Miracle-dz/UniFAR-FTUs huggingface dataset:
Development of a quantitative mass spectrometry multi-attribute method for characterization, quality control testing and disposition of biologics

Regulatory agencies have recently recommended a Quality by Design (QbD) approach for the manufacturing of therapeutic molecules. A QbD strategy requires deep understanding at the molecular level of the attributes that are crucial for safety and efficacy and for insuring that the desired quality of the purified protein drug product is met at the end of the manufacturing process. A mass spectrometry (MS)-based approach to simultaneously monitor the extensive array of product quality attributes (PQAs) present on therapeutic molecules has been developed. This multi-attribute method (MAM) uses a combination of high mass accuracy / high resolution MS data generated by Orbitrap technology and automated identification and relative quantification of PQAs with dedicated software (Pinpoint). The MAM has the potential to replace several conventional electrophoretic and chromatographic methods currently used in Quality Control to release therapeutic molecules. The MAM represents an optimized analytical solution to focus on the attributes of the therapeutic molecule essential for function and implement QbD principles across process development, manufacturing and drug disposition.
Immunoreactive gastric inhibitory polypeptide.

IN 1906 extracts of mucosa from the upper small intestine from pigs were tested as a treatment of diabetes in the hope that “the internal secretion of the pancreas might be stimulated and initiated by the substance of the nature of a hormone yielded by the duodenal mucous membrane” (1). La Barre (2) introduced the name incretin for an unidentified substance that was thought to exert this effect. With the advent of insulin RIAs in the early 1960s (3), it was shown that insulin levels in the blood after ingestion of glucose were elevated out of proportion to the concentration of blood glucose when compared with the response to glucose given iv (4, 5). It was suggested that the potentiation of insulin secretion after oral glucose was mediated by a humoral substance which was released from the gut during glucose absorption and which stimulated insulin secretion (4, 5). Some years later a polypeptide was found (6, 7), which, due to its inhibitory effect on gastric acid secretion in dogs (8), was named gastric .
High-Resolution Computed Tomography of Single Breast Cancer Microcalcifications in Vivo

Microcalcification is a hallmark of breast cancer and a key diagnostic feature for mammography. We recently described the first robust animal model of breast cancer microcalcification. In this study, we hypothesized that high-resolution computed tomography (CT) could potentially detect the genesis of a single microcalcification in vivo and quantify its growth over time. Using a commercial CT scanner, we systematically optimized acquisition and reconstruction parameters. Two ray-tracing image reconstruction algorithms were tested: a voxel-driven “fast” cone beam algorithm (FCBA) and a detector-driven “exact” cone beam algorithm (ECBA). By optimizing acquisition and reconstruction parameters, we were able to achieve a resolution of 104 μm full width at half-maximum (FWHM). At an optimal detector sampling frequency, the ECBA provided a 28 μm (21%) FWHM improvement in resolution over the FCBA. In vitro, we were able to image a single 300 μm X 100 μm hydroxyapatite crystal. In a syngeneic rat model of breast cancer, we were able to detect the genesis of a single microcalcification in vivo and follow its growth longitudinally over weeks. Taken together, this study provides an in vivo “gold standard” for the development of calcification-specific contrast agents and a model system for studying the mechanism of breast cancer microcalcification.
Adolescent witnesses to a peer suicide.

OBJECTIVE This case-control study attempts to evaluate the psychological impact of witnessing a suicide on high school students. METHOD Twenty-eight high school students witnessed a firearms suicide and the serious injury of another student while riding a school bus. They were assessed 2 months after the event, and their responses were compared with 28 demographically similar adolescents from another community who had not been exposed to suicide. RESULTS The exposed students, when compared with the controls, had higher rates of new-onset anxiety disorder and a trend for increased rates of new-onset post-traumatic stress disorder (PTSD). Within the exposed group, measures of the closeness of the relationship to both the suicide victim and the student who was injured were correlated with the severity of PTSD symptomatology. Within the exposed group, other factors that predisposed to new-onset disorder included family history of affective illness, family history of suicide attempt, and stressful life events occurring in the year before exposure. CONCLUSIONS In combination with the extant literature, this study demonstrates that adolescents who witness a traumatic suicidal death are at risk for the development of psychopathology, specifically, anxiety disorders and PTSD.
Immunocytochemical demonstration of salmon GnRH and chicken GnRH‐II in the brain of masu salmon, Oncorhynchus masou

We have recently developed sensitive and specific radioimmunoassays (RIAs) for salmon gonadotropin‐releasing hormone (sGnRH) and chicken GnRH‐II (cGnRH‐II) and have measured the contents of both GnRHs in the rainbow trout brain. Our results showed that contents of the two GnRHs are variable among different brain regions. Therefore, in order to confirm the differential distribution of the two GnRHs by a different technique, we examined the distribution of immunoreactive sGnRH and cGnRH‐II in the brain of masu salmon by using immunocytochemical techniques.
Lymphoplasmacytic Chronic Cholecystitis and Biliary Tract Disease in Patients With Lymphoplasmacytic Sclerosing Pancreatitis

Lymphoplasmacytic sclerosing pancreatitis (LPSP) represents a distinctive form of chronic pancreatitis characterized by diffuse fibroinflammatory infiltrates that can involve both the pancreatic ducts and acinar parenchyma. Several cases of inflammatory infiltrates within the gallbladder have been reported in association with LPSP, but the spectrum of gallbladder pathology in patients with LPSP has not been systematically reviewed. Many patients with LPSP have distal CBD fibrosis, strictures, and inflammation, features that overlap somewhat with primary sclerosing cholangitis (PSC). In PSC, a pattern of gallbladder pathology termed “diffuse acalculous lymphoplasmacytic chronic cholecystitis” has been previously described as showing a triad of diffuse, mucosal-based, plasma cell-rich inflammatory infiltrates. We studied 20 gallbladders from patients with LPSP and compared them with 20 gallbladders in PSC, 20 gallbladders with chronic cholelithiasis, and 10 gallbladders from patients with benign (non-LPSP) pancreatic disease. The following features were evaluated: degree and composition of mucosal inflammation and deep (mural) inflammation, lymphoid nodules, metaplasia, dysplasia/neoplasia, fibrosis, muscular hypertrophy, Rokitansky-Aschoff sinuses, and cholesterolosis. The majority (60%) of gallbladders in LPSP contained moderate or marked inflammatory infiltrates and lymphoid nodules, frequencies similar to PSC but significantly higher than in chronic cholelithiasis and benign non-LPSP pancreatic disease. LPSP gallbladders received the highest scores for deep inflammation of all groups, and 35% of LPSP gallbladders showed transmural chronic cholecystitis. Overall, “diffuse lymphoplasmacytic chronic cholecystitis” was present in 50% of PSC cases and 25% of LPSP cases, but in only 5% of chronic cholelithiasis and none of non-LPSP benign pancreatic disease. Mucosal inflammation in LPSP gallbladders correlated significantly with the presence of inflammation in the extrapancreatic portion of the CBD. These findings suggest that inflammatory pathology of the gallbladder is frequently associated with LPSP and that it is part of the spectrum of biliary tract disease in these patients, rather than a simple reflection of the pancreatitis itself.
Deficiency of the immunostimulatory cytokine IL-21 promotes intestinal neoplasia via dysregulation of the Th1/Th17 axis

ABSTRACT IL-21 has reported activity in promoting both Th1 and Th17 immune responses. Its role in sporadic human colorectal cancer is unknown. We aimed to delineate the role of IL-21 in a model of sporadic intestinal carcinogenesis. We found that in APCMIN/+ mice, ablation of IL-21 increased intestinal tumorigenesis. Expression of pro-inflammatory Th17-associated genes, including RORγt and IL-17A, was increased in the intestine in the absence of IL-21, while expression of antitumor Th1-associated genes Tbet, IFNγ, granzyme B, and perforin was decreased. Similarly, the IL-21-deficient APCMIN/+ mouse intestines had fewer infiltrating T cells as well as decreased effector memory T cells, NK cells, and granzyme B-expressing cells. Finally, our data suggest that IL-21 impairs Th17 immune responses as mesenteric lymph nodes from IL-21-deficient mice had increased IL-17A expression, and naive helper T cells from IL-21-deficient mice were more prone to differentiate into IL-17A-secreting cells.
The future of teratology research is in vitro

Birth defects induced by maternal exposure to exogenous agents during pregnancy are preventable, if the agents themselves can be identified and avoided. Billions of dollars and manhours have been dedicated to animal-based discovery and characterisation methods over decades. We show here, via a comprehensive systematic review and analysis of this data, that these methods constitute questionable science and pose a hazard to humans. Mean positive and negative predictivities barely exceed 50%; discordance among the species used is substantial; reliable extrapolation from animal data to humans is impossible, and virtually all known human teratogens have so far been identified in spite of, rather than because of, animal-based methods. Despite strict validation criteria that animal-based teratology studies would fail to meet, three in vitro alternatives have done so. The embryonic stem-cell test (EST) is the best of these. We argue that the poor performance of animal-based teratology alone warrants its cessation; it ought to be replaced by the easier, cheaper and more repeatable EST, and resources made available to improve this and other tests even further.
Study on the Rationality and Validity of Probit Models of Domino Effect to Chemical Process Equipment caused by Overpressure

Overpressure is one important cause of domino effect in accidents of chemical process equipments. Some models considering propagation probability and threshold values of the domino effect caused by overpressure have been proposed in previous study. In order to prove the rationality and validity of the models reported in the reference, two boundary values of three damage degrees reported were considered as random variables respectively in the interval [0, 100%]. Based on the overpressure data for damage to the equipment and the damage state, and the calculation method reported in the references, the mean square errors of the four categories of damage probability models of overpressure were calculated with random boundary values, and then a relationship of mean square error vs. the two boundary value was obtained, the minimum of mean square error was obtained, compared with the result of the present work, mean square error decreases by about 3%. Therefore, the error was in the acceptable range of engineering applications, the models reported can be considered reasonable and valid.
Meta-Analysis Digital Subtraction Angiography Versus Real-Time Fluoroscopy for Detection of Intravascular Penetration Prior to Epidural Steroid Injections : Meta-Analysis of Prospective Studies

Methods: A targeted Pubmed search was conducted, yielding 49 reports and 4 manuscripts, which were analyzed using Review Manager Software (Rev Man 5.2). Inclusion/exclusion criteria: peer-reviewed prospective reports comparing the sensitivity of DSA to RTF in the same individuals without change in needle position between comparative imaging. Pooled estimate of odds ratios with 95% confidence interval using a random effect model was applied.
Electrical and Electrostatic Discharge Solid Rocket Booster Ignition

In missile propulsion technology it is conventional to employ solid rocket boosters. These boosters are loaded with solid propellants, which a re energetic compositions where raw materials are comprised of solid particulates, such as fuel, and oxidizer particles, in which are dispersed and immobilized throughout a binder (polymeric) matrix. The processability of these compositions is not simple because it is d ifficult to incorporate a high percentage of solids in polymeric matrix. Its has been problemati c to formulate a safe composition so as to prevent an accidental ignition of solid propellant or other device that uses energetic materials. Accidents and incidents with solid rocket motor, du ring production, handling and storage, without apparent causes, led to studies by independ ent groups [1,2,3,4]. These studies generated important conclusions on the realm of sol id rocket motor safety; furthermore, subsequent investigations suggest that spontaneous motor ignition can be attributed to electrostatic discharge. The solid composite propellant grain can be conside red in a microscale heterogeneous system in which conductive and nonconductive particles and different types of binders had direct influence in the grain electrical characteristics. Nonconductive particles have a geometrical effect to influence the spacing of the conductive p articles [5]. The aim of this paper is to present the methodologi es and the respective results of electrical and electrostatic discharge tests. These results al low us to choose a less ESD sensitive formulation of solid propellant increasing the reli ability in manufacturing, handling and storage of solid rocket motor.
The effect of atrial pacing site on electrophysiological properties of the atrioventricular junction and induction of atrioventricular nodal reentry in patients with typical atrioventricular nodal reentrant tachycardia.

BACKGROUND Clinical studies in humans have shown the site of atrial stimulation to influence atrioventricular (AV) conduction times and refractory periods, the demonstration of dual AV nodal (AVN) pathways, and induction of AVN reentry. These studies often found conflicting results. Moreover, among enrolled patients a minority of them were found to have AVN reentrant tachycardia (AVNRT). AIM The purpose of this study was to investigate the effect of right and left atrial pacing on the electrophysiological properties of the AV junction in the typical AVNRT population. METHODS Ninety-two consecutive patients with typical AVNRT were included. Atrial pacing was performed from the high right atrium (HRA) and the left atrium via the proximal coronary sinus (CS). RESULTS Stimulation from either the HRA or the CS could result in dual AVN physiology and AVNRT. No site-dependent differences in the ease of induction of dual AVN pathways with variability of initiation from either site were found. However, AVNRT was easier to induce from the HRA. With CS pacing the leftward but not the rightward AVN approaches were the entry point to the AV node because of significantly shorter AH conduction times compared to HRA pacing. Conduction over the leftward AVN extensions could initiate the tachycardia with significantly shorter critical AH interval compared to conduction over the rightward AVN extensions; however, the AH interval during AVNRT and its cycle length were not significantly different. CONCLUSIONS Rightward and leftward AVN extensions are regular features of the AV node. Their different electrophysiological properties lead to variation in the demonstration of discontinuous AVN conduction and AVNRT during right and left atrial pacing. Despite the observation that the left AVN extensions could compose the entry point to the reentrant circuit, there is no evidence that they constitute the critical component of sustained typical AVNRT.
Electrically enhanced transdermal delivery of a macromolecule

The purpose of this study was to establish the delivery parameters for the enhanced transdermal delivery of dextran sulfate (MW 5000 Da). Full‐thickness pig skin or epidermis separated from human cadaver skin was used. Silver‐silver chloride electrodes were used to deliver the current (0.5 mA cm−2). For electroporation experiments, one or more pulses were given using an exponential decay pulse generator. The correct polarity for iontophoresis and pulsing was first established as cathode in the donor. The amount of drug delivered increased with increasing donor concentration up to a point, but not any further. The amount delivered also increased with pulse voltage, the delivery being twice as much as with iontophoresis alone (144.5 ± 10.35 μg cm−2), when 6 pulses of 500 V were applied at time zero before iontophoresis (276 ± 45.2 μg cm−2). It was observed that the amount delivered was a function of increasing pulse length when the apparent charge delivered was kept constant. Transport through pig skin (107.4 ± 24.4 μg cm−2) was found to be comparable with that through human epidermis (84.9 ± 18.4 μ g cm−2). In conclusion, we have demonstrated the transdermal delivery of a 5000 Da molecular weight dextran sulfate using iontophoresis. It was also seen that iontophoretic delivery could be enhanced by simultaneous electroporation.
Massively Increased Caries Susceptibility in an Irf6 Cleft Lip/Palate Model

Patients with cleft lip/palate (CLP) have been reported, in some studies, to exhibit an increased prevalence of caries, although the underlying cause for this increase is unknown. In genetically defined mouse models, studies of postnatal sequelae associated with CLP have been hampered by neonatal lethality. Using a conditional targeting approach, we ablated the major CLP gene Irf6 only in the late embryonic oral epithelium (Irf6 cKO), bypassing the role of the gene in lip and palate morphogenesis and thus ensuring survival to adulthood. We report that Irf6 cKO mice present with 1) dysplastic salivary glands due to disruptions of epithelial junctional complexes, likely secondary to elevated activation of RHO GTPases, and 2) increased salivary cell proliferation. These changes result in significantly reduced saliva flow rate and buffering capacity and increased mucus acidity. A marked decrease in expression of CCL27, one of the major mucosal and skin cytokines, was found that correlated with increased bacterial colonization of the oral cavity with the cariogenic pathogen Streptococcus mutans and other bacteria. When placed on a high-sugar diet, Irf6 cKO mice show a 35-fold increase in presentation and severity of dental caries as compared with wild-type control mice. Strikingly, within the 8-wk test period, many molars extensively dissolved, and there was progressive loss of the alveolar bone, likely as a result of increased colonization of periodontal pathogens. These data provide the first mechanistic insight into the heightened caries susceptibility associated with CLP and indicate a direct role for the major CLP gene Irf6 in salivary gland development and a significant role in regulating oral immunity. Our data suggest that careful evaluation of salivary gland function and the implementation of early oral health preventive strategies are warranted to reduce the burden of dental care in this at-risk population.
ALMA observations of a $z$ ≈ 3.1 Protocluster: Star Formation from Active Galactic Nuclei and Lyman-Alpha Blobs in an Overdense Environment

We exploit Atacama Large Interferometer Array (ALMA) 870 μm observations to measure the star formation rates (SFRs) of eight X-ray detected active galactic nuclei (AGNs) in a z ≈ 3.1 protocluster, four of which reside in extended Lyα haloes (often termed Lyman-alpha blobs: LABs). Three of the AGNs are detected by ALMA and have implied SFRs of ≈220–410 M⊙ yr−1; the non-detection of the other five AGNs places SFR upper limits of ≲210 M⊙ yr−1. The mean SFR of the protocluster AGNs (≈110–210 M⊙ yr−1) is consistent (within a factor of ≈0.7–2.3) with that found for co-eval AGNs in the field, implying that the galaxy growth is not significantly accelerated in these systems. However, when also considering ALMA data from the literature, we find evidence for elevated mean SFRs (up-to a factor of ≈5.9 over the field) for AGNs at the protocluster core, indicating that galaxy growth is significantly accelerated in the central regions of the protocluster. We also show that all of the four protocluster LABs are associated with an ALMA counterpart within the extent of their Lyα emission. The SFRs of the ALMA sources within the LABs (≈150–410 M⊙ yr−1) are consistent with those expected for co-eval massive star-forming galaxies in the field. Furthermore, the two giant LABs (with physical extents of ≳100 kpc) do not host more luminous star formation than the smaller LABs, despite being an order of magnitude brighter in Lyα emission. We use these results to discuss star formation as the power source of LABs.
A Personal History of the MASTER Trial and Its Link to the Clinical Trials Network of the Australian and New Zealand College of Anaesthetists

The aim of this paper is to link the history of the Multicentre Australian Study of Epidural Anaesthesia in high risk surgery, the MASTER Trial, the first National Health and Medical Research Council (NHMRC) funded multicentre randomised clinical trial In Australia led by anaesthetist researchers, and the decision of The Australian and New Zealand College of Anaesthetists (ANZCA) to establish a clinical trials network, in 2003, to the success of contemporary researchers in Australia and New Zealand in anaesthesia and perioperative medicine.
Relationships among leadership, organizational commitment, and ocb in uruguayan health institutions

We develop and test a model that relates leadership behaviors, organizational commitment, and organizational citizenship behaviors (OCBs). We test the model using structural equations with a sample of 116 doctors from Uruguay. Consistent with expectations, our results show that transactional leadership behaviors increase followers' continuance commitment and decrease their growth commitment, whereas transformational leadership behaviors increase followers' growth commitment and also their normative commitment. Besides, organizational commitment mediates in the relationship between leadership and OCB. The turbulent socio-economic context of hospitals in Uruguay makes this sample of special interest, since almost all the research published in the field to date has been conducted in developed economies, and during times of macroeconomic prosperity or stability.
Screening, isolation and production of lipase/esterase producing Bacillus sp. strain DVL2 and its potential evaluation in esterificationand resolution reactions

The isolate DVL2 was isolated from common city garbage using the tributyrin as substrate. The isolate resulted in orange fluoresce under UV light on rohodamine olive oil agar plate detecting the lipase production. Three production media (PM1, PM2 and PM3) were evaluated for lipase/esterase production. In culture filterate (extracellular enzyme) and cell free extract i.e. extract after sonication of cells (intracellular enzyme), both lipase and esterase activity were detected. But esterase activity was found to be associated only with bacterial cells. The maximum intracellular (112 IU/L) and extracellular (33 IU/L) lipase production were obtained in Production medium 2 after 24 and 36 h respectively whereas the maximum production of esterase (extracellular, intracellular and membrane bound) was obtained in Production medium 2 after 24 h. The DVL2 lipase/esterase was found to esterify stearic acid with ethanol resulting in the formation of ethyl stearate which was confirmed by thin layer chromatography. Furthermore DVL2 lipase gave positive results when applied for resolution of chiral auxillary viz. 1-acetyl phenyl ethanol.