Miracle-dz/UniFAR-FTUs huggingface dataset:
Practice guidelines for pharmacists: The management of osteoarthritis

Osteoarthritis (OA) is the most common form of arthritis, affecting more than 1 in 8 Canadians. With an aging population, the prevalence of OA in Canada is rising. From 2010 to 2031, the prevalence of OA is projected to increase from 13.8% to 18.6%, with the total direct costs projected to increase from $2.9 billion to $7.6 billion, an almost 2.6-fold increase. OA has traditionally been thought to be a progressive disease of the synovial joints that is due to daily “wear and tear” from excessive and repetitive force on joint cartilage. While this is partially true, OA is now believed to be a systemic disorder due to an imbalance between joint destruction and repair. The result is a breakdown of cartilage and bone, leading to symptoms of pain, stiffness and functional disability. The joints most commonly affected by OA (in order of prevalence) are the hands, knees, hips and spine. OA is more prevalent with age, affecting nearly half the population older than 70. In addition to advancing age, female gender is a significant risk factor. Other risk factors include obesity, quadriceps muscle weakness, family history, joint injury and joint overuse or injury (e.g., participation in certain sports).
Correlated sequence-signatures as markers of protein-protein interaction.

As protein-protein interaction is intrinsic to most cellular processes, the ability to predict which proteins in the cell interact can aid significantly in identifying the function of newly discovered proteins, and in understanding the molecular networks they participate in. Here we demonstrate that characteristic pairs of sequence-signatures can be learned from a database of experimentally determined interacting proteins, where one protein contains the one sequence-signature and its interacting partner contains the other sequence-signature. The sequence-signatures that recur in concert in various pairs of interacting proteins are termed correlated sequence-signatures, and it is proposed that they can be used for predicting putative pairs of interacting partners in the cell. We demonstrate the potential of this approach on a comprehensive database of experimentally determined pairs of interacting proteins in the yeast Saccharomyces cerevisiae. The proteins in this database have been characterized by their sequence-signatures, as defined by the InterPro classification. A statistical analysis performed on all possible combinations of sequence-signature pairs has identified those pairs that are over-represented in the database of yeast interacting proteins. It is demonstrated how the use of the correlated sequence-signatures as identifiers of interacting proteins can reduce significantly the search space, and enable directed experimental interaction screens.
SOFTWARE METRICS VALIDATION METHODOLOGIES IN SOFTWARE ENGINEERING

In the software measurement validations, assessing the validation of software metrics in software engineering is a very difficult task due to lack of theoretical methodology and empirical methodology [41, 44, 45]. During recent years, there have been a number of researchers addressing the issue of validating software metrics. At present, software metrics are validated theoretically using properties of measures. Further, software measurement plays an important role in understanding and controlling software development practices and products. The major requirement in software measurement is that the measures must represent accurately those attributes they purport to quantify and validation is critical to the success of software measurement. Normally, validation is a collection of analysis and testing activities across the full life cycle and complements the efforts of other quality engineering functions and validation is a critical task in any engineering project. Further, validation objective is to discover defects in a system and assess whether or not the system is useful and usable in operational situation. In the case of software engineering, validation is one of the software engineering disciplines that help build quality into software. The major objective of software validation process is to determine that the software performs its intended functions correctly and provides information about its quality and reliability. This paper discusses the validation methodology, techniques and different properties of measures that are used for software metrics validation. In most cases, theoretical and empirical validations are conducted for software metrics validations in software engineering [1-50].
Are Molecular Alphabets Universal Enabling Factors for the Evolution of Complex Life ?

Terrestrial biosystems depend on macromolecules, and this feature is often considered as a likely universal aspect of life. While opinions differ regarding the importance of small-molecule systems in abiogenesis, escalating biological functional demands are linked with increasing complexity in key molecules participating in biosystem operations, and many such requirements cannot be efficiently mediated by relatively small compounds. It has long been recognized that known life is associated with the evolution of two distinct molecular alphabets (nucleic acid and protein), specific sequence combinations of which serve as informational and functional polymers. In contrast, much less detailed focus has been directed towards the potential universal need for molecular alphabets in constituting complex chemically-based life, and the implications of such a requirement. To analyze this, emphasis here is placed on the generalizable replicative and functional characteristics of molecular alphabets and their concatenates. A primary replicative alphabet based on the simplest possible molecular complementarity can potentially enable evolutionary processes to occur, including the encoding of secondarily functional alphabets. Very large uniquely specified (‘non-alphabetic’) molecules cannot feasibly underlie systems capable of the replicative and evolutionary properties which characterize complex biosystems. Transitions in the molecular evolution of alphabets can be related to progressive bridging of barriers which enable higher levels of biosystem organization. It is thus highly probable that molecular alphabets are an obligatory requirement for complex chemically-based life anywhere in the universe. In turn, reference to molecular alphabets should be usefully applied in current definitions of life.
Characterization of the Microbial Community and Activity of Nitrate-Reducing, Benzene-Degrading Enrichment Cultures

Benzene is a natural component of crude oil. It is highly toxic, carcinogenic, and persistent contaminant. This work studied anaerobic benzene-degrading, nitrate-reducing enrichment cultures that were previously cultivated for over twenty years. Amplicon sequencing of nitratereducing cultures amended with benzene and benzene degradation intermediates provided evidence for a process by which Peptococcaceae is responsible for initial substitution of the benzene ring, followed by further degradation by Azoarcus. A qPCR study found an increase in copy number of Peptococcaceae and the abcA subunit of a putative anaerobic benzene carboxylase (Abc) associated with Peptococcaceae was correlated with benzene degradation. Further study of an Azoarcus-enrichment culture found that it was capable of degrading the BTEX compounds, but only under limited conditions. Finally, a metagenome was assembled for the benzene-degrading, nitrate-reducing culture. Annotation of metatranscriptome data to this metagenome provided further evidence for carboxylation of the benzene ring by Peptococcaceae.
Targeting mitochondrial biogenesis for promoting health

Summary Mitochondrial biogenesis is a key physiological process that is required for normal growth and development and for maintenance of ongoing cellular energy requirements during aging. Of equivalent and/or greater importance is the regulated enhancement of mitochondrial biogenesis upon physiological demand coupled to multiple cellular insults. Basically, cellular survival mechanisms following a variety of disease-related pathophysiological insults are entrained by convergent mechanisms designed to regain homeostatic control of mitochondrial biogenesis. Recent molecular studies represent a clearly defined approach to maximize normative cellular expression of mitochondrial biogenesis for maintenance of cellular energy requirements and as an anti-aging strategy in healthy human populations. This report focuses on mitochondrial transcription factor A, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PINK1 and Parkin. Designing agents to target mitochondrial function represents a compelling therapeutic strategy for enhancement of cellular expression of mitochondrial biogenesis in diverse human populations afflicted with metabolic, degenerative, neurodegenerative, and metastatic diseases.
Combined use of ionophore and virginiamycin for finishing Nellore steers fed high concentrate diets

Zebu cattle fed high concentrate diets may present inconsistent performance due to the occurrence of metabolic disorders, like acidosis. The isolated use of ionophores and virginiamycin in high grain diets can improve animal performance and reduce the incidence of such disorders, but recent studies suggested that their combination may have an additive effect. Thus, 72 Nellore steers, 389 ± 15 kg initial body weight (BW), were confined and fed for 79 days to evaluate the combination of virginiamycin and salinomycin on performance and carcass traits. Animals were allocated to a randomized complete block design by BW, in a 2 × 2 factorial arrangement of treatments, with two concentrate levels (73 and 91 %) and two virginiamycin levels (0 and 15 mg kg-1), and salinomycin (13 mg kg-1) included in all diets. The interaction was not significant (p > 0.05). Dry matter intake (DMI), average daily gain (ADG), gain-to-feed ratio (G:F), starch consumed, and fecal starch content were higher (p 0.05) between treatments. Starch consumed and estimated dietary net energy for maintenance (NEm) and gain (NEg) were higher (p < 0.05) for virginiamycin-treated animals, with no substantial effects on carcass traits. The inclusion of virginiamycin in finishing diets containing salinomycin reduced DMI while maintaining ADG and improving NEm and NEg, suggesting an additive effect of virginiamycin and ionophores, but without affecting carcass quality.
Capacity Building Challenges of Municipal Councillors in the Mangaung Metropolitan Municipality in the Free State Province

Through the introduction of the relatively new council structures for metropolitan municipalities in South Africa, and the new mandate for municipalities, the traditional role of councillors has broadened to encompass additional responsibilities and functions. Therefore, municipal councillors (proportional public representative (PR) councillors) require specific competencies and skills in order to ensure the effective operation of their local municipality. The efficacy of municipal councillors in respect of service delivery is increasingly being questioned in the wake of recent service delivery protests and negative reporting on the state of the local government sphere. The current state of affairs relating to municipal councillors raises numerous questions about the required skills and capacity building challenges to successfully execute their mandate. The aim of this article is to further investigate by means of an interview schedule the training and capacity building challenges of municipal councillors in the Mangaung Metropolitan Municipality in the Free State Province. A qualitative research methodology is adopted for the realisation of the above aim. An interview schedule was utilised as a tool that contains the predetermined questions prepared in order to acquire the insight, knowledge and application of the persons involved and familiar with Capacity Building Challenges of Municipal Councillors in the Mangaung Metropolitan Municipality in the Free State Province
Ambulatory Continuous Peripheral Nerve Blocks in Children and Adolescents: A Longitudinal 8-Year Single Center Study

BACKGROUND:Although the role of regional anesthesia in pediatric patients has been increasing over the last few years, there are only a few small case series that describe the use of ambulatory continuous peripheral nerve blocks (CPNBs) in this patient population. In this report, we describe our experience with the use of ambulatory CPNBs in 1285 children. METHODS:Data were collected for consecutive children who had a CPNB placed between January 2005 and December 2011 at The Children’s Hospital of Philadelphia from the departmental regional anesthesia database. Data collected included demographics, the site of catheter placement and technique of nerve block, presence of sensory/motor blockade, use of perioperative opioids, and any complications related to CPNBs. RESULTS:Continuous infusions of local anesthetics were administered via the catheters in 1285 outpatients. The mean duration of the CPNB was 50.7 ± 14.4 hours (mean ± SD). Among patients discharged home with the CPNBs, 969 (75.4%) of the patients required either no supplemental opioids or oral opioids only on an “as needed” basis in the postoperative period (confidence interval, 73.0%–77.8%). Two patients were readmitted for IV pain management after they were discharged home with the CPNB catheters. No neurological deficit related to the CPNBs was identified in any of the patients at their 6-month follow-up with the orthopedic surgeon (confidence interval, 0%–0.29%). CONCLUSION:This audit of 1285 children shows ambulatory CPNBs can provide postoperative analgesia and may reduce the need for inpatient parenteral opioid therapy.
Inhibition of Lymphocyte Blastogenesis by Factor(s) in Alloxan-diabetic Rat Plasma

Supplementation of rat lymphocyte cultures with plasma from alloxan-diabetic rats produced a dose-dependent suppression of mitogen-induced blastogenic responses. Viability measurements indicated that this inhibition was not due to a direct cytotoxic effect of alloxan-diabetic plasma on rat mononuclear leukocytes in vitro. This inhibition was not explained by hyperglycemia alone and was observed when blastogenesis was induced in vitro by phytohemagglutinin (PHA), concanavalin A (con A), or allogeneic cells. Peripheral blood lymphocytes from alloxan-diabetic rats appeared to be more sensitive than normal cells to the inhibitory effect of diabetic plasma. Heating at 56° for 60 minutes produced only a partial loss of the inhibition by diabetic plasma. Alloxan-diabetic rat plasma promoted an increased accumulation of adenosine 3′,5′-monophosphate (cyclic AMP) in mononuclear leukocytes. Insulin (1 and 100 μU./ml.) in vitro enhanced PHA-induced blastogenesis but failed to reverse the inhibition caused by diabetic plasma. Ultrafiltration through a cellulose dialysis membrane with an exclusion size of 12,000 molecular weight did not remove the inhibitory factor(s). These results indicate that a depressed cellular immune response is produced during an insulin-deficient diabetic state. The suppressed in-vitro blastogenic response of lymphocytes from alloxan-diabetic rats appears to involve some circulating inhibitory factor(s) in diabetic plasma. This inhibition may be explained, in part, by the ability of diabetic plasma to elevate cyclic AMP in mononuclear leukocytes.
Evolving Self-Assembly in Autonomous Homogeneous Robots: Experiments with Two Physical Robots

This research work illustrates an approach to the design of controllers for self-assembling robots in which the self-assembly is initiated and regulated by perceptual cues that are brought forth by the physical robots through their dynamical interactions. More specifically, we present a homogeneous control system that can achieve assembly between two modules (two fully autonomous robots) of a mobile self-reconfigurable system without a priori introduced behavioral or morphological heterogeneities. The controllers are dynamic neural networks evolved in simulation that directly control all the actuators of the two robots. The neurocontrollers cause the dynamic specialization of the robots by allocating roles between them based solely on their interaction. We show that the best evolved controller proves to be successful when tested on a real hardware platform, the swarm-bot. The performance achieved is similar to the one achieved by existing modular or behavior-based approaches, also due to the effect of an emergent recovery mechanism that was neither explicitly rewarded by the fitness function, nor observed during the evolutionary simulation. Our results suggest that direct access to the orientations or intentions of the other agents is not a necessary condition for robot coordination: Our robots coordinate without direct or explicit communication, contrary to what is assumed by most research works in collective robotics. This work also contributes to strengthening the evidence that evolutionary robotics is a design methodology that can tackle real-world tasks demanding fine sensory-motor coordination.
The granzyme B inhibitor, PI-9, is present in endothelial and mesothelial cells, suggesting that it protects bystander cells during immune responses.

Proteinase inhibitor 9 (PI-9) is a 42-kDa human intracellular serpin present in cytotoxic lymphocytes (CLs). PI-9 is an extremely efficient inhibitor of the pro-apoptotic CL granule proteinase granzyme B and is thought to function in the cytosol of CLs to protect against apoptosis induced by endogenously expressed or released granzyme B, particularly during target cell killing. Here we show by immunohistochemistry that PI-9 is also present in endothelial cells, in every tissue examined. Cultured endothelial cells express functional PI-9 (as assessed by binding to recombinant granzyme B) localized to the cytoplasm and nucleus. Immunohistochemistry also showed PI-9 in mesothelial cells, and this was confirmed by analysis of primary cells cultured from pleural and serous effusions. Granzyme B expression was not detected in either endothelial or mesothelial cells. In both cell types, PI-9 is up-regulated at the mRNA and protein level by exposure to the phorbol ester PMA, consistent with a response to inflammatory stimuli. We postulate that PI-9 is present in these lining cell types to protect against misdirected, free granzyme B released during a local immune response.
Decoding P4-ATPase substrate interactions

Abstract Cellular membranes display a diversity of functions that are conferred by the unique composition and organization of their proteins and lipids. One important aspect of lipid organization is the asymmetric distribution of phospholipids (PLs) across the plasma membrane. The unequal distribution of key PLs between the cytofacial and exofacial leaflets of the bilayer creates physical surface tension that can be used to bend the membrane; and like Ca2+, a chemical gradient that can be used to transduce biochemical signals. PL flippases in the type IV P-type ATPase (P4-ATPase) family are the principle transporters used to set and repair this PL gradient and the asymmetric organization of these membranes are encoded by the substrate specificity of these enzymes. Thus, understanding the mechanisms of P4-ATPase substrate specificity will help reveal their role in membrane organization and cell biology. Further, decoding the structural determinants of substrate specificity provides investigators the opportunity to mutationally tune this specificity to explore the role of particular PL substrates in P4-ATPase cellular functions. This work reviews the role of P4-ATPases in membrane biology, presents our current understanding of P4-ATPase substrate specificity, and discusses how these fundamental aspects of P4-ATPase enzymology may be used to enhance our knowledge of cellular membrane biology.
Tripartite Motif-Containing Protein 38 Negatively Regulates TLR3/4- and RIG-I–Mediated IFN-β Production and Antiviral Response by Targeting NAP1

Recognition of RNA virus through TLR and RIG-I–like receptor results in rapid expression of type I IFNs, which play an essential role in host antiviral responses. However, the mechanisms to terminate the production of type I IFNs are not well defined. In the current study, we identified a member of the tripartite motif (TRIM) family, TRIM38, as a negative regulator in TLR3/4- and RIG-I–mediated IFN-β signaling. Knockdown of TRIM38 expression by small interfering RNA resulted in augmented activation of IFN regulatory factor 3 and enhanced expression of IFN-β, whereas overexpression of TRIM38 had opposite effects. Coimmunoprecipitation and colocalization experiments demonstrated that TRIM38 interacted with NF-κB–activating kinase-associated protein 1 (NAP1), which is required for TLR-induced IFN regulatory factor 3 activation and IFN-β production. As an E3 ligase, TRIM38 promoted K48-linked polyubiquitination and proteasomal degradation of NAP1. Thus, knockdown of TRIM38 expression resulted in higher protein level of NAP1 in primary macrophages. Consistent with the inhibitory roles in TLR3/4- and RIG-I–mediated IFN-β signaling, knockdown of TRIM38 significantly inhibited the replication of vesicular stomatitis virus. Overexpression of TRIM38 resulted in enhanced replication of vesicular stomatitis virus. Therefore, our results demonstrate that TRIM38 is a negative regulator for TLR and RIG-I–mediated IFN-β production by targeting NAP1 for ubiquitination and subsequent proteasome-mediated degradation.
Preparing Future Leaders: An Integrated Quality Improvement Residency Curriculum.

BACKGROUND AND OBJECTIVES The Accreditation Council for Graduate Medical Education (ACGME) has recognized the importance of quality improvement (QI) training and requires that accredited residencies in all specialties demonstrate that residents are "integrated and actively participate in interdisciplinary clinical quality improvement and patient safety activities. " However, competing demands in residency training may make this difficult to accomplish. The study's objective is to develop and evaluate a longitudinal curriculum that meets the ACGME requirement for QI and patient safety training and links to patient-centered medical home (PCMH) practices. METHODS Residents in the Worcester Family Medicine Residency (WFMR) participated in a faculty-developed quality improvement curriculum that included web-based tutorials, quality improvement projects, and small-group sessions across all 3 years of residency. They completed self-evaluations of knowledge and use of curricular activities annually and at graduation, and comparisons were made between two graduating classes, as well as comparison of end of PGY2 to end of PGY3 for one class. RESULTS Graduating residents who completed the full 3 years of the curriculum rated themselves as significantly more skilled in nine of 15 areas assessed at end of residency compared to after PGY2 and reported confidence in providing future leadership in a focus group. Five areas were also rated significantly higher than prior-year residents. CONCLUSIONS Involving family medicine residents in a longitudinal curriculum with hands-on practice in implementing QI, patient safety, and chronic illness management activities that are inclusive of PCMH goals increased their self-perceived skills and leadership ability to implement these new and emerging evidence-based practices in primary care.