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Recent advances in site-specific protein modification include the increasingly popular incorporation of unnatural amino acid(s) using amber codon, a method developed by Schultz and coworkers. In this study, we employ this technique to introduce propargyllysine (PrK) in human fibroblast growth factor 2 (FGF2). Owing to an alkyne moiety in its side chain, PrK is compatible with Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC). We successfully tested CuAAC-mediated conjugation of FGF2 with two compounds - a fluorophore carboxyrhodamine 110 or a cytotoxic drug monomethyl auristatin E (MMAE). In the case of the MMAE conjugate we improved the initial poor conjugation yield to achieve nearly 100% efficiency after extensive optimization. The detergent-based optimization approach may help overcome problems with the CuAAC reaction yield for protein modification with hydrophobic compounds, such as MMAE.

Huntington disease (HD) is a dominantly inherited disorder caused by a CAG expansion mutation in the huntingtin (HTT) gene, which results in the HTT protein that contains an expanded polyglutamine tract. The adult form of HD exhibits a late onset of the fully symptomatic phase. However, there is also a long presymptomatic phase, which has been increasingly investigated and recognized as important for the disease development. Moreover, the juvenile form of HD, evoked by a higher number of CAG repeats, resembles a neurodevelopmental disorder and has recently been the focus of additional interest. Multiple lines of data, such as the developmental necessity of HTT, its role in the cell cycle and neurogenesis, and findings from pluripotent stem cells, suggest the existence of a neurodevelopmental component in HD pathogenesis. Therefore, we discuss the early molecular pathogenesis of HD in pluripotent and neural stem cells, with respect to the neurodevelopmental aspects of HD. Electronic supplementary material The online version of this article (doi:10.1007/s12035-017-0477-7) contains supplementary material, which is available to authorized users.

Summary Protein aggregation is enhanced upon exposure to various stress conditions and aging, which suggests that the quality control machinery regulating protein homeostasis could exhibit varied capacities in different stages of organismal lifespan. Recently, an efficient metazoan disaggregase activity was identified in vitro, which requires the Hsp70 chaperone and Hsp110 nucleotide exchange factor, together with single or cooperating J-protein co-chaperones of classes A and B. Here, we describe how the orthologous Hsp70s and J-protein of Caenorhabditis elegans work together to resolve protein aggregates both in vivo and in vitro to benefit organismal health. Using an RNAi knockdown approach, we show that class A and B J-proteins cooperate to form an interactive flexible network that relocalizes to protein aggregates upon heat shock and preferentially recruits constitutive Hsc70 to disaggregate heat-induced protein aggregates and polyQ aggregates that form in an age-dependent manner. Cooperation between class A and B J-proteins is also required for organismal health and promotes thermotolerance, maintenance of fecundity, and extended viability after heat stress. This disaggregase function of J-proteins and Hsc70 therefore constitutes a powerful regulatory network that is key to Hsc70-based protein quality control mechanisms in metazoa with a central role in the clearance of aggregates, stress recovery, and organismal fitness in aging.

Hsp70 participates in a broad spectrum of protein folding processes extending from nascent chain folding to protein disaggregation. This versatility in function is achieved through a diverse family of J-protein cochaperones that select substrates for Hsp70. Substrate selection is further tuned by transient complexation between different classes of J-proteins, which expands the range of protein aggregates targeted by metazoan Hsp70 for disaggregation. We assessed the prevalence and evolutionary conservation of J-protein complexation and cooperation in disaggregation. We find the emergence of a eukaryote-specific signature for interclass complexation of canonical J-proteins. Consistently, complexes exist in yeast and human cells, but not in bacteria, and correlate with cooperative action in disaggregation in vitro. Signature alterations exclude some J-proteins from networking, which ensures correct J-protein pairing, functional network integrity and J-protein specialization. This fundamental change in J-protein biology during the prokaryote-to-eukaryote transition allows for increased fine-tuning and broadening of Hsp70 function in eukaryotes. DOI: http://dx.doi.org/10.7554/eLife.24560.001, eLife digest All cells must maintain their proteins in a correctly folded shape to survive. The task of sustaining a healthy set of proteins has increased with the rise of complex life from prokaryotes (such as bacteria) that form simple single-celled organisms to eukaryotes (such as yeast, plants and multicellular animals). As a result of organisms ageing or acquiring genetic mutations, or under stressful conditions such as high temperature, proteins can lose their normal shape and clump together to form “aggregates”. These aggregates are potentially toxic to cells and have been linked to many human diseases including neurodegeneration and cancer. Cells contain molecular machines that help break down aggregates and subsequently recycle or rescue trapped proteins. Some of these machines are based around a protein called Hsp70, which can perform a wide range of protein folding processes. So-called J-proteins help Hsp70 to select aggregates to be targeted for break down. It used to be thought that different classes of J-proteins interacted with Hsp70 separately. However, in 2015, researchers showed that in humans, two different classes of J-proteins can bind to each other to form a “complex”, which has distinct aggregate selection properties. Now, Nillegoda et al. – including several of the researchers involved in the 2015 study – have examined the evolutionary history of these J-protein complexes. This revealed that different classes (A and B) of J-proteins first cooperated after prokaryotes and eukaryotes diverged from each other. In particular, the molecular machinery that breaks down aggregates in yeast cells – but not the machinery found in bacteria – depends on complexes formed from the two classes of J-proteins. Further investigation revealed that in humans, J-proteins have structural features that ensure they pair up correctly to perform unique activities. Furthermore, Nillegoda et al. suggest that cooperation between J-proteins may have enabled organisms such as humans – which contain over 40 distinct J-proteins – to carry out further specialized protein-folding tasks that do not occur in prokaryotes. Overall, the findings presented by Nillegoda et al. reveal another important layer to protein quality control in eukaryotic cells. The next step is to understand the possible roles of different J-protein complexes play in J-protein associated cellular protein quality control processes such as preventing protein aggregation, refolding or recycling abnormal proteins. This knowledge could ultimately be used to develop treatments for diseases and disorders in which protein aggregates form. DOI: http://dx.doi.org/10.7554/eLife.24560.002

Tests performed in 2013 and 2014 revealed the occurrence of three tick species parasitizing pet cats and dogs in the Wrocław Agglomeration. In total, 1,455 tick specimens were removed from 931 hosts (760 dogs and 171 cats) in 18 veterinary clinics. The dominant tick species was Ixodes ricinus (n=1272; 87.4%), followed by I. hexagonus (n=137; 9.4%) and Dermacentor reticulatus (n=46; 3.2%). Females were the most often collected development stage among I. ricinus and D. reticulatus, and nymphs among I. hexagonus. Additionally, D. reticulatus ticks (n=337) were then collected from vegetation in the Wrocław area to detect Babesia canis; however, none was found positive. Only 9.0% of dog blood samples sent to VETLAB were positive for Babesia spp. Negative results for B. canis from ticks may result from the short period of the occurrence of D. reticulatus in the Wrocław area and therefore the vectorpathogen cycle may not have been fully established at the time of the study. Nevertheless, D. reticulatus is expanding its range, and the size of its population in the Wrocław Agglomeration is increasing. The presence of the pathogenic Babesia spp. combined with the occurrence of its main vector¸ D. reticulatus, suggests that the epizootiological situation in the area can change and may pose a new veterinary problem in the future.Dermacentor reticulatus, Babesia canis, pets, Wrocław, Poland.

Polyglutamine (polyQ) disorders share many similarities, such as a common mutation type in unrelated human causative genes, neurological character, and certain aspects of pathogenesis, including morphological and physiological neuronal alterations. The similarities in pathogenesis have been confirmed by findings that some experimental in vivo therapy approaches are effective in multiple models of polyQ disorders. Additionally, mouse models of polyQ diseases are often highly similar between diseases with respect to behavior and the features of the disease. The common features shared by polyQ mouse models may facilitate the investigation of polyQ disorders and may help researchers explore the mechanisms of these diseases in a broader context. To provide this context and to promote the understanding of polyQ disorders, we have collected and analyzed research data about the characterization and treatment of mouse models of polyQ diseases and organized them into two complementary Excel data tables. The data table that is presented in this review (Part I) covers the behavioral, molecular, cellular, and anatomic characteristics of polyQ mice and contains the most current knowledge about polyQ mouse models. The structure of this data table is designed in such a way that it can be filtered to allow for the immediate retrieval of the data corresponding to a single mouse model or to compare the shared and unique aspects of many polyQ models. The second data table, which is presented in another publication (Part II), covers therapeutic research in mouse models by summarizing all of the therapeutic strategies employed in the treatment of polyQ disorders, phenotypes that are used to examine the effects of the therapy, and therapeutic outcomes. Electronic supplementary material The online version of this article (doi:10.1007/s12035-012-8315-4) contains supplementary material, which is available to authorized users.

Mouse models of human diseases are created both to understand the pathogenesis of the disorders and to find successful therapies for them. This work is the second part in a series of reviews of mouse models of polyglutamine (polyQ) hereditary disorders and focuses on in vivo experimental therapeutic approaches. Like part I of the polyQ mouse model review, this work is supplemented with a table that contains data from experimental studies of therapeutic approaches in polyQ mouse models. The aim of this review was to characterize the benefits and outcomes of various therapeutic strategies in mouse models. We examine whether the therapeutic strategies are specific to a single disease or are applicable to more than one polyQ disorder in mouse models. In addition, we discuss the suitability of mouse models in therapeutic approaches. Although the majority of therapeutic studies were performed in mouse models of Huntington disease, similar strategies were also used in other disease models. Electronic supplementary material The online version of this article (doi:10.1007/s12035-012-8316-3) contains supplementary material, which is available to authorized users.

Over the last two decades proteins have become increasingly important in human therapy and diagnosis. Engineering therapeutic proteins through improving their biological activity and stability has been a major interest in our group. In this mini-review we summarize our research on three proteins with pharmaceutical potential - serine protease inhibitor from squash seeds (CMTI), bovine pancreatic trypsin inhibitor (BPTI), and human fibroblast growth factor 1 (FGF1). To improve the functional properties of these proteins we used multiple techniques such as homology approach, rational design, total chemical synthesis, site-directed mutagenesis and phage display. The physicochemical properties of the obtained protein variants were evaluated using protein crystallography, spectroscopic techniques, enzymatic assays, stability measurements as well as numerous biological tests.

Fibroblast growth factor 1 (FGF1) and its receptors (FGFRs) regulate crucial biological processes such as cell proliferation and differentiation. Aberrant activation of FGFRs by their ligands can promote tumor growth and angiogenesis in many tumor types, including lung or breast cancer. The development of FGF1-targeting molecules with potential implications for the therapy of FGF1-driven tumors is recently being considered a promising approach in the treatment of cancer. In this study we have used phage display selection to find scFv antibody fragments selectively binding FGF1 and preventing it from binding to its receptor. Three identified scFv clones were expressed and characterized with regard to their binding to FGF1 and ability to interfere with FGF1-induced signaling cascades activation. In the next step the scFvs were cloned to scFv-Fc format, as dimeric Fc fusions prove beneficial in prospective therapeutic application. As expected, scFvs-Fc exhibited significantly increased affinity towards FGF1. We observed strong antiproliferative activity of the scFvs and scFvs-Fc in the in vitro cell models. Presented antibody fragments serve as novel FGF1 inhibitors and can be further utilized as powerful tools to use in the studies on the selective cancer therapy.

In the structure of the title compound, C(29)H(18)F(3)N(3), belonging to the space group P6(5) (or P6(1)), three symmetry-independent molecules are arranged in two chains, with two molecules alternating along the 3(2) axes, whereas the remaining molecule forms a chain along [0001] due to the 6(5) screw axis. The conformation of each of the molecules is stabilized by an intramolecular C-H...N hydrogen bond, with C...N distances in the range 2.964 (6)-3.069 (5) A at room temperature (293 K) and 2.943 (4)-3.084 (4) A at low temperature (100 K). One molecule has its -CF(3) group ordered even at 293 K, which can be explained only by considering its involvement in two weak intermolecular C-H...F interactions, with C...F distances in the range 3.084 (6)-3.302 (5) A at 293 K and 3.070 (3)-3.196 (3) A at 100 K, and also a C-F...N interaction, with a C...N distance of 3.823 (5) A at 293 K and 3.722 (4) A at 100 K. The trifluoromethyl groups in the two remaining molecules are disordered at 293 K, whereas at 100 K the continuous (dynamic) positional disorder of one of the -CF(3) groups (of the molecule forming the chain along [0001]) is totally eliminated while the -CF(3) group disorder remains for the third molecule.

The biogenesis of human microRNAs (miRNAs) includes two RNA cleavage steps in which the activities of the RNases Drosha and Dicer are involved. miRNAs of diverse lengths are generated from different genes, and miRNAs that are heterogeneous in length are produced from a single miRNA gene. We determined the solution structures of many miRNA precursors and analysed the structural basis of miRNA length diversity using a new measure: the weighted average length of diced RNA (WALDI). We found that asymmetrical structural motifs present in precursor hairpins are primarily responsible for the length diversity of miRNAs generated by Dicer. High-resolution northern blots of miRNAs and their precursors revealed that both Dicer and Drosha cleavages of imperfect specificity contributed to the miRNA length heterogeneity. The relevance of these findings to the dynamics of the dicing complex, mRNA regulation by miRNA, RNA interference and miRNA technologies are discussed.

Absorption, photo- and electroluminescence spectra of some trityl substituted 1 H -pyrazolo[3,4- b ]quinolines derivatives (methyl- and phenyl substituted) and fabrication of the single layered organic light emitting diodes are reported. The bulky trityl substituent was introduced to prevent aggregation and crystallization of the dopant in polymer matrix. Role of ground state dipole moments in the observed red Stokes shift, electroluminescent features and photocarrier transport is explored. The maximally achieved brightness about 50 Cd/m 2 is observed in the spectral range extending from 443 nm up to 462 nm. The voltage threshold was varied from 7.8 V up to 10 V. The brightness-current dependences show an existence of at least two types of carrier injections.

Comparison of the crystal structures of two pentadehydropeptides containing DeltaPhe residues, namely (Z,Z)-N-(tert-butoxycarbonyl)glycyl-alpha,beta-phenylalanylglycyl-alpha,beta-phenylalanylglycine (or Boc(0)-Gly(1)-Delta(Z)Phe(2)-Gly(3)-Delta(Z)Phe(4)-Gly(5)-OH) methanol solvate, C(29)H(33)N(5)O(8) x CH(4)O, (I), and (E,E)-N-(tert-butoxycarbonyl)glycyl-alpha,beta-phenylalanylglycyl-alpha,beta-phenylalanylglycine (or Boc(0)-Gly(1)-Delta(E)Phe(2)-Gly(3)-Delta(E)Phe(4)-Gly(5)-OH), C(29)H(33)N(5)O(8), (II), indicates that the Delta(Z)Phe residue is a more effective inducer of folded structures than the Delta(E)Phe residue. The values of the torsion angles phi and psi show the presence of two type-III' beta-turns at the Delta(Z)Phe residues and one type-II beta-turn at the Delta(E)Phe residue. All amino acids are linked trans to each other in both peptides. Beta-turns present in the peptides are stabilized by intramolecular 4-->1 hydrogen bonds. Molecules in both structures form two-dimensional hydrogen-bond networks parallel to the (100) plane.

The antioxidizing properties of curcumin, a highly pleiotropic substance used for centuries in traditional medicine has been confirmed by numerous experimental and clinical studies. Curcumin exhibits anti-inflammatory, antiproliferative and anti-angiogenic actions inhibiting the development and progression of tumors but the efficacy of this compound to influence gastric acid secretion n in the stomach and to affect the gastric mucosal damage induced by non-topical ulcerogenes such as stress has been little studied. We determined the effect of curcumin on basal and pentagastrin- or histamine-stimulated gastric secretion, in rats with surgically implemented gastric fistulas and we assessed the contribution of gastric secretion, endogenous prostaglandin (PG), endogenous nitric oxide (NO), as well as sensory afferent nerves in the mechanisms underlying the potential gastroprotective effects of curcumin against stress-induced gastric mucosal lesions. Rats exposed to water immersion and restraint stress (WRS) for 3.5 h were pretreated either with: 1) vehicle (saline); 2) curcumin (2.5 - 100 mg/kg i.g.) or 3) curcumin (50 mg/kg i.g.) combined with or without indomethacin (5 mg/kg i.p.), SC-560 (5 mg/kg i.g.) or rofecoxib (10 mg/kg i.g.); 4) curcumin (50 mg/kg i.g.) co-administered with (L-NNA (20 mg/kg i.p.) with or without L-arginine (200 mg/kg i.g.), a substrate for NO-synthase; 5) curcumin (50 mg/kg i.g.) administered in rats with intact or capsaicin-induced functional ablation of sensory nerve fibers, and 6) curcumin (50 mg/kg i.g.) administered with capsazepine (5 mg/kg i.g.), the antagonist of vanilloid TRPV1 receptor. The number of gastric lesions was determined by planimetry, the gastric blood flow (GBF) was assessed by H2-gas clearance technique, the plasma gastrin concentrations were measured using the radioimmunoassay (RIA) and the expression of mRNA for tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in gastric mucosa was evaluated by reverse transcription polymerase chain reaction (RT-PCR). Curcumin dose-dependently reduced the WRS-induced gastric lesions, the dose inhibiting these lesions by 50% being about 50 mg/kg. These effects of curcumin were accompanied by an increase in GBF and the reduction in basal and histamine- or pentagastrin-stimulated gastric acid secretion. The protective and hyperemic activities of curcumin (50 mg/kg i.g.) against WRS lesions were significantly attenuated (P0.05) in rats pretreated with rofecoxib and SC-560 and completely reversed (P0.01) by indomethacin. L-NNA significantly reduced (P0.05) the decrease in WRS-induced lesions and the accompanying rise in GBF caused by curcumin and these effects were restored by concurrent treatment with L-arginine (200 mg/kg i.g.). The curcumin-induced decrease in the number of WRS-induced gastric lesions and accompanying increase in the GBF were significantly attenuated (P0.05) in capsaicin-denervated rats and in those pretreated with capsazepine. These effects of curcumin in rats with capsaicin denervation were restored by concomitant treatment with exogenous calcitonin gene related pepetide (CGRP) combined with curcumin and subsequently exposed to WRS. The expression of mRNA for TNF-α, COX-2 and iNOS was significantly increased (P0.05) in vehicle-pretreated control rats exposed to WRS and significantly attenuated (P0.05) by curcumin administered in graded dosages. We conclude that curcumin exerts gastroprotective and hyperemic activities against experimental stress-induced gastric lesions by mechanism involving endogenous prostaglandins, NO, the neuropeptides such as CGRP released from capsaicin-sensitive afferent nerves and the activation of vanilloid TRPV1 receptors located on these sensory nerve terminals.

BACKGROUND Cardiovascular risk factors are common in individuals with chronic spinal cord injury (SCI), and their prevalence increases with age. The actual prevalence of overt cardiovascular disease (CVD) in this population has not been well established. METHODS Electrocardiograms (ECGs) were examined for abnormalities in 43 individuals with abnormal lipid profiles being followed in the outpatient SCI clinic of our institution. The mean age of the study population of predominantly men was 43 +/- 9.9 years and the mean duration of injury 16.6 +/- 8 years. RESULTS ECG abnormalities were common and present in 60.5% of participants. ST-T wave abnormalities were the most commonly observed (35%). Evidence of previous myocardial infarction was present in 7% of all individuals and in 12% of those with ECG abnormalities. The only clinical parameter differentiating the group with normal vs abnormal ECG was the duration of injury (19.5 +/- 8 y vs 12 +/- 5 y; P = 0.0026). Analysis of variance showed that injury duration was the sole predictor of abnormal ECG with 68% accuracy (P = 0.006). Among those with ECG abnormalities, although no significant differences were detected between those with and without evidence of previous myocardial infarction, mean total cholesterol and low-density lipoprotein were higher, and mean high-density lipoprotein was lower. Mean age and injury duration were greater in those with evidence of previous myocardial infarction. CONCLUSION Although age is an important risk factor for CVD in the population of individuals without disabilities, injury duration is at least as important as age in those with SCI. Our findings support the recommendation that individuals with SCI and abnormal lipids should be screened for CVD regardless of age.

Background The polyglutamine (polyQ) family of disorders comprises 9 genetic diseases, including several types of ataxia and Huntington disease. Approximately two decades of investigation and the creation of more than 130 mouse models of polyQ disorders have revealed many similarities between these diseases. The disorders share common mutation types, neurological characteristics and certain aspects of pathogenesis, including morphological and physiological neuronal alterations. All of the diseases still remain incurable. Description The large volume of information collected as a result of the investigation of polyQ models currently represents a great potential for searching, comparing and translating pathogenesis and therapeutic information between diseases. Therefore, we generated a public database comprising the polyQ mouse models, phenotypes and therapeutic interventions tested in vivo. The database is available at http://conyza.man.poznan.pl/. Conclusion The use of the database in the field of polyQ diseases may accelerate research on these and other neurodegenerative diseases and provide new perspectives for future investigation.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder caused by expansion of CTG triplet repeats in 3'-untranslated region of DMPK gene. The pathomechanism of DM1 is driven by accumulation of toxic transcripts containing expanded CUG repeats (CUG(exp)) in nuclear foci which sequester several factors regulating RNA metabolism, such as Muscleblind-like proteins (MBNLs). In this work, we utilized very short chemically modified antisense oligonucleotides composed exclusively of locked nucleic acids (all-LNAs) complementary to CUG repeats, as potential therapeutic agents against DM1. Our in vitro data demonstrated that very short, 8- or 10-unit all-LNAs effectively bound the CUG repeat RNA and prevented the formation of CUG(exp)/MBNL complexes. In proliferating DM1 cells as well as in skeletal muscles of DM1 mouse model the all-LNAs induced the reduction of the number and size of CUG(exp) foci and corrected MBNL-sensitive alternative splicing defects with high efficacy and specificity. The all-LNAs had low impact on the cellular level of CUG(exp)-containing transcripts and did not affect the expression of other transcripts with short CUG repeats. Our data strongly indicate that short all-LNAs complementary to CUG repeats are a promising therapeutic tool against DM1.

Differential evolution is currently one of the most popular population based stochastic meta-heuristics. In the paper, we propose an extension of the Differential Evolution algorithm for multi-objective optimization problem with constraints of chemotherapy scheduling for a medical treatment. The differential evolution idea is used with some significant improvements concerning the DE strategies and parameters adaptation. The numerical results show that the proposed algorithm is stable and robust in handling medical applications especially for a chemotherapy planning process.

Protein aggregates are the hallmark of stressed and ageing cells, and characterize several pathophysiological states1, 2. Healthy metazoan cells effectively eliminate intracellular protein aggregates3, 4, indicating that efficient disaggregation and/or degradation mechanisms exist. However, metazoans lack the key heat-shock protein disaggregase HSP100 of non-metazoan HSP70-dependent protein disaggregation systems5, 6, and the human HSP70 system alone, even with the crucial HSP110 nucleotide exchange factor, has poor disaggregation activity in vitro4, 7. This unresolved conundrum is central to protein quality control biology. Here we show that synergic cooperation between complexed J-protein co-chaperones of classes A and B unleashes highly efficient protein disaggregation activity in human and nematode HSP70 systems. Metazoan mixed-class J-protein complexes are transient, involve complementary charged regions conserved in the J-domains and carboxy-terminal domains of each J-protein class, and are flexible with respect to subunit composition. Complex formation allows J-proteins to initiate transient higher order chaperone structures involving HSP70 and interacting nucleotide exchange factors. A network of cooperative class A and B J-protein interactions therefore provides the metazoan HSP70 machinery with powerful, flexible, and finely regulatable disaggregase activity and a further level of regulation crucial for cellular protein quality control. published

BACKGROUND Elevated plasma levels of creatine kinase (CPK) are found in various neuromuscular conditions as a result of muscle damage and necrosis. Elevated CPK has also been described in elite wheelchair athletes and in able-bodied individuals after strenuous exercise. METHODS The incidence of elevated CPK in individuals with spinal cord injury (SCI) has not been well established. We reviewed laboratory data from 581 individuals with chronic SCI. RESULTS Most individuals with SCI (73.3%) had CPK values within 95% confidence intervals for able-bodied individuals. The highest levels were seen in African Americans (21% had CPK values > 95 confidence intervals for able-bodied individuals). Significant associations between CPK and the following independent variables were identified: impairment group, gender, duration of injury, body mass index, and ethnic group. Multiple regression analysis revealed significant correlations between CPK and oxygen consumption (beta .37, P < .01) in 32 individuals who performed the exercise test. CONCLUSIONS These findings are important for clinicians evaluating symptoms of fatigue and myopathy in individuals with SCI.

Cardiometabolic syndrome in individuals who are aging with spinal cord injury (SCI) increases the risk of cardiovascular disease and diabetes. Longitudinal research is needed on the natural progression of cardiometabolic syndrome in SCI.To identify the magnitude of changes in biomarkers of cardiometabolic syndrome and diabetes over time in people aging with SCI, and to discern how these biomarkers relate to demographics of race/ethnicity and sex.This cohort study was a follow-up of a convenience sample of 150 participants (mean age, 51.3; duration of SCI, 27.3 years) from a full cohort of 845 who participated in research in which physiologic and serologic data on cardiovascular disease had been prospectively collected (1993-1997). Inclusion criteria were adults with traumatic-onset SCI. Average years to follow-up were 15.7 ± 0.9. Assessments were age, race, level and completeness of injury, duration of injury, blood pressure, body mass index, waist circumference, serum lipids, fasting glucose, hemoglobin A1c, and medications used. Primary outcome was meeting at least 3 of the criteria for cardiometabolic syndrome.The frequency of cardiometabolic syndrome increased significantly from 6.7% to 20.8% or 38.2% according to 2 definitions. It was significantly higher in Hispanics and apparently higher in women. Diabetes increased significantly by a factor of 6.7.Our data indicate clinically important increases in the frequency of cardiometabolic syndrome, especially among Hispanic and female participants, and a similar increase in diabetes among individuals aging with SCI. Clinical practice guidelines need to be customized for women and Hispanics with SCI.

Huntington disease (HD) is a brain disorder characterized by the late onset of motor and cognitive symptoms, even though the neurons in the brain begin to suffer dysfunction and degeneration long before symptoms appear. There is currently no cure. Several molecular and developmental effects of HD have been identified using neural stem cells (NSCs) and differentiated cells, such as neurons and astrocytes. Still, little is known regarding the molecular pathogenesis of HD in pluripotent cells, such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Therefore, we examined putative signaling pathways and processes involved in HD pathogenesis in pluripotent cells. We tested naïve mouse HD YAC128 iPSCs and two types of human HD iPSC that were generated from HD and juvenile-HD patients. Surprisingly, we found that a number of changes affecting cellular processes in HD were also present in undifferentiated pluripotent HD iPSCs, including the dysregulation of the MAPK and Wnt signaling pathways and the dysregulation of the expression of genes related to oxidative stress, such as Sod1. Interestingly, a common protein interactor of the huntingtin protein and the proteins in the above pathways is p53, and the expression of p53 was dysregulated in HD YAC128 iPSCs and human HD iPSCs. In summary, our findings demonstrate that multiple molecular pathways that are characteristically dysregulated in HD are already altered in undifferentiated pluripotent cells and that the pathogenesis of HD might begin during the early stages of life., Summary: This research demonstrates that dysregulation of signaling pathways is a very early event in the pathogenesis of Huntington disease and that these pathways are already dysregulated in cells at the stage of pluripotency.

Twenty-seven cases of isolated pulmonic valve endocarditis seen between 1986–1998, including five from our own institution, were reviewed. These cases were compared with a previous study from 1960–1985 in which 28 cases were reported. The current study revealed a male-to-female ratio of 2:1 as compa

We used daily time-series analysis to evaluate associations between ambient carbon monoxide, nitrogen dioxide, particulate matter [less than and equal to] 10 microm in aerodynamic diameter (PM(10)), or ozone concentrations, and hospital admissions for cardiopulmonary illnesses in metropolitan Los Angeles during 1992-1995. We performed Poisson regressions for the entire patient population and for subgroups defined by season, region, or personal characteristics, allowing for effects of temporal variation, weather, and autocorrelation. CO showed the most consistently significant (p