Miracle-dz/UniFAR-FTUs huggingface dataset:
One aptamer, two functions: the full-length aptamer inhibits AMPA receptors, while the short one inhibits both AMPA and kainate receptors

AMPA and kainate receptors, along with NMDA receptors, are distinct subtypes of glutamate ion channels. Excessive activity of AMPA and kainate receptors has been implicated in neurological diseases, such as epilepsy and neuropathic pain. Antagonists that block their activities are therefore potential drug candidates. In a recent article in the Journal of Biological Chemistry by Jaremko et al. 2017, we have reported on the discovery and molecular characterization of an RNA aptamer of a dual functionality: the full-length RNA (101 nucleotide) inhibits AMPA receptors while the truncated or the short (55 nucleotide) RNA inhibits both the AMPA and kainate receptors. The full-length RNA aptamer was isolated through a specially designed, systematic evolution of ligands by exponential enrichment (SELEX) using only a single type of AMPA receptors expressed in HEK-293 cells. The design feature and the results of our recent article are highlighted here, as they demonstrate the utility of the SELEX approach and the potential of using a single AMPA receptor type to develop potent, novel RNA aptamers targeting multiple subunits and AMPA/kainate receptor subtypes with length-dependent functionalities.
On the Optimal Set of Elementary Siphons in Petri Nets for Deadlock Control in FMS

Petri nets has been proved to be a tool with strong abilities to describe discrete dynamic event systems (DEDS) such as flexible manufacturing systems (FMS) for their excellent properties over most of other tools. Siphons arising in Petri nets can be used to illustrate, analyze and control deadlock phenomena in FMS. Due to the deficiency of siphons, which is well known, elementary siphons come to be an important concept in Petri net theory, which is of great significance in designing structurally simple supervisors for plant net models. Our previous work has demonstrated that different sets of elementary siphons may lead to different effects in terms of the reachable states or the behaviors of controlled net systems, and the one leads to the maximal number of reachable states is denoted as an optimal set of elementary siphons. In this paper, algorithms to generate the optimal set of elementary siphons with high computational efficiency are well discussed and developed. Experimental results show that the optimal set of elementary siphons may produce more permissive behaviors in the controlled net system when the same deadlock control policies are applied
A His19 to Ala mutant of melanoma growth-stimulating activity is a partial antagonist of the CXCR2 receptor.

Melanoma growth stimulating activity (MGSA) and IL-8 are related chemokines that are potent chemoattractants and activators of neutrophils both in vitro and in vivo. Increasing evidence suggests that these molecules play an important role in inflammation; thus, antagonists of their action could be useful therapeutically as antiinflammatory agents. We have generated an MGSA mutant, H19A, that shows a dissociation between receptor binding and biologic activity. The biologic activity of the H19A mutant is between 133-fold and 282-fold less potent than that of wild-type MGSA measured by three independent assays of neutrophil function, i.e., elastase release chemotaxis and the up-regulation of CD18. In addition, pretreatment of cells with the H19A mutant inhibited the ability of MGSA to induce elastase release and chemotaxis and to increase intracellular calcium. However, competition binding studies in cells transfected with the CXCR2 receptor and in neutrophils demonstrate that the receptor affinity of the H19A mutant is only 13-fold less than that of wild-type MGSA. These studies suggest that the mutant MGSA is defective in activating signaling through the receptor and indicate that binding to the receptor is not sufficient to activate a biologic response. The dissociation between receptor binding and activation for this mutant suggests that it should be possible to design antagonists of MGSA that may be of clinical utility.
Presence of IL-17 in synovial fluid identifies a potential inflammatory osteoarthritic phenotype

Purpose Osteoarthritis (OA) is a common and heterogeneous arthritic disorder. Patients suffer pain and their joints are characterized by articular cartilage loss and osteophyte formation. Risk factors for OA include age and obesity with inflammation identified as a key mediator of disease pathogenesis. Interleukin-17A (IL-17) is a pro-inflammatory cytokine that has been implicated in inflammatory diseases such as rheumatoid arthritis. IL-17 can upregulate expression of inflammatory cytokines and adipocytokines. The aim of this study was to evaluate IL-17 levels in the synovial fluid of patients with end-stage knee and hip OA in relation to inflammation- and pain-related cytokines and adipocytokines in synovial fluid and serum, and clinical and radiographic disease parameters. Methods This is a cross-sectional study of 152 patients undergoing total hip and knee arthroplasty for OA. IL-17, IL-6, leptin, adiponectin, visfatin, resistin, C-C Motif Chemokine Ligand 2 (CCL2), C-C Motif Chemokine Ligand 7 (CCL7) and nerve growth factor (NGF) protein levels were measured in synovial fluid and serum using enzyme-linked immunosorbent assay (ELISA). Baseline characteristics included age, sex, body mass index, co-morbidities, pain and function, and radiographic analyses (OA features, K&L grade, minimal joint space width). Results 14 patients (9.2%) had detectable IL-17 in synovial fluid. These patients had significantly higher median concentrations of IL-6, leptin, resistin, CCL7 and NGF. Osteophytes, sclerosis and minimum joint space width were significantly reduced in patients with detectable IL-17 in synovial fluid. No differences were found in pain, function and comorbidities. IL-17 concentrations in synovial fluid and serum were moderately correlated (r = 0.482). Conclusion The presence of IL-17 in the synovial fluid therefore identifies a substantial subset of primary end-stage OA patients with distinct biological and clinical features. Stratification of patients on the basis of IL-17 may identify those responsive to therapeutic targeting.
Comparison of DSM-IV symptoms in elementary school-age children with PDD versus clinic and community samples

This study compares DSM-IV symptoms in children (ages 6 to 12 years) with pervasive developmental disorder (PDD), clinic controls, and community-based samples. Parents/teachers completed the Child Symptom Inventory–4 for four samples: PDD (N= 284/284) and non-PDD psychiatric clinic referrals (N= 189/181) and pupils in regular (N= 385/404) and special (N= 61/60) education classes. The PDD group received higher symptom severity ratings than the regular education group, but was similar to the non-PDD clinic sample. Screening prevalence rates were highest for ADHD, ODD, and generalized anxiety disorder. PDD subtypes exhibited differentially higher rates of psychiatric symptoms. The magnitude of rater and gender differences in symptom severity ratings was modest. Clinic-referred children with PDD exhibit a pattern of psychiatric symptoms highly similar to nonPDD clinic referrals. Although much additional research is needed on comorbidity, these symptoms have important treatment implications.
Clinical Implications of Antipsychotic-Induced Hyperprolactinemia in Patients With Schizophrenia Spectrum or Bipolar Spectrum Disorders: Recent Developments and Current Perspectives

Hyperprolactinemia is increasingly studied as a frequent and potentially important consequence of antipsychotic medication treatment. Some individuals presenting with hyperprolactinemia remain asymptomatic, but others may exhibit a wide range of clinical symptoms resulting from either the direct effects of prolactin on body tissues (galactorrhea, gynecomastia) or endocrine-related secondary effects (sexual and reproductive dysfunction in the short term, and possibly the risk of tumorigenesis and osteoporosis in the longer term). Short-term side effects may negatively impact medication compliance, and long-term effects have the potential for serious health consequences. Antipsychotic medications have differing propensities to cause prolactin elevation. The first-generation antipsychotics, as well as the second-generation antipsychotic risperidone and its active metabolite paliperidone, have been shown to cause marked and sustained elevations in prolactin levels, whereas others of the second-generation antipsychotics appear to have little or no effect on prolactin levels or may decrease prolactin. A comprehensive overview of antipsychotics and hyperprolactinemia is presented together with a review of emerging evidence about the short- and long-term health risks of hyperprolactinemia.
A randomized non-pharmacological intervention study for prevention of ischaemic heart disease: baseline results Inter99 (1)

Background Various strategies have been used to induce lifestyle changes to reduce ischaemic heart disease (IHD) with various successes. The aim of Inter99 is to assess the effect on IHD incidence of individually tailored non-pharmacological intervention on lifestyle using a newly developed computer-based health educational tool. The article describes the study and baseline results. Methods From a population of 61,301 individuals two random samples (high intensity intervention group (A), n = 11,708; low intensity intervention group (B), n = 1308) are screened to assess their absolute risk of IHD. Those at high risk receive individual lifestyle counselling. Individuals in group A are furthermore offered lifestyle counselling in groups on smoking cessation or physical activity/diet over a 6-month period. Individuals in group B are referred to their GP. High-risk persons are re-counselled after 1 and 3 years and the whole group is re-invited after 5 years. The remaining 48,285 (group C) are followed by questionnaire. The total population is followed through central registers. Intermediate end-points are changes in lifestyle, cholesterol, blood pressure and body mass index. Final end-point is reduction in incidence of IHD. Results The randomization leads to comparable groups. Participation rate was 52.5%. A total of 60% fulfilled the predetermined criteria for being at high risk for developing IHD. After an individual lifestyle counselling 41% accepted group-based counselling. Conclusion This large randomized population based trial discloses a noticeable need for and acceptance of lifestyle intervention in the general population. Eur J Cardiovasc Prevention Rehab 10:377-386 © 2003 Lippincott Williams & Wilkins.
Solving Problems with Extended Reachability Goals through Reinforcement Learning on Propositionally Constrained State Spaces

Finding a near-optimal action policy towards a goal state can be a complex task for intelligent autonomous agents, especially in a model-free environment with unknown rewards and under state space constraints. In such a situation, it is not possible to plan ahead which is the best action to execute at each moment, and to discover the states that can be visited during the plan execution requires foreknowing the conditions to be preserved for each environment state. We present here a new approach to discover the action policy for an environment under propositional constraints on states in MDP problems. The constraints are used by a strong probabilistic planning algorithm to reduce a state space whose transition probabilities are estimated by an action-learning reinforcement learning algorithm, thus simplifying the agent's state space exploration and helping in the definition of the planning problem. The execution constraints, or preservation goals, comprised within the representation of the final goal, composes the extended reach ability goals. Experiments to validate the proposal were performed on an antenna coverage problem and produced interesting and promising results, demonstrating fast convergence to condition-preserving near-optimal policies that keep valid a set of propositions while reaching a final goal.
A New Population of Human Adult Dental Pulp Stem Cells: A Useful Source of Living Autologous Fibrous Bone Tissue (LAB)

Stem cells, derived from human adult dental pulp of healthy subjects 30‐45 years of age, were cultured, and cells were selected using a FACSorter. A new c‐kit+/CD34+/CD45− cell population of stromal bone producing cells (SBP/DPSCs) was selected, expanded, and cultured. These SBP/DPSCs are highly clonogenic and, in culture, differentiate into osteoblast precursors (CD44+/RUNX‐2+), still capable of self‐renewing, and then in osteoblasts, producing, in vitro, a living autologous fibrous bone (LAB) tissue, which is markedly positive for several bone antibodies. This tissue constitute an ideal source of osteoblasts and mineralized tissue for bone regeneration. In fact, after in vivo transplantation into immunocompromised rats, LAB formed lamellar bone‐containing osteocytes.
Parent Perceptions of How Nurse Encounters Can Provide Caring Support for the Family in Early Acute Care After Children’s Severe Traumatic Brain Injury

ABSTRACT: Objective: A child’s severe traumatic brain injury (TBI) creates a family crisis requiring extensive cultural, informational, psychological, and environmental support. Nurses need to understand parents’ expectations of caring in early acute care so they can tailor their attitudes, beliefs, and behaviors appropriately to accommodate the family’s needs. Methods: In a previous qualitative study of 42 parents or caregivers from 37 families of children with moderate-to-severe TBI, parents of children with severe TBI (n = 25) described their appraisals of nurse caring and uncaring behaviors in early acute care. Swanson’s theory of caring was used to categorize parents’ descriptions to inform nursing early acute care practices and family-centered care. Results: Caring nurse encounters included (a) involving parents in the care of their child and reflecting on all sociocultural factors shaping family resources and responses (knowing); (b) respecting that family grief can be co-mingled with resilience and that parents are typically competent to be involved in decision making (maintaining belief); (d) actively listening and engaging parents to fully understand family values and needs (being with); (e) decreasing parents’ workload to get information and emotional support and provide a safe cultural, psychological, and physical environment for the family (doing for); and (f) providing anticipatory guidance to navigate the early acute care system and giving assistance to learn and adjust to their situation (enabling). Conclusion: Application of Swanson’s caring theory is prescriptive in helping individual nurses and early acute care systems to meet important family needs after children’s severe TBI.
General Dynamic Model for Skid-Steer Mobile Manipulators With Wheel–Ground Interactions

The design of motion controllers that could reduce terrain disturbances propagated to the arm and optimize the trajectories of skid-steer mobile manipulators (SSMMs) working in agricultural, construction, or mining environments requires accurate physical models capable of correctly representing disturbances caused by changes in terrain slope, loss of traction, and other wheel-ground interactions. Therefore, this paper develops the forward dynamics equations of motion and proposes a general model for SSMMs. The novelty of the model is that it considers a floating-base with nonpermanent wheel-ground contacts, i.e., the mobile base has 6-degree of freedom (DOF) and the wheels may lose contact with the terrain. Unlike the existing models, the proposed one is general because the procedure can be extended to MMs with an arbitrary number of arms or wheels and does not restrict the mobile base to planar 2-D motions. Furthermore, it takes into account the loss of traction and the deformation of the wheel–ground contacts. The experimental results involving a small SSMM with a 3-DOF arm and an industrial skid-steer loader validate the physical fidelity of the model. Although the focus of this paper is not in control aspects, one of the examples shows the role physically accurate models can have in the design of end-effector motion controllers, and its potential application to the design of controllers capable of decoupling the arm motion from ground disturbances.
Prion-like activity of Cu/Zn superoxide dismutase

Neurodegenerative diseases belong to a larger group of protein misfolding disorders, known as proteinopathies. There is increasing experimental evidence implicating prion-like mechanisms in many common neurodegenerative disorders, including Alzheimer disease, Parkinson disease, the tauopathies, and amyotrophic lateral sclerosis (ALS), all of which feature the aberrant misfolding and aggregation of specific proteins. The prion paradigm provides a mechanism by which a mutant or wild-type protein can dominate pathogenesis through the initiation of self-propagating protein misfolding. ALS, a lethal disease characterized by progressive degeneration of motor neurons is understood as a classical proteinopathy; the disease is typified by the formation of inclusions consisting of aggregated protein within and around motor neurons that can contribute to neurotoxicity. It is well established that misfolded/oxidized SOD1 protein is highly toxic to motor neurons and plays a prominent role in the pathology of ALS. Recent work has identified propagated protein misfolding properties in both mutant and wild-type SOD1, which may provide the molecular basis for the clinically observed contiguous spread of the disease through the neuroaxis. In this review we examine the current state of knowledge regarding the prion-like properties of SOD1 and comment on its proposed mechanisms of intercellular transmission.
The B1 Subunit of the H+ATPase Is a PDZ Domain-binding Protein

The 56-kDa B1 subunit of the vacuolar H+ATPase has a C-terminal DTAL amino acid motif typical of PDZ-binding proteins that associate with the PDZ protein, NHE-RF (Na+/H+ exchanger regulatory factor). This B1 isoform is amplified in renal intercalated cells, which play a role in distal urinary acid-base transport. In contrast, proximal tubules express the B2 isoform that lacks the C-terminal PDZ-binding motif. Both the B1 56-kDa subunit and the 31-kDa (E) subunit of the H+ATPase are pulled down by glutathione S-transferase NHE-RF bound to GSH-Sepharose beads. These subunits associate in vivo as part of the cytoplasmic V1 portion of the H+ATPase, and the E subunit was co-immunoprecipitated from rat kidney cytosol with NHE-RF antibodies. The interaction of H+ATPase subunits with NHE-RF was inhibited by a peptide derived from the C terminus of the B1 but not the B2 isoform. NHE-RF colocalized with H+ATPase in either the apical or the basolateral region of B-type intercalated cells, whereas NHE-RF staining was undetectable in A-intercalated cells. In proximal tubules, NHE-RF was located in the apical brush border. In contrast, H+ATPase was concentrated in a distinct membrane domain at the base of the brush border, from which NHE-RF was absent, consistent with the expression of the truncated B2 subunit isoform in this tubule segment. The colocalization of NHE-RF and H+ATPase in B- but not A-intercalated cells suggests a role in generating, maintaining, or modulating the variable H+ATPase polarity that characterizes the B-cell phenotype.
Reforma szkolnictwa wyższego w Niemczech: akademickie przedsiębiorstwo w budowie

The latest developments of the higher education reform in Germany are analyzed in this paper. For this purpose, some historical milestones are described before presenting a brief historical outline the implementation of the Bologna model from 1999 to 2010. Some difficulties and challenges for implementing the Bologna model are placed at the financial and at the political level. They are related both with the organization and governance of higher education and with the differentiation of the system. Another set of controversial issues concerns the very meaning of higher education in a country with a Iow fertility rate and a severe shortage of highly qualified manpower. Is today and tomorrow’s higher education supposed to be a highly structured and more intellectual form of vocational education, or can the traditional, Humboldtian way of conceiving higher education (search for knowledge for its own sake) be compatible with the Bologna model? These questions are examined critically in the paper.
Long-term renal consequences of hypertension for normal and diseased kidneys

Substantial evidence indicates that the adverse effects of hypertension on the kidney depend on the degree to which systemic blood pressure elevations are transmitted to the renal microvasculature. Such blood pressure transmission and consequent susceptibility to hypertensive renal damage is markedly exacerbated in states characterized by preglomerular vasodilation and an impairment of the normally protective renal autoregulatory mechanisms, e.g. diabetes or chronic renal disease. Moreover, this pathophysiology gives rise to the prediction that prevention of hypertension-induced barotrauma will require blood pressure to be reduced well into the normotensive range in such patients, as is being recognized in the currently recommended blood pressure goals. Agents that block the renin-angiotensin system should be preferred as initial therapy as they may provide additional risk reductions and minimize the potassium and magnesium depletion associated with the diuretic use usually necessary to achieve the lower blood pressure targets. The current failure to achieve optimal blood pressure reductions may be contributing not only to the still escalating incidence of end-stage renal disease in diabetic patients, but also to their greatly increased cardiovascular morbidity and mortality.
Activation of the Programmed Cell Death Pathway by Inhibition of Proteasome Function in Plants*

Proteasomes constitute the major machinery to degrade or process proteins by ATP/ubiquitin-mediated proteolysis. Recent findings suggest a pivotal role of the ubiquitin/proteasome pathway in the regulation of apoptosis in animal cells. Here we show that virus-induced gene silencing of two different subunits of the 26 S proteasome, the α6 subunit of the 20 S proteasome and RPN9 subunit of 19 S regulatory complex, both activated the programmed cell death (PCD) program, accompanied by reduced proteasome activity and accumulation of polyubiquitinated proteins. These results demonstrate that disruption of proteasome function leads to PCD in plant cells. The affected cells showed morphological markers of PCD, including nuclear condensation and DNA fragmentation, accompanied by the 10-fold higher production of reactive oxygen species and increased ion leakage for 3-fold. Similar to apoptosis in animal system, mitochondrial membrane potential was decreased, cytochrome c released from mitochondria to cytosol, and caspase 9- and caspase 3-like proteolytic activities detected in the cells. Interestingly, this proteasome-mediated PCD stimulated the expression of only a subset of transcripts that are highly induced during pathogen-mediated hypersensitive response cell death, indicating that the two PCD pathways are differentially regulated. Taken together, these results provide the first direct evidence that proteasomes play a role in the regulatory program of PCD in plants. Controlled inhibition of proteasome activities may be involved in developmentally or environmentally activated plant cell death programs.