CHARACTERIZATION OF ENGINEERED SURFACES

In the recent years there has been an increasing interest in manufacturing products where surface topography plays a functional role. These surfaces are called engineered surfaces and are used in a variety of industries like semi conductor, data storage, micro- optics, MEMS etc. Engineered products are designed, manufactured and inspected to meet a variety of specifications such as size, position, geometry and surface finish to control the physical, chemical, optical and electrical properties of the surface. As the manufacturing industry strive towards shrinking form factor resulting in miniaturization of surface features, measurement of such micro and nanometer scale surfaces is becoming more challenging. Great strides have been made in the area of instrumentation to capture surface data, but the area of algorithms and procedures to determine form, size and orientation information of surface features still lacks the advancement needed to support the characterization requirements of R&D and high volume manufacturing. This dissertation addresses the development of fast and intelligent surface scanning algorithms and methodologies for engineered surfaces to determine form, size and orientation of significant surface features. Object recognition techniques are used to identify the surface features and CMM type fitting algorithms are applied to calculate the dimensions of the features. Recipes can be created to automate the characterization and process multiple features simultaneously. The developed methodologies are integrated into a surface analysis toolbox developed in MATLAB environment. The deployment of the developed application on the web is demonstrated

Elucidating the effects of mutation and evolutionary divergence upon protein structure quantitative stability/flexibility relationships

The importance of flexibility and stability on protein function has been recognized for over five decades. A protein must be flexible enough to mediate a reaction pathway, yet rigid enough to achieve high fidelity in molecular recognition. To understand these relationships, the main focus of our research has been a comparative investigation of proteins' dynamics and thermodynamics across both "depth" and "breadth". Specifically, we compare stability and flexibility properties across a set of human c-type lysozyme point mutations (depth), as well as across a set of functionally related ß-lactamase protein orthologs (breadth). To accomplish these tasks we employ a Distance Constraint Model (DCM), which provides a robust statistical mechanical description of proteins and the relationships therein. The DCM is based on network rigidity that provides mechanical mechanism for enthalpy-entropy compensation, from which Quantitative Stability/Flexibility Relationships (QSFR) can be calculated. Our results suggest that DCM can be used for predicting stability of proteins with an average percent error of 4.3%. Deciphering changes in flexibility, DCM results suggest that the influence of mutations can lead to frequent, large and long-range effects in protein dynamics. Our breadth analyses indicate that QSFR and physiochemical property characterization of orthologs in a protein family parallel evolutionary relationship. Going further, we present protocols for clustering protein structures using their QSFR properties, thus paving way for comprehensive quantitative stability/flexibility relationship analysis across protein families and superfamilies. To summarize, the results presented in this work provide a complete description of proteins that account for their stability, flexibility and function

Visual impairment and eye health and safety among Latino farmworkers

Agriculture is one of the most dangerous industries in the United States. Everyone who works in agriculture is exposed to environmental risk factors that can result in occupational eye injury and illness. These risks are particularly high for migrant and seasonal farmworkers. Vision problems increase the risk of occupational injuries in farmworkers. Workers rely on distance vision when driving cars, vans, and farm equipment. They rely on close vision to read pesticide labels and avoid branches and other hazards when picking orchard crops. Few farmworkers utilize healthcare in the US due to their immigration status, low income, lack of health insurance, and the limited number of migrant facilities. The overall goals of this project are to: (1) assess the prevalence of visual impairment in Latino farmworkers in North Carolina and (2) assess the use of ocular protection and examine farmworker knowledge, perceptions, and risk beliefs about eye health and safety. Interviews and standardized vision examinations were conducted with 300 Latino farmworkers. About 75% of farmworkers reported never having had their eyes checked. For distance vision, 3.4% had vision problems in the right eye, 3.1% in the left eye, and 1.3% with both eyes. For near vision, 10% had vision problems in the right eye, 10.3% in the left eye, and 6.9% in both eyes. Visual impairment was most common among farmworkers aged 40 years and older. Farmworkers reported difficulty watching TV (19.7%) and doing work requiring near vision (25%). Responses to vision tasks did not accurately predict vision problems identified by examinations; sensitivities for each question were 60% or less. Farmworkers need routine vision exams to identify problems and reduce the risk of occupational injury. Farmworkers reported low rates of eye protection use (8.3%) in this study. Majority (92.3%) of farmworkers in our study report that growers or contractors they work for do not provide eye protection despite the Occupational Safety and Health Standards. Approximately 70% of the farmworkers in this study reported that they are not well trained in preventing eye injuries and 81% of the workers believe that their chances of getting an eye injury at work on any given day are extremely low. Self-efficacy was apparent in issues related to risky behavior. While farmworkers indicated that they could recognize when their co-workers took risks, many farmworkers themselves chose to take risks to the eyes in order to save time or get more work done. Understanding farmworker knowledge, perceptions, and risk beliefs about eye health and safety are important when designing interventions and promoting the use of eye protection. The results of this research are built upon previous studies focused on eye health and provide vital information for defining the need for screening, designing interventions, and implementing programs that are targeted to reduce eye conditions in such a vulnerable, medically underserved population

Overview of Attention Deficit Hyperactivity Disorder in Young Children

Attention deficit hyperactivity disorder (ADHD) is a complex disorder, which can be seen as a disorder of life time, developing in preschool years and manifesting symptoms (full and/or partial) throughout the adulthood; therefore, it is not surprising that there are no simple solutions. The aim of this paper is to provide a short and concise review which can be used to inform affected children and adults; family members of affected children and adults, and other medical, paramedical, non-medical, and educational professionals about the disorder. This paper has also tried to look into the process of how ADHD develops; what are the associated problems; and how many other children and adults are affected by such problems all over the world basically to understand ADHD more precisely in order to develop a better medical and or non-medical multimodal intervention plan. If preschool teachers and clinicians are aware of what the research tells us about ADHD, the varying theories of its cause, and which areas need further research, the knowledge will assist them in supporting the families of children with ADHD. By including information in this review about the connection between biological behavior, it is hoped that preschool teachers and clinicians at all levels will feel more confident about explaining to parents of ADHD children, and older ADHD children themselves about the probable causes of ADHD

Diagnosed Skin Diseases Among Migrant Farmworkers in North Carolina: Prevalence and Risk Factors

Skin diseases are common among farmworkers, yet little research documents their prevalence and risk factors. This analysis documents the prevalence of skin diseases among farmworkers in North Carolina, examines variation in the prevalence across the agricultural season, and delineates factors associated with skin disease. Data are from a longitudinal surveillance study with assessments at approximately three-week intervals from May through October 2005. The sample included 304 farmworkers from 45 camps with 1048 data points. Data collection included a structured interview and a standard set often digital photographs. A board-certified dermatologist reviewed the photographs and made specific diagnoses in five categories: inflammatory disease, infection, pigmentary disorder, tumor, and trauma. The prevalences of the five skin disease categories and specific diagnoses are described with counts and frequencies for the entire season and for six time periods. The inflammatory disease and infectious disease categories are modeled with an extension of logistic regression that accounts for repeated measures and clustering of farmworkers within camps. Farmworkers experience high levels of inflammatory skin disease (57.2%) including acne, folliculitis, and contact dermatitis; infectious skin disease (73.8%) including tinea pedis, onychomycosis, and warts; pigmentary disorders (19.1%); and trauma (34.5%). The odds of inflammatory skin disease decreased with age, while those for infectious skin disease increased with age. The odds of inflammatory skin disease increased with pesticide exposure and decreasing housing quality. Skin diseases are highly prevalent among farmworkers. Research is needed to delineate specific factors causing high levels of infection and inflammation in this population

Narrative-based computational modelling of the Gp130/JAK/STAT signalling pathway.

BACKGROUND: Appropriately formulated quantitative computational models can support researchers in understanding the dynamic behaviour of biological pathways and support hypothesis formulation and selection by "in silico" experimentation. An obstacle to widespread adoption of this approach is the requirement to formulate a biological pathway as machine executable computer code. We have recently proposed a novel, biologically intuitive, narrative-style modelling language for biologists to formulate the pathway which is then automatically translated into an executable format and is, thus, usable for analysis via existing simulation techniques. RESULTS: Here we use a high-level narrative language in designing a computational model of the gp130/JAK/STAT signalling pathway and show that the model reproduces the dynamic behaviour of the pathway derived by biological observation. We then "experiment" on the model by simulation and sensitivity analysis to define those parameters which dominate the dynamic behaviour of the pathway. The model predicts that nuclear compartmentalisation and phosphorylation status of STAT are key determinants of the pathway and that alternative mechanisms of signal attenuation exert their influence on different timescales. CONCLUSION: The described narrative model of the gp130/JAK/STAT pathway represents an interesting case study showing how, by using this approach, researchers can model biological systems without explicitly dealing with formal notations and mathematical expressions (typically used for biochemical modelling), nevertheless being able to obtain simulation and analysis results. We present the model and the sensitivity analysis results we have obtained, that allow us to identify the parameters which are most sensitive to perturbations. The results, which are shown to be in agreement with existing mathematical models of the gp130/JAK/STAT pathway, serve us as a form of validation of the model and of the approach itself

Palbociclib in Combination With Fulvestrant in Women With Hormone Receptor-Positive/HER2-Negative Advanced Metastatic Breast Cancer: Detailed Safety Analysis From a Multicenter, Randomized, Placebo-Controlled, Phase III Study (PALOMA-3).

Background Palbociclib enhances endocrine therapy and improves clinical outcomes in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Because this is a new target, it is clinically important to understand palbociclib's safety profile to effectively manage toxicity and optimize clinical benefit.Materials and methods Patients with endocrine-resistant, HR-positive/HER2-negative MBC (n = 521) were randomly assigned 2:1 to receive fulvestrant (500 mg intramuscular injection) with or without goserelin with oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments at baseline and day 1 of each cycle included blood counts on day 15 for the first 2 cycles. Hematologic toxicity was assessed by using laboratory data.Results A total of 517 patients were treated (palbociclib, n = 345; placebo, n = 172); median follow-up was 8.9 months. With palbociclib, neutropenia was the most common grade 3 (55%) and 4 (10%) adverse event; median times to onset and duration of grade ≥3 episodes were 16 and 7 days, respectively. Asian ethnicity and below-median neutrophil counts at baseline were significantly associated with an increased chance of developing grade 3-4 neutropenia with palbociclib. Dose modifications for grade 3-4 neutropenia had no adverse effect on progression-free survival. In the palbociclib arm, febrile neutropenia occurred in 3 (<1%) patients. The percentage of grade 1-2 infections was higher than in the placebo arm. Grade 1 stomatitis occurred in 8% of patients.Conclusion Palbociclib plus fulvestrant treatment was well-tolerated, and the primary toxicity of asymptomatic neutropenia was effectively managed by dose modification without apparent loss of efficacy. This study appears at ClinicalTrials.gov, NCT01942135.Implications for practice Treatment with palbociclib in combination with fulvestrant was generally safe and well-tolerated in patients with hormone receptor (HR)-positive metastatic breast cancer. Consistent with the drug's proposed mechanism of action, palbociclib-related neutropenia differs in its clinical time course, patterns, and consequences from those seen with chemotherapy. Neutropenia can be effectively managed by a dose reduction, interruption, or cycle delay without compromising efficacy. A significant efficacy gain and a favorable safety profile support the consideration of incorporating palbociclib into the routine management of HR-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

A Comprehensive Approach to Identify Reliable Reference Gene Candidates to Investigate the Link between Alcoholism and Endocrinology in Sprague-Dawley Rats

Gender and hormonal differences are often correlated with alcohol dependence and related complications like addiction and breast cancer. Estrogen (E2) is an important sex hormone because it serves as a key protein involved in organism level signaling pathways. Alcoholism has been reported to affect estrogen receptor signaling; however, identifying the players involved in such multi-faceted syndrome is complex and requires an interdisciplinary approach. In many situations, preliminary investigations included a straight forward, yet informative biotechniques such as gene expression analyses using quantitative real time PCR (qRT-PCR). The validity of qRT-PCR-based conclusions is affected by the choice of reliable internal controls. With this in mind, we compiled a list of 15 commonly used housekeeping genes (HKGs) as potential reference gene candidates in rat biological models. A comprehensive comparison among 5 statistical approaches (geNorm, dCt method, NormFinder, BestKeeper, and RefFinder) was performed to identify the minimal number as well the most stable reference genes required for reliable normalization in experimental rat groups that comprised sham operated (SO), ovariectomized rats in the absence (OVX) or presence of E2 (OVXE2). These rat groups were subdivided into subgroups that received alcohol in liquid diet or isocalroic control liquid diet for 12 weeks. Our results showed that U87, 5S rRNA, GAPDH, and U5a were the most reliable gene candidates for reference genes in heart and brain tissue. However, different gene stability ranking was specific for each tissue input combination. The present preliminary findings highlight the variability in reference gene rankings across different experimental conditions and analytic methods and constitute a fundamental step for gene expression assays

Disulfiram/copper selectively eradicates AML leukemia stem cells in vitro and in vivo by simultaneous induction of ROS-JNK and inhibition of NF-κB and Nrf2

© 2017 The Authors. Published by Nature Publishing Group. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1038/cddis.2017.176Acute myeloid leukemia (AML) is a heterogeneous malignancy. Despite the advances in past decades, the clinical outcomes of AML patients remain poor. Leukemia stem cells (LSCs) is the major cause of the recurrence of AML even after aggressive treatment making, promoting development of LSC-targeted agents is an urgent clinical need. Although the antitumor activity of disulfiram (DS), an approved anti-alcoholism drug, has been demonstrated in multiple types of tumors including hematological malignancies such as AML, it remains unknown whether this agent would also be able to target cancer stem cells like LSCs. Here, we report the in vitro and in vivo activity of DS in combination with copper (Cu) against CD34(+)/CD38(+) leukemia stem-like cells sorted from KG1α and Kasumi-1 AML cell lines, as well as primary CD34(+) AML samples. DS plus Cu (DS/Cu) displayed marked inhibition of proliferation, induction of apoptosis, and suppression of colony formation in cultured AML cells while sparing the normal counterparts. DS/Cu also significantly inhibited the growth of human CD34(+)/CD38(+) leukemic cell-derived xenografts in NOD/SCID mice. Mechanistically, DS/Cu-induced cytotoxicity was closely associated with activation of the stress-related ROS-JNK pathway as well as simultaneous inactivation of the pro-survival Nrf2 and nuclear factor-κB pathways. In summary, our findings indicate that DS/Cu selectively targets leukemia stem-like cells both in vitro and in vivo, thus suggesting a promising LSC-targeted activity of this repurposed agent for treatment of relapsed and refractory AML