Miracle-dz/UniFAR-FTUs huggingface dataset:
Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance

Significance Inflammation is a critical contributor to the pathogenesis of metabolic disorders associated with obesity. A group of molecules crucial in regulating the immune system are costimulatory molecules, including CD40. Our current study shows that CD40 acts as a double-edged sword in the metabolic syndrome through the initiation of differential signaling cascades. The CD40-TNF receptor-associated factor (TRAF) 2/3/5 signaling pathway protects against metabolic dysfunction and inflammation associated with obesity; conversely, the CD40-TRAF6 pathway contributes to the detrimental consequences of obesity. In the present study, we therefore designed, validated, and used a small-molecule inhibitor that blocks CD40-TRAF6 interactions. The improvement of insulin resistance by this specific CD40-TRAF6 inhibitor could represent a therapeutic breakthrough in the field of immunometabolism. The immune system plays an instrumental role in obesity and insulin resistance. Here, we unravel the role of the costimulatory molecule CD40 and its signaling intermediates, TNF receptor-associated factors (TRAFs), in diet-induced obesity (DIO). Although not exhibiting increased weight gain, male CD40−/− mice in DIO displayed worsened insulin resistance, compared with wild-type mice. This worsening was associated with excessive inflammation of adipose tissue (AT), characterized by increased accumulation of CD8+ T cells and M1 macrophages, and enhanced hepatosteatosis. Mice with deficient CD40-TRAF2/3/5 signaling in MHCII+ cells exhibited a similar phenotype in DIO as CD40−/− mice. In contrast, mice with deficient CD40-TRAF6 signaling in MHCII+ cells displayed no insulin resistance and showed a reduction in both AT inflammation and hepatosteatosis in DIO. To prove the therapeutic potential of inhibition of CD40-TRAF6 in obesity, DIO mice were treated with a small-molecule inhibitor that we designed to specifically block CD40-TRAF6 interactions; this compound improved insulin sensitivity, reduced AT inflammation, and decreased hepatosteatosis. Our study reveals that the CD40-TRAF2/3/5 signaling pathway in MHCII+ cells protects against AT inflammation and metabolic complications associated with obesity whereas CD40-TRAF6 interactions in MHCII+ cells aggravate these complications. Inhibition of CD40-TRAF6 signaling by our compound may provide a therapeutic option in obesity-associated insulin resistance.
The clinical decision-making process of prescribing power mobility for a child with cerebral palsy.

PURPOSE Powered mobility has been shown to be an effective method for children with disabilities to achieve independent mobility. The purpose of this case report is to describe the physical therapist's clinical decision making related to power mobility for a child with multiple disabilities. CASE DESCRIPTION Power wheelchair evaluation for a nine-year-old child was conducted using Furumasu's tasks for wheelchair readiness moving through a doorway, maneuvering through three cones, and driving in a hallway. Ongoing team assessment with family consultation informed clinical decision-making. OUTCOMES A mid-wheel-drive chair afforded improved performance on Furumasu's tasks compared with a rear-wheel-drive chair. SUMMARY This case describes the clinician's role in prescribing power wheelchairs to affect the user's functional skills, as well as how, in the absence of evidence, clinical experience and patients' needs can guide clinical decision-making.
Autologous Chondrocyte Implantation Postoperative Care and Rehabilitation

Autologous chondrocyte implantation is an advanced, cell-based orthobiological technology used for the treatment of chondral defects of the knee. It has been in clinical use since 1987 and has been performed on 12 000 patients internationally; but despite having been in clinical use for more than 15 years, the evidence base for rehabilitation after autologous chondrocyte implantation is notably deficient. The authors review current clinical practice and present an overview of the principles behind autologous chondrocyte implantation rehabilitation practices. They examine the main rehabilitation components and discuss their practical applications within the overall treatment program, with the aim of facilitating the formulation of appropriate, individualized patient rehabilitation protocols for autologous chondrocyte implantation.
The Economic Burden of Schizophrenia in the United States in 2013.

OBJECTIVE The objective of this study was to estimate the US societal economic burden of schizophrenia and update the 2002 reported costs of $62.7 billion given the disease management and health care structural changes of the last decade. METHODS A prevalence-based approach was used to assess direct health care costs, direct non-health care costs, and indirect costs associated with schizophrenia (ICD-9 codes 295.xx) for 2013, with cost adjustments where necessary. Direct health care costs were estimated using a retrospective matched cohort design using the Truven Health Analytics MarketScan Commercial Claims and Encounters, Medicare Supplemental, and Medicaid Multistate databases. Direct non-health care costs were estimated for law enforcement, homeless shelters, and research and training. Indirect costs were estimated for productivity loss from unemployment, reduced work productivity among the employed, premature mortality (ie, suicide), and caregiving. RESULTS The economic burden of schizophrenia was estimated at $155.7 billion ($134.4 billion-$174.3 billion based on sensitivity analyses) for 2013 and included excess direct health care costs of $37.7 billion (24%), direct non-health care costs of $9.3 billion (6%), and indirect costs of $117.3 billion (76%) compared to individuals without schizophrenia. The largest components were excess costs associated with unemployment (38%), productivity loss due to caregiving (34%), and direct health care costs (24%). CONCLUSIONS Schizophrenia is associated with a significant economic burden where, in addition to direct health care costs, indirect and non-health care costs are strong contributors, suggesting that therapies should aim at improving not only symptom control but also cognition and functional performance, which are associated with substantial non-health care and indirect costs.
Monoamine oxidase inhibition by monoterpene indole alkaloids and fractions obtained from Psychotria suterella and Psychotria laciniata

Alkaloid fractions of Psychotria suterella (SAE) and Psychotria laciniata (LAE) as well as two monoterpene indole alkaloids (MIAs) isolated from these fractions were evaluated against monoamine oxidases (MAO-A and -B) obtained from rat brain mitochondria. SAE and LAE were analysed by HPLC-PDA and UHPLC/HR-TOF-MS leading to the identification of the compounds 1, 2, 3 and 4, whose identity was confirmed by NMR analyses. Furthermore, SAE and LAE were submitted to the enzymatic assays, showing a strong activity against MAO-A, characterized by IC50 values of 1.37 ± 1.05 and 2.02 ± 1.08 μg/mL, respectively. Both extracts were also able to inhibit MAO-B, but in higher concentrations. In a next step, SAE and LAE were fractionated by RP-MPLC affording three and four major fractions, respectively. The RP-MPLC fractions were subsequently tested against MAO-A and -B. The RP-MPLC fractions SAE-F3 and LAE-F4 displayed a strong inhibition against MAO-A with IC50 values of 0.57 ± 1.12 and 1.05 ± 1.15 μg/mL, respectively. The MIAs 1 and 2 also inhibited MAO-A (IC50 of 50.04 ± 1.09 and 132.5 ± 1.33 μg/mL, respectively) and -B (IC50 of 306.6 ± 1.40 and 162.8 ± 1.26 μg/mL, respectively), but in higher concentrations when compared with the fractions. This is the first work describing the effects of MIAs found in neotropical species of Psychotria on MAO activity. The results suggest that species belonging to this genus could consist of an interesting source in the search for new MAO inhibitors.
Transforming the Cement Industry into a Key Environmental Infrastructure for Urban Ecosystem: A Case Study of an Industrial City in China

Under the dual pressure of environmental constraints and increasingly thin profit margins, the cement industry in China is in a predicament. To alleviate the environmental and the economic pressure of the cement industry and to tackle the problem of delayed environmental infrastructure construction, this article introduced an urban ecosystem in which the cement industry was transformed into an effective complement to environmental infrastructure. The Xinfeng Cement Industrial Park in China, which has a production capacity of 5 million tonnes per annum (Mt/a) of clinker, was chosen as a case study. Our methodology involved proposing technologies to develop an efficient cement plant‐centered urban ecosystem; evaluating its environmental and economic performance; identifying barriers in its promotion; and proposing supportive policies. Results showed that the city's waste recycling ratio rose from about 50% to 70%, saving 0.6 Mt/a of coal equivalent and reducing about 3.0 Mt/a of resulting carbon dioxide (CO2) emissions. The life span of the city's landfill site was extended by about 30 years. The total investment was 3.2 billion yuan (about US$480 million), 1 with an average payback period of 3 years. The Xinfeng Cement Industrial Park was transformed from an energy‐intensive consumer and a significant CO2 emitter to a key industrial waste recycler, a crucial municipal waste co‐processor, an important new building material supplier, and a potential energy producer. Last, the “not‐in‐my‐back‐yard” (NIMBY) effect from constructing new environmental infrastructure was also avoided.
Potential sites of action of TNPA: a dopamine-2 receptor agonist.

The purpose of this study was to correlate potential mechanisms with site(s) of action for TNPA-induced ocular hypotension. In response to R(-)-2, 10, 11-trihydroxy-N-propyl-noraporphine hydrobromide (TNPA, 75 microg), a D2 dopamine receptor agonist, the intraocular pressure decreased by 4.5 and 8 mm Hg at 1 and 2 hr, respectively, as measured by pneumatonometry. The levels of norepinephrine in aqueous humor, as determined by high performance liquid chromatography with electrochemical detection, were reduced by 38% and 79% at 1 and 2 hr, respectively, following topical application of TNPA (75 microg). Following pretreatment with raclopride (750 microg), a D2 receptor antagonist, and a subsequent challenge with TNPA (75 microg), the depression of intraocular pressure and levels of norepinephrine induced by TNPA (75 microg, 2 hr) were antagonized. In order to examine sites of action, immunohistochemistry of D2 dopamine receptors was performed in the ciliary body of normal and sympathetically denervated rabbits utilizing a goat polyclonal D2 receptor IgG and anti-goat IgG-FITC. Results from immunolocalization experiments demonstrated that D2 receptors are present on postganglionic sympathetic nerves in the ciliary body of normal rabbits but minimally detectable in that of sympathectomized rabbits. It is concluded that immunohistochemical identification of D2 receptors in the ciliary body associated with the suppression of aqueous norepinephrine levels by topical application of the D2 receptor agonist, TNPA, provide strong evidence of prejunctional (neuronal) site of action of TNPA. Antagonism of TNPA-induced ocular hypotension by raclopride coupled with the immunohistochemical and norepinephrine data suggest that D2 dopamine receptors are located on postganglionic sympathetic neurons in the ciliary body.
Sterical Hindrance Promotes Selectivity of the Autophagy Cargo Receptor NDP52 for the Danger Receptor Galectin-8 in Antibacterial Autophagy

A crystal structure of an autophagy receptor with a ligand reveals how Salmonella is specifically targeted for degradation. Targeting Salmonella for Degradation Salmonella infection damages host intracellular vesicle membranes, which exposes carbohydrates that are detected by galectins. Galectin-8 selectively recruits the cargo receptor NDP52 to stimulate autophagy, a process of intracellular degradation, of the damaged vesicular structures and associated bacteria. Li et al. solved the crystal structure of the binding domain of NDP52 in complex with the carbohydrate recognition domain of galectin-8. NDP52 formed a hooklike structure that bound to a hydrophobic pocket on galectin-8. Two adjacent amino acids in this pocket were critical for binding to NDP52. Amino acids in these positions were altered in other galectins, thereby explaining the selectivity of NDP52 for galectin-8 and how galectin-8 activates autophagy in Salmonella-infected cells. Autophagy, the process of lysosome-dependent degradation of cytosolic components, is a mechanism by which cells selectively engulf invading pathogens to protect themselves against infection. Galectin-8, a cytosolic protein with specificity for β-galactoside–containing glycans, binds endosomal and lysosomal membranes that have been damaged, for example, by pathogens, and selectively recruits the autophagy cargo receptor NDP52 to induce autophagy. We solved the crystal structure of the NDP52–galectin-8 complex to show how NDP52 exclusively binds galectin-8 and, consequently, why other galectins do not restrict the growth of Salmonella in human cells.
Insomnia in HIV Infection: A Systematic Review of Prevalence, Correlates, and Management

Objective: Insomnia in people with HIV and AIDS has been widely but inconsistently reported. We present the results of a systematic review of the subject. Methods: MEDLINE, EMBASE, PSYCHLIT, and CINAHL databases were searched, and inclusion criteria were applied. The study results were then collated and described. Results: Twenty-nine studies were identified, and there was wide variation in both method and quality. Insomnia was reported frequently and at all stages of HIV infection. Early reports of sleep-specific electroencephalographic changes were not confirmed. The role of immune dysregulation, virus progression, and adverse drug effects in contributing to insomnia is unclear. The presence of cognitive impairment, an AIDS-defining illness, and treatment with efavirenz were found to be significant risk factors, but the most notable association was with psychologic morbidity. There was limited evidence for the effect of specific treatments for insomnia in HIV infection. Conclusions: This review found that psychologic morbidity was a major determinant of insomnia in HIV infection. Further study would be of value in clarifying the role of other factors, as well as measuring the impact of insomnia on functioning and quality of life in this population. HIV = human immunodeficiency virus; AIDS = acquired immunodeficiency syndrome; CNS = central nervous system; PSG = polysomnography; EEG = electroencephalogram; CIDI = Composite International Diagnostic Interview; PSQI = Pittsburgh Sleep Quality Index; SWS = slow wave sleep; CDC = Centers for Disease Control and Prevention; REM = rapid eye movement; OR = odds ratio; CI = confidence intervals; GH = growth hormone.
Negotiation Theory for French-German Business

Revision with unchanged content. Negotiations are frequent companions of businesses as planning and the coordination of projects need consensus of the parties in­volved. The way a national culture views and weights common va­lues is neatly linked to the educational, organisational and historical circumstances found in the respective culture. By explaining these underlying systems, planning be­forehand and future steps will be­come more predictable and understan­dable. Theoretical models focusing on tactics and strategies commonly found in business ne­gotiations and concepts as framing or the structure of negotiations in phases and time models have general relevance, but this book focuses on intercultural negotiations where an understanding of these concepts might vary substantially between the parties invol­ved and may lead to contradictory situations. Covering the most detailed descripti­ons of national cultures found in the research lite­rature gives us a clear picture of what can and equally important cannot be ascribed to the natio­nal culture of a person. Equally sui­table as an introduction on this matter as well as a companion du­ring a negotiation, this book explains theoreti­cal and practical fin­dings.
Macular Vascular Fractal Dimension in the Deep Capillary Layer as an Early Indicator of Microvascular Loss for Retinopathy in Type 2 Diabetic Patients.

Purpose To determine the ability of fractal dimension to detect early changes in the retinal microvascular network imaged by optical coherence tomography angiography (OCT-A) in type 2 diabetic patients. Methods Sixty-seven patients with type 2 diabetic mellitus (DM) (48 with no diabetic retinopathy [DR], 19 with minimal DR) and 40 control subjects. Macular OCT-A images of the superficial and deep retinal capillary layers in a 2.5-mm diameter concentric annular zone (excluding the foveal avascular zone) were subdivided into six annular rings and four quadrants. A custom automated algorithm was developed to quantify the complexity and density of the two retinal capillary layers by fractal analysis. Results Compared to controls, the fractal dimensional parameter (Dbox) of the two retinal capillary layers in most regions was significantly lower in diabetic patients with minimal DR (P < 0.05). The Dbox of the diabetic patients with no DR was also decreased in most regions of the deep retinal capillary layer (P < 0.05), but not in the superficial retinal capillary layer (P > 0.05). Based on the receiver operating characteristic curve analysis, the Dbox values for the deep retinal capillary layer had the highest index to discriminate diabetic patients with and without minimal DR from controls. Conclusions Fractal dimension based on OCT-A has the potential to quantitatively characterize retinal microvascular changes in the early stage of DM. Changes in the fractal dimension in the deep retinal capillary layer could be an early indicator of microvasculature changes associated with retinopathy in type 2 diabetic patients.
Rapid donor T‐cell engraftment increases the risk of chronic graft‐versus‐host disease following salvage allogeneic peripheral blood hematopoietic cell transplantation for bone marrow failure syndromes

The risk of graft‐rejection after allogeneic hematopoietic cell transplantation using conventional cyclophosphamide‐based conditioning is increased in patients with bone marrow failure syndromes (BMFS) who are heavily transfused and often HLA‐alloimmunized. Fifty‐six patients with BMFS underwent fludarabine‐based reduced‐intensity conditioning and allogeneic peripheral blood progenitor cell (PBPC) transplantation at a single institution. The conditioning regimen consisted of intravenous cyclophosphamide, fludarabine, and equine antithymocyte globulin. Graft‐versus‐host disease (GVHD) prophylaxis included cyclosporine A alone or in combination with either mycophenolate mofetil or methotrexate. To reduce the risk of graft‐rejection/failure, unmanipulated G‐CSF mobilized PBPCs obtained from an HLA‐identical or single HLA‐antigen mismatched relative were transplanted rather than donor bone marrow. Despite a high prevalence of pretransplant HLA‐alloimmunization (41%) and a heavy prior transfusion burden, graft‐failure did not occur with all patients having sustained donor lympho‐hematopoietic engraftment. The cumulative incidence of grade II–IV acute‐GVHD and chronic‐GVHD was 51.8% and 72%, respectively; with 87.1% surviving at a median follow‐up of 4.5 years. A multivariate analysis showed pretransplant alloimmunization and rapid donor T‐cell engraftment (≥95% donor by day 30) were both significantly (P < 0.05) associated with the development of chronic‐GVHD (adjusted HR 2.13 and 2.99, respectively). These data show fludarabine‐based PBPC transplantation overcomes the risk of graft‐failure in patients with BMFS, although rapid donor T‐cell engraftment associated with this approach appears to increase the risk of chronic‐GVHD. (Clinicaltrials.gov identifier: NCT00003838). Am. J. Hematol. 88:874–882, 2013. © 2013 Wiley Periodicals, Inc.
Inconsistencies in Risk Analyses for Ambient Air Pollutant Regulations

This article describes inconsistencies between health risk analyses that the U.S. Environmental Protection Agency (EPA) uses to support its decisions on primary National Ambient Air Quality Standards (NAAQS), and in the associated Regulatory Impact Analyses (RIAs) that accompany each NAAQS rulemaking. Quantitative risk estimates are prepared during the NAAQS‐setting deliberations using inputs derived from statistical associations between measured pollutant concentrations and health effects. The resulting risk estimates are not directly used to set a NAAQS, but incorporated into a broader evidence‐based rationale for the standard that is intended to demonstrate conformity with the statutory requirement that primary NAAQS protect the public health with a margin of safety. In a separate process, EPA staff rely on the same risk calculations to prepare estimates of the benefits of the rule that are reported in its RIA for the standard. Although NAAQS rules and their RIAs are released simultaneously, the rationales used to set the NAAQS have become inconsistent with their RIAs’ estimates of benefits, with very large fractions of RIAs’ risk‐reduction estimates being attributed to populations living in areas that will already be attaining the respective NAAQS. This article explains the source of this inconsistency and provides a quantitative example based on the 2012 revision of the fine particulate matter (PM2.5) primary NAAQS. This article also demonstrates how this inconsistency is amplified when criteria pollutant co‐benefits are calculated in RIAs for non‐NAAQS rules, using quantitative examples from the 2011 Mercury and Air Toxics Standards and the currently proposed Clean Power Plan.
Helicobacter pylori Heat Shock Protein A: Serologic Responses and Genetic Diversity

ABSTRACT Helicobacter pylori synthesizes an unusual GroES homolog, heat shock protein A (HspA). The present study was aimed at an assessment of the serological response to HspA in a group of Chinese patients with defined gastroduodenal pathologies and determination of whether diversity is present in the nucleotide sequences encoding HspA in isolates from these patients. Serum samples collected from 154 patients who had an upper gastrointestinal pathology and the presence of H. pylori defined by biopsy were tested for an immunoglobulin G (IgG) serologic response to H. pylori HspA by an enzyme linked immunosorbant assay. HspA-encoding nucleotide sequences in H. pylori isolates from 14 patients (7 seropositive and 7 seronegative for HspA) were analyzed by PCR and direct sequencing of the PCR products. The sequencing results were compared to those of 48 isolates from other parts of the world. Of the 154 known H. pylori-positive patients, 54 (35.1%) were seropositive for HspA. The A domain (GroES homology) of HspA was highly conserved in the 14 isolates tested. Although the B domain (metal-binding site unique to H. pylori) resembled that in the known major variant, particular amino acid substitutions allowed definition of an HspA variant associated with isolates from East Asia. There were no associations between patient characteristics and HspA seropositivity or amino acid sequences. We confirmed in this study that the clinical outcomes of H. pylori infection are not related to HspA antigenicity or to sequence variation. However, B-domain sequence variation may be a marker for the study of the genetic diversity of H. pylori strains of different geographic origins.