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Characterization of antibody responses elicited by human immunodeficiency virus type 1 primary isolate trimeric and monomeric envelope glycoproteins in selected adjuvants.

We previously reported that soluble, stable YU2 gp140 trimeric human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein immunogens could elicit improved breadth of neutralization against HIV-1 isolates compared to monomeric YU2 gp120 proteins. In this guinea pig immunization study, we sought to extend these data and determine if adjuvant could quantitatively or qualitatively alter the neutralizing response elicited by trimeric or monomeric immunogens. Consistent with our earlier studies, the YU2 gp140 immunogens elicited higher-titer neutralizing antibodies against homologous and heterologous isolates than those elicited by monomeric YU2 gp120. Additionally, the GlaxoSmithKline family of adjuvants AS01B, AS02A, and AS03 induced higher levels of neutralizing antibodies compared to emulsification of the same immunogens in Ribi adjuvant. Further analysis of vaccine sera indicated that homologous virus neutralization was not mediated by antibodies to the V3 loop, although V3 loop-directed neutralization could be detected for some heterologous isolates. In most gp120-inoculated animals, the homologous YU2 neutralization activity was inhibited by a peptide derived from the YU2 V1 loop, whereas the neutralizing activity elicited by YU2 gp140 trimers was much less sensitive to V1 peptide inhibition. Consistent with a less V1-focused antibody response, sera from the gp140-immunized animals more efficiently neutralized heterologous HIV-1 isolates, as determined by two distinct neutralization formats. Thus, there appear to be qualitative differences in the neutralizing antibody response elicited by YU2 gp140 compared to YU2 monomeric gp120. Further mapping analysis of more conserved regions of gp120/gp41 may be required to determine the neutralizing specificity elicited by the trimeric immunogens.

Adjuvants, Immunologic↗

Assessment of the transcriptional activation potential of the HMG chromosomal proteins.

Chromosomal proteins HMG-14, HMG-17, and HMG-1 are among the most abundant, ubiquitous, and evolutionarily conserved nonhistone proteins. Analysis of their structure reveals features which are similar to those of certain transcription factors. The distribution of charged amino acid residues along the polypeptide chains is asymmetric: positive charges are clustered toward the N-terminal region, while negative charges are clustered toward the C-terminal region. The residues in the C-terminal region have the potential to form alpha helices with negatively charged surfaces. The abilities of HMG-14, -17, and -1 to function as transcriptional activators were studied in Saccharomyces cerevisiae cells expressing LexA-HMG fusion proteins (human HMG-14 and -17 and rat HMG-1) which bind to reporter molecules containing the beta-galactosidase gene downstream from a lexA operator. Fusion constructs expressing deletion mutants of HMG-14, -17, and -1 were also tested. Analysis of binding to the lexA operator with in vitro-synthesized fusion proteins shows that there are more sites for HMG-14, -17, and -1 binding than for LexA binding and that only the fusion constructs which contain the C-terminal, acidic domains of HMG-17 bind the lexA operator specifically. None of the LexA-HMG fusion protein constructs elevate the level of beta-galactosidase activity in transfected yeast cells. Thus, although HMG-14, -17, and -1 are structurally similar to acidic transcriptional activators, these chromosomal proteins do not function as activators in this test system.

Animals↗

Saccharomyces cerevisiae Nip7p is required for efficient 60S ribosome subunit biogenesis.

The Saccharomyces cerevisiae temperature-sensitive (ts) allele nip7-1 exhibits phenotypes associated with defects in the translation apparatus, including hypersensitivity to paromomycin and accumulation of halfmer polysomes. The cloned NIP7+ gene complemented the nip7-1 ts growth defect, the paromomycin hypersensitivity, and the halfmer defect. NIP7 encodes a 181-amino-acid protein (21 kDa) with homology to predicted products of open reading frames from humans, Caenorhabditis elegans, and Arabidopsis thaliana, indicating that Nip7p function is evolutionarily conserved. Gene disruption analysis demonstrated that NIP7 is essential for growth. A fraction of Nip7p cosedimented through sucrose gradients with free 60S ribosomal subunits but not with 80S monosomes or polysomal ribosomes, indicating that it is not a ribosomal protein. Nip7p was found evenly distributed throughout the cytoplasm and nucleus by indirect immunofluorescence; however, in vivo localization of a Nip7p-green fluorescent protein fusion protein revealed that a significant amount of Nip7p is present inside the nucleus, most probably in the nucleolus. Depletion of Nip7-1p resulted in a decrease in protein synthesis rates, accumulation of halfmers, reduced levels of 60S subunits, and, ultimately, cessation of growth. Nip7-1p-depleted cells showed defective pre-rRNA processing, including accumulation of the 35S rRNA precursor, presence of a 23S aberrant precursor, decreased 20S pre-rRNA levels, and accumulation of 27S pre-rRNA. Delayed processing of 27S pre-rRNA appeared to be the cause of reduced synthesis of 25S rRNA relative to 18S rRNA, which may be responsible for the deficit of 60S subunits in these cells.

Alleles↗

Time-resolved mapping in calves reveals bovine herpesvirus 1 shift from mucosal replication to trigeminal ganglion neuroinvasion with promyelocytic leukemia protein-centered host-virus antagonism.

Although bovine herpesvirus 1 (BoHV-1) causes massive losses of cattle, the transition from mucosal replication to neuroinvasion remains poorly understood. Using a controlled calf model, we integrated quantitative virology and transcriptomics to map its pathogenesis and define the role of promyelocytic leukemia protein (PML). Calves inoculated intranasally and ocularly (1.4 × 106 plaque-forming units/head) were sampled daily (1-14 days post-infection, dpi) for glycoprotein B (gB) qPCR. Tissues were analyzed at 4 and 14 dpi to measure viral DNA via gB-specific qPCR, and for mRNA-seq of trigeminal ganglia (TG). Shedding peaked at 3-6 dpi, being highest in nasal samples, lower in ocular samples, and substantially lower in rectal samples, and declined by 10-14 dpi. At 4 dpi, among the tissues sampled, the tonsils exhibited the highest viral burden. TG exhibited low viral levels at 4 dpi, although they remained detectable at 14 dpi, indicating neuroinvasion. The TG program shifted from early proteostasis priming (4 dpi) to immune/extracellular matrix activation with synaptic repression (14 dpi). In MDBK/Vero cells, IFN-α resulted in higher bovine PML (bPML) levels and enlarged PML nuclear bodies (PML-NBs), reducing very early viral DNA levels, whereas BoHV-1 disrupted PML-NB integrity. The different bPML isoforms exerted different effects on viral infection. STRING analysis revealed a conserved PML-SUMO1-UBE2I-DAXX-SP100 core. These findings delineate the mucosal-to-neuronal trajectory, establish PML as both an effector and viral target in complementary in vitro systems, and identify SUMO/ubiquitin-linked proteostasis as a tractable target for antiviral intervention.IMPORTANCEAlthough bovine herpesvirus 1 (BoHV-1) remains a major challenge to cattle health, the early transition from mucosal replication to trigeminal neuroinvasion has not been clearly mapped in natural-host calves. By integrating daily shedding kinetics, tissue viral DNA profiling, and time-resolved trigeminal ganglion transcriptomics, we delineate when and how BoHV-1 reaches the sensory neurons. Promyelocytic leukemia protein (PML) is identified as a key intrinsic antiviral factor that is upregulated by IFN-α and restricts very early viral genome accumulation, while viral BoHV-1-encoded infected cell protein 0 actively dismantles PML nuclear bodies. The discovery of opposing isoform-specific PML functions and a conserved PML-SUMO proteostasis hub provides mechanistic insight into BoHV-1 immune evasion. These findings refine our understanding of the mucosal-to-neuronal trajectory of infection and highlight proteostasis-linked antiviral pathways as promising targets for intervention.

Animals↗

Body fat distribution in the Finnish population: environmental determinants and predictive power for cardiovascular risk factor levels.

STUDY OBJECTIVE: The aim was to examine (1) whether health habits are associated with body fat distribution, as measured by the waist/hip girth ratio, and (2) to what extent environmental factors, including anthropometric characteristics, explain the variability in levels of cardiovascular risk factors. DESIGN: The study was a population based cross sectional survey, conducted in the spring of 1987 as a part of an international research project on cardiovascular epidemiology. SETTING: The survey was conducted in three geographical areas of eastern and south western Finland. SUBJECTS: 2526 men and 2756 women aged 25-64 years took part in the study, corresponding to a survey participation rate of 82%. MEASUREMENTS AND MAIN RESULTS: In men, waist/hip ratio showed stronger associations with exercise (Pearson's r = -0.24), resting heart rate (r = 0.10), alcohol consumption (r = 0.07), smoking (r = 0.05), and education (r = -0.23) than did body mass index. Jointly, exercise, resting heart rate, alcohol consumption, education, and age explained 18% of variance in male waist/hip ratio, but only 9% of variance in male body mass index. In women, environmental factors were more predictive for body mass index than for waist/hip ratio, with age and education being the strongest determinants. Waist/hip ratio and body mass index were approximately equally strong predictors of cardiovascular risk factor levels. The additional predictive power of waist/hip ratio over and above body mass index was tested in a hierarchical, stepwise regression. In this conservative type of analysis the increase in explained variance uniquely attributable to waist/hip ratio was 2-3% for female and 1-2% for male lipoprotein levels, and less than 0.5% for female and 0-2% for male blood pressure values. CONCLUSIONS: The distribution of abdominal obesity in Finland is significantly influenced by health habits and sociodemographic factors in both men and women. This in turn is obviously one reason for the relatively small "independent" effect of body fat distribution on cardiovascular risk factor levels.

Adipose Tissue↗

Dynamics and mechanics of motor-filament systems.

Motivated by the cytoskeleton of eukaryotic cells, we develop a general framework for describing the large-scale dynamics of an active filament network. In the cytoskeleton, active cross-links are formed by motor proteins that are able to induce relative motion between filaments. Starting from pair-wise interactions of filaments via such active processes, our framework is based on momentum conservation and an analysis of the momentum flux. This allows us to calculate the stresses in the filament network generated by the action of motor proteins. We derive effective theories for the filament dynamics which can be related to continuum theories of active polar gels. As an example, we discuss the stability of homogenous isotropic filament distributions in two spatial dimensions.

Biomechanical Phenomena↗

Comparative genomic sequence analysis coupled to chromatin immunoprecipitation: a screening procedure applied to search for regulatory elements at the RET locus.

RET gene expression is characterized by high tissue and stage specificity during the development of neural crest derivatives and in the pathogenesis of inherited cancer syndromes and Hirschsprung disease. Identifying all elements contributing to its transcriptional regulation might provide new clues to clarify both developmental and pathogenic mechanisms. We previously demonstrated that chromatin acetylation affects RET transcription; therefore, we have set up a strategy based on analysis of sequences conserved among species at the RET locus, combined with the characterization of their chromatin structure, to identify new potential regulatory elements. The histone acetylation level was evaluated by the chromatin immunoprecipitation method applied to cells displaying different degrees of endogenous RET expression. Real-time quantitative PCR of immunoprecipitated DNA-protein complexes and transfection experiments, with constructs expressing a reporter gene in which the putative regulatory regions are inserted, indicate a correlation between histone acetylation and endogenous RET expression and highlight conserved sequences with potential regulatory roles. This paper presents a reliable screening procedure to unearth elements able to affect gene regulation at the transcriptional level in a large genomic region.

Acetylation↗

Simple sequence repeat length polymorphisms mapped to rat chromosome 11.

Two genes and two anonymous DNA loci were mapped to rat chromosome 11 using F2 intercross progeny of Fischer (F344/N) and Lewis (LEW/N) inbred rats. These four loci formed a single linkage group covering 21.5 cM with the following map order: somatostatin (SST)-D11N161-D11N18-cell surface protein (MOX2). These four loci were typed by PCR-based simple sequence repeat (SSR) length polymorphism detection. For each marker four to seven different alleles were detected using a panel of 13 inbred rat strains (F344/N, LEW/N, BN/SsN, BUF/N, LER/N, MR/N, MNR/N, LOU/MN, ACI/N, WBB1/N, WBB2/N, SHR/N, WKY/N). Comparative gene mapping analysis suggests syntenic conservation between rat chromosome 11 and mouse Chromosome 16.

Alleles↗

The repertoire of olfactory C family G protein-coupled receptors in zebrafish: candidate chemosensory receptors for amino acids.

BACKGROUND: Vertebrate odorant receptors comprise at least three types of G protein-coupled receptors (GPCRs): the OR, V1R, and V2R/V2R-like receptors, the latter group belonging to the C family of GPCRs. These receptor families are thought to receive chemosensory information from a wide spectrum of odorant and pheromonal cues that influence critical animal behaviors such as feeding, reproduction and other social interactions. RESULTS: Using genome database mining and other informatics approaches, we identified and characterized the repertoire of 54 intact "V2R-like" olfactory C family GPCRs in the zebrafish. Phylogenetic analysis - which also included a set of 34 C family GPCRs from fugu - places the fish olfactory receptors in three major groups, which are related to but clearly distinct from other C family GPCRs, including the calcium sensing receptor, metabotropic glutamate receptors, GABA-B receptor, T1R taste receptors, and the major group of V2R vomeronasal receptor families. Interestingly, an analysis of sequence conservation and selective pressure in the zebrafish receptors revealed the retention of a conserved sequence motif previously shown to be required for ligand binding in other amino acid receptors. CONCLUSION: Based on our findings, we propose that the repertoire of zebrafish olfactory C family GPCRs has evolved to allow the detection and discrimination of a spectrum of amino acid and/or amino acid-based compounds, which are potent olfactory cues in fish. Furthermore, as the major groups of fish receptors and mammalian V2R receptors appear to have diverged significantly from a common ancestral gene(s), these receptors likely mediate chemosensation of different classes of chemical structures by their respective organisms.

Amino Acid Sequence↗

Ci-FoxA-a is the earliest zygotic determinant of the ascidian anterior ectoderm and directly activates Ci-sFRP1/5.

This work focuses on the anteroposterior patterning of the ectoderm in the invertebrate chordate Ciona intestinalis. Previous work indicated that, by the eight-cell stage, the anterior and posterior animal blastomeres have acquired different properties, including a differential responsiveness to inducing signals from the underlying mesendoderm. Here, we investigated the molecular basis of this distinction. For this, we studied the regulation of the earliest marker specific for the anterior ectoderm, Ci-sFRP1/5, which is activated at the 64-cell stage. We first found that the activation of this marker in the anterior ectoderm does not involve communication with other lineages. We then identified, by phylogenetic footprinting and deletion analysis, a short conserved minimal enhancer driving the onset of expression of Ci-sFRP1/5. We showed that this enhancer was a direct target of the Ci-FoxA-a gene, a FoxA/HNF3 orthologue expressed in anterior ectodermal and mesendodermal lineages from the eight-cell stage. Gain- and loss-of-function experiments revealed that Ci-FoxA-a is necessary and sufficient within the ectoderm to impose an ectodermal anterior identity, and to repress the posterior programme. Thus, Ci-FoxA-a constitutes a major early zygotic anterior determinant for the ascidian ectoderm, acting autonomously in this territory, prior to the onset of vegetal inductions. Interestingly, while vertebrate FoxA2 are also involved in the regionalization of the ectoderm, they are thought to act during gastrulation to control, in the mesendoderm, the expression of organizer signals. We discuss the evolution of chordate ectodermal patterning in light of our findings.

Animals↗

Chicken homeobox gene Msx-1: structure, expression in limb buds and effect of retinoic acid.

A chicken gene carrying a homeobox highly homologous to the Drosophila muscle segment homeobox (msh) gene was isolated and designated as Msx-1. Conceptual translation from the longest ORF gave a protein of 259 amino acids lacking the conserved hexapeptide. Northern analysis detected a single 2.6 kb transcript. As early as day 2 of incubation, the transcript was detected but was not found in adult tissue. In situ hybridization analysis revealed that Msx-1 expression is closely related to a particular mesenchymal cell lineage during limb bud formation. In early stage embryos, Msx-1 was expressed in the somatopleure. When primordial mesenchyme cells for limb bud were generated from the Wolffian ridge of the somatopleure, Msx-1 expression began to diminish in the posterior half of the limb bud then in the presumptive cartilage-forming mesenchyme. In developing limb buds, remarkable expression was seen in the apical ectodermal ridge (AER), which is responsible for the sustained outgrowth and development of the limb. The Msx-1 transcripts were found in the limb mesenchymal cells in the region covering the necrotic zone and ectodermal cells overlying such mesenchymal cells. Both ectodermal and mesenchymal expression in limb bud were rapidly suppressed by local treatment of retinoic acid which can generate mirror-image duplication of digits. This indicates that retinoic acid alters the marginal presumptive non-cartilage forming mesenchyme cell lineage through suppression of Msx-1 expression.

Amino Acid Sequence↗

Cloning and developmental expression of Sna, a murine homologue of the Drosophila snail gene.

The genetic analysis of dorsoventral patterning in Drosophila has identified a zinc-finger gene, snail, that is required for mesoderm formation. The cloning and nuclease protection analysis of a Xenopus homologue of this gene has suggested a possible role in the mesoderm of vertebrates. Here, we describe the cloning of a murine homologue of snail, Sna, and in situ hybridisation studies of its developmental expression. Sequence analysis reveals substantial conservation of the second to fifth zinc fingers, but not of the first zinc finger in the Sna gene. Expression occurs in the ectoplacental cone, parietal endoderm, embryonic and extraembryonic mesoderm, in neural crest and in condensing precartilage. Based on the timing and spatial restriction of expression in embryonic mesoderm, we suggest that Sna might be required for the early development of this tissue, as is the case for its Drosophila counterpart. In addition, we propose that Sna might have an analogous role in the development of neural crest. The expression in condensing precartilage indicates that this gene also has a later function in chondrogenesis.

Amino Acid Sequence↗

Clinical effect of canal plugging on paroxysmal positional vertigo.

A 63-year-old woman had disabling positional vertigo for four months. She showed intense direction-changing apogeotropic nystagmus. Conservative treatment failed to resolve her vertigo. From the findings of the nystagmus, cupulolithiasis of the right lateral canal was suspected. Plugging of this canal successfully eliminated the nystagmus and positional vertigo. Positional vertigo can sometimes be disabling and unresponsive to conservative therapy. Careful analysis of the nystagmus may allow selection of the most appropriate treatment.

Female↗

Her-2/neu expression as a predictive factor for response to anthracycline-based chemotherapy in a mexican population of locally advanced breast cancer patients.

Breast cancer is the second most frequent tumor in Mexico 30-50% are diagnosed in locally advanced stages requiring neoadjuvant chemotherapy. The overexpression of HER-2/neu has been identified as a chemotherapy response predictor. The objective of our study was to identify response predictive factors to anthracycline-based neoadjuvant chemotherapy in locally advanced breast cancer. Data were collected from clinical records of patients with neoadjuvant anthracycline-based chemotherapy, for clinical stage III breast cancer from 1992 to 1997. Paraffin blocks were reviewed to determine histologic grade, HER-2/neu expression, and ploidy. Patients were divided in two groups: A, 56 cases responding to chemotherapy and, B, 20 nonresponders. Mean age was 50.1 and 45.4 for groups A and B, respectively (OR 7.02, p = 0.004), and those premenopausal were 43% and 70%, respectively (OR 3.1, p = 0.04). Mean tumor size was 5 cm in responders and 8 cm for nonresponders (OR 4, p = 0.02). Clinical stage III-B 16% and 70% for groups A and B (OR 12.2, p = 0.000); tumors were aneuploid in 39% of responders and 18.7% for nonresponders. HER-2 /neu was overexpressed in 64.2% and 50% for groups A and B (OR 3.6, p = 0.06). On multivariate analysis significance was conserved only for age, clinical stage, and size. HER-2/neu lost significance. Age and size were importantly related to tumor response, a higher percentage of HER-2/neu overexpression was observed in responders, without significance due to small sample size. It would be important to study a larger number of patients to obtain more conclusive results.

Adult↗

Frameless stereotactic aspiration and thrombolysis of spontaneous intracerebral hemorrhage.

INTRODUCTION: To test the feasibility and safety of a minimally invasive technique, we report our experience in treating spontaneous intracerebral hemorrhage (ICH) patients by using frameless stereotactic clot aspiration-thrombolysis and its effects on their 30-day survival. We compared the observed cohort mortality with its predicted 30-day ICH mortality, by using previously validated methods. METHODS: Selection criteria were diagnosis of hypertensive ICH > or =35 cc, reduced level of consciousness, and no brainstem compression. Frameless stereotactic puncture/clot aspiration followed by intraclot external catheter placement was performed. Two milligrams of recombinant tissue plasminogen activator (rtPA) was administered q12 hours until ICH volume < or =10 cc, or the catheter fenestrations were no longer in continuity with the clot. RESULTS: Fifteen patients were treated, mean age was 60.7 years. Hemorrhage locations included basal ganglia (13), thalamic (1), and lobar (1); mean systolic blood pressure; and admission ICH volumes were 229.3 mmHg and 59.1 cc, respectively. Median time from ictus to clot aspiration/thrombolysis was 1 (range 0-3) day. Mean hematoma volume was reduced to 17% of pretreatment size. Complications were ventriculitis (6.6%) and clot enlargement (13.3%). Two patients were dead at 30 days. Median Glasgow Coma Scale (GCS) scores were 10.5 (4-15) at admission and 11.0 (3-15) at discharge. By using the most conservative estimate for analysis, probability of observing two or fewer deaths among 15 patients with an overall probability of dying calculated at 0.33 was p = 0.079. CONCLUSIONS: In this selected cohort of patients with ICH, stereotactic aspiration and thrombolytic washout seemed to be feasible and to have a trend towards improved 30-day survival, when using their predicted mortality data as "historical control." Complications did not exceed expected incidence rates. Based on the experience presented here as well as previous similar reports, a larger, randomized study addressing dose escalation, patient selection, and best therapeutic window is needed.

Biopsy, Fine-Needle↗

[Theoretical perspectives on medicine and the medical profession: an anthropological approach].

The medical field and profession are studied from the theoretical point of view of the social sciences. The most representative works on this subject are presented. The analysis shows that conservative positivism and orthodox Marxism are the main obstacles to development in this field of study. At the same time it suggests the concept of culture and the anthropological method of research as the best means for the overcoming of some of the main contradictions which paralyse its progress.

Anthropology, Cultural↗

Coping with rising food costs in a closed economy: feeding behavior and nocturnal hypothermia in pigeons.

The pigeon's response to increasing fixed-ratio schedules in a 24-hr closed economy is marked by changes in feeding behavior during the daily light phase and by changes in body temperature during the dark phase. The time course of these responses to increasing behavioral cost of obtaining food is very different. Feeding is most affected immediately, within the first day of exposure to moderate fixed ratios. The number of times the pigeons produce the food hopper each day decreases, and the rate at which they eat from the food hopper (grams per minute) when it is available increases, as the fixed ratio is raised. Body temperature is affected later, falling to progressively lower resting levels during the dark phase as body weight drops at the higher fixed ratios when food intake is reduced. The changes in feeding and in body temperature that occur as the fixed-ratio schedule increases seem to reduce daily energy expenditures, within the constraints imposed by the experiment. The ascending and descending limbs of the bitonic function obtained when total daily operant responding is plotted as a function of fixed-ratio schedule in the closed economy is possibly related to the occurrence of thermoregulatory strategies for energy conservation. The energetic analysis of performances in the closed economy requires consideration of a variety of energetic strategies available to the species being studied.

Animals↗

Evaluating microbial purification during soil treatment of wastewater with multicomponent tracer and surrogate tests.

Soil treatment of wastewater has the potential to achieve high purification efficiency, yet the understanding and predictability of purification with respect to removal of viruses and other pathogens is limited. Research has been completed to quantify the removal of virus and bacteria through the use of microbial surrogates and conservative tracers during controlled experiments with three-dimensional pilot-scale soil treatment systems in the laboratory and during the testing of full-scale systems under field conditions. The surrogates and tracers employed included two viruses (MS-2 and PRD-1 bacteriophages), one bacterium (ice-nucleating active Pseudomonas), and one conservative tracer (bromide ion). Efforts have also been made to determine the relationship between viruses and fecal coliform bacteria in soil samples below the wastewater infiltrative surface, and the correlation between Escherichia coli concentrations measured in percolating soil solution as compared with those estimated from analyses of soil solids. The results suggest episodic breakthrough of virus and bacteria during soil treatment of wastewater and a 2 to 3 log (99-99.9%) removal of virus and near complete removal of fecal coliform bacteria during unsaturated flow through 60 to 90 cm of sandy medium. Results also suggest that the fate of fecal coliform bacteria may be indicative of that of viruses in soil media near the infiltrative surface receiving wastewater effluent. Concentrations of fecal coliform in percolating soil solution may be conservatively estimated from analysis of extracted soil solids.

Bacteriophages↗