Miracle-dz/UniFAR-FTUs huggingface dataset:
Correct primary structure assessment and extensive glyco-profiling of cetuximab by a combination of intact, middle-up, middle-down and bottom-up ESI and MALDI mass spectrometry techniques

The European Medicines Agency received recently the first marketing authorization application for a biosimilar monoclonal antibody (mAb) and adopted the final guidelines on biosimilar mAbs and Fc-fusion proteins. The agency requires high similarity between biosimilar and reference products for approval. Specifically, the amino acid sequences must be identical. The glycosylation pattern of the antibody is also often considered to be a very important quality attribute due to its strong effect on quality, safety, immunogenicity, pharmacokinetics and potency. Here, we describe a case study of cetuximab, which has been marketed since 2004. Biosimilar versions of the product are now in the pipelines of numerous therapeutic antibody biosimilar developers. We applied a combination of intact, middle-down, middle-up and bottom-up electrospray ionization and matrix assisted laser desorption ionization mass spectrometry techniques to characterize the amino acid sequence and major post-translational modifications of the marketed cetuximab product, with special emphasis on glycosylation. Our results revealed a sequence error in the reported sequence of the light chain in databases and in publications, thus highlighting the potency of mass spectrometry to establish correct antibody sequences. We were also able to achieve a comprehensive identification of cetuximab’s glycoforms and glycosylation profile assessment on both Fab and Fc domains. Taken together, the reported approaches and data form a solid framework for the comparability of antibodies and their biosimilar candidates that could be further applied to routine structural assessments of these and other antibody-based products.
Eye movement task related to frontal lobe functioning in children with attention deficit disorder.

OBJECTIVE Attention-deficit hyperactivity disorder (ADHD) has been postulated to be related to dysfunction of the prefrontal cortex. In the oculomotor delayed response task, a subject is cued as to where he or she should look (shift visual gaze to) but must delay a short period and then shift gaze to the location where the cue previously existed but no longer exists (a memory-guided saccade). Dependent measures from this task provide information on three functions tentatively tied to prefrontal cortex functioning: the ability to inhibit response (during the delay period), preparation of motor response (inversely tied to the latency of shifting visual gaze), and accuracy of working visuospatial memory (accuracy of the memory-guided saccade). METHOD Thirteen children with ADHD and 10 normal controls, aged 9 to 12 years, were tested using an 800-msec delay period. RESULTS Children with ADHD showed, relative to normal controls, deficits on inhibiting response during the delay period but no differences in latency (preparation of motor response) or accuracy of visuospatial memory. CONCLUSIONS These results support the hypothesis that the primary deficit in ADHD is difficulty in inhibition of response. This deficit may be associated with pathology located outside the dorsolateral prefrontal cortex.
MK-383 (Tirofiban) induces a GPIIb/IIIa receptor conformation which differs from the resting and activated receptor

The platelet integrin αIIb β3 (GPIIb/IIIa) acts as a receptor for fibrinogen, playing a critical role in platelet aggregation. GPIIb/IIIa antagonists, which block the receptor-ligand interaction, have been accused of causing occasional thrombocytopenia, probably via drug-induced platelet activation or immunogenic neoepitopes. We, therefore, analyzed the effects of the GPIIb/IIIa antagonist MK-383 (tirofiban) on platelet activation and GpIIb/IIIa conformation. At a concentration of 10-7 mol/l, MK-383 completely inhibited fibrinogen binding to in vitro stimulated platelets. Simultaneously, the GPIIb/IIIa expression density increased, similar to that on activated platelets, but no effect on P-selectin expression or the formation of platelet-leukocyte aggregates could be observed, indicating that MK-383 binding did not induce general platelet activation. The GPIIb/IIIa receptor conformation was further analyzed by fluorescence resonance energy transfer analysis between fluorochrome-labeled antibodies against different GpIIb/IIIa epitopes. As a result, MK-383 induced a receptor conformation that differed from the resting as well as the activated receptor as induced by ADP or TRAP-6. This conformational modulation of GPIIb/IIIa presents an interesting mechanism which may be linked to receptor recruitment without inducing general platelet activation.
Clinical significance of matrix metalloproteinase-3 in systemic lupus erythematosus patients: a potential biomarker for disease activity and damage.

OBJECTIVES To assess the serum level of matrix metalloproteinase-3 (MMP-3) in systemic lupus erythematosus (SLE) patients and correlate it with clinical manifestations, laboratory findings, disease activity and damage. METHODS Forty-two female SLE patients were included in the present study. Full history taking, thorough examination and investigations were performed. Disease activity was assessed using the SLE disease activity index (SLEDAI). Furthermore, Systemic Lupus International Collaborating Clinics /American College of Rheumatology damage index (SLICC/ACR DI) was also assessed. Renal biopsy was done in those with lupus nephritis. Thirty age and sex matched subjects were included as control. Serum MMP-3 was measured by ELISA. RESULTS The mean serum MMP-3 level in SLE patients was significantly higher (80.9±45.8 ng/ml) than in the control (10.01±2.6 ng/ml) (p <0.0001). The level in patients with arthritis, nephritis or hematologic disorders were significantly higher than in those without (p<0.0001, p=0.02 and p=0.04 respectively). The MMP-3 was significantly different among the subclasses of renal biopsy (p=0.01) being higher in those with class IV (137.5±45.6 ng/ml). It significantly correlated with the SLEDAI, SLICC, white blood cells and platelet counts (r=0.37, p=0.02; r=0.36, p=0.02; r=0.32, p 0.04 and r=0.38, p=0.01 respectively). On linear regression analysis with age, disease duration and body mass index as independent factors, the SLEDAI and SLICC were not significant predictors. CONCLUSION Serum MMP-3 was found to be high in SLE patients and associated with arthritis, nephritis and hematological manifestations. Matrix metalloproteinase-3 correlated with disease activity and damage making it a possible biomarker and its measure of considerable interest related to the potential therapeutic responses and disease outcome.
Photoperiodic modulation of gonadotrophin secretion in castrated Japanese quail.

Male Japanese quail were castrated when sexually immature and immediately exposed to one of the following stimulatory lighting regimes for 52 days: 11 h light: 13 h darkness/day (11L : 13D), 12L : 12D, 13L : 11D, 14L : 10D, 15L : 9D, 16L : 8D, 20L : 4D or 23L : 1D. One group was retained on short days (8L : 16D). Clearcut differences in the plasma levels of LH and FSH emerged between the various groups. Levels remained very low in castrated quail on 8L : 16D but were much greater in those on 14L : 10D, 15L : 9D, 16L : 8D, 20L : 4D and 23L : 1D, eventually becoming 15 to 20 times higher. Less pronounced castration responses developed on 13L : 11D, 12L : 12D or 11L : 13D. Alterations in photoperiod after day 52 caused an appropriate rise or fall in LH secretion. Photoperiodically induced suppressions were rapid, being highly significant within 4 days, but increases usually had a slower time course. When sexually mature quail (on 16L : 8D) were castrated and transferred to 8L :16D they also exhibited a rapid suppression in LH secretion. Thus in quail, unlike some mammals, the photoperiodic control over gonadotrophin secretion is independent of the reproductive status of the animal at the time of castration. The results confirm the view that changes in sensitivity of the hypothalamo-pituitary axis to gonadal steroids are not a primary factor in the neural mechanisms underlying photoperiodism in quail.
Windows 99: a source of suburban pediatric trauma.

BACKGROUND Falls from windows in urban areas cause a significant number of pediatric injuries. Window falls have not been well described in the nonurban setting. We describe the epidemiology of window falls from residential homes among pediatric patients at a suburban Level I trauma center. METHODS A review of patients admitted from January 1991 through November 1999 to a center serving a rapidly growing suburban area was performed. RESULTS A total of 2,322 children, ages 0-14 years, were admitted during the study period. Falls comprised 41% of these admissions, and 11% of falls were from windows, greater than twice the national average. More than 39% of children who fell from windows were admitted directly to the intensive care unit. Overall mortality rate was 4%. Ages 0 to 4 years comprised the largest percentage (83%), and all children who died were in this age group. Children < or = 4 years were more likely to have an Abbreviated Injury Score > or = 2 (head injury) than those ages 10 to 14 years (p = 0.032). More than 31% of all children injured in window falls seen at the study institution between 1991 and 1999 were admitted in the last 2 years. CONCLUSION Pediatric falls from windows in this suburban area appear to be increasing, with an incidence greater than the national average. Children at greatest risk are less than 4 years old. Further research in injury prevention at the national level aimed at suburban areas may be warranted.
Oil price, macroeconomic environment and stock market performance in an oil-exporting country: evidence from Nigeria

This study examines the dynamic interaction between indicators of macroeconomic environment, oil price and stock market performance in Nigeria from 1985 to 2014 using the autoregressive distributed lag (ARDL) bounds testing approach to cointegration analysis. The results suggest the existence of a long-run equilibrium relationship between indicators of macroeconomic environment, oil price and stock market performance in Nigeria. Stock market performance is found to be significantly related to movements in oil price in the long-run as well as in the short-run. The long-run influence of oil price on the Nigerian macroeconomic environment is found to be stronger than the short-run effect with all the indicators of the macroeconomic environment (exchange rate, inflation rate and broad money supply) responding significantly to oil price in the long-run.
What Role Does Race Play in Adolescent Suicidal Ideation?

ABSTRACT Epidemiological data indicate that suicide rates have been decreasing among 15–19-year-olds in the United States; however, rates have been increasing among some minority groups. Research has identified numerous risk factors for adolescent suicide and suicide-related behaviors, but models testing these risk factors within different racial or ethnic groups are scarce. The current study tested a model of adolescent suicide ideation in a sample of 258 high school students, comparing the model fit across two racial groups. The model significantly fit the data for both groups indicating that the relationship between suicide exposure and current suicidal ideation is mediated by reasons for living and level of depressive symptoms. Ways in which the results improve our understanding of risk factors in diverse adolescents are discussed.
Structural Transformation and Income Distribution: Kuznets and Beyond

This paper explores the question of structural transformation and income distribution through the eyes of the pioneer in such analysis, Simon Kuznets. It argues that his 1955 paper stands the test of time in providing insights which are relevant to understanding current phenomena like the evolution of Chinese inequality. The paper shows how the Kuznetsian framework can be used, for example, in predicting the differential relationship between urbanization and inequality in India versus China, in assessing the detail of the contribution of sectoral mean and inequality evolution to overall inequality change, and in linking the recent inequality of opportunity literature to rural-urban migration. Thus the original Kuznets framework has the seeds of getting us beyond Kuznets as sometimes (mis)understood in the literature on structural transformation and income distribution.
Encouraging knowledge contribution in IT support: social context and the differential effects of motivation type

Purpose – This paper aims to investigate how to promote two types of knowledge contribution tasks. The authors focus on the role of supervisor and coworker support on motivation, and their effects on two different contribution tasks. Motivating employees to contribute knowledge is quite challenging. While previous studies have tried to understand how to promote knowledge contribution, few have differentiated between knowledge contribution tasks. Design/methodology/approach – Information technology support was chosen as the context of this study, and data were collected from system administrators within a Fortune 500 company via a web-based survey. Findings – Results show the differential effects of two forms of motivation on different contribution tasks, and supervisor support is positively associated with intrinsic motivation. Specifically, while intrinsic motivation is positively associated with challenging knowledge contribution, external motivation is positively related to mundane knowledge contributi.
Health care costs associated with depressive and anxiety disorders in primary care.

OBJECTIVE The authors examined the overall health care costs associated with depression and anxiety among primary care patients. METHOD Of 2,110 consecutive primary care patients in a health maintenance organization, 1,962 were screened with the 12-item General Health Questionnaire. A stratified random sample of 615 patients were selected for further diagnostic assessment; 373 of these patients completed the Composite International Diagnostic Interview at baseline and 328 were reassessed 12 months later. Computerized cost records were used to calculate total health care costs for the 6-month period surrounding the baseline assessment and a similar period surrounding the follow-up assessment. Cost accounting data were available for 327 patients at baseline and for 206 patients at both assessments. RESULTS Primary care patients with DSM-III-R anxiety or depressive disorders at baseline had markedly higher baseline costs ($2,390) than patients with subthreshold disorders ($1,098) and those with no anxiety or depressive disorder ($1,397). Large cost differences persisted after adjustment for medical morbidity. Cost differences reflected higher utilization of general medical services rather than higher mental health treatment costs. Although most patients with baseline anxiety or depressive disorders showed significant improvement, longitudinal analyses did not show any clear relationship between change in psychiatric diagnosis and change in health care cost. CONCLUSIONS Among primary care patients, anxiety and depressive disorders are associated with markedly higher health care costs even after adjustment for medical comorbidity. In this small sample, improvement in depression over 1 year was not clearly associated with decreases in cost.
Pericardial Tamponade: a Rare Complication of Sternal Bone Marrow Biopsy

Injury of the heart with concomitant pericardial tamponade as a result of sternal bone marrow biopsy is rare. An 80-year-old man was admitted with dehydration and non-specified abdominal pain to the regional hospital. Sternal aspiration biopsy was performed because of anemia and thrombocytopenia. Later on, because of the back pain, general weakness and blood pressure drop, an echocardiography examination was indicated. Pericardial fluid collection was found. Anticipated ascending aortic dissection was excluded on computed tomography scan, but pericardial fluid collection was confirmed. Transfer to our cardiac surgical facility ensued. Limited heart tamponade was affirmed on echocardiography and surgery was immediately indicated. Blood effusion was found in upper mediastinal fat tissue and 300 mL of blood were evacuated from opened pericardial space. Stab wound by sternal biopsy needle at the upper part of ascending aorta was repaired by pledgeted suture. Postoperative course was uneventful.
Associations of key diet-quality indexes with mortality in the Multiethnic Cohort: the Dietary Patterns Methods Project.

BACKGROUND Healthy dietary patterns have been linked positively with health and longevity. However, prospective studies in diverse populations in the United States addressing dietary patterns and mortality are limited. OBJECTIVE We assessed the ability of the following 4 diet-quality indexes [the Healthy Eating Index-2010 (HEI-2010), the Alternative HEI-2010 (AHEI-2010), the alternate Mediterranean diet score (aMED), and the Dietary Approaches to Stop Hypertension (DASH)] to predict the reduction in risk of mortality from all causes, cardiovascular disease (CVD), and cancer. DESIGN White, African American, Native Hawaiian, Japanese American, and Latino adults (n = 215,782) from the Multiethnic Cohort completed a quantitative food-frequency questionnaire. Scores for each dietary index were computed and divided into quintiles for men and women. Mortality was documented over 13-18 y of follow-up. HRs and 95% CIs were computed by using adjusted Cox models. RESULTS High HEI-2010, AHEI-2010, aMED, and DASH scores were all inversely associated with risk of mortality from all causes, CVD, and cancer in both men and women (P-trend < 0.0001 for all models). For men, the HEI-2010 was consistently associated with a reduction in risk of mortality for all causes (HR: 0.75; 95% CI: 0.71, 0.79), CVD (HR: 0.74; 95% CI: 0.69, 0.81), and cancer (HR: 0.76; 95% CI: 0.70, 0.83) when lowest and highest quintiles were compared. In women, the AHEI and aMED showed large reductions for all-cause mortality (HR: 0.78; 95% CI: 0.74, 0.82), the AHEI showed large reductions for CVD (HR: 0.76; 95% CI: 0.69, 0.83), and the aMED showed large reductions for cancer (HR: 0.84; 95% CI: 0.76, 0. 92). CONCLUSION These results, in a US multiethnic population, suggest that consuming a dietary pattern that achieves a high diet-quality index score is associated with lower risk of mortality from all causes, CVD, and cancer in adult men and women.
Convergence of entorhinal and CA3 inputs onto pyramidal neurons and interneurons in hippocampal area CA1—An anatomical study in the rat

The entorhinal cortex (EC) conveys information to hippocampal field CA1 either directly by way of projections from principal neurons in layer III, or indirectly by axons from layer II via the dentate gyrus, CA3, and Schaffer collaterals. These two pathways differentially influence activity in CA1, yet conclusive evidence is lacking whether and to what extent they converge onto single CA1 neurons. Presently we studied such convergence. Different neuroanatomical tracers injected into layer III of EC and into CA3, respectively, tagged simultaneously the direct entorhino‐hippocampal fibers and the indirect innervation of CA1 neurons by Schaffer collaterals. In slices of fixed brains we intracellularly filled CA1 pyramidal cells and interneurons in stratum lacunosum‐moleculare (LM) and stratum radiatum (SR). Sections of these slices were scanned in a confocal laser scanning microscope. 3D‐reconstruction was used to determine whether boutons of the labeled input fibers were in contact with the intracellularly filled neurons. We analyzed 12 pyramidal neurons and 21 interneurons. Perforant path innervation to pyramidal neurons in our material was observed to be denser than that from CA3. All pyramidal neurons and 17 of the interneurons received contacts of both perforant pathway and Schaffer input on their dendrites and cell bodies. Four interneurons, which were completely embedded in LM, received only labeled perforant pathway input. Thus, we found convergence of both projection systems on single CA1 pyramidal and interneurons with dendrites that access the layers where perforant pathway fibers and Schaffer collaterals end. © 2007 Wiley‐Liss, Inc.
Maternal factors required for oocyte developmental competence in mice: Transcriptome analysis of non-surrounded nucleolus (NSN) and surrounded nucleolus (SN) oocytes

During mouse antral follicle development, the oocyte chromatin gradually transforms from a less condensed state with no Hoechst-positive rim surrounding the nucleolus (NSN) to a fully condensed chromatin state with a Hoechst-positive rim surrounding the nucleolus (SN). Compared with SN oocytes, NSN oocytes display a higher gene transcription activity and a lower rate of meiosis resumption (G2/M transition), and they are mostly arrested at the two-cell stage after in vitro fertilization. To explore the differences between NSN and SN oocytes, and the maternal factors required for oocyte developmental competence, we compared the whole-transcriptome profiles between NSN and SN oocytes. First, we found that the NSN and SN oocytes were different in their metabolic pathways. In the phosphatidylinositol signaling pathway, the SN oocytes tend to produce diacylglycerol, whereas the NSN oocytes tend to produce phosphatidylinositol (3,4,5)-trisphosphate. For energy production, the SN oocytes and NSN oocytes differed in the gluconeogenesis and in the synthesis processes. Second, we also found that the key genes associated with oocyte meiosis and/or preimplantation embryo development were differently expressed in the NSN and SN oocytes. Our results illustrate that during the NSN-SN transition, the oocytes change their metabolic activities and accumulate maternal factors for further oocyte maturation and post-fertilization embryo development.
MIMO testbed with an insight into signal strength distribution around transmitter/receiver sites

This paper presents a high precision test-bed to obtain an insight into the operation of a multiple element antenna (MEA) communication system in an indoor environment. In this system, transmitter and receiver are equipped with 180deg or 90deg 3 dB hybrids whose two output ports are terminated with co-polar monopole antennas. By feeding the signal to one of the remaining two ports of the hybrids various radiation patterns are established. These in turn create various communication channels formed by MEA and a surrounding scattering environment. The testbed allows for the signal strength measurements around the receiver/transmitter sides for various radiation pattern modes generated by transmitting and receiving array antennas operating in conjuncture with the hybrids. Details concerning mechanical, electrical and electronics hardware and associated measurement software are described. Initial measurement results in the ISM 2.4 GHz band for a 2times2 MIMO system that includes Bluetooth modules equipped with planar monopoles and 180deg/90deg hybrids are given