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Fungi produce a wealth of pharmacologically bioactive secondary metabolites (SMs) from biosynthetic gene clusters (BGCs). It is common practice for drug discovery efforts to treat species' secondary metabolomes as being well represented by a single or a small number of representative genomes. However, this approach misses the possibility that intraspecific population dynamics, such as adaptation to environmental conditions or local microbiomes, may harbor novel BGCs that contribute to the overall niche breadth of species. Using 94 isolates of Aspergillus flavus, a cosmopolitan model fungus, sampled from seven states in the United States, we dereplicate 7,821 BGCs into 92 unique BGCs. We find that more than 25% of pangenomic BGCs show population-specific patterns of presence/absence or protein divergence. Population-specific BGCs make up most of the accessory-genome BGCs, suggesting that different ecological forces that maintain accessory genomes may be partially mediated by population-specific differences in secondary metabolism. We use ultra-high-performance high-resolution mass spectrometry to confirm that these genetic differences in BGCs also result in chemotypic differences in SM production in different populations, which could mediate ecological interactions and be acted on by selection. Thus, our results suggest a paradigm shift that previously unrealized population-level reservoirs of SM diversity may be of significant evolutionary, ecological, and pharmacological importance. Last, we find that several population-specific BGCs from A. flavus are present in Aspergillus parasiticus and Aspergillus minisclerotigenes and discuss how the microevolutionary patterns we uncover inform macroevolutionary inferences and help to align fungal secondary metabolism with existing evolutionary theory.

The apparent rarity of sex in many fungal species has raised questions about how much sex is needed to purge deleterious mutations and how differences in frequency of sex impact fungal evolution. We sought to determine how differences in the extent of recombination between populations of Aspergillus flavus impact the evolution of genes associated with the synthesis of aflatoxin, a notoriously potent carcinogen. We sequenced the genomes of, and quantified aflatoxin production in, 94 isolates of A. flavus sampled from seven states in eastern and central latitudinal transects of the United States. The overall population is subdivided into three genetically differentiated populations (A, B, and C) that differ greatly in their extent of recombination, diversity, and aflatoxin-producing ability. Estimates of the number of recombination events and linkage disequilibrium decay suggest relatively frequent sex only in population A. Population B is sympatric with population A but produces significantly less aflatoxin and is the only population where the inability of nonaflatoxigenic isolates to produce aflatoxin was explained by multiple gene deletions. Population expansion evident in population B suggests a recent introduction or range expansion. Population C is largely nonaflatoxigenic and restricted mainly to northern sampling locations through restricted migration and/or selection. Despite differences in the number and type of mutations in the aflatoxin gene cluster, codon optimization and site frequency differences in synonymous and nonsynonymous mutations suggest that low levels of recombination in some A. flavus populations are sufficient to purge deleterious mutations.IMPORTANCE Differences in the relative frequencies of sexual and asexual reproduction have profound implications for the accumulation of deleterious mutations (Muller's ratchet), but little is known about how these differences impact the evolution of ecologically important phenotypes. Aspergillus flavus is the main producer of aflatoxin, a notoriously potent carcinogen that often contaminates food. We investigated if differences in the levels of production of aflatoxin by A. flavus could be explained by the accumulation of deleterious mutations due to a lack of recombination. Despite differences in the extent of recombination, variation in aflatoxin production is better explained by the demography and history of specific populations and may suggest important differences in the ecological roles of aflatoxin among populations. Furthermore, the association of aflatoxin production and populations provides a means of predicting the risk of aflatoxin contamination by determining the frequencies of isolates from low- and high-production populations.

Nutcracker esophagus ( NE), Jackhammer esophagus ( JHE), distal esophageal spasm ( DES), and hypertensive lower esophageal sphincter ( HTLES) are defined by esophageal manometric findings. Some patients with these esophageal motility disorders also have abnormal gastroesophageal reflux. It is unclear to what extent these patients' symptoms are caused by the motility disorder, the acid reflux, or both. The aim of this study was to determine the effectiveness of laparoscopic Nissen fundoplication ( LNF) on esophageal motility disorders, gastroesophageal reflux, and patient symptoms. Between 2007 and 2013, we performed high-resolution esophageal manometry on 3400 patients, and 221 patients were found to have a spastic esophageal motility disorder. The medical records of these patients were reviewed to determine the manometric abnormality, presence of gastroesophageal symptoms, and amount of esophageal acid exposure. In those patients that underwent LNF, we compared pre- and postoperative esophageal motility, gastroesophageal symptom severity, and esophageal acid exposure. Of the 221 patients with spastic motility disorders, 77 had NE, 2 had JHE, 30 had DES, and 112 had HTLES. The most frequently reported primary and secondary symptoms among all patients were: heartburn and/or regurgitation, 69.2%; respiratory, 39.8%; dysphagia, 35.7%; and chest pain, 22.6%. Of the 221 patients, 192 underwent 24-hour pH monitoring, and 103 demonstrated abnormal distal esophageal acid exposure. Abnormal 24-hour pH monitoring was detected in 62% of patients with heartburn and regurgitation, 49% of patients with respiratory symptoms, 36.8 % of patients with dysphagia, and 32.6% of patients with chest pain. Sixty-six of the 103 patients with abnormal 24-hour pH monitoring underwent LNF. Thirty-eight (13 NE, 2 JHE, 6 DES, and 17 HTLES) of these 66 patients had a minimum of 6-month postoperative follow-up that included clinical evaluation, esophageal manometry, and 24-hour pH monitoring. Postoperatively, all 38 patients had normal distal esophageal acid exposure. Of these 38 patients, symptoms resolved in 28 and improved in 10. Of six patients (one with NE, two JHE, and three with HTLES) that underwent postoperative esophageal manometry, five exhibited normal motility. Typical reflux symptoms are common among patients with esophageal hypermotility disorders. Abnormal 24-hour pH monitoring is present in the majority of patients with who report typical reflux symptoms and almost half of patients who report respiratory symptoms. Conversely, the majority of patients who report dysphagia or chest pain have normal distal esophageal acid exposure. Based on a small number of patients in this study, it also appears that motility disorders often improve after LNF. LNF is associated with resolution or improvement in reflux related symptoms and esophageal motility parameters in patients exhibiting abnormal esophageal acid exposure. This suggests that patient symptoms are due to abnormal acid exposure and not the motility disorder. [ABSTRACT FROM AUTHOR]

The article presents information on petroglyphs discovered in southeastern Colorado. The author notes that several different types of petrogylphs have been found with the best coming from Las Animas County, Colorado and that the report is designed to examine previous research on these images and discuss the relationship among them. Previous research has linked pictographs and petrogylphs to the plains cultures, but a link between the images in Colorado and those cultures has not been determined. Chipped or pecked into stone, the images discovered in Colorado along the Apishapa River depict goats, deer and buffalo.

The article presents an in-depth review of the geological study of the region of Trinidad, Colorado. Details are given overviewing several investigations by private and governmental officials since 1846. A comprehensive discussion of the various geological layers of the rock formations in Trinidad is given, pointing out the composition and characteristics of several historical epochs, including the Jurassic, Cretaceous, and Cenozoic eras. Lists and descriptions of dozens of local rock formations, fossils and minerals present are given.

The article presents information on archaeological surveys conducted in Las Animas County, Colorado. It is said that this county is both the largest in the state, and the least studied by archaeologists. This is due, in part, to the frequently inaccessible terrain, and a dearth of paved or marked roads. Many sites were surveyed in the region near Trinidad, and along the Purgatoire and Apishapa Rivers. Information is presented on the Native American artifacts found at these sites, such as stone implements, petroglyphs and projectile points.

The article reports on an archaeological survey that took place in Las Animas County, Colorado that began in June 1941. The report discusses the physical geography of Las Animas County, the geological aspects of the land and the peoples they believed occupied the sites surveyed. They believe the sites were populated by Plains Indians and suggest that the Ute, Kiowa and Apache all made camps within the county. It reports on the number of sites encountered and what types of sites they found. They found cave dwellings and stone enclosures and shelters. They also observed pictographs and petrogylphs.

The article presents a list of Native American relic collections and collectors in southern Colorado, including the F. Watson collection of Segundo, the W. R. Ross collection of Greeley, and the H. Valentine collection of Trinidad.

The article presents discussion of archaeological research projects which can be conducted in Colorado while resources are limited due to the national participation in World War II. Details are given noting the importance of classifying and analyzing previously collected data in the archaeological discipline and calls are given for further focus on such elements when resources are limited. Suggested projects include the identification of unreported sites, the discovery of previously unreported materials, and comprehensive synthesis of regional characteristics.

The article presents a discussion of the history of the calumet or peace-pipe of the Native Americans of Colorado. Comments are given outlining the significance of the pipe to Native American culture, noting its prevalence in several different societies in Minnesota. Details are given noting several instances of archaeological discoveries of pipes and their materials at a location in Trinidad, Colorado. Description is offered of the pipes found and the conditions of the site, along with speculation on its arrival in Colorado.

Transient lower esophageal sphincter relaxations (tLESRs) are vagally mediated in response to gastric cardiac distension. Nine volunteers, eight gastroesophageal reflux disease (GERD) patients, and eight fundoplication patients were studied. Manometry with an assembly that included a barostat bag was done for 1 h with and 1 h without barostat distension to 8 mmHg. Recordings were scored for tLESRs and barostat bag volume. Fundoplication patients had fewer tLESRs (0.4 +/- 0.3/h) than either normal subjects (2.4 +/- 0.5/h) or GERD patients (2.0 +/- 0.3/h). The tLESRs rate increased significantly in normal subjects (5.8 +/- 0.9/h) and GERD patients (5.4 +/- 0.8/h) during distension but not in the fundoplication group. All groups exhibited similar gastric accommodation (change in volume/change in pressure) in response to distension. Fundoplication patients exhibit a lower tLESR rate at rest and a marked attenuation of the response to gastric distension compared with either controls or GERD patients. Gastric accommodation was not impaired with fundoplication. This suggests that the receptive field for triggering tLESRs is contained within a wider field for elicitation of gastric receptive relaxation and that only the first is affected by fundoplication.

Background & Aims: In certain cases of achalasia, particularly those in early stages with minimal endoscopic or radiographic abnormalities, the diagnosis may rely on manometry, which is the most sensitive test for the disease. The aim of this study was to critically evaluate the manometric criteria in a population of patients with idiopathic achalasia., Methods: Clinical histories and manometric recordings of 58 patients with idiopathic achalasia and 43 control subjects were analyzed with regard to esophageal body contraction amplitude, peristaltic effectiveness in terms of both completeness and propagation velocity, lower esophageal sphincter (LES) resting pressure, LES relaxation pressure, and intraesophageal-intragastric pressure gradient. Variants of achalasia were defined by finding manometric features that significantly differed from the remainder of achalasia patients, such that the diagnosis might be questioned., Results: Four manometrically distinct variants were identified. These variants were characterized by (1) the presence of high amplitude esophageal body contractions, (2) a short segment of esophageal body aperistalsis, (3) retained complete deglutitive LES relaxation, and (4) intact transient LES relaxation. In each instance, the most extreme variant is discussed and compared with the remainder of the achalasia population and with controls., Conclusions: The significance in defining these variants of achalasia lies in the recognition that these sometimes confusing manometric findings are consistent with achalasia when combined with additional clinical data supportive of the diagnosis. Furthermore, such variants provide important clues into the pathophysiology of this rare disorder.

Introduction: Dysphagia is common after Nissen fundoplication but the relationship between dysphagia and bolus transit is poorly defined. This study compared bolus transit of fundoplication patients to normal individuals., Methods: Twelve fundoplication patients and 20 healthy volunteers rated their ability to swallow eight bolus consistencies from no difficulty (0) to extreme difficulty (3) to compute a dysphagia score (range = 0-24). A 16-lumen manometric assembly was positioned across the esophagogastric junction (EGJ) and subjects were imaged fluoroscopically in a supine posture while swallowing 5 cc liquid barium and a 5-cc marshmallow-like viscoelastic barium bolus. Videofluoroscopic images were analyzed for total esophageal transit time and the fraction of time required to cross the EGJ. Manometric tracings were analyzed for the intrabolus pressure proximal to the EGJ, intragastric pressure, and distal peristaltic amplitude for each bolus., Results: Dysphagia scores for fundoplication patients were significantly higher (7.3 +/- 5.1, range = 1-17) than for normals (0.5 +/- 0.6, range = 0-2). This correlated with longer total transit times for liquids and solids (r = 0.60, P < 0.01) and a greater percentage of transit time attributable to the EGJ transit. Retrograde flow at the EGJ (escape of bolus proximally up the esophagus) and peristaltic dysfunction were more frequent in fundoplication patients. However, no differences existed in manometric parameters between groups., Conclusions: Fundoplication impairs both liquid and solid esophageal bolus transit. Dysphagia perceived by fundoplication patients correlated with increased transit time, particularly across the EGJ. Combined quantitative evaluation with manometry and fluoroscopy reveals functional defects in fundoplication subjects, which are not evident by either modality alone., (Copyright 2000 Academic Press.)

Patients with gastroesophageal reflux disease (GERD) experience a wide spectrum of symptoms, varying both in quality and severity. This review summarizes clinical observations of esophageal sensitivity and symptom perception in GERD patients. The Bernstein test, although lacking standardization, remains a useful tool in determining esophageal sensitivity to acid stimuli. Ambulatory 24-hour pH monitoring with symptom event marking and subsequent symptom-reflux correlation between acid reflux events and esophageal symptomatology now provides an alternative method for establishing esophageal acid sensitivity. The intraesophageal balloon distention test (IEBD) was developed to assess esophageal sensitivity to mechanical stimuli. Variants of each of these tests have been applied to the evaluation of uncomplicated GERD patients and patients with esophagitis and Barrett's metaplasia, who generally demonstrate less esophageal sensitivity than the former group. Studies using these methods have demonstrated increased esophageal sensitivity in patients with esophageal chest pain and have also identified a subset of patients with esophageal symptoms yet normal esophageal acid exposure, a condition referred to as "hypersensitive esophagus." The Bernstein test, 24-hour pH monitoring with symptom assessment, and IEBD have each contributed to our understanding of esophageal pain syndromes; it is hoped that future work in this area will lead to improved and more specific therapy for these patients.

Objective: Our aim was to assess the efficacy and mechanism of solid bolus transit through the esophagus., Methods: Eight healthy volunteers were studied with concurrent manometry and videofluoroscopy while swallowing 5 ml liquid barium, a 5-6 mm diameter bread ball, and 4 g chewed bread in both a supine and upright posture. As many as four successive swallows were performed until clearance was achieved., Results: The esophageal clearance of liquid barium was 100% with the first swallow. Clearance of the unchewed bread ball occurred with the first swallow in only 6.7% of trials in the upright posture and 5.9% in the supine posture. After four swallows, clearance was 100% and 52.9% in the upright and supine postures, respectively. Chewed bread was more readily cleared than unchewed bread, with 100% clearance after two swallows in the upright posture and 91% clearance after four swallows in the supine posture. The most common locus of bread stasis was at the aortic arch and carina. The bread boluses were noted to move more effectively when localized in the head as opposed to the tail of the bolus composite. Nonocclusive contractions often occurred at the bolus tail despite the increased peristaltic amplitude seen with the chewed bread. Failed peristalsis, a frequent cause for solid clearance failure, was observed during 30% of all bread swallows. This usually occurred distal to the stopping point of the bolus, suggesting it to be the result rather than the cause of impaired transit., Conclusions: Although infrequently perceived by these normal subjects and in contradistinction to liquid clearance, bread is rarely cleared from the esophagus with a single swallow. Mastication and an upright posture facilitate the esophageal transport of solids. Bolus composition and impaired bolus transit alter the amplitude and conductance of peristalsis. Manometric data pertaining to liquid clearance through the esophagus do not readily apply to bread.