, evidence has accumulated that supports one or the other model, but it has been very difficult to distinguish between them. Recently, a considerable body of work from mouse embryos has been interpreted as favouring the latter model, and as suggesting that a 'head organiser', required for the induction of the forebrain, is spatially separate from the classic organiser (Hensen's node). An extraembryonic tissue, the 'anterior visceral endoderm' (AVE), was proposed to be the source of forebrain-inducing signals. It is difficult to find tissues that are directly equivalent embryologically or functionally to the AVE in other vertebrates, which led some (e.g. Kessel, 1998) to propose that mammals have evolved a new way of patterning the head. We will present evidence from the chick embryo showing that the hypoblast is embryologically and functionally equivalent to the mouse AVE. Like the latter, the hypoblast also plays a role in head development. However, it does not act like a true organiser. It induces pre-neural and pre-forebrain markers, but only transiently. Further development of neural and forebrain phenotypes requires additional signals not provided by the hypoblast. In addition, the hypoblast plays a role in directing cell movements in the adjacent epiblast. These movements distance the future forebrain territory from the developing organiser (Hensen's node), and we suggest that this is a mechanism to protect the forebrain from caudalising signals from the node. These mechanisms are consistent with all the findings obtained from the mouse to date. We conclude that the mechanisms responsible for setting up the forebrain and more caudal regions of the nervous system are probably similar among different classes of higher vertebrates. Moreover, while reconciling the two main models, our findings provide stronger support for Nieuwkoop's ideas than for the concept of multiple organisers, each inducing a distinct region of the CNS.     

How many factors does the sense of community index assess?

Studies of university students’ sense of community (SOC) use various scales, one of which is the widely used Sense of Community Index (SCI), conceptualized as a 4‐factor model: membership, influence, needs fulfillment, and shared emotional connection. Research has been unable to show a reliable 4‐factor solution. One possible explanation may be that negatively worded items contribute to lack of model fit, which would be consistent with the claim that SOC was conceptualized as a unipolar positive construct. Data were collected using a positively worded SCI (N = 794). Four models were tested with confirmatory factor analysis in structural equation modeling: 1‐factor, theorized four‐factor, revised 3‐factor, and revised 4‐factor. None of the models showed good fit, though the fit of the 1‐factor model was improved over the 4‐factor. More studies are needed to attempt replication with a positively worded SCI.     

Donation of embryos for stem cell research--how many couples consent?

BACKGROUND: The huge potential of human embryonic stem cells has been a subject of wide discussion as regards the ethical and legal justification of using human embryos for establishing such cell lines. The opinions of infertile couples and their willingness to donate their supernumerary embryos for stem cell research have not been investigated earlier. METHODS: We conducted an analysis of the answers of couples who were asked to give informed consent as regards donating their embryos for stem cell research in our IVF unit in 2001-2002. RESULTS: Ninety-two percent of the couples gave informed consent as regards establishing and characterizing embryonic stem cell lines from the embryos which could not be used in their infertility treatment. Discussion in the Swedish media during May to December, 2001 regarding the importance and ethical justification of stem cell research made informing the couples easier. CONCLUSION: A high proportion, 92%, of couples who underwent infertility treatment in Sweden preferred donating their supernumerary embryos for stem cell research rather than letting them be discarded.     

Anti-GBM glomerulonephritis: a T cell-mediated autoimmune disease?

Anti-glomerular basement membrane (GBM) glomerulonephritis, which was among the earliest recognized human autoimmune diseases, is characterized by the presence of anti-GBM antibody. It has been a prototypical example of autoantibody-mediated autoimmune disease. However, decades of research on this disease, based either on clinical observations or experimental models, have revealed that T cell-mediated cellular immunity may potentially be a more important mediator of glomerulonephritis. We have made several breakthroughs in understanding the T cell-mediated mechanism causing this disease in a rat model based on Goodpasture's antigen, non-collagen domain 1 of alpha3 chain of type IV collagen (Col4alpha3NC1). We demonstrated that anti-GBM glomerulonephritis was induced by either passive transfer of Col4 alpha3NC1-specific T cells or active immunization with the nephritogenic T cell epitope of Col4alpha3NC1. Immunization with the T cell epitope also triggered production of anti-GBM antibodies to diversified GBM antigens. Thus, a single nephritogenic T cell epitope alone is sufficient to induce the clinical spectrum of anti-GBM glomerulonephritis, including proteinuria, glomerular injury, and anti-GBM antibody. A possible T cell-mediated mechanism for causing human anti-GBM disease is proposed.     

What is the significance of HLA-DR antigen expression in the extraglomerular mesangium in glomerulonephritis?

Introduction and Aims

The HLA-DR antigen is a HLA class II molecule involved in the presentation of antigenic peptides to the T cell receptor, thus regulating the immune response. Renal expression of the HLA-DR antigen may indicate specific sites of immunologically-mediated kidney injury in glomerulonephritis (GN). The aim of our study was to assess the presence of the HLA-DR antigen along the nephron including the extraglomerular mesangium in GN.

Methods

A cross-sectional study of 22 patients with glomerulonephritis, mean age: 46.59 ± 10.77 years, 14 male and 8 female, was conducted. Conventional stains, as well as immunohistochemistry for the HLA-DR Antigen Alpha-Chain were employed on kidney biopsies. Immunohistochemistry was assessed using a semi-quantitative score: 0-absent, 1-mild, 2-moderate, 3-intense. Statistical analysis was performed using SPSS17.

Results

Four patients presented Focal and Segmental Glomerulosclerosis (FSGS), 5 patients: membranoproliferative GN, 7 patients: membranous nephropathy, 3 patients: mesangial proliferative GN, 2 patients: minimal change disease (MCD), and 1 patient: crescentic GN. Regarding the percentage of cases with HLA-DR positive cells along the nephron out of 22 patients: glomerular endothelial cells were 100% positive, intraglomerular mesangium cells were 81.8% positive, podocytes were 36.4% positive, extraglomerular mesangium cells were 31.8% positive, proximal tubule cells were 95.5% positive, distal tubule cells were 68.2% positive, interstitial capillaries were 77.3% positive, and cells of interstitial infiltrates were 27.3% positive. The percentage of cases staining positively for the HLA-DR antigen in the extraglomerular mesangium was 25% in FSGS, 60% in membranoproliferative GN, 0% in membranous nephropathy, 33.3% in mesangial proliferative GN, 100% in minimal change disease and 0% in crescentic GN.

Conclusions

A prominent HLA-DR antigen distribution was found on glomerular endothelial cells, intraglomerular mesangium cells and proximal and distal tubular cells. Extraglomerular mesangium cells and podocytes stained variably for the HLA-DR antigen, as did the cells of the interstitial infiltrates. The extraglomerular mesangium which serves as a portal of entry into the intraglomerular mesangium is endowed with antigen-presenting capabilities and is a region where induction of immune reactions could take place.     

One lump or two? One butt but two buttocks

Future revisions of anatomical terminologies will have to give more consideration to the relationships between terms and referents, and the relationships between referents, because computer applications require greater precision. Median anatomical entities and paired entities that closely flank the median plane present common problems in nomenclature, semantics, and ontology. Some of these problems represent vestiges of usage in classical Latin. For example, the use of plural words for polite names of some body parts, and singular words for euphemisms for naughty words. Clin. Anat. 32:22–24, 2019. © 2019 Wiley Periodicals, Inc.     

How many cases of disease in a pedigree imply familial disease?

The ability to perform whole‐exome and, increasingly, whole‐genome sequencing on large numbers of individuals has led to increased efforts to identify rare genetic variants that affect the risk of both common and rare diseases. In such applications, it is important to identify families that are segregating the rare variants of interest. For rare diseases or rare familial forms of common diseases, pedigrees with multiple affected members are clearly harbouring risk variants. For more common diseases, however, it may be unclear whether a family with a few affected members is segregating a familial disease, is the result of multiple sporadic cases, or is a mixture of familial cases and phenocopies. We provide calculations for the probability that a family is harbouring familial disease, presented in general terms that admit working guidelines for selecting families for current sequencing studies. Using examples motivated by our own studies of thyroid cancer and published studies of colorectal cancer, we show that for common diseases, families with exactly two affected first‐degree relatives have only a moderate probability of segregating familial disease, but this probability is higher for families with three or more affected relatives, and those families should therefore be prioritised in sequencing studies.     

Major Surface Protease of Trypanosomatids: One Size Fits All?

Major surface protease (MSP or GP63) is the most abundant glycoprotein localized to the plasma membrane of Leishmania promastigotes. MSP plays several important roles in the pathogenesis of leishmaniasis, including but not limited to (i) evasion of complement-mediated lysis, (ii) facilitation of macrophage (Mø) phagocytosis of promastigotes, (iii) interaction with the extracellular matrix, (iv) inhibition of natural killer cellular functions, (v) resistance to antimicrobial peptide killing, (vi) degradation of Mø and fibroblast cytosolic proteins, and (vii) promotion of survival of intracellular amastigotes. MSP homologues have been found in all other trypanosomatids studied to date including heteroxenous members of Trypanosoma cruzi, the extracellular Trypanosoma brucei, unusual intraerythrocytic Endotrypanum spp., phytoparasitic Phytomonas spp., and numerous monoxenous species. These proteins are likely to perform roles different from those described for Leishmania spp. Multiple MSPs in individual cells may play distinct roles at some time points in trypanosomatid life cycles and collaborative or redundant roles at others. The cellular locations and the extracellular release of MSPs are also discussed in connection with MSP functions in leishmanial promastigotes.Trypanosomatids are a very diverse group of protozoa including many species of medical, veterinary, and/or economical importance. Leishmania spp. cause disease on the continents of Asia, Africa, Europe, and North and South America; Trypanosoma cruzi is the etiology of Chagas'' disease in South and Central America; and Trypanosoma brucei infections result in African sleeping sickness. Four genera of heteroxenous trypanosomatids transmitted by insect vectors infect a wide range of hosts including humans, animals, and plants. Six genera of monoxenous trypanosomatids parasitize numerous species of insects. Due to this diversity, the life cycle of Leishmania spp. is presented as a model to which other heteroxenous and monoxenous groups will be briefly contrasted.During their life cycle, Leishmania spp. shuttle between a flagellated promastigote stage in the sand fly vector and a nonmotile amastigote stage in a mammalian host. During blood meals on infected hosts, the sand fly vectors ingest amastigote-laden macrophages (Mø). These amastigotes transform to procyclic promastigotes in the sand fly gut, multiply by binary fission, and eventually develop into metacyclic promastigotes, the infective stage for mammalian hosts including humans. The sand fly vectors, upon taking another blood meal, inoculate the metacyclic promastigotes into the dermis, where they are phagocytized by Mø of the mammalian hosts. Amastigotes, transformed from metacyclic promastigotes, multiply in parasitophorous vacuoles (PV) of the host''s Mø. Multiplication of amastigotes eventually leads to rupture of the infected Mø and release of amastigotes, which infect additional Mø, perpetuating the cycle of replication (38).Other trypanosomatids divert this model of the life cycle in different ways. (i) T. cruzi is transmitted to humans by the reduviid (or kissing) bug by fecal contamination of skin wounds or mucous membranes while taking a blood meal. In the human host, T. cruzi exists in amastigote and trypomastigote forms. The intracellular amastigote stage multiplies within virtually any cell. The extracellular trypomastigotes are disseminated in the blood to all parts of the body (38). (ii) T. brucei is transmitted to humans by a tsetse fly during blood meals. This parasite lives extracellularly as trypomastigotes in blood, lymph, and cerebrospinal fluid (90). (iii) Two species of Endotrypanum are parasites of forest-dwelling tree sloths in South America. Both Endotrypanum schaudinni and Endotrypanum monterogeii have an unusual intraerythrocytic stage (53, 75) as trypomastigotes and epimastigotes, respectively, even though both use sand flies as vectors (24). (iv) Phytomonas spp., transmitted between plants by phytophagous insects, infect several plants of great economic importance in widespread geographic regions (13). (v) All monoxenous trypanosomatids are parasites of various insects. They consist of six genera, including Blastocrithidia, Crithidia, Leptomonas, Herpetomonas, Rhynchoidomonas, and Phytomonas (87).Leishmania spp. harbor a zinc metalloprotease, discovered in the mid-1980s, on their surfaces (14, 15, 36, 37, 88). This enzyme, accounting for about 1% of the total protein in promastigotes of Leishmania major and Leishmania mexicana (2, 10) and being potentially important during different stages of the life cycle, soon became the object of much investigation (8, 70, 71, 107). Although referred to here as major surface protease (MSP), this zinc metalloprotease has also been termed GP63, surface acid protease, promastigote surface protease, EC 3.4.24.36, and leishmanolysin.MSPs of Leishmania spp. belong to the M8 family of endopeptidases, sharing several characteristics with mammalian matrix metalloproteases. Similarities include degradation of the extracellular matrix, cell surface localization, protease activity requiring Zn²⁺, and inhibition of protease activity by chelating agents and α-2-macroglobulin (for a review, see reference 70). Many, but not all, of the Leishmania MSPs are bound to the outer leaves of the plasma membranes of promastigotes by a glycosylphosphatidylinositol (GPI) anchor (9). MSPs are encoded by multiple MSP genes that may vary in sequence, especially in the untranslated regions. MSP genes of all Leishmania spp. studied to date are usually in tandem array and are often differentially expressed during various life cycle stages (72, 91, 92, 101). This heterogeneity in MSP genes without affecting enzymatic domains makes stage-specific regulation possible. Unlike other eukaryotic cells, trypanosomatids do not have classic promoters for RNA polymerase II. Long arrayed protein-coding genes are transcribed to polycistronic RNA precursors. Mature mRNAs derive from a coupled process in which trans splicing of a capped splicing leader at the 5′ end of one gene is coupled to polyadenylation addition of the upstream gene (20). Redundancy in certain genes including MSP genes appears to be a mechanism to affect mature mRNA production, and therefore, protein abundance.The genomes of L. major, Leishmania infantum, and Leishmania braziliensis contain 4, 5, and 33 MSP genes, respectively, in tandem array on chromosome 10 with an additional 2, 3, and 6 MSP-like genes, respectively, located on chromosome 28 and/or 31 (49, 84). These numbers differ significantly from the earlier reported 7 and ≥18 MSP genes in tandem array detected by partial digestion of genomic DNAs and Southern blotting of L. major and the South American Leishmania chagasi, respectively (91, 101). The latter species is considered synonymous with L. infantum by many authors (60, 65, 66, 76, 89). This divergence in number of MSP genes appears related to the different parasitic strains used in these studies (MHOM/IL/81Friedlin zymodeme MON-103 versus NIH S [MHOM/SN/74/Seisman] of L. major; JPCM5 [MCAN/ES/98/LLM-877] versus MHOM/BR/00/1669 of L. infantum), although the biological significance remains to be assessed. Alternatively, variation might be caused by technical challenges in genome sequencing. Identical tandem-arrayed genes may not have been able to be correctly resolved for gene copy number. In contrast, Southern blots of the partially digested genomic DNA subjected to resolution by electrophoresis are capable of detecting gene copy numbers of identical tandem-arrayed genes.Another GPI-anchored molecule, lipophosphoglycan (LPG), is the dominant molecule on the surfaces of Leishmania sp. promastigotes. Intriguingly, protective roles for LPG and MSP overlap, including resistance to complement-mediated lysis (CML) and facilitation of phagocytosis by host Mø. LPG also functions in the binding to and release of the parasite from the midgut of the sand fly vector, accounting for retrograde migration of the metacyclic promastigote to the sand fly proboscis (6, 16). Since roles for both MSP and LPG overlap, they may function synergistically in the pathogenesis of leishmaniasis or they may function redundantly, with the failure of one being compensated for by the other.     

One size fits all? Race,gender and body mass index among U.S. adults.

This study examined the extent to which factors presumed to be correlated with body mass index (BMI) vary across four race- and gender-specific groups. Data were drawn from the American Changing Lives Survey to estimate separate multivariate regression models for the total study sample that included African-American males, Caucasian males, African-American females and Caucasian females. The dependant variable of interest was BMI. Independent variables included age, human capital variables, relationship and support measures, health status and behavior measures, and stress and outlook measures. Results from the pooled model indicated that BMI was associated with a number of factors such as employment status, chronic illness, financial strain and religiosity. However, race- and gender-specific regression models revealed that predictors of BMI varied considerably for African-American men, Caucasian men, African-American women and Caucasian women. In other words, these models disentangled important correlations not observed in the pooled model. These findings suggest that addressing racial disparities in body weight-related outcomes requires health practitioners to modify obesity prevention and treatment efforts to incorporate a broader array of factors inherent to specific racial and gender populations.