Miracle-dz/UniFAR-FTUs huggingface dataset:
Intracellular substrate cleavage: a novel dimension in the biochemistry, biology and pathology of matrix metalloproteinases

Matrix metalloproteinases (MMPs), originally discovered to function in the breakdown of extracellular matrix proteins, have gained the status of regulatory proteases in signaling events by liganding and processing hormones, cytokines, chemokines, adhesion molecules and other membrane receptors. However, MMPs also cleave intracellular substrates and have been demonstrated within cells in nuclear, mitochondrial, various vesicular and cytoplasmic compartments, including the cytoskeletal intracellular matrix. Unbiased high-throughput degradomics approaches have demonstrated that many intracellular proteins are cleaved by MMPs, including apoptotic regulators, signal transducers, molecular chaperones, cytoskeletal proteins, systemic autoantigens, enzymes in carbohydrate metabolism and protein biosynthesis, transcriptional and translational regulators, and proteins in charge of protein clearance such as lysosomal and ubiquitination enzymes. Besides proteolysis inside cells, intracellular proteins may also be modulated by MMPs in the extracellular milieu. Indeed, many intracellular proteins exit cells by non-classical secretion mechanisms or by various conditions of cell death by apoptosis, necrosis and NETosis, and become accessible to extracellular proteases. Intracellular substrate proteolysis by MMPs is involved in innate immune defense and apoptosis, and affects oncogenesis and pathology of cardiac, neurological, protein conformational and autoimmune diseases, including ischemia-reperfusion injury, cardiomyopathy, Parkinson’s disease, cataract, multiple sclerosis and systemic lupus erythematosus. Since the same MMP may affect physiology and pathology in different and even opposite ways, depending on its extracellular or subcellular localization, an additional layer of complexity is added to therapeutic MMP inhibition. Hence, further elucidation of intracellular MMP localizations and intracellular substrate proteolysis is a new challenge in MMP research.
Nuclear phosphoinositides and their roles in cell biology and disease

Since the late 1980s, a growing body of evidence has documented that phosphoinositides and their metabolizing enzymes, which regulate a large variety of cellular functions both in the cytoplasm and at the plasma membrane, are present also within the nucleus, where they are involved in processes such as cell proliferation, differentiation, and survival. Remarkably, nuclear phosphoinositide metabolism operates independently from that present elsewhere in the cell. Although nuclear phosphoinositides generate second messengers such as diacylglycerol and inositol 1,4,5 trisphosphate, it is becoming increasingly clear that they may act by themselves to influence chromatin structure, gene expression, DNA repair, and mRNA export. The understanding of the biological roles played by phosphoinositides is supported by the recent acquisitions demonstrating the presence in the nuclear compartment of several proteins harboring phosphoinositide-binding domains. Some of these proteins have functional roles in RNA splicing/processing and chromatin assembly. Moreover, recent evidence shows that nuclear phospholipase Cβ1 (a key phosphoinositide metabolizing enzyme) could somehow be involved in the myelodysplastic syndrome, i.e. a hematopoietic disorder that frequently evolves into an acute leukemia. This review aims to highlight the most significant and updated findings about phosphoinositide metabolism in the nucleus under both physiological and pathological conditions.
ADP1 affects abundance and endocytosis of PIN-FORMED proteins in Arabidopsis

Auxin, as a vital plant hormone, regulates almost every aspect of plant growth and development. We previously identified a dominant mutant, adp1-D, displaying loss of apical dominance. We also demonstrated that down-regulation of local auxin biosynthesis in adp1-D was responsible for the bushy phenotype of this mutant. Consistent with the reduction of local auxin biosynthesis, we recently discovered that protein abundance of PIN1, PIN3, and PIN7 was reduced in adp1-D without accompanying transcription level changes. Additionally, subcellular analysis revealed that over-expression of ADP1 inhibited endocytosis of PIN proteins. Taken together, we conclude that ADP1 regulates plant architecture through the fine-tuning of local auxin biosynthesis and through post-transcriptional regulation of auxin transporters.
Client Perception of Therapeutic Factors in Group Psychotherapy and Growth Groups: An Empirically-Based Hierarchical Model

Abstract To assess group participants’ perceptions of therapeutic factors, we developed an extensive questionnaire of 155 items that was administered to 489 members of 78 psychotherapy and growth groups of client–centered/experiential, psychoanalytic, behavioral, Gestalt and drama– and bodily oriented orientations. Using multivariate analyses we found a model that reveals the structure and connections of therapeutic factors as they are differentiated in the experience of the group members. Our model encompasses three hierarchical levels of abstraction: 28 Basic scales that appeared to be structured into seven main scales (Group Cohesion, Interactional Confirmation, Cathartic Self–Revelation, Self–Insight and Progress, Observational Experiences, Getting Directives, and Interactional Confrontation) and two dimensions (Relational Climate and Psychological Work). Validity for these therapeutic factors was found in their grounded content, statistically analyzed constructs, importance ratings, and correlations to intermediate outcome measures.
Functional O-GlcNAc modifications: Implications in molecular regulation and pathophysiology

Abstract O-linked β-N-acetylglucosamine (O-GlcNAc) is a regulatory post-translational modification of intracellular proteins. The dynamic and inducible cycling of the modification is governed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) in response to UDP-GlcNAc levels in the hexosamine biosynthetic pathway (HBP). Due to its reliance on glucose flux and substrate availability, a major focus in the field has been on how O-GlcNAc contributes to metabolic disease. For years this post-translational modification has been known to modify thousands of proteins implicated in various disorders, but direct functional connections have until recently remained elusive. New research is beginning to reveal the specific mechanisms through which O-GlcNAc influences cell dynamics and disease pathology including clear examples of O-GlcNAc modification at a specific site on a given protein altering its biological functions. The following review intends to focus primarily on studies in the last half decade linking O-GlcNAc modification of proteins with chromatin-directed gene regulation, developmental processes, and several metabolically related disorders including Alzheimer’s, heart disease and cancer. These studies illustrate the emerging importance of this post-translational modification in biological processes and multiple pathophysiologies.
Transcriptome-wide studies uncover the diversity of modes of mRNA recruitment to eukaryotic ribosomes

Abstract The conventional paradigm of translation initiation in eukaryotes states that the cap-binding protein complex eIF4F (consisting of eIF4E, eIF4G and eIF4A) plays a central role in the recruitment of capped mRNAs to ribosomes. However, a growing body of evidence indicates that this paradigm should be revised. This review summarizes the data which have been mostly accumulated in a post-genomic era owing to revolutionary techniques of transcriptome-wide analysis. Unexpectedly, these techniques have uncovered remarkable diversity in the recruitment of cellular mRNAs to eukaryotic ribosomes. These data enable a preliminary classification of mRNAs into several groups based on their requirement for particular components of eIF4F. They challenge the widely accepted concept which relates eIF4E-dependence to the extent of secondary structure in the 5′ untranslated regions of mRNAs. Moreover, some mRNA species presumably recruit ribosomes to their 5′ ends without the involvement of either the 5′ m7G-cap or eIF4F but instead utilize eIF4G or eIF4G-like auxiliary factors. The long-standing concept of internal ribosome entry site (IRES)-elements in cellular mRNAs is also discussed.
Defining the limits: Protein aggregation and toxicity in vivo

Abstract The proper folding of proteins to their functional forms is essential to cellular homeostasis. Perhaps not surprisingly, cells have evolved multiple pathways, some overlapping and others complementary, to resolve mis-folded proteins when they arise, ranging from refolding through the action of molecular chaperones to elimination through regulated proteolytic mechanisms. These protein quality control pathways are sufficient, under normal conditions, to maintain a functioning proteome, but in response to diverse environmental, genetic and/or stochastic events, protein mis-folding exceeds the corrective capacity of these pathways, leading to the accumulation of aggregates and ultimately toxicity. Particularly devastating examples of these effects include certain neurodegenerative diseases, such as Huntington’s Disease, which are associated with the expansion of polyglutamine tracks in proteins. In these cases, protein mis-folding and aggregation are clear contributors to pathogenesis, but uncovering the precise mechanistic links between the two events remains an area of active research. Studies in the yeast Saccharomyces cerevisiae and other model systems have uncovered previously unanticipated complexity in aggregation pathways, the contributions of protein quality control processes to them and the cellular perturbations that result from them. Together these studies suggest that aggregate interactions and localization, rather than their size, are the crucial considerations in understanding the molecular basis of toxicity.
Glitazones et insuffisance cardiaque : résultats des études PROactive, ADOPT, DREAM et RECORD

Les thiazolidinediones (TZD) sont des medicaments insulino-sensibilisateurs utilises dans le traitement du diabete de type 2, mais greves d'un risque accru d'insuffisance cardiaque congestive (ICC). Ainsi, l'odds ratio d'ICC a ete de 1,43 (pioglitazone vs placebo) chez des patients diabetiques a haut risque cardiovasculaire de l'etude PROactive, de 1,22 (rosiglitazone vs metformine) et 2,20 (rosiglitazone vs metformine) dans l'essai clinique ADOPT et de 2,15 (rosiglitazone vs metformine ou sulfamides) dans l'analyse intermediaire de l'etude RECORD. Dans quatre registres de surveillance en situation de vie reelle, le risque relatif d'ICC sous TZD varie de 1,06 a 1,76 (de 1,10 a 1,44 en combinaison avec l'insuline) par rapport a un traitement sans TZD. Ce risque accru d'ICC doit etre apprecie en fonction des benefices potentiels apportes par les glitazones.
Ubiquitin-dependent protein degradation at the yeast endoplasmic reticulum and nuclear envelope

Abstract The endoplasmic reticulum (ER) is the primary organelle in eukaryotic cells where membrane and secreted proteins are inserted into or across cell membranes. Its membrane bilayer and luminal compartments provide a favorable environment for the folding and assembly of thousands of newly synthesized proteins. However, protein folding is intrinsically error-prone, and various stress conditions can further increase levels of protein misfolding and damage, particularly in the ER, which can lead to cellular dysfunction and disease. The ubiquitin-proteasome system (UPS) is responsible for the selective destruction of a vast array of protein substrates, either for protein quality control or to allow rapid changes in the levels of specific regulatory proteins. In this review, we will focus on the components and mechanisms of ER-associated protein degradation (ERAD), an important branch of the UPS. ER membranes extend from subcortical regions of the cell to the nuclear envelope, with its continuous outer and inner membranes; the nuclear envelope is a specialized subdomain of the ER. ERAD presents additional challenges to the UPS beyond those faced with soluble substrates of the cytoplasm and nucleus. These include recognition of sugar modifications that occur in the ER, retrotranslocation of proteins across the membrane bilayer, and transfer of substrates from the ER extraction machinery to the proteasome. Here, we review characteristics of ERAD substrate degradation signals (degrons), mechanisms underlying substrate recognition and processing by the ERAD machinery, and ideas on the still unresolved problem of how substrate proteins are moved across and extracted from the ER membrane.
Whole Body Gait Function during Stair Ascending and Level Walking in Patients Following Total Knee Arthroplasty

The ability to climb stairs is a highly demanding task for the musculoskeletal system, and gait adaptations after total knee arthroplasty (TKA) might be more pronounced during stair climbing than during level walking. The purpose of this study was to compare full body kinematics and kinetics between patients with good functioning TKA and a healthy control group during stair ascending and level walking. Eighteen patients after TKA (67.8 ± 8.1 yrs) and 20 age-matched healthy controls (66.1 ± 6.4 yrs) participated in this study. Full body kinematic and kinetic data was collected during stair ascending and level walking. Patients after TKA showed differences in sagittal plane knee moments during both stair ascending and level walking compared to the controls. The hip of the patients was more externally rotated in both conditions (p<0.001), although there were no differences in the passive range of motion (p=0.630). The trunk angles only showed a few deviations between patients and controls. Differences between patients and controls were found more often during level walking than during stair ascending. The study shows that considering adjacent joints gives more additional information for treatment recommendations than the additional analysis of the trunk when comparing patients after TKA to healthy seniors. To reduce the higher knee flexion moment during stair ascending in patients, we recommend the strengthening of the calf muscles. It seems that stair ascending does not provide additional information to guide actual treatment recommendations compared to level walking alone.
Platelet derived growth factor (PDGF) contained in Platelet Rich Plasma (PRP) stimulates migration of osteoblasts by reorganizing actin cytoskeleton

Platelet-rich plasma (PRP) is a platelet concentrate in a small volume of plasma. It is highly enriched in growth factors able to stimulate the migration and growth of bone-forming cells. PRP is often used in clinical applications, as dental surgery and fracture healing. Platelet derived growth factor (PDGF), is highly concentrated in PRP and it was shown in our previous studies to provide the chemotactic stimulus to SaOS-2 osteoblasts to move in a microchemotaxis assay. Aim of the present studies is to analyze the effects of a PRP pretreatment (short time course: 30–150 min) of SaOS-2 cells with PRP on the organization of actin cytoskeleton, the main effector of cell mobility. The results indicate that a pretreatment with PRP increases chemokinesis and chemotaxis and concomitantly induces the organization of actin microfilaments, visualized by immunocytochemistry, in a directionally elongated phenotype, which is characteristic of the cells able to move. PRP also produces a transient increase in the expression of PGDF α receptor. This reorganization is blocked by the immunoneutralization of PDGF demonstrating the responsibility of this growth factor in triggering the mechanisms responsible for cellular movements.
Kir4.1-mediated spatial buffering of K+: Experimental challenges in determination of its temporal and quantitative contribution to K+ clearance in the brain

Neuronal activity results in release of K+ into the extracellular space of the central nervous system. If the excess K+ is allowed to accumulate, neuronal firing will be compromised by the ensuing neuronal membrane depolarization. The surrounding glial cells are involved in clearing K+ from the extracellular space by molecular mechanism(s), the identity of which have been a matter of controversy for over half a century. Kir4.1-mediated spatial buffering of K+ has been promoted as a major contributor to K+ removal although its quantitative and temporal contribution has remained undefined. We discuss the biophysical and experimental challenges regarding determination of the contribution of Kir4.1 to extracellular K+ management during neuronal activity. It is concluded that 1) the geometry of the experimental preparation is crucial for detection of Kir4.1-mediated spatial buffering and 2) Kir4.1 enacts spatial buffering of K+ during but not after neuronal activity.
Process Groups

Abstract A Process Group is a group that studies its own behavior to enable its members to learn about group dynamics, individual dynamics, and interpersonal communications. (Swiller, Lang, & Halperin, 1993) Not only is social life identical with communication, but all communication (and hence all genuine social life) is educative. To be a recipient of a communication is to have an enlarged and changed experience. (Dewey, 1916)
Intervención para reducir riesgo en conductas sexuales de adolescentes: un ensayo aleatorizado y controlado

Objective. To test the efficacy of a behavioral intervention designed to decrease risk sexual behaviors for HIV/AIDS and unplanned pregnancies in Mexican adolescents. Material and Methods. Randomized controlled trial with four follow ups; 832 adolescents recruited from high schools, age 14-17, were randomly assigned to the experimental or control group. The six hour intervention used active learning strategies, and was delivered in two sessions on two consecutive Saturdays. The study was carried out in Monterrey, Mexico, 2002-2005. Results. GEE analysis indicated no differences in sexual relationships’ intentions between the two conditions, however, the experimental group had higher intentions to use condoms and contraceptives (mean differences 0.15 and 0.16, CI 95%) in the next three months, as compared with the control group. Theoretical variables, such as control beliefs, were significant mediators of the intervention. Conclusions. The behavioral intervention represents an important effort in promoting safe sexual behaviors among Mexican adolescents.
A randomized phase I clinical and biologic study of two schedules of sorafenib in patients with myelodysplastic syndrome or acute myeloid leukemia: a NCIC (National Cancer Institute of Canada) Clinical Trials Group Study

Sorafenib is a small molecule inhibitor of RAF kinase, VEGFR-2, c-KIT, and FLT3. In this randomized phase I study, eligible patients had relapsed/refractory acute myeloid leukemia (AML), and one prior induction regimen, or were age >65 with untreated myelodysplastic syndrome (MDS) or secondary AML. Sorafenib was given orally for 28 days (cont) or 14 days (int) every 4 weeks at three dose levels (100, 200, and 400 mg BID); 300 mg cont was also tested. Forty-two patients were enrolled (median age 71 [37–82]; prior chemotherapy: 22). Dose-limiting toxicity (DLT) was: 100 mg BID: 0/7 patients; 200 mg BID: 2/12 patients; 400 mg BID: 1/17 patients. Sorafenib 400 mg cont was not tolerated in this population: 6/8 received <14 days of treatment due to toxicity; no DLT was seen with 300 mg cont. One CR was seen in a patient with AML with FLT3-ITD. Flow cytometry studies suggest that sorafenib inhibits ERK phosphorylation via c-KIT. The recommended phase II dose in AML is 300 mg BID continuously, and testing in combination and in FLT3-ITD AML is warranted.
Surgical site infections: Assessing risk factors, outcomes and antimicrobial sensitivity patterns

A prospective study was carried out on 1125 surgeries for the incidence of surgical site infections (SSIs). The etiologic agent was isolated, identified and the antibiotic susceptibility pattern was determined using standard methods. The risk associated with SSIs was assessed by multivariate regression logistic analysis. A case-control study was carried out for the outcome of SSIs. The outcomes measured were: length of intensive care unit (ICU) stay (in days), length of ward stay (in days), costs incurred (in rupees) by the patient, and mortality rate. The results indicated that 12% of patients undergoing surgery developed SSI. Staphylococcus aureus (33%) and Enterococcus spp. (33%) were the commonest etiologic agents. Patients with SSIs had a significantly extended ICU and ward stay (p<0.001), and incurred higher hospital costs (p<0.001) when compared to those who did not develop SSIs. The mortality rate was high in patients who developed SSIs. The risk factors associated with SSIs were age above 45 years (p=0.012), female (p=0.070), diabetic status (p<0.001) and surgeries such as gastrectomy, prostatectomy, hysterectomy, cholecystectomy and appendectomy. Surgical site wound infection, though preventable, still remains as high as 12%. Determining the antimicrobial patterns of the organisms causing SSIs will enable institutions to restrict the use of antimicrobials and take active measures in preventing the spread of drug resistance in a hospital.
Recent strategies and methods for improving insulin delivery

Subcutaneous insulin has been used to treat diabetes since the discovery of insulin itself. However, despite a number of different formulations and routes of administration, intensive insulin therapy without limitations, such as too low bioavailability, has not enjoyed widespread clinical acceptance. Attempts to find effective, well‐tolerated routes for delivering insulin began in the late 1920s and as of today, an ideal insulin delivery is still formidable. The most recent advances in insulin delivery are focused on using the inhalation route. The recent European filing of inhaled insulin (Exubera) is providing hope for alternative delivery routes, for example. This article reviews recent advances and approaches that hold promise toward the successful development of insulin delivery for the management of diabetes. Drug Dev. Res. 63:151–160, 2004. © 2004 Wiley‐Liss, Inc.
Gene expression profiles identify both MyD88-independent and MyD88-dependent pathways involved in the maturation of dendritic cells mediated by heparan sulfate: A novel adjuvant

The traditional vaccine adjuvant research is mainly based on the trial and error method, and the mechanisms underlying the immune system stimulation remaining largely unknown. We previously demonstrated that heparan sulfate (HS), a TLR-4 ligand and endogenous danger signal, effectively enhanced humoral and cellular immune responses in mice immunized by HBsAg. This study aimed to evaluate whether HS induces better humoral immune responses against inactivated Hepatitis A or Rabies Vaccines, respectively, compared with traditional adjuvants (e.g. Alum and complete Freund's adjuvant). In order to investigate the molecular mechanisms of its adjuvanticity, the gene expression pattern of peripheral blood monocytes derived DCs (dendritic cells) stimulated with HS was analyzed at different times points. Total RNA was hybridized to Agilent SurePrint G3 Human Gene Expression 8 × 60 K one-color oligo-microarray. Through intersection analysis of the microarray results, we found that the Toll-like receptor signaling pathway was significantly activated, and NF-kB, TRAF3 and IRF7 were activated as early as 12 h, and MyD88 was activated at 48 h post-stimulation. Furthermore, the expression of the surface marker CD83 and the co-stimulatory molecules CD80 and CD86 was up-regulated as early as 24 h. Therefore, we speculated that HS-induced human monocyte-derived DC maturation may occur through both MyD88-independent and dependent pathways, but primarily through the former (TRIF pathway). These data provide an important basis for understanding the mechanisms underlying HS enhancement of the immune response.