Miracle-dz/UniFAR-FTUs huggingface dataset:
Non-eosinophilic asthma and the innate immune response

Pathological heterogeneity of asthma The concept that there may be heterogeneity of the underlying pathology of asthma has a long pedigree: 80 years ago, Rackemann1 suggested that a subgroup of patients with intrinsic asthma had disease driven by bacterial infection of the upper and lower respiratory tract and the authors of an early postmortem study2 were struck by the heterogeneity of lower airway inflammatory response in fatal asthma. However, since then the prevailing view, largely driven by bronchial biopsy studies of limited numbers of patients with relatively mild disease, has been that there are more similarities than differences in the pathology of subtypes of asthma. Thus, asthma is currently viewed as a condition characterised by TH2 cytokine-mediated eosinophilic airway mucosal inflammation.3,4 The development of simple methods to assess airway inflammation non-invasively using induced sputum which are applicable to a wide variety of patients5 has renewed interest in investigation of the pathological heterogeneity of asthma. Using this technique, Turner et al 6 unexpectedly found that just under half of 34 patients studied during a minor asthma exacerbation had no sputum eosinophilia. Fahy et al 7 made a similar observation in patients studied during a more significant exacerbation; many patients had sputum evidence of neutrophilic airway inflammation. Subsequently non-eosinophilic asthma has been shown to be present in 25% of patients presenting to an adult respiratory clinic with symptomatic asthma,8,9 in patients with occupational asthma10 and in up to 50% of patients with asthma treated with high doses of inhaled corticosteroids.11 The concept that non-eosinophilic asthma represents a pathologically distinct form of the disease is supported by work by Wenzel et al 12 showing that a subgroup of patients with …
Soil Bacterial Community Shift Correlated with Change from Forest to Pasture Vegetation in a Tropical Soil

ABSTRACT The change in vegetative cover of a Hawaiian soil from forest to pasture led to significant changes in the composition of the soil bacterial community. DNAs were extracted from both soil habitats and compared for the abundance of guanine-plus-cytosine (G+C) content, by analysis of abundance of phylotypes of small-subunit ribosomal DNA (SSU rDNA) amplified from fractions with 63 and 35% G+C contents, and by phylogenetic analysis of the dominant rDNA clones in the 63% G+C content fraction. All three methods showed differences between the forest and pasture habitats, providing evidence that vegetation had a strong influence on microbial community composition at three levels of taxon resolution. The forest soil DNA had a peak in G+C content of 61%, while the DNA of the pasture soil had a peak in G+C content of 67%. None of the dominant phylotypes found in the forest soil were detected in the pasture soil. For the 63% G+C fraction SSU rDNA sequence analysis of the three most dominant members revealed that their phyla changed from Fibrobacter andSyntrophomonas assemblages in the forest soil toBurkholderia and Rhizobium–Agrobacteriumassemblages in the pasture soil.
Development and optimization of polymeric nanoparticles of antitubercular drugs using central composite factorial design*

Objective: The objective of the present study was to develop sustained release biodegradable polymeric nanoparticles (PNs) of two anti-tubercular drugs (ATDs), rifampicin (RIF) and isoniazid (INH) using circumscribed central composite factorial design (CCD) and evaluate in vivo uptake potential using rhodamine labeled PNs (RPNs). Methods: CCD was employed to study the influence of independent formulation factors, drug:polymer ratio (D:P) and surfactant concentration (SC), on dependent physicochemical characteristics, particle size (PS), polydispersity index (PI) and percentage entrapment efficiency (%EE) of the drugs. Optimized PNs prepared using response surface methodology (RSM) were evaluated for in vitro kinetics at endosomal macrophage pH 5.2 and physiological pH 7.4 and in vivo targeting potential in peritoneal macrophages (PMs) by fluorescence microscopy (FM) and confocal laser scanning microscopy (CLSM). Results: Optimized PNs exhibited spherical and porous surface with a mean PS of 202 nm, PI of 0.178, zeta potential of -25.49 mV and %EE of 76.12% and 54.25% for RIF and INH, respectively. Conclusions: Highly hydrophilic INH could be encapsulated with lypophilic RIF with efficiency. In vivo uptake studies of RPNs in PMs suggested endocytosis of RPNs without any surface adsorption phenomenon. Hence, further studies need to be performed for establishing the pharmacokinetic potential of PNs.
Doing it for themselves?
 P
 erformance appraisal in project‐based organisations, the role of employees, and challenges to theory

We explore performance appraisal in project‐based organisations and provide novel insights into appraisal processes in this context. These include the central role of employees in orchestrating the appraisal process, the multiple actors that have input to appraisal including project managers, the distance between employees and their official line managers, and the weak coordinating role of human resource specialists in these systems. We draw attention to the drawbacks of current theorising on appraisal to predict and explain outcomes from appraisal systems that are not premised on stable line manager/employee dyads. Theorising based primarily on social exchange theories needs to be reconsidered in this context and new theories developed. We also question how human resource specialists can better support employees, and managers of all kinds, in their implementation roles in polyadic human resource management systems to ensure transparency, equity, and fairness of appraisal processes in a project‐based organisational context.
A simple physical description of DNA dynamics: quasi-harmonic analysis as a route to the configurational entropy

It has become increasingly apparent that the dynamic as well as the structural properties of biological macromolecules are important to their function. However, information concerning molecular flexibility can be difficult to obtain experimentally at the atomic level. Computer modelling techniques such as molecular dynamics (MD) have therefore proved invaluable in advancing our understanding of biomolecular flexibility. This paper describes how a combination of atomistic MD simulations and quasi-harmonic analysis can be used to describe the dynamics of duplex DNA, with a particular emphasis on methods for calculating differences in configurational entropies. We demonstrate that DNA possesses remarkably simple mechanical properties relative to globular proteins, making it an ideal system for exploring biomolecular flexibility in general. Our results also highlight the importance of solvent viscosity in determining the dynamic behaviour of DNA in aqueous solution.
Compact and Supply-Voltage-Scalable Temperature Sensors for Dense On-Chip Thermal Monitoring

This paper presents compact and voltage-scalable temperature sensor circuits for implementing dynamic thermal management (DTM) in high-performance microprocessors and Systems-on-Chips (SoC). The proposed sensor front ends require only 6 to 8 NMOS transistors, resulting in more than one order of magnitude smaller area than the previous state of the art. The sensor supply voltage can be scaled down to 0.6 V, so it can be integrated with digital circuits employing a dynamic-voltage-scaling technique without additional power distribution and regulation. Sensor front ends with three different sizes (115, 279, and 400 μm2) and their back ends have been prototyped in a 65 nm CMOS technology. The measurement results of the 279 μm2 front end at 0.6 V show a worst-case error of 7.0° C across 64 instances 0° C to 100° C after a low-cost one-temperature-point calibration. With the same conditions, the measurements of the 400 μm2 front end show a worst-case error of 5.4° C across 64 instances. The compact sensor designs make it possible to integrate an order of magnitude more sensors on a chip with little additional overhead and thereby enable very dense thermal monitoring in digital VLSI systems.
The role of matrix metalloproteinases ‐9 and ‐2 in development of neonatal chronic lung disease

Aim: Matrix metalloproteinases (MMPs) ‐9 and ‐2 degrade type‐IV collagen, a major constituent of lung basement membrane, and may have a role in the pathogenesis of neonatal chronic lung disease (CLD). We determined factors influencing MMP levels in neonatal bronchoalveolar lavage (BAL) fluid to establish whether an imbalance between MMP and its inhibitor could be implicated in CLD. Methods: We measured MMP‐9 and ‐2 and tissue inhibitor of metalloproteinase‐1 (TIMP‐1) levels in 316 BAL fluid samples from 121 babies of gestational ages 23 to 42 wk over the first 14 d of life to determine effects of gestation and postnatal age. Median MMP‐9, ‐2, TIMP‐1 and MMP‐9/TIMP‐1 ratio in BAL were further studied in a subgroup of 85 babies >33 wk gestation to determine their ability to predict CLD and to establish effects of antenatal corticosteroid therapy (ANCS). Results: MMP‐9, ‐2 and TIMP levels did not vary with postnatal age over the first week. Median MMP‐9 levels and MMP‐9/TIMP‐1 ratio increased with decreasing gestation in preterm babies. The MMP‐9/TIMP‐1 ratio was higher in babies who developed CLD, implying a proteinase/antiproteinase imbalance, but this association disappeared when controlled for gestational age. ANCS had no effect on BAL fluid MMP or TIMP levels.
Individual, provider, and system risk factors for breast and cervical cancer screening among underserved Black, Latina, and Arab women.

BACKGROUND Socioeconomic and racial/ethnic disparities in breast and cervical cancer screening persist. An exploratory study was conducted to better understand co-occurring risk factors in underserved groups that could inform interventions to improve screening adherence. The objective of this study was to examine associations between breast and cervical cancer screening adherence and co-occurring risk factors in three racial/ethnic groups of underserved women. METHODS Black, Latina, and Arab women (N=514), ages 21 to 70 years, were enrolled into the Kin Keeper(SM) randomized controlled trial in communities around Detroit, Michigan. We used participant baseline assessments (e.g., demographic characteristics, health literacy) to explore screening risks using an additive approach and multivariate logistic analyses. RESULTS For black women, having more health literacy risks were associated with reduced odds of a clinical breast exam (CBE), mammogram, and Papanicolaou (Pap) test; more competing priorities were associated with reduced odds of a Pap test; lack of doctor mammogram recommendation was significantly associated with decreased odds of CBE. For Latina women, lack of doctor recommendations were significantly associated with decreased odds of CBE, mammogram, and Pap test. For Arab women, lack of doctor recommendations were significantly associated with decreased odds of CBE, mammogram, and Pap test; more competing priorities were significantly associated with reduced odds of CBE and Pap test. All results were significant at p<0.05. CONCLUSIONS Characteristics associated with breast and cervical screening adherence differs among Black, Latina, and Arab underserved women. Interventions to improve screening should be tailored for racial/ethnic groups with particular attention to competing survival priorities, health literacy risks factors, and provider recommendations.
Sam68 regulates cell proliferation and cell adhesion‐mediated drug resistance (CAM‐DR) via the AKT pathway in non‐Hodgkin's lymphoma

Sam68 (Src‐associated in mitosis 68 kDa), a substrate for tyrosine kinase c‐Src during mitosis, is up‐regulated in a variety of human cancers and acts oncogenically promoting tumour progression. This study has explored biological function and clinical significance of Sam68 in non‐Hodgkin's lymphoma (NHL).
Macular Edema severity detection in colour fundus images based on ELM classifier

Diabetic Macular Edema is a complication of diabetic retinopathy which is a cause of vision loss. It is assessed by detecting the hard exudates present in the color fundus images. The proposed method has two stages, there are detection of hard exudates and classification of diabetic macular edema severity from color fundus images. A feature extraction technique is used to capture the global features like intensity, color and texture of the fundus images and discriminate the normal from abnormal images. In this, the detection of hard exudates are done by using extreme learning machine classifier. This can be used to improve the detection accuracy. Disease severity classification is assessed by using regional property of the hard exudates in the retinal image. The detection performance has a sensitivity of 99% with specificity between 85% and 98%. The severity classification accuracy is 98% for the abnormal images.
Colocalization of the Homophilic Binding Site and the Neuritogenic Activity of the Cell Adhesion Molecule L1 to Its Second Ig-like Domain (*)

The cell adhesion molecule L1 has been implicated in mediating cell-cell adhesion and in promoting neurite outgrowth. The extracellular region of L1 contains six immunoglobulin (Ig)-like domains in the amino-terminal region, followed by five fibronectin type III-like repeats. L1 is capable of undergoing homophilic binding as well as heterophilic interactions. To map the homophilic binding domain in L1, three glutathione S-transferase (GST) fusion proteins (GST-Ig1-2-3, GST-Ig4-5-6, and GST-Fn) were prepared and coupled to Covaspheres and their homophilic binding activity was determined using the Covasphere-to-substratum binding assay. Only GST-Ig1-2-3 was capable of homophilic binding. Next, His-tagged recombinant Ig-domain proteins (His-Ig1-2, His-Ig1, and His-Ig2) were expressed and subjected to similar assays. Only His-Ig1-2 and His-Ig2 were capable of homophilic interactions. Binding of His-Ig2-conjugated Covaspheres to substrate-coated His-Ig2 was inhibited by anti-Ig1-2-3 Fab and soluble His-Ig2. These results indicate that the L1 homophilic binding site resides within Ig2. To examine effects of these L1 recombinant proteins on neurite outgrowth, neural retinal cells were cultured on different substrate-coated fusion proteins. Both GST-Ig1-2-3 and His-Ig2 were potent inducers of neurite extension. These results thus indicate that the L1 Ig-like domain 2 alone is sufficient to mediate L1-L1 interaction and promote neurite outgrowth from retinal cells.
A Molecularly Annotated Model of Patient-Derived Colon Cancer Stem–Like Cells to Assess Genetic and Nongenetic Mechanisms of Resistance to Anti-EGFR Therapy

Purpose: Patient-derived xenografts (“xenopatients”) of colorectal cancer metastases have been essential to identify genetic determinants of resistance to the anti-EGFR antibody cetuximab and to explore new therapeutic strategies. From xenopatients, a genetically annotated collection of stem-like cultures (“xenospheres”) was generated and characterized for response to targeted therapies. Experimental Design: Xenospheres underwent exome-sequencing analysis, gene expression profile, and in vitro targeted treatments to assess genetic, biological, and pharmacologic correspondence with xenopatients, and to investigate nongenetic biomarkers of therapeutic resistance. The outcome of EGFR family inhibition was tested in an NRG1-expressing in vivo model. Results: Xenospheres faithfully retained the genetic make-up of their matched xenopatients over in vitro and in vivo passages. Frequent and rare genetic lesions triggering primary resistance to cetuximab through constitutive activation of the RAS signaling pathway were conserved, as well as the vulnerability to their respective targeted treatments. Xenospheres lacking such alterations (RASwt) were highly sensitive to cetuximab, but were protected by ligands activating the EGFR family, mostly NRG1. Upon reconstitution of NRG1 expression, xenospheres displayed increased tumorigenic potential in vivo and generated tumors completely resistant to cetuximab, and sensitive only to comprehensive EGFR family inhibition. Conclusions: Xenospheres are a reliable model to identify both genetic and nongenetic mechanisms of response and resistance to targeted therapies in colorectal cancer. In the absence of RAS pathway mutations, NRG1 and other EGFR ligands can play a major role in conferring primary cetuximab resistance, indicating that comprehensive inhibition of the EGFR family is required to achieve a significant therapeutic response. Clin Cancer Res; 24(4); 807–20. ©2017 AACR. See related commentary by Napolitano and Ciardiello, p. 727
MEN1 tumor‐suppressor protein localizes to telomeres during meiosis

Multiple endocrine neoplasia type 1 is an autosomal dominant cancer predisposition syndrome caused by mutations in the tumor‐suppressor gene MEN1. The gene encodes a nuclear protein, menin, with no recognized functional motifs. Menin has been shown negatively to regulate transcriptional activation mediated by JunD, although the significance of this interaction in normal cell physiology and how the absence of menin leads to tumorigenesis are unknown. Menin is highly expressed in testes. We used immunocytochemistry to explore its role in meiosis and found that it localizes exclusively at telomeres. JunD was not found at telomeres in meiotic cells. In view of elevated telomerase activity or abnormal telomere structure in virtually all malignancies, regulation of telomere function would be an appealing role for a tumor suppressor. However, menin does not specifically associate with telomeres in somatic cells, as indicated by lack of co‐localization with the known telomeric protein TRF2. Cells overexpressing menin had normal telomerase activity, and tumors with homozygous MEN1 mutations showed no aberrations in telomere length, indicating that menin does not directly regulate telomerase activity. The role of menin at meiotic telomeres appears to be independent of JunD and may not have a counterpart in somatic cells. These results suggest that menin may play different roles in different tissues through interactions with different proteins. © 2002 Wiley‐Liss, Inc.
Distinguishing normal from abnormal gestational sac growth in early pregnancy.

In order to evaluate normal and abnormal gestational sac development, serial sonograms were performed in 83 women whose initial sonogram demonstrated a gestational sac lacking a detectable embryo. Of 53 normal gestations, the mean sac growth was 1.13 mm/day (range, 0.71‐1.75). In comparison, of 30 abnormal gestations, 24 demonstrated sac growth, and of these, the mean growth was 0.70 mm/day (range, 0.14‐1.71). Based on these observations, we suggest that gestational sac growth of less than or equal to 0.6 mm/day is evidence for abnormal development. Analysis of the initial and follow‐up scans for the 53 normal gestations showed that a living embryo was always detected when the mean gestational sac was greater than 25 mm in average diameter, and a yolk sac was always seen when the mean sac diameter was greater than 20 mm. In comparison, of 30 abnormal gestations, six were greater than 25 mm without a detectable embryo, and four were greater than 20 mm without a yolk sac. Recommendations for the optimal time of a follow‐up sonogram are presented based on the initial sac size.
[miR-378 suppresses HBV-related hepatocellular carcinoma tumor growth by directly targeting the insulin-like growth factor 1 receptor].

OBJECTIVE To investigate the impact and mechanism of microRNA (miR)-378 on hepatocellular carcinoma (HCC) cell growth. METHODS The human hepatoma cell line HepG2 and its derivative HepG2.2. 15 (stably expressing hepatitis B virus (HBV)) were transduced with lentiviruses expressing miR-378 or non-expressing controls (nc-Lv). Effects on cell proliferation were assessed by the MTT assay and on colony-formation efficiency by clonogenic assay. Targets of miR-378 were predicted by bioinformatic analysis and validated by luciferase reporter assay in the human embryonic kidney cell line HEK293. Real-time polymerase chain reaction and western blotting were used to monitor expression of the endogenous targets in miR-378- overexpressing HepG2 and HepG2.2. 15 cells. RESULTS The HepG2 and HepG2.2. 15 cells transduced with lentivirus expressing miR-378 showed significantly lower cell proliferation and colony formation than the control cells transduced with nc-Lv (P less than 0.01 and P less than 0.05, respectively). The insulin-like growth factor 1 receptor (IGF1R) was predicted as a potential target of miR-378, and luciferase reporter activity of IGF1R was significantly decreased in the HEK293 cells co-transfected with miR-378 (by 41.8% vs. the control cells, P less than 0.01). Moreover, the miRNA-378-mediated effect was narrowed down to the 3'-untranslated region (UTR) of IGF1R. The miRNA-378-mediated reduction of IGF1R specifically involved its protein expression (P less than 0.01) and not its mRNA expression (P more than 0.05). CONCLUSION miR-378 may suppress growth characteristics of HBV-related HCC by directly targeting the IGF1R 3'-UTR and inhibiting its protein expression.
Triiodothyronine stimulation of cyclic adenosine 3',5'-monophosphate accumulation in fat cells.

White fat cells from normal rats treated with 200 μg of L-3,5,3’-triiodothyronine (T-3) exhibited an increased lipolytic response to norepinephrine and dibutyryl cyclic adenosine 3’, 5’-monophosphate. No increase in lipolytic response of T-3 treated cells was observed in the presence of growth hormone and dexamethasone. Cells from both hypophysectomized and normal rats treated with T-3 showed marked increases in accumulation of cyclic adenosine 3’,5’-monophosphate (cyclic AMP) and glycerol release as compared to control cells in the presence of catecholamine and theophylline. Little effect of T-3 treatment was seen on cyclic AMP accumulation in the presence of catecholamine alone or in the absence of lipolytic agents. The administration of 25 micrograms of T-3 to normal female rats 18 hours prior to sacrifice was equally as effective as 200 micrograms in stimulating cyclic AMP accumulation of fat cells incubated with catecholamines and theophylline. There was a lag period of about 5½ hours after subcutane.
Supplemental ubiquinol in patients with advanced congestive heart failure

Patients with CHF, NYHA class IV, often fail to achieve adequate plasma CoQ10 levels on supplemental ubiquinone at dosages up to 900 mg/day. These patients often have plasma total CoQ10 levels of less than 2.5 μg/ml and have limited clinical improvement. It is postulated that the intestinal edema in these critically ill patients may impair CoQ10 absorption. We identified seven patients with advanced CHF (mean EF 22%) with sub‐therapeutic plasma CoQ10 levels with mean level of 1.6 μg/ml on an average dose of 450 mg of ubiquinone daily (150–600 mg/day). All seven of these patients were changed to an average of 580 mg/day of ubiquinol (450–900 mg/day) with follow‐up plasma CoQ10 levels, clinical status, and EF measurements by echocardiography. Mean plasma CoQ10 levels increased from 1.6 μg/ml (0.9–2.0 μg/ml) up to 6.5 μg/ml (2.6–9.3 μg/ml). Mean EF improved from 22% (10–35%) up to 39% (10–60%) and clinical improvement has been remarkable with NYHA class improving from a mean of IV to a mean of II (I to III). Ubiquinol has dramatically improved absorption in patients with severe heart failure and the improvement in plasma CoQ10 levels is correlated with both clinical improvement and improvement in measurement of left ventricular function.