bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional characterization of retinal ganglion cells using tailored nonlinear modeling
Authors: Shi Qing , Gupta Pranjal , Boukhvalova Alexandra , Singer Joshua H. , Butts Daniel A.
Published: September 2018

There are 20-50 functionally- and anatomically-distinct ganglion cell types in the mammalian retina; each type encodes a unique feature of the visual world and conveys it via action potentials to the brain. Individual ganglion cells receive input from unique presynaptic retinal circuits, and the characteristic patterns of light-evoked action potentials in each ganglion cell type therefore reflect computations encoded in synaptic input and in postsynaptic signal integration and spike generation. Unfortunately, there is a dearth of tools for characterizing retinal ganglion cell computation. Therefore, we developed a statistical model, the separable Nonlinear Input Model, capable of characterizing the large array of distinct computations reflected in retinal ganglion cell spiking. We recorded ganglion cell responses to a correlated noise (“cloud”) stimulus designed to accentuate the important features of retinal processing in an in vitro preparation of mouse retina and found that this model accurately predicted ganglion cell responses at high spatiotemporal resolution. It identified multiple receptive fields (RFs) reflecting the main excitatory and suppressive components of the response of each neuron. Most significantly, our model succeeds where others fail, accurately identifying ON-OFF cells and segregating their distinct ON and OFF selectivity and demonstrating the presence of different types of suppressive receptive fields. In total, our computational approach offers rich description of ganglion cell computation and sets a foundation for relating retinal computation to retinal circuitry.
Spidey: A Tool for mRNA-to-Genomic Alignments
Authors: Wheelan Sarah J. , Church Deanna M. , Ostell James M.
Published: September 2018

We have developed a computer program that aligns spliced sequences to genomic sequences, using local alignment algorithms and heuristics to put together a global spliced alignment. Spidey can produce reliable alignments quickly, even when confronted with noise from alternative splicing, polymorphisms, sequencing errors, or evolutionary divergence. We show how Spidey was used to align reference sequences to known genomic sequences and then to the draft human genome, to align mRNAs to gene clusters, and to align mouse mRNAs to human genomic sequence. We compared Spidey to two other spliced alignment programs; Spidey generally performed quite well in a very reasonable amount of time.
High-Throughput Variation Detection and Genotyping Using Microarrays
Authors: Cutler David J. , Zwick Michael E. , Carrasquillo Minerva M. , Yohn Christopher T. , Tobin Katherine P. , Kashuk Carl , Mathews Debra J. , Shah Nila A. , Eichler Evan E. , Warrington Janet A. , Chakravarti Aravinda
Published: September 2018

The genetic dissection of complex traits may ultimately require a large number of SNPs to be genotyped in multiple individuals who exhibit phenotypic variation in a trait of interest. Microarray technology can enable rapid genotyping of variation specific to study samples. To facilitate their use, we have developed an automated statistical method (ABACUS) to analyze microarray hybridization data and applied this method to Affymetrix Variation Detection Arrays (VDAs). ABACUS provides a quality score to individual genotypes, allowing investigators to focus their attention on sites that give accurate information. We have appliedABACUS to an experiment encompassing 32 autosomal and eight X-linked genomic regions, each consisting of ∼50 kb of unique sequence spanning a 100-kb region, in 40 humans. At sufficiently high-quality scores, we are able to read ∼80% of all sites. To assess the accuracy of SNP detection, 108 of 108 SNPs have been experimentally confirmed; an additional 371 SNPs have been confirmed electronically. To access the accuracy of diploid genotypes at segregating autosomal sites, we confirmed 1515 of 1515 homozygous calls, and 420 of 423 (99.29%) heterozygotes. In replicate experiments, consisting of independent amplification of identical samples followed by hybridization to distinct microarrays of the same design, genotyping is highly repeatable. In an autosomal replicate experiment, 813,295 of 813,295 genotypes are called identically (including 351 heterozygotes); at an X-linked locus in males (haploid), 841,236 of 841,236 sites are called identically.
Microcredit and technology adoption
Authors: Mariyono Joko
Published: September 2018

Purpose

The purpose of this paper is to analyze the impact of microcredit and agronomic technology on farm households’ prosperity, and to determine important factors affecting farmers’ access to microcredit and technology adoption in Indonesian intensive farming.

Design/methodology/approach

The focus of the study was farmers engaging with chili-based agribusiness in rural areas. Data for this study were compiled from a survey that interviewed 250 farm households. Samples of the study were randomly selected from chili farming community in three regions of Java during 2013–2014. Data were analyzed using structural equation modeling (SEM).

Findings

Microcredit provided positive direct and indirect impacts on household prosperity. Microcredit indirectly impacted the well-being through the mediation of technology adoption. Farmers’ characteristics and agribusiness environment determined farmers’ decision to access microcredit and adopt advanced technology. Microcredit and technology have enhanced farmers’ well-being through pathways that enabled farmers to develop farming scale.

Practical implications

The government should offer more alternatives to advanced technology and flexible procedures of access to credit at the same time to ensure sustained pathways of rural economic growth in Indonesia.

Originality/value

This paper applied a SEM to a proposition of simultaneous causal interrelations among microcredit, technology and farmers’ prosperity.
Applying the physics of notation to the evaluation of a security and privacy requirements engineering methodology
Authors: Diamantopoulou Vasiliki , Mouratidis Haralambos
Published: September 2018

Purpose

The purpose of this study is the analysis of a security and privacy requirements engineering methodology. Such methodologies are considered an important part of systems’ development process when they contain and process a large amount of critical information, and thus need to remain secure and ensure privacy.

Design/methodology/approach

These methodologies provide techniques, methods and norms for tackling security and privacy issues in information systems. In this process, the utilisation of effective, clear and understandable modelling languages with sufficient notation is of utmost importance, as the produced models are used not only among IT experts or among security specialists but also for communication among various stakeholders, in business environments or among novices in an academic environment.

Findings

The qualitative analysis revealed a partial satisfaction of these principles.

Originality/value

This paper evaluates the effectiveness of a security and privacy requirements engineering methodology, namely, Secure Tropos, on the nine principles of the theory of notation.
Is too much inclusive leadership a good thing? An examination of curvilinear relationship between inclusive leadership and employees’ task performance
Authors: Xiaotao Zheng , Yang Xiaoling , Diaz Ismael , Yu Mingchuan
Published: September 2018

Purpose

The purpose of this paper is to examine the inclusive leadership’s too-much-of-a-good-thing effect (TMGT effect) and illustrate the possibility of the potential drawbacks of inclusive leadership.

Design/methodology/approach

In total, 191 questionnaires were valid and used in the study. Employee participants were asked to report their direct supervisor’s inclusive leadership. Employees’ direct supervisors were asked to rate employees’ task performance to minimize common method variance. The authors use regression analysis to test the hypothesis.

Findings

An inverted U-shape characterizes the relationship between inclusive leadership and subordinates’ task performance. Specifically, employees’ task performance is low when the supervisor’s inclusive leadership is low; task performance increases when inclusive leadership is from low to moderate levels, and task performance decreases when inclusive leadership is from moderate to high levels.

Originality/value

The study sheds light on inclusive leadership, especially the inclusive leadership in Chinese context. In addition, this finding is important as it investigates the inclusion’s TMGT effect which is rare in organizational research, and the findings also provide additional evidence of TMGT effect in management fields.
Twelve years of low nutrient input stimulates growth of trees and dwarf shrubs in the treeline ecotone
Authors: Möhl Patrick , Mörsdorf Martin A. , Dawes Melissa A. , Hagedorn Frank , Bebi Peter , Viglietti Davide , Freppaz Michele , Wipf Sonja , Körner Christian , Thomas Frank M. , Rixen Christian
Published: September 2018

Almost all natural terrestrial ecosystems are nutrient limited in terms of growth, and we expect treeline vegetation to be no exception. However, direct constraints of low temperature on tissue formation may superimpose effects of low nutrient availability.

We examined growth responses of two tree (Larix deciduaandPinus uncinata) and two dwarf shrub species (Vaccinium myrtillusandVaccinium gaultherioides) to 12 years of moderate fertilizer addition (NPK applied at a rate of 15 and 30 kg nitrogen ha−1 a−1) along an elevation gradient within the treeline ecotone in the Swiss Alps (2,083 to 2,225 m a.s.l.). We measured annual top‐ and side‐shoot increments as well as stem ring width in trees and shoot increments in dwarf shrubs.

Fertilizer addition increased soil nutrient availability, indicated by enhanced soil extractable N, higher concentrations of N, P and K in leaves and higher foliar δ15N.

Fertilizer addition stimulated annual growth of all four species: by 11%–20% forL. deciduaand 15%–36% forP. uncinata(depending on trait) and by 8%–16% for the two dwarf shrub species. Growth stimulation by the higher fertilizer dose was not significantly stronger than by the lower dose (except forV. gaultherioides), suggesting an overall low nutrient demand for growth and saturation at a rather low nutrient input.

Synthesis. Even slightly enhanced nutrient availability can stimulate growth of trees and dwarf shrubs in an alpine treeline ecosystem. Ongoing atmospheric nutrient deposition, in conjunction with global warming, may accelerate plant growth at the treeline.
Beyond “bouncing back”: Towards an integral, capability‐based understanding of organizational resilience
Authors: Darkow Philipp M.
Published: September 2018

Academic debates surrounding the notion of resilience still face dissent about definitions, contexts, and managerial implications. By summarizing recent literature on resilience, this paper reveals two dominating paradigms, which I label the Plan to Resist Approach and the Containing Crisis Approach. By pinpointing and challenging the underlying assumptions of both approaches, I elucidate their potential shortcomings. To overcome these limitations, I develop an integral, capability‐based concept of organizational resilience, which builds on a temporal perspective on crises. Thereby it highlights the importance of enacting different yet specific capabilities at different phases of crises. This concept allows integrating the insights of the reviewed literature and sheds light on the recovery phase as being a so far neglected aspect in resilience research.
Influence of Physical Exercise on the Dialytic Adequacy Parameters of Patients on Hemodialysis
Authors: García Testal Alicia , García Maset Rafael , Hervás Marín David , Pérez‐Domínguez Borja , Royo Maicas Pilar , Rico Salvador Inmaculada Soledad , Meléndez‐Oliva Erika , Molina Aracil Javier , Murgui Chiva MªJosé , Del pozo Blanco Olga , Olagüe Díaz Pau , Fernández Najera Jose Enrique , Torregrosa De Juan Eduardo , Benedito Carrera Caterina , Segura‐Ortí Eva
Published: September 2018

It has been suggested that physical exercise in chronic hemodialysis could improve dialysis dose and reduce postdialysis rebound. A randomized controlled trial was performed to compare a group of patients doing physical exercise during the first 2 h of hemodialysis sessions and another group doing physical exercise at home. The descriptive variables, dialysis doses measured by KtV, and rebounds (urea, creatinine, potassium, phosphorus), were recorded. For 69 patients: the mean KtV was 1.84; the 30‐min rebound of creatinine was 32.37%, urea 24.39%, potassium 15.31%, and phosphorus 51.29%. For each patient, the basal measurement was compared with those determined when performing physical exercise; no statistically significant differences were observed between the changes determined to dose and rebound in the group with hemodialysis exercise compared to those of the home exercise group. In conclusion, performing physical exercise during the first 2 hours of hemodialysis sessions neither lowered postdialysis molecules rebound nor improved dialysis dose.
The emergence of human capital: Roles of social capital and coordination that drive unit performance
Authors: Harris Christopher M. , Wright Patrick M. , McMahan Gary C.
Published: September 2018

Empirical work on human capital has tended to focus on the direct effects of human capital on performance, whereas little attention has been paid to behaviours through which human capital influences performance. This study uses the “human capital emergence” model to examine relationships among human capital, social capital, coordination, and performance over a 2‐year period of time. Findings indicate that human capital, social capital, and coordination each influence performance. Human capital and social capital also positively predict coordination. Lastly, coordination mediates the relationships between human capital and performance and social capital and performance.
Lactobacillus reuteri F‐9‐35 Prevents DSS‐Induced Colitis by Inhibiting Proinflammatory Gene Expression and Restoring the Gut Microbiota in Mice
Authors: Sun Mao‐cheng , Zhang Fu‐cheng , Yin Xue , Cheng Bi‐jun , Zhao Chang‐hui , Wang Yan‐ling , Zhang Zheng‐zhe , Hao Hong‐wei , Zhang Tie‐hua , Ye Hai‐qing
Published: September 2018

Probiotics are considered to be a potential treatment for ulcerative colitis (UC). The aim of this study was to compare the preventive effect of a space flight‐induced mutant L. reuteri F‐9‐35 and its wild type on UC in vivo. Female mice were randomly assigned to five groups: one normal and four colitic. Mice from colitis groups were daily gavaged with 0.2 mL 12% (w/v) skim milk containing the mutant or wild type (1 × 1011 CFU/mL), skim milk alone or distilled water for the whole experiment period, starting 7 days before colitis induction. UC was induced by administrating mice with 3.5% (w/v) dextran sulfate sodium (DSS) in drinking water for 7 days, after which DSS was removed and maintained for 3 days as a recovery phase. The results showed that the mice fed with L. reuteri F‐9‐35 had less inflammatory phenotype according to macroscopic and histological analysis, reduced myeloperoxidase activity, and lower expression of proinflammatory genes (Tumor necrosis factor‐α, cyclooxygenase‐2 and interleukin‐6) in colonic tissue compared with control. Furthermore, L. reuteri F‐9‐35 protected the mice from gut microbiota dysbiosis from DDS induced colitis. Neither wild type nor the milk alone had such beneficial effects. From above we conclude that L. reuteri F‐9‐35 has great potential in the prevention of UC as a dietary supplement.

Practical Application

Ulcerative colitis (UC) is the most common inflammatory bowel diseases and there is still a lack of safe and effective treatments. Consumption of L. reuteri F‐9‐35 may effective in preventing human UC.
In Vitro Digestion of Lipids in Real Foods: Influence of Lipid Organization Within the Food Matrix and Interactions with Nonlipid Components
Authors: Calvo‐Lerma Joaquim , Fornés‐Ferrer Victoria , Heredia Ana , Andrés Ana
Published: September 2018

In vitro digestion research has scarcely addressed the assessment of the complexity of digestion in real food. The aim of the present study was to evaluate the influence of intestinal conditions, nonlipid components, and lipid organization within the food matrix on lipolysis extent. A selection of 52 foods was studied under different simulated intestinal conditions, including those related to patients with cystic fibrosis (pH6, bile salts 1 mM due to decreased pancreatic and biliary secretions) and to healthy subjects (pH7, bile salts 10 mM). Linear mixed regression models were applied to explain associations of food properties with lipolysis. Normal intestinal conditions allowed for optimal lipolysis in most of the foods in contrast to the altered intestinal scenario (30 compared with 1 food reaching > 90% lipolysis). Lipid‐protein and lipid‐starch interactions were evidenced to significantly affect lipolysis (P < 0.001) in all the digestion conditions, decreasing in those foods with low fat and high protein or high starch content. In addition, under decreased intestinal pH and bile concentration, lipolysis was lower in foods with complex solid structures and continuous lipid phase than in the oil‐in‐water continuous aqueous phase (global P < 0.01). However, in the normal conditions lipid organization within the food matrix did not show a significant effect on lipolysis (global P = 0.08). In conclusion, food properties play a crucial role in lipolysis, which should be considered when establishing dietary recommendations.

Practical Application

Food composition, lipid organization within the food matrix, and gastrointestinal conditions are key factors affecting lipolysis. Knowledge on that can be used to modulate lipolysis performance after food ingestion. Different applications are foreseen, as food design and nutritional recommendations for the general populations and specific target groups. The most immediate application is related to the scope of the research project that frames this work (www.mycyfapp.eu). These results have contributed to the development of a mobile app for cystic fibrosis patients, which includes an algorithm for enzyme dose prediction based on food properties. The app is currently being tested in a clinical trial setting.
Targeting the ICOS/ICOS‐L pathway in a mouse model of established allergic asthma disrupts T follicular helper cell responses and ameliorates disease
Authors: Uwadiae Faith I. , Pyle Chloe J. , Walker Simone A. , Lloyd Clare M. , Harker James A.
Published: September 2018

Background

Allergic asthma is characterized by chronic inflammation and remodelling of the airways, associated with dysregulated type 2 immune responses and allergen‐specific IgE. T follicular helper cells (TFH) are crucial in T‐dependent B‐cell responses and have been implicated in allergic airway disease (AAD). TFH, unlike other CD4+ T cells, are uniquely reliant on continuous ICOS signalling to maintain their phenotype after T‐cell priming; therefore, disrupting this signal can impair TFH responses. However, the contribution of TFH to disease during chronic aero‐allergen exposure and the therapeutic potential of targeting these cells have not been evaluated.

Methods

To establish AAD, female BALB/c mice were repeatedly exposed to house dust mite or Alternaria alternata three times a week for up to 5 weeks. To examine the impact of TFH on AAD, mice were allergen exposed for 5 weeks and co‐administered anti‐ICOS Ligand‐targeted antibodies, three times a week for the last 2 weeks.

Results

TFH were first observed in the lung‐draining lymph nodes and with further exposure were also found locally within the lungs. TFH accumulated with sustained allergen exposure, alongside germinal centre (GC) B cells. Blockade of ICOS signalling after AAD establishment successfully depleted TFH but did not affect the differentiation of other CD4+ T‐cell subsets. This reduced GC responses, allergen‐specific IgE, inflammation, pulmonary IL‐13 and airway hyper‐responsiveness.

Conclusions

TFH are crucial in the regulation of AAD and the ICOS/ICOS‐L pathway could represent a novel therapeutic target in allergic asthma.
Increased Plasma‐Free Hemoglobin Levels Identify Hemolysis in Patients With Cardiogenic Shock and a Trans valvular Micro‐Axial Flow Pump
Authors: Esposito Michele L. , Morine Kevin J. , Annamalai Shiva K. , O’Kelly Ryan , Aghili Nima , Pedicini Robert , Breton Catalina , Mullin Andrew , Hamadeh Anas , Kiernan Michael S. , DeNofrio David , Kapur Navin K.
Published: September 2018

Hemolysis is a potential limitation of percutaneously delivered left‐sided mechanical circulatory support pumps, including trans valvular micro‐axial flow pumps (TVP). Hemolytic biomarkers among durable left ventricular assist devices include lactate dehydrogenase (LDH) >2.5 times the upper limit of normal (ULN) and plasma‐free hemoglobin (pf‐Hb) >20 mg/dL. We examined the predictive value of these markers among patients with cardiogenic shock (CS) receiving a TVP. We retrospectively studied records of 116 consecutive patients receiving an Impella TVP at our institution between 2012 and 2017 for CS. Twenty‐three met inclusion/exclusion criteria, and had sufficient pf‐Hb data for analysis. Area under receiver‐operator characteristic (ROC) curve for diagnosing hemolysis were calculated. Mean age was 62 ± 14 years and ejection fraction was 15 ± 5%. Mean duration of support was 5.4 ± 3.5 days. Pre‐device LDH levels were >2.5x ULN in 71% (n = 5/7) of 5.0 and 29% of CP patients, while pre‐device pf‐Hb levels were >20 mg/dL in 14% (n = 1/7) of 5.0 and 25% (n = 4/16) of CP patients. Given elevated baseline LDH and pf‐Hb levels, we defined hemolysis as a pf‐Hb level >40 mg/dL within 72 h post‐implant plus clinical evidence of device‐related hemolysis. We identified that 30% (n = 7/23) had device‐related hemolysis. Using ROC curve‐derived cut‐points, an increase in delta pf‐Hb by >27mg/dL, not delta LDH, within 24 h after TVP implant (delta pf‐Hb: C‐statistic = 0.79, sensitivity: 57%, specificity: 93%, p <0.05) was highly predictive of hemolysis. In conclusion, we identified a change in pf‐Hb, not LDH, levels is highly sensitive and specific for hemolysis in patients treated with a TVP for CS.
Neuropeptide Y treatment induces retinal vasoconstriction and causes functional and histological retinal damage in a porcine ischaemia model
Authors: Christiansen Anders T. , Sørensen Nina B. , Haanes Kristian A. , Blixt Frank W. , la Cour Morten , Warfvinge Karin , Klemp Kristian , Woldbye David P. D. , Kiilgaard Jens F.
Published: September 2018

Purpose

To investigate the effects of intravitreal neuropeptide Y (NPY) treatment following acute retinal ischaemia in an in vivo porcine model. In addition, we evaluated the vasoconstrictive potential of NPY on porcine retinal arteries ex vivo.

Methods

Twelve pigs underwent induced retinal ischaemia by elevated intraocular pressure clamping the ocular perfusion pressure at 5 mmHg for 2 hr followed by intravitreal injection of NPY or vehicle. After 4 weeks, retinas were evaluated functionally by standard and global‐flash multifocal electroretinogram (mfERG) and histologically by thickness of retinal layers and number of ganglion cells. Additionally, the vasoconstrictive effects of NPY and its involved receptors were tested using wire myographs and NPY receptor antagonists on porcine retinal arteries.

Results

Intravitreal injection of NPY after induced ischaemia caused a significant reduction in the mean induced component (IC) amplitude ratio (treated/normal eye) compared to vehicle‐treated eyes. This reduction was accompanied by histological damage, where NPY treatment reduced the mean thickness of inner retinal layers and number of ganglion cells. In retinal arteries, NPY‐induced vasoconstriction to a plateau of approximately 65% of potassium‐induced constriction. This effect appeared to be mediated via Y1 and Y2, but not Y5.

Conclusion

In seeming contrast to previous in vitro studies, intravitreal NPY treatment caused functional and histological damage compared to vehicle after a retinal ischaemic insult. Furthermore, we showed for the first time that NPY induces Y1‐ and Y2‐ but not Y5‐mediated vasoconstriction in retinal arteries. This constriction could explain the worsening in vivo effect induced by NPY treatment following an ischaemic insult and suggests that future studies on exploring the neuroprotective effects of NPY might focus on other receptors than Y1 and Y2.
Increased tacrolimus blood concentration by Beni‐Madonna – a new hybrid citrus cultivar categorized as ‘Tangor’, in a liver transplant patient: likely furanocoumarin‐mediated inhibition of CYP3A4 or P‐glycoprotein
Authors: Ushijima Kentaro , Mizuta Koichi , Otomo Shinya , Ogaki Keiko , Sanada Yukihiro , Hirata Yuta , Ihara Yoshiyuki , Urahashi Taizen , Imai Yasushi , Fujimura Akio
Published: September 2018

Adverse event

A drug interaction leading to greater exposure to tacrolimus.

Drug implicated

Tacrolimus and Beni‐Madonna (a new cultivar citrus categorized as ‘Tangor’).

The patient

A 9‐month‐old girl with biliary atresia (body weight, 7.5 kg) taking tacrolimus after liver transplantation.

Evidence that links the drug to the event

The time course was consistent with the appearance of the interaction, which was confirmed by an increase in the blood concentration of tacrolimus. Dihydroxybergamottin was detected in peel of Beni‐Madonna and in peel and fruit pulp of grapefruit.

Management

Avoiding Beni‐Madonna intake.

Mechanism

Inhibition of activity of CYP3A4, P‐glycoprotein, or both, by Beni‐Madonna.

Implication for therapy

Clinicians should be aware of this potential interaction, and patients taking drugs such as tacrolimus (the kinetics of which are affected by grapefruit juice) should avoid Beni‐Madonna intake.

Hypothesis to be tested

Further study is required to determine if other Citrus species categorized as Tangor contain furanocoumarins.
Oral fluoroquinolones and risk of fibromyalgia
Authors: Ganjizadeh‐Zavareh Saeed , Sodhi Mohit , Spangehl Tori , Carleton Bruce , Etminan Mahyar
Published: September 2018

The Food and Drug Administration (FDA) has recently included a black box warning on fibromyalgia‐like symptoms with fluoroquinolones (FQs) but no large epidemiologic study is to date available. We undertook a case–control study using a random sample of 9 053 240 subjects obtained from the PharMetrics Plus health claims database in the United States. Cases received at least two fibromyalgia diagnoses coded by a rheumatologist matched to ten randomly selected controls. After identifying 5148 cases of fibromyalgia and 51 480 controls, the adjusted rate ratio (RR) of fibromyalgia for use of any fluoroquinolones, amoxicillin and azithromycin were 1.63 (95% CI: 1.41–1.87), 1.64 (95% CI: 1.46–1.85) and 1.68 (95% CI, 1.49–1.89), respectively. The adjusted RR for any use of FQ compared to any use of amoxicillin or azithromycin was 0.99 (95% CI: 0.83–1.18) and azithromycin is 0.97 (95%CI: 0.82–1.16), respectively. The risk of fibromyalgia with FQs is similar to that with amoxicillin and azithromycin.
Osteoanabolic and dual action drugs
Authors: Tabacco Gaia , Bilezikian John P.
Published: September 2018

Teriparatide (TPTD) and abaloparatide (ABL) are the only osteoanabolic drugs available, at this time, for treatment of osteoporosis. TPTD is a 34‐amino acid fragment that is identical in its primary sequence to the 34 amino acids of full‐length human parathyroid hormone [hPTH(1‐84)]. ABL is identical to parathyroid hormone‐related peptide (PTHrP) through the first 22 residues with significantly different amino acids inserted thereafter, between residues 22 and 34. The osteoanabolic actions of PTH are due directly to its effects on cells of the osteoblast lineage and indirectly by stimulating IGF‐I synthesis and suppressing sclerostin and associated enhancement of Wnt signalling. Both TPTD and ABL are ligands that bind to and activate the PTH receptor type 1 (PTHR1) receptor but they appear to do so differently: ABL favours the transient, more anabolic configuration of the receptor. Both TPTD and ABL reduce the risk of vertebral fractures and non‐vertebral fractures. Both drugs are administered for a maximum of 24 months, and should be followed by an antiresorptive agent to maintain gains in bone mineral density (BMD). Romosozumab, a monoclonal antibody that binds to and inhibits sclerostin, appears to have dual actions by stimulating bone formation and reducing bone resorption. In the pivotal clinical trial, romosozumab, administered as a 210 mg monthly subcutaneous dose, significantly reduced new vertebral fractures and in a subsequent study reduced both vertebral and non‐vertebral fractures.
Lack of ethnic differences in the pharmacokinetics and pharmacodynamics of evolocumab between Caucasian and Asian populations
Authors: Wang Chen , Zheng Qingshan , Zhang Mingqiang , Lu Hong
Published: September 2018

Aims

To evaluate the potential ethnic differences in the pharmacokinetics (PK) and pharmacodynamics (PD) of evolocumab in Caucasian and Asian populations using population PK/PD modelling analysis.

Methods

Data from different ethnic groups in 5 Phase I clinical trials, including two American studies, one Japanese study and two Chinese studies, were chosen for model building and evaluation. A target‐mediated drug disposition model together with an indirect response model best captured evolocumab binding and the removal of unbound proprotein convertase subtilisin/kexin type 9 (PCSK9) as well as a reduction in circulating low‐density lipoprotein cholesterol (LDL‐C). Ethnicity and other related factors (body weight, target expression level etc.) were analysed as potential covariates.

Results

The estimated linear clearance and volume of evolocumab were 0.24 l day–1 and 2.75 l, respectively, which was consistent with the previous modelling results from the American trials. The time course of the LDL‐C reduction was described by an indirect response model with the elimination rate of LDL‐C being modulated by unbound PCSK9. The concentration of unbound PCSK9 associated with the half‐maximal inhibition of LDL‐C elimination was 1.28 nmol l–1. Both the PK and PD characteristics were consistent between the Caucasian and Asian populations.

Conclusion

The target‐mediated drug disposition model successfully described the PK and PD characteristics of evolocumab, and this analysis found no significant differences in the PK/PD relationship for its LDL‐C lowering effects between Caucasians and Asians.
In vitro functional evaluation of isolaureline, dicentrine and glaucine enantiomers at 5‐HT2 and α1 receptors
Authors: Heng Hui Li , Chee Chin Fei , Thy Chun Keng , Tee Jia Ti , Chin Sek Peng , Herr Deron R. , Buckle Michael J. C. , Paterson Ian C. , Doughty Stephen W. , Abd. Rahman Noorsaadah , Chung Lip Yong
Published: September 2018

Compounds with activity at serotonin (5‐hydroxytryptamine) 5‐HT2 and α1 adrenergic receptors have potential for the treatment of central nervous system disorders, drug addiction or overdose. Isolaureline, dicentrine and glaucine enantiomers were synthesized, and their in vitro functional activities at human 5‐HT2 and adrenergic α1 receptor subtypes were evaluated. The enantiomers of isolaureline and dicentrine acted as antagonists at 5‐HT2 and α1 receptors with (R)‐isolaureline showing the greatest potency (pKb = 8.14 at the 5‐HT2C receptor). Both (R)‐ and (S)‐glaucine also antagonized α1 receptors, but they behaved very differently to the other compounds at 5‐HT2 receptors: (S)‐glaucine acted as a partial agonist at all three 5‐HT2 receptor subtypes, whereas (R)‐glaucine appeared to act as a positive allosteric modulator at the 5‐HT2A receptor.
Secochiliolide ester derivatives: Preparation and evaluation of their antitrypanosomal and antimalarial efficacy
Authors: Ronchi Romina J. , Beaufay Claire , Bero Joanne , Robirosa Juan B. , Mazzuca Marcia , Palermo Jorge A. , Quetin‐Leclercq Joëlle , Sánchez Marianela
Published: September 2018

In the present study, a series of new esters of secochiliolide acid (SA), a diterpene isolated from Nardophyllum bryoides, were synthesized in good yield. All compounds were evaluated for their in vitro antiparasitic properties (on Plasmodium falciparum and Trypanosoma brucei brucei) and cytotoxicity (on WI38, normal mammalian cells). They displayed moderate antitrypanosomal activity with IC50 values between 2.55 and 18.14 μm, with selectivity indices >10, and low antiplasmodial effects with IC50 > 29 μm. The only exception was the n‐hexyl ester of SA, which showed a strong and selective antiplasmodial activity (IC50 = 1.99 μm and selectivity index = 117.0). The in vivo antimalarial efficacy of this compound was then assessed according to the 4‐day suppressive test of Peters in mice. An intraperitoneal treatment at 50 mg kg−1 day−1 induced a slight parasitaemia reduction by 56% which was statistically significant on day 4 post‐infection and an increase in the survival time.
Technetium‐99m radiolabeling and biological study of epirubicin for in vivo imaging of multi‐drug‐resistant Staphylococcus aureus infections via single photon emission computed tomography
Authors: Khan Naeem‐Ul‐Haq , Naqvi Syed Ali Raza , Roohi Samina , Sherazi Tauqir A. , Khan Zulfiqar Ali , Zahoor Ameer Fawad
Published: September 2018

The development of functional imaging is a promising strategy for diagnosis and treatment of infectious and cancerous diseases. In this study, epirubicin was developed as a [99mTc]‐labeled radiopharmaceutical for the imaging of multi‐drug‐resistant Staphylococcus aureus infections. The labeling was carried out using sodium pertechnetate (Na99mTcO4; ~370 MBq). The other parameters such as amount of ligand, reducing agent (SnCl2.2H2O), and pH were optimized. The highest labeling yield ≥96.98% was achieved when 0.3 mg epirubicin, 13 μg SnCl2.2H2O, and ~370 MBq Na99mTcO4 were incubated at pH 7 for 15 min in the presence of ascorbic acid at room temperature. Radiochemical purity, stability, charge, and glomerular filtration rate were studied to evaluate the biological compatibility for in vivo administration. Biodistribution investigations showed radiotracer uptake (13.89 ± 1.56% ID/gm organ) by liver and 7.79 ± 0.38% ID/gm organ by kidneys at 30 min post‐injection which promisingly wash out at 24 hr post‐injection. Scintigraphy study showed selective uptake in S. aureus‐infected tissues in contrast to turpentine oil‐induced inflamed tissues. Target‐to‐non‐target ratio (6.7 ± 0.05) was calculated at 1 hr post‐injection using SPECT gamma camera. The results of this study reveal that the [99mTc]‐epirubicin can be a choice of imaging and monitoring the treatment process of multi‐drug resistant S. aureus bacterial infections.
A propeller‐like small molecule as a novel G‐quadruplex DNA binder: The study of fluorescent sensing property and preferential interactions with human telo21 structure
Authors: Sun Ning , Li Dongli , Hou Jinqiang , Long Wei , Guo Qi , Lu Yujing , Zhang Kun , Yuan Wenchang , Wong Wing‐Leung
Published: September 2018

A new propeller‐like small molecule was synthesized with three terminal amino side groups. The molecule was found to be a selective nucleic acid binder towards telo21 G‐quadruplex DNA compared with other representative nucleic acids including single‐stranded DNA (dA21), duplex DNA (ds26) and RNA. The fluorescent signal of the molecule upon interaction with telo21 G‐quadruplex structure shows remarkable enhancement (Fmax/F0 = 17.9) while interaction with other nucleic acids shows the signal enhancement which is less than 2.1. In addition, a good linear relationship of binding signal correlated with the concentration of telo21 DNA was obtained. Molecular docking study was also performed to acquire the binding behaviour and its interaction modes of the molecule with the structure of human telomeric DNA G‐quadruplex. The modelling results show that the three conjugated terminal units (dimethylaminobenzyl groups) associated through the ethylene bridges with the central methylated pyridine ring formed a co‐planar conformation upon stacking onto the G‐quartets via pi‐pi stacking interactions. This could be the key reason that the molecule shows excellent fluorescent signal of binding towards telo21 G‐quadruplex DNA rather than other types of nucleic acids.
Biophysical screening methods for extracellular domain peptide receptors, application to natriuretic peptide receptor C ligands
Authors: Conole Daniel , Myers Samuel H. , Mota Filipa , Hobbs Adrian J. , Selwood David L.
Published: September 2018

Endothelium‐derived C‐type natriuretic peptide possesses cytoprotective and anti‐atherogenic functions that regulate vascular homeostasis. The vasoprotective effects of C‐type natriuretic peptide are somewhat mediated by the natriuretic peptide receptor C, suggesting that this receptor represents a novel therapeutic target for the treatment of cardiovascular diseases. In order to facilitate our drug discovery efforts, we have optimized an array of biophysical methods including surface plasmon resonance, fluorescence polarization and thermal shift assays to aid in the design, assessment and characterization of small molecule agonist interactions with natriuretic peptide receptors. Assay conditions are investigated to explore the feasibility and dynamic range of each method, and peptide‐based agonists and antagonists are used as controls to validate these conditions. Once established, each technique was compared and contrasted with respect to their drug discovery utility. We foresee that such techniques will facilitate the discovery and development of potential therapeutic agents for NPR‐C and other large extracellular domain membrane receptors.
Novel synthetic chalcone‐coumarin hybrid for Aβ aggregation reduction, antioxidation, and neuroprotection
Authors: Lee Shin‐Ying , Chiu Ya‐Jen , Yang Shu‐Mei , Chen Chiung‐Mei , Huang Chin‐Chang , Lee‐Chen Guey‐Jen , Lin Wenwei , Chang Kuo‐Hsuan
Published: September 2018

Background

Aggregation of misfolded amyloid β (Aβ) in senile plaques causes oxidative stress and neuronal death in Alzheimer's disease (AD). Compounds possessing antiaggregation and antioxidant properties are promising candidate compounds for AD treatment.

Methods

We examined the potential of synthetic derivatives of licochalcone A and coumarin for inhibiting Aβ aggregation, scavenging reactive oxygen species (ROS), and providing neuroprotection by using biochemical assays and Tet‐On Aβ‐GFP 293/SH‐SY5Y cell models for AD.

Results

Among test compounds, LM‐031, a novel chalcone‐coumarin hybrid, inhibited Aβ aggregation and scavenged free oxygen radicals. LM‐031 markedly reduced Aβ misfolding and ROS as well as promoted neurite outgrowth and inhibited acetylcholinesterase in Tet‐On Aβ‐GFP 293/SH‐SY5Y cells. Mechanistic studies showed upregulation of the HSPB1 chaperone, NRF2/NQO1/GCLC pathway, and CREB/BDNF/BCL2 pathway. Decreased neurite outgrowth upon the induction of Aβ‐GFP was rescued by LM‐031, which was counteracted by knockdown of HSPB1, NRF2, or CREB.

Conclusion

Taken together, these findings demonstrate that LM‐031 exhibited antiaggregation, antioxidant, and neuroprotective effects against Aβ toxicity by enhancing HSPB1 and the NRF2‐related antioxidant pathway as well as by activating the CREB‐dependent survival and antiapoptosis pathway. These results imply that LM‐031 may be a new therapeutic compound for AD.
Survival differences in nasopharyngeal carcinoma among racial and ethnic minority groups in the United States: A retrospective cohort study
Authors: Challapalli Sai D. , Simpson Matthew C. , Adjei Boakye Eric , Walker Ronald J. , Antisdel Jastin L. , Ward Greg M. , Osazuwa‐Peters Nosayaba
Published: September 2018

Objective

The literature on nasopharyngeal carcinoma survival in the United States has focused mostly on Whites or Asians and not much is known about survivorship in other minority racial and ethnic groups. We aimed to determine the disease‐specific survival rate and prognostic factors for nasopharyngeal carcinoma survival across the minority United States population.

Design

A retrospective cohort study.

Setting

The Surveillance, Epidemiology and End Results (SEER) 13 database from 1992 to 2014 was queried for adult cases of nasopharyngeal carcinoma (n = 2549).

Participants

Eligible cases were Blacks, Hispanics, Asians/Pacific Islanders, American Indians/Alaska Natives; White patients were excluded.

Main Outcomes Measure

A multivariable competing risk survival analysis yielded hazard ratios (HR) for competing mortality and was used to identify independent prognostic factors for survival.

Results

Non‐Hispanic American Indians/Alaska Natives consistently had the worst cause‐specific survival of any group and that non‐Hispanic Asians/Pacific Islanders consistently had the best survival (P < 0.001). Even after adjusting for other poor prognostic factors in the study, including older age, keratinising histology, and lack of radiation treatment, non‐Hispanic American Indians/Alaska Natives had more than double hazards of death from nasopharyngeal cancer compared with non‐Hispanic Asians/Pacific Islanders (aHR = 2.63, 95% CI 1.67, 4.13).

Conclusions

There are disparities in nasopharyngeal carcinoma survival among racial and ethnic minority groups in the United States, with American Indians/Alaskan Natives faring worst. It is critical that future research focuses on nasopharyngeal carcinoma among this population to improve survivorship and mitigate cancer‐related health disparities.
Benign paroxysmal positional vertigo in children
Authors: Yao Qingxiu , Song Qiang , Wang Hui , Shi Haibo , Yu Dongzhen
Published: September 2018

Objective

To describe the clinical features of benign paroxysmal positional vertigo (BPPV) in children.

Design

A retrospective study.

Setting

Six children diagnosed with BPPV between March 2014 and March 2015 were retrospectively evaluated. BPPV was diagnosed using the Dix‐Hallpike and supine roll tests and treated with either the modified Epley particle repositioning procedure or Lempert or Gufoni manoeuvre. Follow‐up was performed at 1‐week intervals until vertigo and nystagmus disappeared during positional testing.

Participants

A total of six children were followed up for a period of 10‐22 months.

Main outcome measures

Clinical features such as history, nystagmus and symptoms of vertigo, dizziness and nausea.

Results

Six children were diagnosed with BPPV using positional testing and treated with the modified Epley or Lempert/Gufoni particle repositioning procedures. Four children were diagnosed with posterior canal BPPV, while the remaining two were diagnosed with horizontal canal BPPV. One girl reported a history of head trauma, one girl had a family history of vertigo, and one boy reported hearing loss in the same ear as that affected by BPPV. Overall, 83.33% of children (5/6) were completely relieved of vertigo following one treatment session. The remaining child was asymptomatic after two sessions. No child reported relapse of vertigo during the follow‐up period.

Conclusions

BPPV can be diagnosed accurately by taking a detailed medical history and by use of positional testing. BPPV in children can be successfully identified and treated.
Outcomes for individuals turned down for living kidney donation
Authors: Reese Peter P. , Allen Matthew B. , Carney Caroline , Leidy Daniel , Levsky Simona , Pendse Ruchita , Mussell Adam S. , Bermudez Francisca , Keddem Shimrit , Thiessen Carrie , Rodrigue James R. , Emanuel Ezekiel J.
Published: September 2018

Background

A better understanding of the consequences of being turned down for living kidney donation could help transplant professionals to counsel individuals considering donation.

Methods

In this exploratory study, we used survey instruments and qualitative interviews to characterize nonmedical outcomes among individuals turned down for living kidney donation between July 1, 2010 and December 31, 2013. We assembled a comparator group of kidney donors.

Results

Among 83 turned‐down donors with contact information at a single center, 43 (52%) participated in the study (median age 53 years; 53% female; 19% black). Quality of life, depression, financial stress, and provider empathy scores were similar between individuals turned down for donation (n = 43) and donors (n = 128). Participants selected a discrete choice response to a statement about the overall quality of their lives; 32% of turned‐down donors versus 7% of donors (P < 0.01) assessed that their lives were worse after the center's decision about whether they could donate a kidney. Among turned‐down donors who reported that life had worsened, 77% had an intended recipient who was never transplanted, versus 36% among individuals who assessed life as the same or better (P = 0.02). In interviews, the majority of turned‐down donors reported emotional impact, including empathy, stress, and other challenges, related to having someone in their lives with end‐stage kidney disease.

Conclusions

Generic instruments measuring quality of life, depression, financial stress, and provider empathy revealed no significant differences between kidney donors and turned‐down donors. However, qualitative interviews revealed preliminary evidence that some turned‐down donors experienced emotional consequences. These findings warrant confirmation in larger studies.
Incorporating the geometry of dispersal and migration to understand spatial patterns of species distributions
Authors: Gimenez Luis
Published: September 2018

Dispersal and migration can be important drivers of species distributions. Because the paths followed by individuals of many species are curvilinear, spatial statistical models based on rectilinear coordinates systems would fail to predict population connectivity or the ecological consequences of migration or species invasions. I propose that we view migration/dispersal as if organisms were moving along curvilinear geometrical objects called smooth manifolds. In that view, the curvilinear pathways become the ‘shortest realised paths’ arising from the necessity to minimise mortality risks and energy costs. One can then define curvilinear coordinate systems on such manifolds. I describe a procedure to incorporate manifolds and define appropriate coordinate systems, with focus on trajectories (1D manifolds), as parts of mechanistic ecological models. I show how a statistical method, known as ‘manifold learning’, enables one to define the manifold and the appropriate coordinate systems needed to calculate population connectivity or study the effects of migrations (e.g. in aquatic invertebrates, fish, insects and birds). This approach may help in the design of networks of protected areas, in studying the consequences of invasion, range expansions, or transfer of parasites/diseases. Overall, a geometrical view to animal movement gives a novel perspective to the understanding of the ecological role of dispersal and migration.