Cytologie du lobe anterieur de l'hypophyse du chien

Summary Detailed histochemical studies have been made on the distribution of various enzymes such as phosphatases, cholinesterases, glycolytic enzymes and respiratory enzymes in various components of the hypothalamus with special reference to the supraoptic and paraventricular nuclei of the Squirrel Monkey. Cytological studies have also been made by the McManus, Einarson, Gomori and Bargmann methods.A few neurons of these nuclei showed scanty Gomori-positive material in the cytoplasm for the Gomori and Bargmann methods. Nissl granules were located in the peripheral cytoplasm of most neurons. No glycogen granules were observed in these neurons. For these reasons, the Squirrel Monkey, like the rat, may not be a suitable species for the study of neurosecretory phenomena.The axons of these neurons were negative for the specific cholinesterase test, though the perikaryon and some parts of the processes gave a moderately positive reaction. These neurons may be non-cholinergic and the cholinergic fibers from an unknown nucleus may end in synapses on their cell bodies. Blood vessels and glial cells in the neurosecretory nuclei showed non-specific cholinesterase activity. This enzyme may hydrolyze the acetylcholine which has escaped splitting by specific cholinesterase. Alkaline phosphatase and acid phosphatase in these neurons may be involved in the metabolism concerned with the production of neurosecretory material. The neurons may be physicochemical receptors and may get enough energy and raw material to synthesize the neurosecretory material from the rich blood supply. Neurons of the supraoptic and paraventricular nuclei as well as other hypothalamic neurons, like neurons of other regions of the brain, are well equipped with the enzymes of the glycolytic pathways and the tricarboxylic acid cycle. Since the glial cells of these nuclei have amylophosphorylase activity and glycolytic pathways, they may work as energy donators to the neurons of the neurosecretory nuclei. T. R. Shanthaveerappa in previous publications.     

Mutants of TETRAHYMENA THERMOPHILA with Temperature-Sensitive Food Vacuole Formation. I. Isolation and Genetic Characterization

Germ-line mutants have been isolated in Tetrahymena thermophila that have recessive, temperature-sensitive defects in phagocytosis. Nitrosoguanidine-mutagenized cells were induced to undergo cytogamy, and clones were isolated that were unable to form food vacuoles after two days of growth at 39°. Most of the mutants belong to a single complementation group, designated vacA. They have defects in oral development—not in phagocytosis per se—that are undetectable under light microscopy. One fertile mutant, phenotypically indistinguishable from the vacA group, has its vac mutation(s) restricted to the macronucleus, and it is a heterokaryon for two other markers. This clone probably resulted from a failure of the two gametic nuclei to fuse after normal exchange. Two additional mutants were studied, but their sterility prevented a full genetic analysis. One of these clones has a rudimentary oral apparatus and defective contractile vacuole pores; both defects may be determined by the same mutation. The other clone has a structurally normal oral apparatus and may be defective in phagocytosis per se.—The induction and characterization of germ-line mutations that affect oral development open the way for the genetic dissection of the morphogenesis of a complex eukaryotic organelle, and make available additional useful mutants for the study of nutrition and transmembrane active transport.     

Similarity of the Structure of DNA from a Variety of Sources

DNA's from diverse cells of different species and from diverse tissues give the same x-ray diffraction pattern. The presently observable structure of DNA appears, then, to be the same in all cells. Thus, DNA in the resting state—the stored genetic material, from sperm of Paracentrotus lividus, Arbacia lixula, and salmon and from T₂ and T₇ bacteriophage—gives a pattern indistinguishable from DNA from very rapidly dividing cells, e.g., human acute leukemic leukocytes, human leukemic myeloid cells, mouse sarcoma 180, and bacteria—E. coli and pneumococci—during their logarithmic growth. The same x-ray patterns are given by DNA's from more slowly dividing tissues, e.g. calf liver, calf thymus, and human normal and leukemic lymphatic tissue. DNA from chicken erythrocytes—a DNA presumably metabolically inert—gives a similar picture. DNA's from several sources with a wide range in nitrogen base ratios, prepared independently by different workers using various methods, have given final products in varying yield; these all gave the same x-ray pattern, suggesting that all DNA is in the double-helical configuration. Finally, separation of the DNA molecule into a number of fractions with a varying adenine + thymine:guanine + cytosine ratio, but a constant adenine:thymine and guanine:cytosine ratio, each giving the same x-ray pattern as the original whole molecule, suggests that DNA cannot exist in significant amounts in forms other than the double-helix. X-ray diffraction photographs of sperm heads, extracted nucleoprotamine, calf thymus nuclei and extracted nucleohistone, and of chicken erythrocyte nuclei, are not all as well defined as those given by extracted DNA, but it is clear from the general characteristics of the pattern that much of the DNA bound to protein in these nuclei has the usual helical configuration, and that the double-helical structure of DNA exists in the cell and is not an artifact.     

Imidazopurinones are markers of physiological genomic damage linked to DNA instability and glyoxalase 1-associated tumour multidrug resistance

Glyoxal and methylglyoxal are reactive dicarbonyl metabolites formed and metabolized in physiological systems. Increased exposure to these dicarbonyls is linked to mutagenesis and cytotoxicity and enhanced dicarbonyl metabolism by overexpression of glyoxalase 1 is linked to tumour multidrug resistance in cancer chemotherapy. We report herein that glycation of DNA by glyoxal and methylglyoxal produces a quantitatively important class of nucleotide adduct in physiological systems—imidazopurinones. The adduct derived from methylglyoxal-3-(2′-deoxyribosyl)-6,7-dihydro-6,7-dihydroxy-6/7-methylimidazo-[2,3-b]purine-9(8)one isomers—was the major quantitative adduct detected in mononuclear leukocytes in vivo and tumour cell lines in vitro. It was linked to frequency of DNA strand breaks and increased markedly during apoptosis induced by a cell permeable glyoxalase 1 inhibitor. Unexpectedly, the DNA content of methylglyoxal-derived imidazopurinone and oxidative marker 7,8-dihydro-8-oxo-2′-deoxyguanosine were increased moderately in glyoxalase 1-linked multidrug resistant tumour cell lines. Together these findings suggest that imidazopurinones are a major type of endogenous DNA damage and glyoxalase 1 overexpression in tumour cells strives to counter increased imidazopurinone formation in tumour cells likely linked to their high glycolytic activity.     

Studies on Sulfhydryl Groups during Cell Division of Sea Urchin Egg : V. Change in contractility of the thread model in relation to cell division

The contractility of the thread model prepared from the KCl-soluble proteins of the egg and in vivo factors for the contraction are investigated in Hemicentrotus, Anthocidaris, and Pseudocentrotus eggs. The contractility of the thread model induced by metal ions or cystine changes during development in the characteristic pattern of high at the metaphase and low at the monaster and the interkinetic stages. The change in contractility is paralleled by the change in the —SH content of the protein. The water-soluble fraction of the eggs has activity in causing contraction of the thread model. This activity changes during development in the same way as the contractility itself. The contraction of the thread induced by the water-soluble fractions is accompanied by a decrease in the —SH content of the thread. The activity of the water-soluble fraction in inducing the contraction is proportional to its ability to decrease the number of —SH groups. On boiling, the activity is largely destroyed. The activity is due to two components, one being non-dialyzable and the other dialyzable. Separately each component has little effect, but when mixed, the activity of the original sample is completely restored.     

Development of On-Chip Multi-Imaging Flow Cytometry for Identification of Imaging Biomarkers of Clustered Circulating Tumor Cells

An on-chip multi-imaging flow cytometry system has been developed to obtain morphometric parameters of cell clusters such as cell number, perimeter, total cross-sectional area, number of nuclei and size of clusters as “imaging biomarkers”, with simultaneous acquisition and analysis of both bright-field (BF) and fluorescent (FL) images at 200 frames per second (fps); by using this system, we examined the effectiveness of using imaging biomarkers for the identification of clustered circulating tumor cells (CTCs). Sample blood of rats in which a prostate cancer cell line (MAT-LyLu) had been pre-implanted was applied to a microchannel on a disposable microchip after staining the nuclei using fluorescent dye for their visualization, and the acquired images were measured and compared with those of healthy rats. In terms of the results, clustered cells having (1) cell area larger than 200 µm² and (2) nucleus area larger than 90 µm² were specifically observed in cancer cell-implanted blood, but were not observed in healthy rats. In addition, (3) clusters having more than 3 nuclei were specific for cancer-implanted blood and (4) a ratio between the actual perimeter and the perimeter calculated from the obtained area, which reflects a shape distorted from ideal roundness, of less than 0.90 was specific for all clusters having more than 3 nuclei and was also specific for cancer-implanted blood. The collected clusters larger than 300 µm² were examined by quantitative gene copy number assay, and were identified as being CTCs. These results indicate the usefulness of the imaging biomarkers for characterizing clusters, and all of the four examined imaging biomarkers—cluster area, nuclei area, nuclei number, and ratio of perimeter—can identify clustered CTCs in blood with the same level of preciseness using multi-imaging cytometry.     

Comparative levels between enzymes of the glycolytic pathway from erythrocytes and somatic tissues of the chicken Gallus gallus domesticus

A comparative study on the glycolytic enzymes from chicken erythrocytes and somatic tissues has been carried out, the results being shown as active units per mg protein in supernatants of 1085, 12,100 and 106,000 g fractionated centrifugation. The profiles of the glycolytic enzymes have been analyzed in terms of their activity relative to hexokinase and as the ratios between pairs of enzymes bearing a product-substrate relationship. Chicken erythrocyte displays a very peculiar profile of glycolytic enzymes. It possesses a FruP2-activated pyruvate kinase of the L isoenzyme type, which does not seem to be the predominant isoenzyme together with the M type, the content in glycolytic enzymes being much lower than in the somatic tissues.     

Adaptation at Specific Loci. II. Demographic and Biochemical Elements in the Maintenance of the Colias Pgi Polymorphism

Demographically oriented sampling in the wild and biochemical study of allozymes in the laboratory have been used to probe maintenance of the phosphoglucose isomerase polymorphism of Colias butterflies.—The several alleles at this locus show negative or no covariation among their frequencies in the wild. This rules out Wahlund effects as a cause of observations of heterozygote excess at this locus in broods that fly as single cohorts. Unusually heavy mortality among adults, due to drought stress or other causes, can preclude manifestation of differential survivorship among phosphoglucose isomerase genotypes. In broods composed of overlapping cohorts, heterozygote deficiency, apparently due to Wahlund effects in time as cohorts of different survivorship experience mix, can be found. Heterozygotes at this locus fly under a broader range of weather conditions than other genotypes.—Previously detected kinetic differentiation among the genotypes extends in greater magnitude to the glycolytic reaction direction, as well as to a broader range of test conditions than examined before. The heterozygote 3/4 is strikingly heterotic for several measures of kinetic functional effectiveness. Other heterozygotes are sometimes heterotic, more often intermediate (but not exactly so, nor additive in any sense) in properties between homozygotes.—Predictions are made from the biochemical analysis and from the insects' thermal ecology concerning distributions of the genotypes in the wild. Some agree with facts already established. Others are tested and confirmed from data already on hand. Still others are to be tested as reported in an accompanying paper.—All available evidence points to a combination of heterozygote advantage and fluctuating-environment selection as responsible for maintaining this polymorphism. There is considerable evidence for the operation of protein-structural constraint on the range of adaptations possible at this locus.     

Emotional Dynamics in the Age of Misinformation

According to the World Economic Forum, the diffusion of unsubstantiated rumors on online social media is one of the main threats for our society. The disintermediated paradigm of content production and consumption on online social media might foster the formation of homogeneous communities (echo-chambers) around specific worldviews. Such a scenario has been shown to be a vivid environment for the diffusion of false claim. Not rarely, viral phenomena trigger naive (and funny) social responses—e.g., the recent case of Jade Helm 15 where a simple military exercise turned out to be perceived as the beginning of the civil war in the US. In this work, we address the emotional dynamics of collective debates around distinct kinds of information—i.e., science and conspiracy news—and inside and across their respective polarized communities. We find that for both kinds of content the longer the discussion the more the negativity of the sentiment. We show that comments on conspiracy posts tend to be more negative than on science posts. However, the more the engagement of users, the more they tend to negative commenting (both on science and conspiracy). Finally, zooming in at the interaction among polarized communities, we find a general negative pattern. As the number of comments increases—i.e., the discussion becomes longer—the sentiment of the post is more and more negative.     

Glyceraldehyde-3-Phosphate Dehydrogenase Activity and F-Actin Associations in Synaptosomes and Postsynaptic Densities of Porcine Cerebral Cortex

1. Glyceraldehyde-3-phosphate dehydrogenase (G3PD) is a glycolytic enzyme that has also been implicated in a wide variety of functions within neurons. Because of the well-documented role of G3PD as an actin-binding protein, we sought evidence for a G3PD–actin complex in synaptosomes and postsynaptic densities (PSDs).2. We have shown G3PD association with 0.5-m synaptosomal particles by immunofluorescence as similarly demonstrated for actin (Toh et al., Nature 264:648–650, 1976). An immunoblot analysis also showed G3PD and actin to be enriched in synaptosomes. Further analysis of subcellular fractions from synaptosomes showed the PSD but not the synaptosomal plasma membranes to be enriched in G3PD and actin.3. Highest levels of G3PD catalytic activity were found in synaptosomes and PSDs. Although synaptosomes showed significant activity for phosphoglyceratekinase (PGK), an enzyme in sequence with G3PD for ATP production in the glycolytic pathway, no such activity was detected in the PSD fraction.4. Our studies indicate that a G3PD–actin complex may exist at the synapse. A physical association of G3PD with endogenous F-actin in synaptosomes and PSDs was demonstrated by combined phalloidin shift velocity sedimentation/immunoblot studies. By this approach, synaptosomal G3PD–actin complexes were also found to be significantly less dense than the PSD G3PD–actin complexes.5. G3PD and PGK catalytic activity in synaptosomes suggests a role in glycolysis, as well as actin binding, in the presynaptic terminals. On the other hand, the high levels of G3PD activity in PSDs but lack of PGK activity suggests that G3PD is involved in nonglycolytic functions, such as actin binding and actin filament network organization.     

Direct Measurements of Oscillatory Glycolysis in Pancreatic Islet β-Cells Using Novel Fluorescence Resonance Energy Transfer (FRET) Biosensors for Pyruvate Kinase M2 Activity

Pulses of insulin released from pancreatic β-cells maintain blood glucose in a narrow range, although the source of these pulses is unclear. We and others have proposed that positive feedback mediated by the glycolytic enzyme phosphofructokinase-1 (PFK1) enables β-cells to generate metabolic oscillations via autocatalytic activation by its product fructose 1,6-bisphosphate (FBP). Although much indirect evidence has accumulated in favor of this hypothesis, a direct measurement of oscillating glycolytic intermediates has been lacking. To probe glycolysis directly, we engineered a family of inter- and intramolecular FRET biosensors based on the glycolytic enzyme pyruvate kinase M2 (PKAR; pyruvate kinase activity reporter), which multimerizes and is activated upon binding FBP. When introduced into Min6 β-cells, PKAR FRET efficiency increased rapidly in response to glucose. Importantly, however, metabolites entering downstream of PFK1 (glyceraldehyde, pyruvate, and ketoisocaproate) failed to activate PKAR, consistent with sensor activation by FBP; the dependence of PKAR on FBP was further confirmed using purified sensor in vitro. Using a novel imaging modality for monitoring mitochondrial flavin fluorescence in mouse islets, we show that slow oscillations in mitochondrial redox potential stimulated by 10 mm glucose are in phase with glycolytic efflux through PKM2, measured simultaneously from neighboring islet β-cells expressing PKAR. These results indicate that PKM2 activity in β-cells is oscillatory and are consistent with pulsatile PFK1 being the mediator of slow glycolytic oscillations.     

Orudis in Management of Rheumatoid Arthritis and Osteoarthrosis of the Hip: Comparison with Indomethacin

In double-blind cross-over studies in 46 patients with rheumatoid arthritis and in 42 patients with osteoarthrosis of the hip, Orudis—a new non-steroidal anti-inflammatory agent—has been shown to be well tolerated and to have comparable therapeutic efficacy with indomethacin when given in equal dosage. Side effects were less severe with Orudis. The results suggest that Orudis will prove valuable in the clinical management of rheumatic diseases.     

Variations in Sulfhydryl, Disulfide, and Protein Content during Synchronous and Asynchronous Growth of HeLa Cells

The cellular contents of protein-bound and nonprotein sulfhydry (—SH) and disulfide (—SS—) groups were measured in both asynchronous and synchronous HeLa S3 cultures. About 90% of these groups are associated with proteins, the majority in the —SH form. The content of protein-bound groups, and hence the total content of —SH and —SS— groups (28 × 10^-15 moles/cell, or 1.1 × 10^-6 moles/g protein on average), changes in parallel with the protein content (which varies between 2 and 4 × 10^-10 g/cell) as asynchronous populations pass from the lag through the exponential to the stationary phase of growth. The concentration of nonprotein —SH groups, in contrast, increases 10-fold during lag phase and decreases in stationary phase; it follows the protein concentration closely during the exponential phase, at a level of about 2.8 × 10^-15 moles/cell. In synchronous cultures the protein content doubles during the cell cycle, possibly in an exponential fashion. The total —SH and —SS— content also doubles, but the rate of increase appears to fluctuate. The concentrations of the protein-bound groups show 2- to 3-fold fluctuations per unit protein: protein-bound —SH groups and mixed —SS— linkages rise to maxima while protein-bound —SS— groups fall to a minimum at the G₁/S transition, and fluctuations in these groups occur again during G₂. In addition, the protein-bound —SH concentration falls continuously during the S phase. The nonprotein —SH concentration undergoes the largest (relative) fluctuations, dropping from 4 × 10^-15moles/cell in early G₁ to about 0.4 × 10^-15 moles/cell (of standard protein content) at the end of G₁, and then rising to 30 times this value by the end of S.     

Metabolic Activities in Extracts of Mesophyll and Bundle Sheath Cells of Panicum miliaceum (L.) in Relation to the C(4) Dicarboxylic Acid Pathway of Photosynthesis

The activities of certain enzymes related to the carbon assimilation pathway in whole leaves, mesophyll cell extracts, and bundle sheath extracts of the C₄ plant Panicum miliaceum have been measured and compared on a chlorophyll basis. Enzymes of the C₄ dicarboxylic acid pathway—phosphoenolpyruvate carboxylase and NADP-malic dehydrogenase—were localized in mesophyll cells. Carbonic anhydrase was also localized in mesophyll cell extracts. Ribose 5-phosphate isomerase, ribulose 5-phosphate kinase, and ribulose diphosphate carboxylase—enzymes of the reductive pentose phosphate pathway—were predominantly localized in bundle sheath extracts. High activities of aspartate and alanine transaminases and glyceraldehyde-3-P dehydrogenase were found about equally distributed between the photosynthetic cell types. P. miliaceum had low malic enzyme activity in both mesophyll and bundle sheath extracts.     

STUDIES ON SULFHYDRYL GROUPS DURING CELL DIVISION OF SEA URCHIN EGG : III. —SH Groups of KCl-Soluble Proteins and Their Change during Cleavage

Sea urchin egg proteins extracted with KCl are mostly TCA-soluble and, conversely, those extracted with TCA are KCl-soluble. Both groups are water-insoluble and show fluctuations in—SH content during the division cycle. The fluctuation of the—SH groups of the KCl-soluble protein of the whole egg is due to a —SH—S—S— interchange within the freely reacting groups and not within the sluggish and masked —SH groups of the protein. The —SH content of the KCl-soluble protein of the egg cortex also fluctuates in a similar way.     

Differential Evolutionary Fate of an Ancestral Primate Endogenous Retrovirus Envelope Gene,the EnvV Syncytin,Captured for a Function in Placentation

Syncytins are envelope genes of retroviral origin that have been co-opted for a role in placentation. They promote cell–cell fusion and are involved in the formation of a syncytium layer—the syncytiotrophoblast—at the materno-fetal interface. They were captured independently in eutherian mammals, and knockout mice demonstrated that they are absolutely required for placenta formation and embryo survival. Here we provide evidence that these “necessary” genes acquired “by chance” have a definite lifetime with diverse fates depending on the animal lineage, being both gained and lost in the course of evolution. Analysis of a retroviral envelope gene, the envV gene, present in primate genomes and belonging to the endogenous retrovirus type V (ERV-V) provirus, shows that this captured gene, which entered the primate lineage >45 million years ago, behaves as a syncytin in Old World monkeys, but lost its canonical fusogenic activity in other primate lineages, including humans. In the Old World monkeys, we show—by in situ analyses and ex vivo assays—that envV is both specifically expressed at the level of the placental syncytiotrophoblast and fusogenic, and that it further displays signs of purifying selection based on analysis of non-synonymous to synonymous substitution rates. We further show that purifying selection still operates in the primate lineages where the gene is no longer fusogenic, indicating that degeneracy of this ancestral syncytin is a slow, lineage-dependent, and multi-step process, in which the fusogenic activity would be the first canonical property of this retroviral envelope gene to be lost.     

THERAPY OF PARKINSON'S DISEASE

The most disabling form of Parkinsonism is that occurring after encephalitis. It may occur in persons of any age. The results of surgical treatment, which has been used for the most part only for seriously handicapped patients, have been discouraging in general, although in a few isolated circumstances operation has been of dramatic benefit.The solanaceous alkaloids—atropine, stramonium and hyoscine—either in pure forms or in mixed extracts or tinctures — are the best established drugs at present for the treatment of the postencephalitic forms of Parkinsonism. They have not proven too helpful for patients in the older age group with paralysis agitans. The antihistaminic compounds, particularly Benadryl,® have been a very valuable addition. They are of greatest value for patients in the older age group. The newer synthetic compounds, Artane® and Panparnit,® are also valuable additions. Amphetamine and the related and subsequently produced agents in this group are very helpful for patients showing undue fatigue and lethargy. Tolserol® is proving helpful, particularly for patients with painful spasms of rigid muscles.     

Food Consumption, Feed Efficiency, Metabolic Rate and Utilization of Glucose in Lines of TRIBOLIUM CASTANEUM Selected for 21-Day Pupa Weight

Growth rate, body composition, cell number, cell size, and the activity of four dehydrogenase enzymes were studied from 10 to 25 days of age in one control (1C) and three lines (3, 9, 10) of Tribolium castaneum that had been subjected to long term selection for large 21-day pupae weight.—Selected lines were two- to three-fold larger in size than the control line throughout development. No major differences in percent of protein were detected among the lines but at any particular age, the selected lines were found to have a higher fat content than the control line. The differences in fat content were closely correlated with development such that all the lines reached very similar levels of percent of fat just prior to pupation. Water content showed an inverse relation to percent of fat.—Selection was observed to have caused major changes in the cellular response to growth. The selected lines had an average of from 17% to 48% larger cells (measured as protein/DNA) and were found to have from 37 to 62% more cells (measured as total DNA) than the control line at all ages from 10 to 19 days of age. In addition, the selected lines had a higher RNA content at all ages studied and higher RNA:DNA ratios at the young ages. In contrast the enzyme activities of ICDH and LDH were 60% lower. The results are interpreted as indicating that a more efficient metabolic machinery had evolved in the rapidly growing selected lines.     

The Role of Model Organisms in the History of Mitosis Research

Mitosis is a cell-cycle stage during which condensed chromosomes migrate to the middle of the cell and segregate into two daughter nuclei before cytokinesis (cell division) with the aid of a dynamic mitotic spindle. The history of mitosis research is quite long, commencing well before the discovery of DNA as the repository of genetic information. However, great and rapid progress has been made since the introduction of recombinant DNA technology and discovery of universal cell-cycle control. A large number of conserved eukaryotic genes required for the progression from early to late mitotic stages have been discovered, confirming that DNA replication and mitosis are the two main events in the cell-division cycle. In this article, a historical overview of mitosis is given, emphasizing the importance of diverse model organisms that have been used to solve fundamental questions about mitosis.Onko Chisin—An attempt to discover new truths by studying the past through scrutiny of the old.     

Evolutionary Dynamics of Human Toll-Like Receptors and Their Different Contributions to Host Defense

Infectious diseases have been paramount among the threats to health and survival throughout human evolutionary history. Natural selection is therefore expected to act strongly on host defense genes, particularly on innate immunity genes whose products mediate the direct interaction between the host and the microbial environment. In insects and mammals, the Toll-like receptors (TLRs) appear to play a major role in initiating innate immune responses against microbes. In humans, however, it has been speculated that the set of TLRs could be redundant for protective immunity. We investigated how natural selection has acted upon human TLRs, as an approach to assess their level of biological redundancy. We sequenced the ten human TLRs in a panel of 158 individuals from various populations worldwide and found that the intracellular TLRs—activated by nucleic acids and particularly specialized in viral recognition—have evolved under strong purifying selection, indicating their essential non-redundant role in host survival. Conversely, the selective constraints on the TLRs expressed on the cell surface—activated by compounds other than nucleic acids—have been much more relaxed, with higher rates of damaging nonsynonymous and stop mutations tolerated, suggesting their higher redundancy. Finally, we tested whether TLRs have experienced spatially-varying selection in human populations and found that the region encompassing TLR10-TLR1-TLR6 has been the target of recent positive selection among non-Africans. Our findings indicate that the different TLRs differ in their immunological redundancy, reflecting their distinct contributions to host defense. The insights gained in this study foster new hypotheses to be tested in clinical and epidemiological genetics of infectious disease.