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BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disease that is characterized by an excessive accumulation of extracellular matrix (ECM) proteins (e.g. collagens) in the parenchyma, which ultimately leads to respiratory failure and death. While current therapies exist to slow the progression, no therapies are available to resolve fibrosis.MethodsWe characterized the O-linked N-Acetylglucosamine (O-GlcNAc) transferase (OGT)/O-GlcNAc axis in IPF using single-cell RNA-sequencing (scRNA-seq) data and human lung sections and isolated fibroblasts from IPF and non-IPF donors. The underlying mechanism(s) of IPF were further investigated using multiple experimental models to modulate collagen expression and accumulation by genetically and pharmacologically targeting OGT. Furthermore, we hone in on the transforming growth factor-beta (TGF-β) effector molecule, Smad3, by co-expressing it with OGT to determine if it is modified and its subsequent effect on Smad3 activation.ResultsWe found that OGT and O-GlcNAc levels are upregulated in patients with IPF compared to non-IPF. We report that the OGT regulates collagen deposition and fibrosis resolution, which is an evolutionarily conserved process demonstrated across multiple species. Co-expression of OGT and Smad3 showed that Smad3 is O-GlcNAc modified. Blocking OGT activity resulted in decreased phosphorylation at Ser-423/425 of Smad3 attenuating the effects of TGF-β1 induced collagen expression/deposition.ConclusionOGT inhibition or knockdown successfully blocked and reversed collagen expression and accumulation, respectively. Smad3 is discovered to be a substrate of OGT and its O-GlcNAc modification(s) directly affects its phosphorylation state. These data identify OGT as a potential target in pulmonary fibrosis resolution, as well as other diseases that might have aberrant ECM/collagen accumulation.

Sensors that implement laser speckle image streaming provide real-time, noninvasive assessment of peripheral blood flow during endovascular revascularization. This single-center feasibility study evaluated a laser speckle-based peripheral blood flow monitoring system in 24 patients with peripheral arterial disease. System-quantified blood flow values showed improvement at the conclusion of the procedure in 20 of 24 patients (83.3%). Of the four patients without improved flow values, waveform morphology improved in three. Waveforms graded as moderate to severe peripheral arterial disease decreased from 71% before the procedure to 25% after the procedure, with improvement in 19 of 24 patients. In this limited population, laser speckle imaging could offer a highly sensitive method of detecting intraprocedural pedal blood flow changes.

BackgroundCell-based functional immune-assays may allow for risk stratification of patients with complex, heterogeneous immune disorders such as sepsis. Given the heterogeneity of patient responses and the uncertain immune pathogenesis of sepsis, these assays must first be defined and calibrated in the healthy population.ObjectiveOur objective was to compare the internal consistency and practicality of two immune assays that may provide data on surrogate markers of the innate and adaptive immune response. We hypothesized that a rapid turnaround, microfluidic-based immune assay (ELLA) would be comparable to a dual-color, enzyme-linked immunospot (ELISpot) assay in identifying tumor necrosis factor (TNF) and interferon (IFN)γ production following ex vivo whole blood stimulation.DesignThis was a prospective, observational cohort analysis. Whole blood samples from ten healthy, immune-competent volunteers were stimulated for either 4 hours or 18 hours with lipopolysaccharide, anti-CD3/anti-CD28 antibodies, or phorbol 12-myristate 13-acetate with ionomycin to interrogate innate and adaptive immune responses, respectively.Measurements and Main ResultsELLA analysis produced more precise measurement of TNF and IFNγ concentrations as compared with ELISpot, as well as a four- to five-log10 dynamic range for TNF and IFNγ concentrations, as compared with a two-log10 dynamic range with ELISpot. Unsupervised clustering accurately predicted the ex vivo immune stimulant used for 90% of samples analyzed via ELLA, as compared with 72% of samples analyzed via ELISpot.ConclusionsWe describe, for the first time, a rapid and precise assay for functional interrogation of the innate and adaptive arms of the immune system in healthy volunteers. The advantages of the ELLA microfluidic platform may represent a step forward in generating a point-of-care test with clinical utility, for identifying deranged immune phenotypes in septic patients.

Chronic cigarette smoking is a major risk factor for many serious diseases. While complete cessation of smoking is the best option to reduce harm from smoking, adverse impacts of smoking on health could persist for several years after cessation. Therefore, Biomarkers of Potential Harm (BoPH) are useful in interim evaluations of the beneficial effects of smoking cessation or switching to potentially lower-risk tobacco products. A 14-day smoking abstinence study was conducted under clinical confinement conditions and enrolled 70 subjects into younger (24–34 years, n = 33) and older (35–60 years, n = 37) age cohorts. Biomarkers of Exposure (BoE), which indicate exposure to nicotine and other toxicants, were measured at baseline, 7 and 14 days. Several BoPH including previously identified eicosanoids (leukotriene 4 (LTE4) and 2,3-dinor thromboxane 2 (2,3-d-TXB2) and others were evaluated. Significant declines in BoE, LTE4, 2,3-d-TXB2, neutrophils, WBC and select RBC, and arterial blood gas parameters were observed in both age cohorts at Days 7 and 14 compared to baseline, while other BoPH (e.g., FeNO) showed age-related effects. Rapid and reproducible reductions in LTE4, 2,3-d-TXB2 WBC, and neutrophil counts were consistently detected following smoking abstinence, indicating the value of these markers as useful BoPH.

The Early Pleistocene was a critical time period in the evolution of eastern African mammal faunas, but fossil assemblages sampling this interval are poorly known from Ethiopia’s Afar Depression. Field work by the Hadar Research Project in the Busidima Formation exposures (~2.7–0.8 Ma) of Hadar in the lower Awash Valley, resulted in the recovery of an early Homo maxilla (A.L. 666-1) with associated stone tools and fauna from the Maka’amitalu basin in the 1990s. These assemblages are dated to ~2.35 Ma by the Bouroukie Tuff 3 (BKT-3). Continued work by the Hadar Research Project over the last two decades has greatly expanded the faunal collection. Here, we provide a comprehensive account of the Maka’amitalu large mammals (Artiodactyla, Carnivora, Perissodactyla, Primates, and Proboscidea) and discuss their paleoecological and biochronological significance. The size of the Maka’amitalu assemblage is small compared to those from the Hadar Formation (3.45–2.95 Ma) and Ledi-Geraru (2.8–2.6 Ma) but includes at least 20 taxa. Bovids, suids, and Theropithecus are common in terms of both species richness and abundance, whereas carnivorans, equids, and megaherbivores are rare. While the taxonomic composition of the Maka’amitalu fauna indicates significant species turnover from the Hadar Formation and Ledi-Geraru deposits, turnover seems to have occurred at a constant rate through time as taxonomic dissimilarity between adjacent fossil assemblages is strongly predicted by their age difference. A similar pattern characterizes functional ecological turnover, with only subtle changes in dietary proportions, body size proportions, and bovid abundances across the composite lower Awash sequence. Biochronological comparisons with other sites in eastern Africa suggest that the taxa recovered from the Maka’amitalu are broadly consistent with the reported age of the BKT-3 tuff. Considering the age of BKT-3 and biochronology, a range of 2.4–1.9 Ma is most likely for the faunal assemblage.

Studies of horse evolution arose during the middle of the 19th century, and several hypotheses have been proposed for their taxonomy, paleobiogeography, paleoecology and evolution. The present contribution represents a collaboration of 19 multinational experts with the goal of providing an updated summary of Pliocene and Pleistocene North, Central and South American, Eurasian and African horses. At the present time, we recognize 114 valid species across these continents, plus 4 North African species in need of further investigation. Our biochronology and biogeography sections integrate Equinae taxonomic records with their chronologic and geographic ranges recognizing regional biochronologic frameworks. The paleoecology section provides insights into paleobotany and diet utilizing both the mesowear and light microscopic methods, along with calculation of body masses. We provide a temporal sequence of maps that render paleoclimatic conditions across these continents integrated with Equinae occurrences. These records reveal a succession of extinctions of primitive lineages and the rise and diversification of more modern taxa. Two recent morphological-based cladistic analyses are presented here as competing hypotheses, with reference to molecular-based phylogenies. Our contribution represents a state-of-the art understanding of Plio-Pleistocene Equus evolution, their biochronologic and biogeographic background and paleoecological and paleoclimatic contexts.

Li and Héroux [...]

Biochronology is important to vertebrate chronology because the primary temporal units developed and applied by vertebrate paleontologists for correlation of terrestrial deposits (Land Mammal Ages, LMA) are all biochronologic units. Specific mammal biochronologic scales have been developed for Europe (MN units or ELMA), Asia (ALMA), North America (NALMA), and South America (SALMA). Each timescale is based on land mammal first appearances and characteristic associations on different continental landmasses. Herein, we summarize and review the bases for recognizing mammalian biochronologic units with the most recent update of the Land Mammal Ages. We correlate these ages with the global magnetochronostratigraphic and geochronologic time scales including the major equid evolutionary events of the last 8 million years.

A new species of mastodon from the Pleistocene of western North America, Mammut pacificus sp. nov. is herein recognized, with specimens identified throughout California and from two localities in southern Idaho. This new taxon differs from the contemporaneous M. americanum in having narrower teeth, most prominently in M3/m3, as well as six sacral vertebrae, femur with a proportionally greater mid-shaft diameter, and no mandibular tusks at any growth stage. All known Pleistocene Mammut remains from California are consistent with our diagnosis of M. pacificus, which indicates that M. americanum was not present in California.

The hexosamine biosynthetic pathway (HBP) generates the substrate for the O-linked β-N-acetylglucosamine (O-GlcNAc) modification of proteins. The HBP also serves as a stress sensor and has been reported to be involved with nuclear factor of activated T-cells (NFAT) activation, which can contribute to multiple cellular processes including cell metabolism, proliferation, and inflammation. In our previously published report, Fibroblast Growth Factor (FGF) 23, an important endocrine pro-inflammatory mediator, was shown to activate the FGFR4/phospholipase Cγ (PLCγ)/nuclear factor of activated T-cells (NFAT) signaling in chronic inflammatory airway diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Here, we demonstrate that FGF23 increased the O-GlcNAc modification of proteins in HBECs. Furthermore, the increase in O-GlcNAc levels by FGF23 stimulation resulted in the downstream activation of NFAT and secretion of interleukin-6 (IL-6). Conversely, inhibition of FGF23 signaling and/or O-GlcNAc transferase (OGT)/O-GlcNAc reversed these effects. Collectively, these data suggest that FGF23 induced IL-6 upregulation and secretion is, at least, partially mediated via the activation of the HBP and O-GlcNAc levels in HBECs. These findings identify a novel link whereby FGF23 and the augmentation of O-GlcNAc levels regulate airway inflammation through NFAT activation and IL-6 upregulation in HBECs. The crosstalk between these signaling pathways may contribute to the pathogenesis of chronic inflammatory airway diseases such as COPD and CF as well as metabolic syndromes, including diabetes.

The modelling of thermal exposure in outdoor urban environments is a highly topical challenge in modern climate research. This paper presents the results derived from a new micrometeorological model that employs an integrated biometeorology module to model Universal Thermal Climate Index (UTCI). This is PALM-4U, which includes an integrated human body-shape parameterization, deployed herein for a pilot domain in Prague, Czech Republic. The results highlight the key role of radiation in the spatiotemporal variability of thermal exposure in moderate-climate urban areas during summer days in terms of the way in which this directly affects thermal comfort through radiant temperature and indirectly through the complexity of turbulence in street canyons. The model simulations suggest that the highest thermal exposure may be expected within street canyons near the irradiated north sides of east–west streets and near streets oriented north–south. Heat exposure in streets increases in proximity to buildings with reflective paints. The lowest heat exposure during the day may be anticipated in tree-shaded courtyards. The cooling effect of trees may range from 4 °C to 9 °C in UTCI, and the cooling effect of grass in comparison with artificial paved surfaces in open public places may be from 2 °C to 5 °C UTCI. In general terms, this study illustrates that the PALM modelling system provides a new perspective on the spatiotemporal differentiation of thermal exposure at the pedestrian level; it may therefore contribute to more climate-sensitive urban planning.

ABSTRACT Objective To compare serum anti-Müllerian hormone (AMH) and other endocrine parameters between patients diagnosed with polycystic ovary syndrome (PCOS) and age-matched ovulatory women. Materials and methods AMH, DHEAS, FSH, LH, PRL, TSH and total testosterone (TT) were prospectively measured in oligo-ovulatory PCOS patients (n = 595) and in ovulatory non-PCOS women (n = 157) referred to a tertiary infertility center. Mean BMI was similar across the two study populations and there were no smokers in the sample. Patients in both groups were further classified into three categories by age: < 25 yrs, 25-34 yrs, and ≥ 35 yrs. Selected clinical and demographic characteristics were tabulated for each group. Results Serum AMH was significantly higher among PCOS patients compared to non-PCOS controls in the non-stratified sample (7.54 ± 5.8 vs. 2.49 ± 2.0 ng/mL, respectively; p < 0.0001), while serum FSH, DHEAS, TSH and prolactin were similar for both groups (p > 0.05). As expected, mean (total) testosterone levels were notably different between PCOS vs. non-PCOS controls (0.84 ± 0.76 vs. 0.43 ± 0.38 ng/mL, respectively; p < 0.001), and mean AMH level was significantly lower in the oldest age category (> 35 yrs) compared to both younger control groups (p < 0.0001). Both DHEAS and total testosterone decreased with age among PCOS patients, although mean serum DHEAS for women age > 35 yrs was significantly lower than DHEAS measured in younger women with PCOS (p < 0.02). For PCOS patients, AMH remained relatively stable irrespective of age. Conclusion Although AMH can serve as a satisfactory marker of ovarian reserve, for PCOS patients the expected decline in AMH associated with reproductive aging appears attenuated despite ovarian senescence. In contrast, mean DHEAS levels were markedly lower among older PCOS women (> 35 yrs) compared to younger PCOS patients.

The extinct ‘New World stilt-legged’, or NWSL, equids constitute a perplexing group of Pleistocene horses endemic to North America. Their slender distal limb bones resemble those of Asiatic asses, such as the Persian onager. Previous palaeogenetic studies, however, have suggested a closer relationship to caballine horses than to Asiatic asses. Here, we report complete mitochondrial and partial nuclear genomes from NWSL equids from across their geographic range. Although multiple NWSL equid species have been named, our palaeogenomic and morphometric analyses support the idea that there was only a single species of middle to late Pleistocene NWSL equid, and demonstrate that it falls outside of crown group Equus. We therefore propose a new genus, Haringtonhippus, for the sole species H. francisci. Our combined genomic and phenomic approach to resolving the systematics of extinct megafauna will allow for an improved understanding of the full extent of the terminal Pleistocene extinction event.

L2 pragmatic instruction in grammar and writing is an area of second language acquisition that is underutilized by many teachers. This paper follows the process of one teacher as the instruction of the pragmatic speech act of requesting is integrated into a low-level grammar class. First, an argument is made for the importance of including explicit pragmatic instruction in an ESL classroom. Then, a recent pedagogical model based on Sociocultural Theory is utilized as a basis for the development of new materials and adaptation of existing materials. Also, the theoretical frameworks of both speech act theory of requesting and politeness theory are examined to inform the materials presented to the students. Finally, the teacher reflects on this process and gives recommendations for others who would integrate pragmatic instruction into their classroom.

Late Pleistocene groundwater discharge deposits (paleowetlands) in the upper Las Vegas Wash north of Las Vegas, Nevada, have yielded an abundant and diverse vertebrate fossil assemblage, the Tule Springs local fauna (TSLF). The TSLF is the largest open-site vertebrate fossil assemblage dating to the Rancholabrean North American Land Mammal Age in the southern Great Basin and Mojave Desert. Over 600 discrete body fossil localities have been recorded from the wash, including an area that now encompasses Tule Springs Fossil Beds National Monument (TUSK). Paleowetland sediments exposed in TUSK named the Las Vegas Formation span the last 250 ka, with fossiliferous sediments spanning ∼100–13 ka. The recovered fauna is dominated by remains of Camelopsand Mammuthus, and also includes relatively common remains of extinct Equusand Bisonas well as abundant vertebrate microfaunal fossils. Large carnivorans are rare, with only Puma concolor and Panthera atrox documented previously. Postcranial remains assigned to the species Canis dirus (dire wolf) and Smilodon fatalis (sabre-toothed cat) represent the first confirmed records of these species from the TSLF, as well as the first documentation of Canis dirus in Nevada and the only known occurrence of Smilodonin southern Nevada. The size of the recovered canid fossil precludes assignment to other Pleistocene species of Canis. The morphology of the felid elements differentiates them from other large predators such as Panthera, Homotherium, and Xenosmilus, and the size of the fossils prevents assignment to other species of Smilodon. The confirmed presence of S. fatalis in the TSLF is of particular interest, indicating that this species inhabited open habitats. In turn, this suggests that the presumed preference of S. fatalis for closed-habitat environments hunting requires further elucidation.

The purpose of this study was to investigate the effects of leaf extract from Lithocarpus polystachyus Rehd. on type II diabetes mellitus (T2DM) and the active ingredients of this effect. In addition, this study determined, for the first time, the underlying molecular and pharmacological mechanisms of the extracts on hyperglycemia using long-term double high diet-fed and streptozotocin (STZ) induced type II diabetic mice. In the present study, leaf extract, phloridzin and trilobatin were assessed in vivo (gavage) and in vitro (non-invasive micro-test technique, NMT) in experimental T2DM mice. The biochemical parameters were measured including blood glucose and blood lipid level, liver biochemical indexes, and hepatic glycogen. The relative expression of glycometabolism-related genes was detected. The effect of leaf extracts on physiological glucose flux in liver tissue from control and T2DM mice was also investigated. Body weight of experimental T2DM mice increased significantly after the first week, but stabilized over the subsequent three weeks; body weight of all other groups did not change during the four weeks' study. After four weeks, all treatment groups decreased blood glucose, and treatment with leaf extract had numerous positive effects: a) promoted in glucose uptake in liver, b) increased synthesis of liver glycogen, c) reduced oxidative stress, d) up-regulation of glucokinase (GK), glucose transporter 2 (GLUT2), insulin receptor (IR) and insulin receptor substrate (IRS) expression in liver, e) down-regulation of glucose-6-phosphatase (G-6-P) expression, and f) ameliorated blood lipid levels. Both treatment with trilobatin or phloridzin accelerated liver glycogen synthesis, decreased oxidative stress and increased expression of GK. IRS and phosphoenolpyruvate carboxykinase (PEPCK) were both up-regulated after treatment with trilobatin. Expression of GLUT2, PEPCK and G-6-P were also increased in liver tissue after treatment with phloridzin. Our data indicate that leaf extract from L. polystachyus Rehd. has a preferable hypoglycemic effects than trilobatin or phloridzin alone. Leaf extract significantly increased glucose uptake and hepatic glycogen synthesis while also inducing a decline of hepatic gluconeogenesis and oxidative stress in T2DM mice. From this study, we draw conclusions that L. polystachyus promoted glycogen synthesis in T2DM mice, and that the active compounds were not only the trilobatin or phloridzin.

This paper provides a system capable of analyzing the combinatorics of a wide range of conventionally implicated and expressive constructions in natural language via an extension of Potts's (2005) L_CI logic for supplementary conventional implicatures. In particular, the system is capable of analyzing objects of mixed conventionally implicated/expressive and at-issue type, and objects with conventionally implicated or expressive meanings which provide the main content of their utterances. The logic is applied to a range of constructions and lexical items in several languages. doi:10.3765/sp.3.8 BibTeX info

Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content genome-wide small interfering RNA (siRNA) screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised-learning approach, using SYSCILIA gold standard, Cildb3.0, a centriole siRNA screen and the GTex project, identifying 591 likely candidates. Intersection of this data with whole exome results from 145 individuals with unexplained JS identified six families with predominantly compound heterozygous mutations in KIAA0586. A c.428del base deletion in 0.1% of the general population was found in trans with a second mutation in an additional set of 9 of 163 unexplained JS patients. KIAA0586 is an orthologue of chick Talpid3, required for ciliogenesis and Sonic hedgehog signaling. Our results uncover a relatively high frequency cause for JS and contribute a list of candidates for future gene discoveries in ciliopathies.

Background. Tympanic membrane perforation may occur when ear pressures are excessive, including valsalva maneuver associated with active labor and vaginal delivery. A pressure differential across the eardrum of about 5 psi can cause rupture; the increased intraabdominal pressure spikes repeatedly manifested by “pushing” during second-stage labor easily approach (and may exceed) this level. Material and Method. We describe a healthy 21-year old nulliparous patient admitted in active labor at 39-weeks' gestational age. Results. Blood appeared asymptomatically in the left ear canal at delivery during active, closed-glottis pushing. Otoscopic examination confirmed perforation of the left tympanic membrane. Complete resolution of the eardrum rupture was noted at postpartum check-up six weeks later. Conclusion. While the precise incidence of intrapartum tympanic membrane rupture is not known, it may be unrecognized without gross blood in the ear canal or subjective hearing loss following delivery. Only one prior published report on tympanic membrane perforation during delivery currently appears in the medical literature; this is the first English language description of the event. Since a vigorous and repetitive valsalva effort is common in normal vaginal delivery, clinicians should be aware of the potential for otic complications associated with the increased intraabdominal pressure characteristic of this technique.

The rich fossil record of horses has made them a classic example of evolutionary processes. However, while the overall picture of equid evolution is well known, the details are surprisingly poorly understood, especially for the later Pliocene and Pleistocene, c. 3 million to 0.01 million years (Ma) ago, and nowhere more so than in the Americas. There is no consensus on the number of equid species or even the number of lineages that existed in these continents. Likewise, the origin of the endemic South American genus Hippidion is unresolved, as is the phylogenetic position of the "stilt-legged" horses of North America. Using ancient DNA sequences, we show that, in contrast to current models based on morphology and a recent genetic study, Hippidion was phylogenetically close to the caballine (true) horses, with origins considerably more recent than the currently accepted date of c. 10 Ma. Furthermore, we show that stilt-legged horses, commonly regarded as Old World migrants related to the hemionid asses of Asia, were in fact an endemic North American lineage. Finally, our data suggest that there were fewer horse species in late Pleistocene North America than have been named on morphological grounds. Both caballine and stilt-legged lineages may each have comprised a single, wide-ranging species.

Sickle Cell Disease (SCD) is an inherited blood disorder affecting approximately 1 in every 365 African American births. Students with SCD are likely to experience ongoing complications that will interfere with their attendance, functioning at school, and overall daily functioning throughout their lives. This article provides education about SCD and its impact on the body, organs, brain, and academic performance. Armed with this knowledge, school psychologists will be better prepared to assess the academic needs of students with SCD, develop a positive environment that facilitates social-emotional development, and advocate for supports within the school setting.