bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell‐based high‐throughput screening identifies galactocerebrosidase enhancers as potential small‐molecule therapies for Krabbe's disease
Authors: Jang Dae Song , Ye Wenjuan , Guimei Tian , Solomon Melani , Southall Noel , Hu Xin , Marugan Juan , Ferrer Marc , Maegawa Gustavo H.B.
Published: September 2016

Krabbe's disease, also known as globoid cell leukodystrophy (GLD), is a lysosomal storage disease caused by the deficiency of the lysosomal enzyme β‐galactocerebrosidase (GALC), resulting in severe neurological manifestations related to demyelination secondary to elevated galactosylsphingosine (psychosine) with its subsequent cytotoxicity. The only available treatment is hematopoietic stem cell transplantation, which delays disease onset but does not prevent long‐term neurological manifestations. This article describes the identification of small molecules that enhance mutant GALC activity, identified by quantitative cell‐based high‐throughput screening (qHTS). Using a specific neurologically relevant murine cell line (145M‐Twi) modified to express common human hGALC‐G270D mutant, we were able to detect GALC activity in a 1,536‐well microplate format. The qHTS of approximately 46,000 compounds identified three small molecules that showed significant enhancements of residual mutant GALC activity in primary cell lines from GLD patients. These compounds were shown to increase the levels of GALC‐G270D mutant in the lysosomal compartment. In kinetic assessments, these small molecules failed to disturb the GALC kinetic profile under acidic conditions, which is highly desirable for folding‐assisting molecules operating in the endoplasmic reticulum and not affecting GALC catalytic properties in the lysosomal compartment. In addition, these small molecules rescued the decreased GALC activity at neutral pH and partially stabilized GALC under heat‐denaturating conditions. These drug‐like compounds can be used as the starting point to develop novel small‐molecule agents to treat the progressive neurodegenerative course of GLD. © 2016 Wiley Periodicals, Inc.
Clinical management of Krabbe disease
Authors: Escolar Maria L. , West Tara , Dallavecchia Alessandra , Poe Michele D. , LaPoint Kathleen
Published: September 2016

Krabbe disease (KD) is a rare neurodegenerative disorder caused by mutations in the gene encoding the galactocerebrosidase enzyme. The early‐ and late‐infantile subtypes, which are the most common forms of the disease, are rapidly progressive and lead to early death, whereas the later‐onset types are clinically heterogeneous. The only disease‐modifying treatment currently available is hematopoietic stem cell transplantation, which is effective only when performed early in the course of the disease. Because most patients with KD are diagnosed too late for treatment, primary care physicians are faced with the challenge of caring for a child with severe neurologic impairment. This Review describes presenting symptoms, diagnosis, and disease manifestations of KD and provides basic guidelines for its management. Symptomatic treatment and supportive care that address the unique requirements of these patients can greatly improve the quality of life of patients and their families. © 2016 Wiley Periodicals, Inc.
Expression of individual mutations and haplotypes in the galactocerebrosidase gene identified by the newborn screening program in New York State and in confirmed cases of Krabbe's disease
Authors: Saavedra‐Matiz Carlos A. , Luzi Paola , Nichols Matthew , Orsini Joseph J. , Caggana Michele , Wenger David A.
Published: September 2016

Newborn screening (NBS) for Krabbe's disease (KD) has been instituted in several states, and New York State has had the longest experience. After an initial screening of dried blood spots, samples from individuals with galactocerebrosidase (GALC) values below a given cutoff level were subjected to additional testing, including sequencing of the GALC gene. This resulted in the identification of mutations that had previously been found in confirmed KD patients and of variants that had never previously been reported. Some individuals had variants considered to be polymorphisms, alone or on the same allele as another mutation. To help with counseling of families on the risk for a newborn to develop KD, expression studies were conducted with these variants identified by NBS. GALC activity was measured in COS1 cells for 140 constructs and compared with mutations that had previously been seen in confirmed cases of KD. When a polymorphism was present on the same allele as the variant, expressed activity was measured with and without the polymorphism. In some cases the presence of the polymorphism greatly lowered the measured GALC activity, possibly making it disease causing. Although it is not possible to predict conclusively whether a variant is severe and will result in infantile KD if two such variants are present or whether a variant is mild and will result in late‐onset disease, some variants clearly are not disease causing. This is the largest expression study of GALC variants/mutations found in NBS and confirmed KD cases. This work will be helpful for counseling families of screen‐positive newborns found to have low GALC activity. © 2016 Wiley Periodicals, Inc.
Lithium improves cell viability in psychosine‐treated MO3.13 human oligodendrocyte cell line via autophagy activation
Authors: Del Grosso Ambra , Antonini Sara , Angella Lucia , Tonazzini Ilaria , Signore Giovanni , Cecchini Marco
Published: September 2016

Globoid cell leukodystrophy (GLD) is a rare, rapidly progressing childhood leukodystrophy triggered by deficit of the lysosomal enzyme galactosylceramidase (GALC) and characterized by the accumulation of galactosylsphingosine (psychosine; PSY) in the nervous system. PSY is a cytotoxic sphingolipid, which leads to widespread degeneration of oligodendrocytes and Schwann cells, causing demyelination. Here we report on autophagy in the human oligodendrocyte cell line MO3.13 treated with PSY and exploitation of Li as an autophagy modulator to rescue cell viability. We demonstrate that PSY causes upregulation of the autophagic flux at the level of autophagosome and autolysosome formation and LC3‐II expression. We show that pretreatment with Li, a drug clinically used to treat bipolar disorders, can further stimulate autophagy, improving cell tolerance to PSY. This Li protective effect is found not to be linked to reduction of PSY‐induced oxidative stress and might not stem from a reduction of PSY accumulation. These data provide novel information on the intracellular pathways activated during PSY‐induced toxicity and suggest the autophagy pathway as a promising novel therapeutic target for ameliorating the GLD phenotype. © 2016 Wiley Periodicals, Inc.
Challenge of phenotype estimation for optimal treatment of Krabbe disease
Authors: Sakai Norio , Otomo Takanobu
Published: September 2016

Krabbe disease is an autosomal recessive, inherited demyelinating disease caused by deficiency of the lysosomal enzyme galactocerebrosidase. It is recognized as one of the predominant genetic diseases showing leukodystrophy from infancy to adulthood. The clinical phenotype and genotype for this disease show considerable variation worldwide, which makes accurate diagnosis difficult. Effective therapy is limited, although hematopoietic stem cell transplantation at an early stage has been established to some extent. We report here the long‐term clinical effect on juvenile Krabbe disease for two brothers who underwent hematopoietic stem cell transplantation at an early stage of their disease. We review research into genotype–phenotype correlation for the possibility of early diagnosis at a presymptomatic stage. Medical care for this intractable disease will improve in the near future as a result of the increasing awareness of its molecular pathology and improvements in medical treatment. © 2016 Wiley Periodicals, Inc.
The role of amiloride in managing patients with lithium‐induced nephrogenic diabetes insipidus
Authors: Lodin Misha , Dwyer James
Published: September 2016

Background

Despite lithium being a highly effective drug, it is commonly associated with inducing nephrogenic diabetes insipidus (NDI) in a high number of patients. In this case report we describe the successful use of amiloride as an effective means to manage and minimise NDI occurring in patients while they are on lithium therapy.

Clinical details

The patient had been taking lithium for management of her bipolar disorder for approximately 5 years. While on this medication the patient suffered from acute kidney impairment, hypernatraemia, reduced urine osmolality, increased plasma osmolality, polyuria, polydipsia and severe dehydration. These clinical results were consistent with an adverse reaction known as NDI acquired from long‐term lithium use and fluid restriction.

Outcomes

Lithium was ceased on day two of admission. Intravenous fluid replacements were provided until the patient's renal function and sodium levels returned to normal. Once the patient was symptomatically stable, lithium was reintroduced at initiating dosage levels concomitantly with amiloride with aims of reversing the concentrating defect and preventing this side effect from occurring again. The patient was discharged 15 days later.

Conclusion

In most cases NDI is reversible with the cessation of lithium. However, a subset of the mental health population is resistant to other forms of therapy, leaving lithium as their only option to successfully manage their mood disorder. For patients who suffer from mental health disorders, the literature has found that amiloride can be an effective means to restore a patient's impaired urine concentrating ability.
Complete NMR assignment and conformational analysis of 17‐α‐ethinylestradiol by using RDCs obtained in grafted graphene oxide
Authors: França José A. A. , Navarro‐Vázquez Armando , Lei Xinxiang , Sun Han , Griesinger Christian , Hallwass Fernando
Published: September 2016

The 1H and 13C NMR spectra of 17‐α‐ethinylestradiol (EE2), a well‐known contraceptive, including diastereotopic methylene groups, were fully assigned with the help of residual dipolar couplings (RDC) measured in the recently developed grafted graphene oxide orienting medium. RDC analysis, which included all 1DCH couplings and the long‐range 2DCH 1H―C≡13C coupling, also pointed to the presence of a minor conformation arising from pseudo‐rotation of the steroid B ring. Saturation‐transfer difference (STD) measurements revealed that the most likely interaction between EE2 and orienting medium occurred on the C and D ring. Copyright © 2016 John Wiley & Sons, Ltd.
Comparison of scale‐up methods for dispersive mixing in twin‐screw extruders
Authors: Dryer Ben , Fukuda Graeme , Webb Jake , Montemayor Kyle , Bigio David I. , Andersen Paul , Wetzel Mark
Published: September 2016

Twin‐screw extrusion processes are commonly refined on laboratory‐scale extruders then scaled‐up to manufacturing systems. When using twin‐screw extrusion to compound filler into a polymer, the dispersion of the filler must be considered during scale‐up. In this work, two scale‐up methods are evaluated for how accurately they scale dispersion as measured by the Residence Stress Distribution, an experimental method that quantifies stress developed in a twin‐screw extruder. The first scale‐up method evaluated is the industry‐standard scaling based on maintaining equivalent volumetric flow rate across extruder sizes. Volumetric scaling is compared to a second, novel scale‐up method, the percent drag flow rule, which maintains the same degree of fill in the strongest dispersive screw elements on all extruder sizes. Both scale‐up rules have been used to scale between three extruder sizes and have been evaluated for how accurately the larger extruders recreate the dispersive mixing of the smallest machine. Results indicate that the percent drag flow scale‐up more accurately maintains dispersive mixing behavior than the volumetric scaling. Furthermore, percent drag flow scale‐up resulted in all three extruder sizes behaving similarly to changes in operating conditions. These results indicate that percent drag flow scale‐up is a valid technique to scale real industrial processes. POLYM. ENG. SCI., 57:345–354, 2017. © 2016 Society of Plastics Engineers
Population Pharmacokinetics and Pharmacodynamics of the Calcimimetic Etelcalcetide in Chronic Kidney Disease and Secondary Hyperparathyroidism Receiving Hemodialysis
Authors: Chen P , Olsson Gisleskog P , Perez‐Ruixo JJ , Xiao J , Wilkins J , Narayanan A , Gibbs JP , Melhem M
Published: September 2016

Etelcalcetide is a novel calcimimetic in development for the treatment of secondary hyperparathyroidism (SHPT). A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed relating etelcalcetide exposures to markers of efficacy (parathyroid hormone [PTH]) and safety (calcium) using data from three clinical studies. The semimechanistic model was developed that included allosteric activation pharmacology and understanding of calcium homeostasis. The temporal profiles for all biomarkers were well described by the model. The cooperativity constant was 4.94, confirming allosteric activation mechanism. Subjects with more severe disease (higher PTH baseline) were predicted to experience less pronounced reduction in PTH (percentage change from baseline), but more reduction in calcium (Ca; percentage change from baseline). There was no evidence that dose adjustment by any covariate was needed. Model‐based simulations provided quantitative support to several elements of dosing, such as starting dose, monitoring, and titration timing for registration trials.
A Portion of Profits to Charity: Corporate Social Responsibility and Firm Profitability
Authors: Pecorino Paul
Published: September 2016

I develop a model in which a firm can choose to donate a portion of its profits to the provision of a public good. Consumers value this public good and are willing to pay a price premium to a firm which makes such a donation. When this price premium is sufficiently large, the firm can raise its net profits by pledging a portion of those profits to provision of the public good. This is more likely when the consumer's marginal valuation of contributions to the public good is high and when the firm (in the absence of donations) has a high ratio of fixed costs to operating profits. I also identify circumstances under which corporate social responsibility makes consumers worse off.
Metabolites replace the parent drug in the drug arena. The cases of fonazepam and nifoxipam
Authors: Katselou Maria , Papoutsis Ioannis , Nikolaou Panagiota , Spiliopoulou Chara , Athanaselis Sotiris
Published: September 2016

Fonazepam (desmethylflunitrazepam) and nifoxipam (3-hydroxy-desmethylflunitrazepam) are benzodiazepine derivatives and active metabolites of flunitrazepam. They recently invaded the drug arena as substances of abuse and alerted the forensic community after being seized in powder and tablet forms in Europe between 2014 and 2016. A review of all the existing knowledge of fonazepam and nifoxipam is reported, concerning their chemistry, synthesis, pharmacology and toxicology, prevalence/use, biotransformation and their analysis in biological samples. To our knowledge, fonazepam and nifoxipam-related intoxications, lethal or not, have not been reported in the scientific literature. All the available information was gathered through a detailed search of PubMed and the World Wide Web.
Formation and Microstructures of Whipped Oils Composed of Vegetable Oils and High‐Melting Fat Crystals
Authors: Mishima Shoko , Suzuki Atsushi , Sato Kiyotaka , Ueno Satoru
Published: September 2016

This paper reports the experimental results of processes used for the formation of whipped oils composed of vegetable oils (salad oil) and high‐melting fat crystals [fully hydrogenated rapeseed oil rich in behenic acid (FHR‐B)]. No emulsifier was added to form this whipped oil. Microprobe FT‐IR spectroscopy, synchrotron radiation microbeam X‐ray diffraction (SR‐μ‐XRD), polarized optical microscopy, and differential scanning calorimetry (DSC) were employed to observe fine fat crystal particles of the most stable polymorph of β (β‐fat crystal), FHR‐B, and their adsorption at the air–oil surface before, during, and after the formation of the whipped oil. The results obtained revealed the following: (1) The preparation of an organogel composed of salad oil and small fibrous β‐fat crystals using a special tempering procedure was a prerequisite for forming whipped oil. (2) The β‐fat crystals were adsorbed at the air–oil surface to encapsulate the air bubbles during the formation process of whipped oil. (3) The values of overrun of the whipped oil reached >200 % after an aeration time of 30 min at 20 °C. (4) The SR‐μ‐XRD experiments demonstrated that the lamellar planes of the β‐fat crystals near the air–oil surface were arranged almost parallel to the air–oil surface plane. The present study provides the first evidence that tiny fat crystal particles may cause aeration in liquid oils without the addition of other whip‐assisting substances such as emulsifier crystals.
The Origins of Religious Homophily in a Medium and Large School
Authors: Cook J. Benjamin , Schwadel Philip , Cheadle Jacob E.
Published: September 2016

How religion influences social interactions, and how social interactions influence religion, are fundamental questions to the sociology of religion. We address these processes and build on Cheadle and Schwadel's (Soc Sci Res 41:1198-1212, 2012 ) analysis of selection and influence in religion-based social tie homogeneity (i.e. network-religion autocorrelation) in small schools by analyzing networks from larger schools, by focusing on differences across schools, and by testing different operationalizations of social influence. Using two waves of full network data from the National Longitudinal Study of Adolescent Health and dynamic longitudinal network SIENA models, we find (1) that both selection and influence impact network-religion autocorrelation; (2) that the factors influencing network-religion autocorrelation vary across school contexts; and (3) that religious influence is proportional to the number of friends in an adolescent's network, which means influence reflects both the size of an individual's network and the consistency of religion among members of the network. We conclude by addressing potential reasons for differences across school contexts and by discussing the theoretical logic behind the total similarity effect that best operationalized religious influence.
How to early recognize mood disorders in primary care: A nationwide, population-based, cohort study
Authors: Castellini G. , Pecchioli S. , Cricelli I. , Mazzoleni F. , Cricelli C. , Ricca V. , Hudziak J.J. , Brignoli O. , Lapi F.
Published: September 2016

Background

Mood disorders are managed predominantly in primary care. However, general practitioners’ (GPs) ability to detect and diagnose patients with mood disorders is still considered unsatisfactory. The aim of the present study was to identify predictors for the early recognition of depressive disorder (DD) and bipolar disorder (BD) in general practice.

Methods

A cohort of 1,144,622 patients (605,285 women, 539,337 men) was investigated, using the Health Search IMS Health Longitudinal Patient Database. Predictors of DD or BD were identified at baseline encompassing somatization-related features, lifestyle variables, medical and psychiatric comorbidities. Patients were followed up as long as the following events occurred: diagnoses of DD or BD, death, end of the registration with the GP, end of the study period.

Results

We found an incidence rate of DD or BD of 53.61 and 1.5 per 10,000 person-years, respectively. For both the conditions, the incidence rate grew with age. Most of the lifestyle variables and medical comorbidities increased the risk of mood disorders. The strongest effect was found for migraine/headache (HR [95% CI] = 1.32 [1.26–1.38]), fatigue (1.32 [1.25–1.39]) irritable bowel syndrome (1.15 [1.08-1.23]), and pelvic inflammation disease (1.28 [1.18–1.38]).

Conclusions

Several predictors, in particular somatic symptoms, could be interpreted as an early sign of a mood disorder, and represent a valid indication for the GPs diagnostic process of mental disorders.
What is the minimal dose of cognitive behavior therapy for psychosis? An approximation using repeated assessments over 45 sessions
Authors: Lincoln T.M. , Jung E. , Wiesjahn M. , Schlier B.
Published: September 2016

Background

The general efficacy of cognitive behavior therapy for psychosis (CBTp) is well established. Although guidelines recommend that CBTp should be offered over a minimum of 16 sessions, the minimal number of sessions required to achieve significant changes in psychopathology has not been systematically investigated. Empirically informed knowledge of the minimal and optimal dose of CBTp is relevant in terms of dissemination and cost-effectiveness.

Methods

We approached the question of what constitutes an appropriate dose by investigating the dose (duration of CBTp) × response (symptomatic improvement) relationship for positive symptoms, negative symptoms and depression. Patients with psychotic disorders (n = 58) were assessed over the course of 45 sessions of CBTp in a clinical practice setting. At baseline and after session 5, 15, 25, and 45, general psychopathology, psychotic symptoms, symptom distress and coping were assessed with self-report questionnaires. Additionally, individually defined target symptoms and coping were assessed after each session.

Results

Significant symptom improvement and reduction of symptom distress took place by session 15, and stayed fairly stable thereafter. The frequency of positive and negative symptoms reached a minimum by session 25.

Conclusions

Our findings support recommendations to provide CBTp over a minimum of 16 sessions and indicate that these recommendations are generalizable to clinical practice settings. However, the findings also imply that 25 sessions are the more appropriate dose. This study contributes to an empirically informed discussion on the minimal and optimal dose of CBTp. It also provides a basis for planning randomized trials comparing briefer and longer versions of CBTp.
Oxford Nanopore MinION Sequencing and Genome Assembly
Authors: Lu Hengyun , Giordano Francesca , Ning Zemin
Published: September 2016

The revolution of genome sequencing is continuing after the successful second-generation sequencing (SGS) technology. The third-generation sequencing (TGS) technology, led by Pacific Biosciences (PacBio), is progressing rapidly, moving from a technology once only capable of providing data for small genome analysis, or for performing targeted screening, to one that promises high quality de novo assembly and structural variation detection for human-sized genomes. In 2014, the MinION, the first commercial sequencer using nanopore technology, was released by Oxford Nanopore Technologies (ONT). MinION identifies DNA bases by measuring the changes in electrical conductivity generated as DNA strands pass through a biological pore. Its portability, affordability, and speed in data production makes it suitable for real-time applications, the release of the long read sequencer MinION has thus generated much excitement and interest in the genomics community. While de novo genome assemblies can be cheaply produced from SGS data, assembly continuity is often relatively poor, due to the limited ability of short reads to handle long repeats. Assembly quality can be greatly improved by using TGS long reads, since repetitive regions can be easily expanded into using longer sequencing lengths, despite having higher error rates at the base level. The potential of nanopore sequencing has been demonstrated by various studies in genome surveillance at locations where rapid and reliable sequencing is needed, but where resources are limited.
Cigarette smoke exposure during adolescence but not adulthood induces anxiety‐like behavior and locomotor stimulation in rats during withdrawal
Authors: de la Peña June Bryan , Ahsan Hafiz Muhammad , Botanas Chrislean Jun , dela Peña Irene Joy , Woo Taeseon , Kim Hee Jin , Cheong Jae Hoon
Published: September 2016

Adolescence is a critical period for cigarette smoking. Studies have shown that adolescent smokers are more likely to become addicted, are less likely to quit, and are more prone to relapse. In the present study, we examined the affective symptoms experienced by adolescents during withdrawal from cigarette smoke exposure. Towards this goal, adolescent male rats were repeatedly exposed to cigarette smoke, through an automated smoking machine, for 14 days. Then, cigarette smoke exposure was discontinued to induce spontaneous withdrawal. During the withdrawal period, anxiety‐like behavior (elevated plus‐maze test), locomotor activity (open‐field test), and learning and memory (passive‐avoidance test) were evaluated. These behavioral evaluations were conducted during the first, third, seventh, and fourteenth day of withdrawal. For comparison, parallel experiments were performed in adult rats. We found that adolescent rats exposed to cigarette smoke experiences increased anxiety‐like behavior and locomotor activity during withdrawal relative to control rats. Learning and memory processes were undisturbed. On the other hand, adult rats exposed to cigarette smoke did not show any statistically significant behavioral alteration during withdrawal. These results are consistent with the notion that adolescents are differentially sensitive to the withdrawal effects of cigarette smoking. This sensitivity might be a factor why adolescent smokers have difficulty quitting and are more prone to relapse.
Examining Biased Assimilation of Brand-related Online Reviews☆
Authors: Mafael Alexander , Gottschalk Sabrina A. , Kreis Henning
Published: September 2016

This paper examines the impact of pre-existing brand attitudes on consumer processing of electronic word-of-mouth (eWOM). This topic is particularly important for brands that simultaneously possess strongly pronounced proponents as well as opponents. Two experimental studies using univalent (study 1, N = 538) and mixed (study 2, N = 262) sets of online reviews find indications for biased assimilation effects of eWOM processing. Consumers perceive positive (negative) arguments in online reviews as more (less) persuasive when having a positive (negative) attitude towards the brand. Perceived persuasiveness in turn influences behavioral intentions and acts as a mediator on the relationship between attitude and behavioral intentions. We examine two moderators of this effect. When priming individuals to focus on other consumers (vs. a self-focus prime), the biased assimilation effect is weaker (study 3a, N = 131). In contrast, we show that biased assimilation becomes stronger under conditions of high (vs. low) cognitive impairment (study 3b, N = 124). Our findings contribute to the literature on the relationship between eWOM and brands and advance our understanding of potential outcomes of brand polarization.
Cocktail supplement with rosiglitazone: a novel inducer for chicken preadipocyte differentiation in vitro
Authors: Cheng Bohan , Wu Mengqi , Xu Songsong , Zhang Xinyang , Wang Yuxiang , Wang Ning , Leng Li , Li Hui
Published: September 2016

The preadipocyte differentiation biological process involves a cascade of transcriptional events that culminates in the expression of peroxisome proliferator-activated receptor (PPAR) γ. The differentiation cocktail [insulin (INS), dexamethasone (DEX) and isobutylmethylxanthine (IBMX)] can induce preadipocyte differentiation in mammals, but it is insufficient for chicken (Gallus gallus) adipogenesis. Oleate can induce chicken preadipocyte differentiation, but these differentiated preadipocytes may not be fully functional. The objective of the current study was to evaluate whether chicken preadipocytes can be induced to mature adipocytes by a novel induction method using differentiation cocktail supplemented with PPARγ agonist(s). Chicken preadipocytes cultured in cocktail supplemented with rosiglitazone or troglitazone resulted in a marked increase in lipid droplet accumulation (P<0.05), glycerol-3-phosphate dehydrogenase (GPDH) activity (P<0.05), mRNA expression level of adipocyte fatty acid-binding protein (aP2; P<0.05), G0/G1 switch gene 2 (G0S2; P<0.05) and lipolysis (P<0.05). In addition, supplementation of the cocktail with rosiglitazone promoted PPARγ mRNA expression (P<0.05). In conclusion, our data indicated that chicken preadipocytes can be induced to mature adipocytes using differentiation cocktail supplemented with rosiglitazone. The results of the present study provide a novel induction method for in vitro chicken preadipocyte differentiation.
Blockade of NF-κB and MAPK pathways by ulinastatin attenuates wear particle-stimulated osteoclast differentiation in vitro and in vivo
Authors: Ru Jiang-Ying , Xu Hai-Dong , Shi Dai , Pan Jun-Bo , Pan Xiao-Jin , Wang Yan-Fen
Published: September 2016

Ulinastatin, a urinary trypsin inhibitor (UTI), is widely used to clinically treat lipopolysaccharide (LPS)-related inflammatory disorders recently. Adherent pathogen-associated molecular patterns (PAMPs), of which LPS is the best-studied and classical endotoxin produced by Gram-negative bacteria, act to increase the biological activity of osteopedic wear particles such as polymethyl-methacrylate (PMMA) and titanium particles in cell culture and animal models of implant loosening. The present study was designed to explore the inhibitory effect of UTI on osteoclastogenesis and inflammatory osteolysis in LPS/PMMA-mediated Raw264.7 cells and murine osteolysis models, and investigate the potential mechanism. The in vitro study was divided into the control group, LPS-induced group, PMMA-stimulated group and UTI-pretreated group. UTI (500 or 5000 units/ml) pretreatment was followed by PMMA (0.5 mg/ml) with adherent LPS. The levels of inflammatory mediators including tumour necrosis factor-α (TNF-α), matrixmetallo-proteinases-9 (MMP-9) and interleukin-6 (IL-6), receptor activation of nuclear factor NF-κB (RANK), and cathepsin K were examined and the amounts of phosphorylated I-κB, MEK, JNK and p38 were measured. In vivo study, murine osteolysis models were divided into the control group, PMMA-induced group and UTI-treated group. UTI (500 or 5000 units/kg per day) was injected intraperitoneally followed by PMMA suspension with adherent LPS (2×108 particles/25 μl) in the UTI-treated group. The thickness of interfacial membrane and the number of infiltrated inflammatory cells around the implants were assessed, and bone mineral density (BMD), trabecular number (Tb.N.), trabecular thickness (Tb.Th.), trabecular separation (Tb.Sp.), relative bone volume over total volume (BV/TV) of distal femur around the implants were calculated. Our results showed that UTI pretreatment suppressed the secretion of proinflammatory cytokines including MMP-9, IL-6, TNF-α, RANK and cathepsin K through down-regulating the activity of nuclear factor kappa B (NF-κB) and MAPKs partly in LPS/PMMA-mediated Raw264.7 cells. Finally, UTI treatment decreased the inflammatory osteolysis reaction in PMMA-induced murine osteolysis models. In conclusion, these results confirm the anti-inflammatory potential of UTI in the prevention of particle disease.
Acute Cervical Disk Herniation Resulting in Sudden and Severe Neurologic Deterioration: A Case Series
Authors: Harel Ran , Knoller Nachshon
Published: September 2016

Objective Nontraumatic acute cervical disk herniation resulting in acute severe neurologic deficit is a rare entity described in a limited number of case reports. We describe the management and outcome in patients presenting with severe neurologic deterioration caused by acutely herniated cervical disks.

Methods Four patients (mean age 39.5 years) presented to our tertiary care academic medical center from September 2012 to September 2013 with severe progressive neurologic deficits due to cervical disk herniation and were included in the series. Patients' surgical, medical, and imaging records were retrospectively reviewed under an Institutional Review Board waiver of informed consent.

Results Patients in the series presented with acute neurologic deterioration, including paraparesis, Brown-Séquard syndrome, or quadriparesis deteriorating to quadriplegia. Emergent magnetic resonance imaging (MRI) scans and emergent decompression and fusion for acute soft disk herniation were performed in all cases. All patients recovered to excellent functional status with Frankel score improvement from B (one patient)/C (three patients) to E (three patients)/D (one patient).

Conclusions Acute cervical disk herniation with acute neurologic deterioration is a medical emergency necessitating emergent MRI and surgical decompression. Clinical presentation varies. In patients with rapid-onset neurologic deterioration, a high level of suspicion for this rare entity is indicated.
Absence of visual experience modifies the neural basis of numerical thinking
Authors: Kanjlia Shipra , Lane Connor , Feigenson Lisa , Bedny Marina
Published: September 2016

Significance

Human numerical reasoning relies on a cortical network that includes frontal and parietal regions. We asked how the neural basis of numerical reasoning is shaped by experience by comparing congenitally blind and sighted individuals. Participants performed auditory math and language tasks while undergoing fMRI. Both groups activated frontoparietal number regions during the math task, suggesting that some aspects of the neural basis of numerical cognition develop independently of visual experience. However, blind participants additionally recruited early visual cortices that, in sighted populations, perform visual processing. In blindness, these “visual” areas showed sensitivity to mathematical difficulty. These results suggest that experience can radically change the neural basis of numerical thinking. Hence, human cortex has a broad computational capacity early in development.
Visualization of the spontaneous emergence of a complex, dynamic, and autocatalytic system
Authors: Ortega-Arroyo Jaime , Bissette Andrew J. , Kukura Philipp , Fletcher Stephen P.
Published: September 2016

Significance

Chemical reproduction is central to biology, and understanding how chemical systems may give rise to complex systems that form self-reproducing cell-like structures is a leading goal for scientists. Here we use an ultrasensitive optical microscopy technique to directly monitor the formation and dynamics of self-replicating supramolecular structures at the single-particle level. As a result, we are able to quantify the kinetics of these systems and changes in nanoparticle distribution over time. Our ability to observe a variety of complex phenomena may contribute to understanding how cell-like systems can emerge from much simpler chemical components and provides a general route to studying assembly and disassembly on the nanoscale.
Convergent evolution of caffeine in plants by co-option of exapted ancestral enzymes
Authors: Huang Ruiqi , O’Donnell Andrew J. , Barboline Jessica J. , Barkman Todd J.
Published: September 2016

Significance

Convergent evolution is responsible for generating similar traits in unrelated organisms, such as wings that allow flight in birds and bats. In plants, one of the most prominent examples of convergence is that of caffeine production, which has independently evolved in numerous species. In this study, we reveal that even though the caffeine molecule is identical in the cacao, citrus, guaraná, coffee, and tea lineages, it is produced by different, previously unknown, biosynthetic pathways. Furthermore, by resurrecting extinct enzymes that ancient plants once possessed, we show that the novel pathways would have evolved rapidly because the ancestral enzymes were co-opted from previous biochemical roles to those of caffeine biosynthesis for which they were already primed.
Omega-3 long-chain polyunsaturated fatty acids support aerial insectivore performance more than food quantity
Authors: Twining Cornelia W. , Brenna J. Thomas , Lawrence Peter , Shipley J. Ryan , Tollefson Troy N. , Winkler David W.
Published: September 2016

Significance

Insect abundance is an important predictor of survival and performance for many taxa of aerial insectivores, which forage on a mixture of aquatic and terrestrial insects that differ in fatty acid composition, particularly omega-3 long-chain polyunsaturated fatty acid (LCPUFA) content. We raised Tree Swallow (
Tachycineta bicolor
) chicks on either a high or low quantity of feed with either high amounts of the LCPUFA found in aquatic insects or an equivalent amount of the precursor omega-3 PUFA, alpha-linolenic acid, but low LCPUFA. LCPUFA content was more important for Tree Swallow chick performance than food quantity. Tree Swallows may be timing breeding to coincide with the peak abundance of high-LCPUFA aquatic insects.
Low-cost functional plasticity of TRPV1 supports heat tolerance in squirrels and camels
Authors: Laursen Willem J. , Schneider Eve R. , Merriman Dana K. , Bagriantsev Sviatoslav N. , Gracheva Elena O.
Published: September 2016

Significance

Thirteen-lined ground squirrels and Bactrian camels are capable of withstanding elevated environmental temperatures. In mammals, the polymodal transient receptor potential vanilloid 1 (TRPV1) ion channel responds to temperatures >40 °C and marks peripheral neurons responsible for detecting noxious heat. However, we find that both squirrels and camels express TRPV1 channels with dramatic decreases in thermosensitivity in the physiologically relevant range. To regain heat sensitivity, squirrel and camel TRPV1 require substitution of a single conserved amino acid. These data point to a common molecular mechanism used by camels and squirrels to adapt to high temperatures and reveal a remarkable functional plasticity of temperature activation of the TRPV1 channel.
Land-use and climate change risks in the Amazon and the need of a novel sustainable development paradigm
Authors: Nobre Carlos A. , Sampaio Gilvan , Borma Laura S. , Castilla-Rubio Juan Carlos , Silva José S. , Cardoso Manoel
Published: September 2016

Significance

The Amazonian tropical forests have been disappearing at a fast rate in the last 50 y due to deforestation to open areas for agriculture, posing high risks of irreversible changes to biodiversity and ecosystems. Climate change poses additional risks to the stability of the forests. Studies suggest “tipping points” not to be transgressed: 4° C of global warming or 40% of total deforested area. The regional development debate has focused on attempting to reconcile maximizing conservation with intensification of traditional agriculture. Large reductions of deforestation in the last decade open up opportunities for an alternative model based on seeing the Amazon as a global public good of biological assets for the creation of high-value products and ecosystem services.
Leveraging premalignant biology for immune-based cancer prevention
Authors: Spira Avrum , Disis Mary L. , Schiller John T. , Vilar Eduardo , Rebbeck Timothy R. , Bejar Rafael , Ideker Trey , Arts Janine , Yurgelun Matthew B. , Mesirov Jill P. , Rao Anjana , Garber Judy , Jaffee Elizabeth M. , Lippman Scott M.
Published: September 2016

Prevention is an essential component of cancer eradication. Next-generation sequencing of cancer genomes and epigenomes has defined large numbers of driver mutations and molecular subgroups, leading to therapeutic advances. By comparison, there is a relative paucity of such knowledge in premalignant neoplasia, which inherently limits the potential to develop precision prevention strategies. Studies on the interplay between germ-line and somatic events have elucidated genetic processes underlying premalignant progression and preventive targets. Emerging data hint at the immune system’s ability to intercept premalignancy and prevent cancer. Genetically engineered mouse models have identified mechanisms by which genetic drivers and other somatic alterations recruit inflammatory cells and induce changes in normal cells to create and interact with the premalignant tumor microenvironment to promote oncogenesis and immune evasion. These studies are currently limited to only a few lesion types and patients. In this Perspective, we advocate a large-scale collaborative effort to systematically map the biology of premalignancy and the surrounding cellular response. By bringing together scientists from diverse disciplines (e.g., biochemistry, omics, and computational biology; microbiology, immunology, and medical genetics; engineering, imaging, and synthetic chemistry; and implementation science), we can drive a concerted effort focused on cancer vaccines to reprogram the immune response to prevent, detect, and reject premalignancy. Lynch syndrome, clonal hematopoiesis, and cervical intraepithelial neoplasia which also serve as models for inherited syndromes, blood, and viral premalignancies, are ideal scenarios in which to launch this initiative.
Autophagy induction stabilizes microtubules and promotes axon regeneration after spinal cord injury
Authors: He Miao , Ding Yuetong , Chu Chen , Tang Jing , Xiao Qi , Luo Zhen-Ge
Published: September 2016

Significance

Autophagy maintains cellular homoeostasis by bulk or selective degradation of cytoplasmic components including organelles or protein aggregates. Its role in axon regeneration remains speculative. Here, we found that boosting autophagy stabilized microtubules by degrading a microtubule destabilizing protein, SCG10 (superior cervical ganglia protein 10), in cultured CNS neurons and promoted axon growth. Furthermore, treatment with a specific autophagy-inducing peptide, Tat-beclin1, attenuated axon retraction, promoted axon regeneration, and improved locomotor functional recovery in mice with spinal cord injury. This study reveals a critical role of autophagy in stabilizing neuronal microtubules and a promising therapeutic effect of an autophagy-inducing reagent on CNS axons following injury.
Learning relay start strategies in swimming: What feedback is best?
Authors: Fischer Sebastian , Braun Claudia , Kibele Armin
Published: September 2016

In the past, studies and book recommendations on relay starts in swimming have been predominantly focused on the change‐over time (COT) as a performance criterion. Aside from the circular backswing start with parallel foot placement, few studies have analysed differences in the take‐off movement including step approaches as well. Although trends could be identified, the results remained still somewhat inconclusive. In contrast, no study has examined as has examined whether a reduction of COT in between wall contact of the income swimmer and the take‐off of the outgoing swimmer is an optimal relay start strategy, as advocated by various swimming experts. Therefore, the purpose of this study was to compare two different relay start strategies: offensive strategy minimizing COT and conservative strategy to maximize horizontal peak force (HPF). In this regard, a learning intervention with 24 elite‐level swimmers (12 females, 12 male) was conducted to compare both strategies regarding relay start time, HPF and COT. Subjects were randomly assigned to two feedback groups: COT versus HPF at take‐off. The results of this study showed a clear advantage for HPF feedback for relay start performance measured by wall contact of the incoming swimmer and head passage at 7.5 m of the outgoing swimmer. In addition, similar reductions in COTs were found in both training groups. In conclusion, swimmers should focus on force production rather than minimizing COT. For the latter, deteriorating consequences for force production must be considered.
MSAProbs-MPI: parallel multiple sequence aligner for distributed-memory systems
Authors: González-Domínguez Jorge , Liu Yongchao , Touriño Juan , Schmidt Bertil
Published: September 2016

Summary:  MSAProbs is a state-of-the-art protein multiple sequence alignment tool based on hidden Markov models. It can achieve high alignment accuracy at the expense of relatively long runtimes for large-scale input datasets. In this work we present MSAProbs-MPI, a distributed-memory parallel version of the multithreaded MSAProbs tool that is able to reduce runtimes by exploiting the compute capabilities of common multicore CPU clusters. Our performance evaluation on a cluster with 32 nodes (each containing two Intel Haswell processors) shows reductions in execution time of over one order of magnitude for typical input datasets. Furthermore, MSAProbs-MPI using eight nodes is faster than the GPU-accelerated QuickProbs running on a Tesla K20. Another strong point is that MSAProbs-MPI can deal with large datasets for which MSAProbs and QuickProbs might fail due to time and memory constraints, respectively.

Availability and Implementation: Source code in C ++ and MPI running on Linux systems as well as a reference manual are available at http://msaprobs.sourceforge.net

Contact:  jgonzalezd@udc.es

Supplementary information:  Supplementary data are available at Bioinformatics online.
Predicting neutropenia risk in patients with cancer using electronic data
Authors: Pawloski Pamala A , Thomas Avis J , Kane Sheryl , Vazquez-Benitez Gabriela , Shapiro Gary R , Lyman Gary H
Published: September 2016

Objectives: Clinical guidelines recommending the use of myeloid growth factors are largely based on the prescribed chemotherapy regimen. The guidelines suggest that oncologists consider patient-specific characteristics when prescribing granulocyte-colony stimulating factor (G-CSF) prophylaxis; however, a mechanism to quantify individual patient risk is lacking. Readily available electronic health record (EHR) data can provide patient-specific information needed for individualized neutropenia risk estimation. An evidence-based, individualized neutropenia risk estimation algorithm has been developed. This study evaluated the automated extraction of EHR chemotherapy treatment data and externally validated the neutropenia risk prediction model.

Materials and Methods: A retrospective cohort of adult patients with newly diagnosed breast, colorectal, lung, lymphoid, or ovarian cancer who received the first cycle of a cytotoxic chemotherapy regimen from 2008 to 2013 were recruited from a single cancer clinic. Electronically extracted EHR chemotherapy treatment data were validated by chart review. Neutropenia risk stratification was conducted and risk model performance was assessed using calibration and discrimination.

Results: Chemotherapy treatment data electronically extracted from the EHR were verified by chart review. The neutropenia risk prediction tool classified 126 patients (57%) as being low risk for febrile neutropenia, 44 (20%) as intermediate risk, and 51 (23%) as high risk. The model was well calibrated (Hosmer-Lemeshow goodness-of-fit test = 0.24). Discrimination was adequate and slightly less than in the original internal validation (c-statistic 0.75 vs 0.81).

Conclusion: Chemotherapy treatment data were electronically extracted from the EHR successfully. The individualized neutropenia risk prediction model performed well in our retrospective external cohort.