bluuebunny/crossref_metadata_2025 huggingface dataset:
Visual function in children with primary brain tumors
Authors: Peragallo Jason H.
Published: December 2018

Purpose of review

To review the recent advances in understanding how primary brain tumors affect vision in children.

Recent findings

Children with primary brain tumors may have vision loss due to involvement of their afferent visual pathways or from papilledema. These vision deficits may go unrecognized until later in life, years after treatment of the primary lesion. Strabismus and cranial nerve palsies may occur as a result of brain tumors. Ophthalmologists can monitor and treat young children at risk for vision loss from amblyopia as a result of effects from their underlying lesion. Advances in imaging techniques have made it possible to quantify damage to the visual pathways with objective tests.

Systematic referrals for evaluation by an ophthalmologist should occur early in the course of treatment of primary brain tumors as these evaluations may improve visual outcomes and quality of life.
Treatment strategies for Leber hereditary optic neuropathy
Authors: Jurkute Neringa , Harvey Joshua , Yu-Wai-Man Patrick
Published: December 2018

Purpose of review

Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) disorder in the population and it carries a poor visual prognosis. In this article, we review the development of treatment strategies for LHON, the evidence base and the areas of unmet clinical need.

Recent findings

There is accumulating evidence that increasing mitochondrial biogenesis could be an effective strategy for protecting retinal ganglion cells in LHON. A number of clinical trials are currently investigating the efficacy of viral-based gene therapy for patients harbouring the m.11778G>A mtDNA mutation. For female LHON carriers of childbearing age, mitochondrial replacement therapy is being offered to prevent the maternal transmission of pathogenic mtDNA mutations.

Although disease-modifying treatment options remain limited, a better understanding of the underlying disease mechanisms in LHON is paving the way for complementary neuroprotective and gene therapeutic strategies for this mitochondrial optic nerve disorder.
Association Study Between Serotonin Transporter Gene and Fluoxetine Response in Mexican Patients With Major Depressive Disorder
Authors: Camarena Beatriz , Álvarez-Icaza Deni , Hernández Sandra , Aguilar Alejandro , Münch Lucía , Martínez Consuelo , Becerra-Palars Claudia
Published: December 2018

Objective

Pharmacogenetic studies have identified genetic variants associated with fluoxetine response in patients with major depression disorder (MDD). The serotonin transporter gene is the principal site of action of selective serotonin reuptake inhibitors. Previous studies analyzing SLC6A4 gene variants are inconsistent and differ among populations. The aim of the present study was to analyze the association between 5-HTTLPR/rs24531 triallelic polymorphism and fluoxetine response in Mexican patients with MDD.

Methods

We analyzed a sample of 150 patients with MDD. Fluoxetine response was assessed according to a reduction in the Hamilton Depression Rating Scale and Montgomery Depression Rating Scale scores of 50% or more at 8 weeks from baseline. In addition, we analyzed the genotype and allele distribution between responder and nonresponder patients in a subgroup of very severe depression patients.

Results

We did not find association between fluoxetine responders and 5-HTTLPR/rs25531 variants (P = 0.0637). However, in the analysis of severe depression at baseline (Hamilton Depression Rating Scale ≥ 25), we observed a high frequency of low activity alleles (S/LG) in nonresponders patients (P = 0.0102).

Conclusions

Our findings showed an association between low activity alleles of SLC6A4 gene and fluoxetine nonresponse in patients with severe depression.
Community dynamics and sensitivity to model structure: towards a probabilistic view of process-based model predictions
Authors: Aldebert Clement , Stouffer Daniel B.
Published: December 2018

Statistical inference and mechanistic, process-based modelling represent two philosophically different streams of research whose primary goal is to make predictions. Here, we merge elements from both approaches to keep the theoretical power of process-based models while also considering their predictive uncertainty using Bayesian statistics. In environmental and biological sciences, the predictive uncertainty of process-based models is usually reduced to parametric uncertainty. Here, we propose a practical approach to tackle the added issue of structural sensitivity, the sensitivity of predictions to the choice between quantitatively close and biologically plausible models. In contrast to earlier studies that presented alternative predictions based on alternative models, we propose a probabilistic view of these predictions that include the uncertainty in model construction and the parametric uncertainty of each model. As a proof of concept, we apply this approach to a predator–prey system described by the classical Rosenzweig–MacArthur model, and we observe that parametric sensitivity is regularly overcome by structural sensitivity. In addition to tackling theoretical questions about model sensitivity, the proposed approach can also be extended to make probabilistic predictions based on more complex models in an operational context. Both perspectives represent important steps towards providing better model predictions in biology, and beyond.
Insights into GABA
A
ergic system alteration in Huntington's disease
Authors: Hsu Yi-Ting , Chang Ya-Gin , Chern Yijuang
Published: December 2018

Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disease that is characterized by a triad of motor, psychiatric and cognitive impairments. There is still no effective therapy to delay or halt the disease progress. The striatum and cortex are two particularly affected brain regions that exhibit dense reciprocal excitatory glutamate and inhibitory gamma-amino butyric acid (GABA) connections. Imbalance between excitatory and inhibitory signalling is known to greatly affect motor and cognitive processes. Emerging evidence supports the hypothesis that disrupted GABAergic circuits underlie HD pathogenesis. In the present review, we focused on the multiple defects recently found in the GABAergic inhibitory system, including altered GABA level and synthesis, abnormal subunit composition and distribution of GABA
A
receptors and aberrant GABA
A
receptor-mediated signalling. In particular, the important role of cation–chloride cotransporters (i.e. NKCC1 and KCC2) is discussed. Recent studies also suggest that neuroinflammation contributes significantly to the abnormal GABAergic inhibition in HD. Thus, GABA
A
receptors and cation–chloride cotransporters are potential therapeutic targets for HD. Given the limited availability of therapeutic treatments for HD, a better understanding of GABAergic dysfunction in HD could provide novel therapeutic opportunities.
Genetic variation within genes associated with mitochondrial function is significantly associated with later age at onset of Parkinson disease and contributes to disease risk
Authors: Billingsley Kimberley J. , Barbosa Ines A. , Bandrés-Ciga Sara , Quinn John P. , Bubb Vivien J. , Deshpande Charu , Botia Juan A. , Reynolds Regina H. , Zhang David , Simpson Michael A. , Blauwendraat Cornelis , Gan-Or Ziv , Gibbs J Raphael , Nalls Mike A. , Singleton Andrew ,   International Parkinson’s Disease Genomics Consortium (IPDGC), Ryten Mina , Koks Sulev
Published: December 2018

Mitochondrial dysfunction has been implicated in the aetiology of monogenic Parkinson’s disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here we comprehensively assessed the role of mitochondrial function associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. First, we identified that a proportion of the “missing heritability” of the PD can be explained by common variation within genes implicated in mitochondrial disease (primary gene list) and mitochondrial function (secondary gene list). Next we calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. Most significantly we further report that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomisation, which showed that 14 of these mitochondrial function associated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD.
Non-academic employability of life science PhDs: the importance of training beyond the bench
Authors: Her Sohyoung , Jacob Mathieu D , Wang Sharon , Xu Songyi , Sealey David CF
Published: December 2018

To better understand how PhD graduates have prepared for the non-academic job market, we surveyed life science PhD and postdoctoral graduates from the University of Toronto who were employed in non-academic sectors. We also surveyed life science PhD and postdoctoral trainees to assess their engagement in career preparation activities. PhD professionals employed in non-academic sectors had engaged in various career preparation activities during their training. Some activities had a higher perceived impact on the path to employment than others. Trainees had also engaged in such activities, but those rated by professionals as having a highly positive impact on their path to employment were engaged in by only a minority of trainees. The proportion of trainees who wished to work in a non-academic sector was higher among those who were closer to program completion. Like professionals, many trainees reported facing barriers to pursuing career development activities. Our findings suggest that PhD trainees seeking to work in non-academic sectors should engage in career preparation activities, particularly those that involve experiential learning. By supporting co-curricular programming and reducing barriers to participation in career development activities, academic administrators and faculty have the opportunity to support trainees’ professional development beyond the laboratory.
Bioinformatic analysis of long-lasting transcriptional and translational changes in the basolateral amygdala following acute stress
Authors: Sillivan Stephanie E , Jones Meghan E , Jamieson Sarah , Rumbaugh Gavin , Miller Courtney A
Published: December 2018

Stress profoundly impacts the brain and increases the risk of developing a psychiatric disorder. The brain's response to stress is mediated by a number of pathways that affect gene expression and protein function throughout the cell. Understanding how stress achieves such dramatic effects on the brain requires an understanding of the brain's stress response pathways. The majority of studies focused on molecular changes have employed repeated or chronic stress paradigms to assess the long-term consequences of stress and have not taken an integrative genomic and/or proteomic approach. Here, we determined the lasting impact of a single stressful event (restraint) on the broad molecular profile of the basolateral amygdala complex (BLC), a key brain region mediating emotion, memory and stress. Molecular profiling performed thirty days post-restraint consisted of small RNA sequencing, RNA sequencing and quantitative mass spectrometry and identified long-lasting changes in microRNA (miRNA), messenger RNA (mRNA) and proteins. Alignment of the three datasets further delineated the regulation of stress-specific pathways which were validated by qPCR and Western Blot analysis. From this analysis, mir-29a-5p was identified as a putative regulator of stress-induced adaptations in the BLC. Further, a number of predicted mir-29a-5p targets are regulated at the mRNA and protein level. The concerted and long-lasting disruption of multiple molecular pathways in the amygdala by a single stress event is expected to be sufficient to alter behavioral responses to a wide array of future experiences, including exposure to additional stressors.
Expanding the toolbox of broad host-range transcriptional terminators for Proteobacteria through metagenomics
Authors: Amarelle Vanesa , Sanches-Medeiros Ananda , Silva-Rocha Rafael , Guazzaroni María-Eugenia
Published: December 2018

As the field of synthetic biology moves towards the utilization of novel bacterial chassis, there is a growing need for biological parts with enhanced performance in a wide number of hosts. Is not unusual that biological parts (such as promoters and terminators), initially characterized in the model bacteria Escherichia coli, do not perform well when implemented in alternative hosts, such as Pseudomonas, therefore limiting the construction of synthetic circuits in industrially relevant bacteria. In order to address this limitation, we present here the mining of transcriptional terminators through functional metagenomics to identify novel parts with broad host-range activity. Using a GFP-based terminator trap strategy and a broad host-range plasmid, we identified 20 clones with potential terminator activity in Pseudomonas putida. Further characterization allowed the identification of 4 unique sequences between 58 bp and 181 bp long that efficiently terminates transcription in P. putida, E. coli, Burkholderia phymatum and two Pseudomonas strains isolated from Antarctica. Therefore, this work presents a new set of biological parts useful for the engineering of synthetic circuits in Proteobacteria.
Urinary AQP5 is independently associated with eGFR decline in patients with type 2 diabetes and nephropathy
Authors: Gao Chao , Zhang Wenzheng
Published: December 2018

AQP5 has been shown to be upregulated in kidney biopsies from patients with diabetic nephropathy. Here we investigate whether urinary baseline AQP5 is independently associated with eGFR decline in patients with type 2 diabetes and nephropathy. Baseline urine samples (n=997) from patients with type 2 diabetes and nephropathy recruited in the Sun-MACRO randomized placebo controlled double blind clinical trial were used for AQP5 measurement, using human AQP5-specific enzyme linked immunosorbent kits. Pearson correlation and multiple linear regression between AQP5 with eGFR slope (calculated by ≥3 serum creatinine during followup) was performed, and association with fast renal function decline, defined as eGFR slope less than 3.0 mL/min/1.73m2/year, was determined by logistic regression. Followup eGFR data over 1.4 years from n=700 were available for analysis. AQP5 was undetectable in 138 patients. Tertiles of AQP5 were 0.4 [0 - 2.2], 7.3 [5.9 - 9.1], and 16.0 [13.0 - 21.6] (ng/mL), respectively (p<0.01). Patients in the highest tertile of AQP5 had significantly higher total cholesterol, lower baseline eGFR, and higher levels of albuminuria compared to the lowest tertile. AQP5 was inversely correlated with eGFR slope (Pearson r = -0.12, p<0.001), and independent of clinical risk factors age, sex, race, and baseline SBP, DBP, HbA1c, Tot. Cholesterol, eGFR, and UACR (β = -0.05, p<0.004). Furthermore, AQP5 was significantly associated with fast eGFR decline (OR = 1.03 (95%CI 1.003 - 1.06), p<0.03). Our data suggest that baseline AQP5 is independently associated with the progression of eGFR decline in patients with type 2 diabetes and nephropathy.
Ezh2-dependent epigenetic reprogramming controls a developmental switch between modes of gastric neuromuscular regulation
Authors: Syed Sabriya A. , Hayashi Yujiro , Lee Jeong-Heon , Yan Huihuang , Lorincz Andrea , Strege Peter R. , Gajdos Gabriella B. , Milosavljevic Srdjan , Nie Jinfu , Rumessen Jüri J. , Gibbons Simon J. , Horvath Viktor J. , Bardsley Michael R. , Redelman Doug D. , Klein Sabine , Saur Dieter , Farrugia Gianrico , Zhang Zhiguo , Urrutia Raul A. , Ordog Tamas
Published: December 2018

Physiological interconversion between specialized cell types has only been described in a few mammalian tissues and the mechanisms remain obscure. Using genetic lineage tracing during postnatal development and in-vitro models we demonstrate conversion of gastric interstitial cells of Cajal (ICC), regulatory cells that electrically pace phasic contractions and mediate nitrergic and cholinergic neural control of smooth muscle cells, into phenotypically distinct “fibroblast-like” interstitial cells (FLC), which only mediate purinergic signaling. Mechanistically, we find this transition to be epigenetically governed by H3K27 trimethylation of cell identity-related promoters whose susceptibility to repression is predicted by H3K27 acetylation patterns in ICC. The phenotypic switch was reversible by inhibition, knockdown or in-vivo genomic inactivation of the polycomb H3K27 methyl-transferase Ezh2. These results demonstrate a role for Ezh2-mediated epigenetic repression in physiological mammalian transdifferentiation and identify FLC as a reserve from which ICC can potentially be restored in common gastrointestinal disorders where ICC are depleted.

GRAPHICAL ABSTRACT

HIGHLIGHTS

Gastric pacemaker cells (ICC) transdifferentiate into quiescent cells (FLC) in vivo

ICC-to-FLC shift switches neural control from nitrergic/cholinergic to purinergic

Ezh2-mediated H3K27me3 represses cell-identity genes during ICC-to-FLC transition

Ezh2 inhibition restores ICC numbers, phenotype and function

eTOC BLURB

Syed et al. find aging to cause transdifferentiation of gastric pacemaker cells (interstitial cells of Cajal, ICC), which also communicate cholinergic and nitrergic neurotransmission to smooth muscle cells, into quiescent “fibroblast-like cells” (FLC), which only mediate purinergic signals. This switch is governed by Ezh2, whose inhibition can reverse ICC depletion.
Genome sequencing analysis identifies high-risk Epstein-Barr virus subtypes for nasopharyngeal carcinoma
Authors: Xu Miao , Yao Youyuan , Chen Hui , Zhang Shanshan , Xiang Tong , Cao Su-Mei , Zhang Zhe , Luo Bing , Liu Zhiwei , Li Zilin , He Guiping , Feng Qi-Sheng , Chen Li-Zhen , Guo Xiang , Jia Weihua , Chen Ming-Yuan , Zhao Bingchun , Zhang Xiao , Xie Shang-Hang , Peng Roujun , Chang Ellen T. , Pedergnana Vincent , Feng Lin , Bei Jin-Xin , Xu Ruihua , Zeng Mu Sheng , Ye Weimin , Adami Hans-Olov , Lin Xihong , Zhai Weiwei , Zeng Yi-Xin , Liu Jianjun
Published: December 2018

Epstein-Barr virus (EBV) infection is ubiquitous worldwide and associated with multiple cancers including nasopharyngeal carcinoma (NPC). The role of EBV viral genomic variation in NPC development and its striking endemicity in southern China has been poorly explored. Through large-scale genome sequencing and association study of EBV isolates from China, we identified two non-synonymous EBV variants withinBALF2strongly associated with NPC risk (conditionalPvalue 1.75×10-6for SNP162476_C and 3.23×10-13for SNP163364_T), whose cumulative effects contributed to 83% of the overall risk in southern China. Phylogenetic analysis of the risk variants revealed a unique origin in southern China followed by clonal expansion. EBVBALF2haplotype carrying the risk variants were shown to reduce viral lytic DNA replication, as a result potentially promoting viral latency. Our discovery has not only provided insight to the unique endemic pattern of NPC occurrence in southern China, but also paved the way for the identification of individuals at high risk of NPC and effective intervention program to reduce the disease burden in southern China.
Skeletal muscle MRI differentiates SBMA and ALS and correlates with disease severity
Authors: Klickovic Uros , Zampedri Luca , Sinclair Christopher , Wastling Stephen , Trimmel Karin , Howard Robin , Malaspina Andrea , Sharma Nikhil , Sidle Katie , Emira Ahmed , Shah Sachit , Yousry Tarek , Hanna Michael , Greensmith Linda , Morrow Jasper , Thornton John , Fratta Pietro
Published: December 2018

Objective: To investigate the use of muscle MRI for the differential diagnosis and as a disease progression biomarker for two major forms of motor neuron disorders, spinal bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS).
Methods: We applied quantitative 3-point Dixon and semi-quantitative T1-weighted and STIR imaging to bulbar and lower limb muscles and performed clinical and functional assessments in ALS (n=21) and SBMA (n=21) patients, alongside healthy controls (n=16). Acquired images were analyzed for the presence of fat infiltration or edema as well as specific patterns of muscle involvement. Quantitative MRI measurements were correlated with clinical parameters of disease severity in ALS and SBMA.
Results: Quantitative imaging revealed significant fat infiltration in bulbar (p<0.001) and limb muscles in SBMA compared to controls (thigh: p<0.001; calf: p=0.001), identifying a characteristic pattern of muscle involvement. In ALS, semi-quantitative STIR imaging detected marked hyperintensities in lower limb muscles, distinguishing ALS from SBMA and controls. Lastly, MRI measurements correlated significantly with clinical scales of disease severity in both ALS and SBMA.
Conclusions: Our findings show that muscle MRI differentiates between SBMA and ALS and correlates with disease severity, supporting its use as a diagnostic tool and biomarker for disease progression. This highlights the clinical utility of muscle MRI in motor neuron disorders and contributes to establish objective outcome measures, which is crucial for the development of new drugs.
SapM mutation to improve the BCG vaccine: genomic, transcriptomic and preclinical safety characterization
Authors: Festjens Nele , Vandewalle Kristof , Houthuys Erica , Plets Evelyn , Vanderschaeghe Dieter , Borgers Katlyn , Hecke Annelies Van , Tiels Petra , Callewaert Nico
Published: December 2018

The Mycobacterium bovis Bacille Calmette Guérin (BCG) vaccine shows variable efficacy in protection against adult tuberculosis (TB). Earlier, we have described a BCG mutant vaccine with a transposon insertion in the gene coding for the secreted acid phosphatase SapM, which led to enhanced long-term survival of vaccinated mice challenged with TB infection. To facilitate development of this mutation as part of a future improved live attenuated TB vaccine, we have now characterized the genome and transcriptome of this sapM::Tn mutant versus parental BCG Pasteur. Furthermore, we show that the sapM::Tn mutant had an equal low pathogenicity as WT BCG upon intravenous administration to immunocompromised SCID mice, passing this important safety test. Subsequently, we investigated the clearance of this improved vaccine strain following vaccination and found a more effective innate immune control over the sapM::Tn vaccine bacteria as compared to WT BCG. This leads to a fast contraction of IFNγ producing Th1 and Tc1 cells after sapM::Tn BCG vaccination. These findings corroborate that a live attenuated vaccine that affords improved long-term survival upon TB infection can be obtained by a mutation that further attenuates BCG. These findings suggest that an analysis of the effectiveness of innate immune control of the vaccine bacteria could be instructive also for other live attenuated TB vaccines that are currently under development, and encourage further studies of SapM mutation as a strategy in developing a more protective live attenuated TB vaccine.
Why Put-Up with Immunity when there is Resistance: An Excursion into the Population and Evolutionary Dynamics of Restriction-Modification and CRISPR-Cas
Authors: Gurney James R , Pleska Maros , Levin Bruce R
Published: December 2018

Bacteria can readily generate mutations that prevent bacteriophage (phage) adsorption and thus make bacteria resistant to infections with these viruses. Nevertheless, the majority of bacteria carry complex innate and/or adaptive immune systems: restriction-modification (RM) and CRISPR-Cas, respectively. Both RM and CRISPR-Cas are commonly assumed to have evolved and be maintained to protect bacteria from succumbing to infections with lytic phage. Using mathematical models and computer simulations, we explore the conditions, under which selection mediated by lytic phage will favor such complex innate and adaptive immune systems, as opposed to simple envelope resistance. The results of our analysis suggest that when populations of bacteria are confronted with lytic phage: (i) In the absence of immunity, resistance to even multiple bacteriophage species with independent receptors can evolve readily. (ii) RM immunity can benefit bacteria by preventing phage from invading established bacterial populations and particularly so when there are multiple bacteriophage species adsorbing to different receptors. (iii) Whether CRISPR-Cas immunity will prevail over envelope resistance depends critically on the length of the co-evolutionary arms race between the bacteria acquiring spacers and the phage generating CRISPR-escape mutants. We discuss the implications of these results in the context of the evolution and maintenance of RM and CRISPR-Cas and highlight fundamental questions that remain unanswered.
The impact of the genetic background on gene deletion phenotypes inSaccharomyces cerevisiae
Authors: Galardini Marco , Busby Bede P. , Vieitez Cristina , Dunham Alistair S. , Typas Athanasios , Beltrao Pedro
Published: December 2018

Loss-of-function (LoF) mutations associated with disease don’t manifest equally in different individuals, a phenomenon known as incomplete penetrance. The impact of the genetic background on incomplete penetrance remains poorly characterized. Here, we systematically assessed the changes in gene deletion phenotypes for 3,786 gene knockouts in fourSaccharomyces cerevisiaestrains and 38 conditions. We observed 16% to 42% of deletion phenotypes changing between pairs of strains with a small fraction conserved in all strains. Conditions causing higher WT growth differences and the deletion of pleiotropic genes showed above average changes in phenotypes. We further illustrate how these changes affect the interpretation of the impact of genetic variants across 925 yeast isolates. These results show the high degree of genetic background dependencies for LoF phenotypes.
Dysregulation of NRAP degradation by KLHL41 contributes to pathophysiology in Nemaline Myopathy
Authors: Jirka Caroline , Pak Jasmine H , Grosgogeat Claire A , Marchetti Michael M , Gupta Vandana A
Published: December 2018

Nemaline myopathy (NM) is the most common form of congenital myopathy that results in hypotonia and muscle weakness. This disease is clinically and genetically heterogeneous, but three recently discovered genes in NM encode for members of the Kelch family of proteins. Kelch proteins act as substrate-specific-adapters for CUL3 E3 ubiquitin ligase to regulate protein turn-over through the ubiquitin-proteasome machinery. Defects in thin filament formation and/or stability are key molecular processes that underlie the disease pathology in NM, however, the role of Kelch proteins in these processes in normal and diseases conditions remains elusive in vivo. Here, we describe a role of NM causing Kelch protein, KLHL41, in premyofibil-myofibil transition during skeletal muscle development through a regulation of the thin filament chaperone, NRAP. KLHL41 binds to the thin filament chaperone NRAP and promotes ubiquitination and subsequent degradation of NRAP, a process that is critical for the formation of mature myofibrils. KLHL41 deficiency results in abnormal accumulation of NRAP in muscle cells. NRAP overexpression in transgenic zebrafish resulted in a severe myopathic phenotype and absence of mature myofibrils demonstrating a role in disease pathology. Reducing Nrap levels in KLHL41 deficient zebrafish rescues the structural and function defects associated with disease pathology. We conclude that defects in KLHL41-mediated ubiquitination of sarcomeric protein contribute to structural and functional deficits in skeletal muscle. These findings further our understanding of how the sarcomere assembly is regulated by disease causing factors in vivo, which will be imperative for developing mechanism-based specific therapeutic interventions.
Gut microbiome communication with bone marrow regulates susceptibility to amebiasis
Authors: Burgess Stacey L. , Leslie Jhansi L. , Uddin Md. Jashim , Oakland Noah , Gilchrist Carol , Brett Moreau G. , Watanabe Koji , Saleh Mahmoud , Simpson Morgan , Thompson Brandon A. , Auble David T. , Turner Stephen D. , Giallourou Natasa , Swann Jonathan , Pu Zhen , Ma Jennie Z. , Haque Rashidul , Petri William A.
Published: December 2018

The gut microbiome provides resistance to infection. However, the mechanisms for this are poorly understood. Colonization with the intestinal bacteriumClostridium scindensprovided protection from the parasiteEntamoeba histolyticavia innate immunity. Introduction ofC. scindensinto the gut microbiota epigenetically altered and expanded bone marrow granulocyte-monocyte-progenitors (GMPs) and provided neutrophil-mediated protection against subsequent challenge withE. histolytica. Adoptive transfer of bone-marrow fromC. scindenscolonized-mice into naïve-mice protected against ameba infection and increased intestinal neutrophils. Because of the known ability ofC. scindensto metabolize the bile salt cholate, we measured deoxycholate and discovered that it was increased in the sera ofC. scindenscolonized mice, as well as in children protected from amebiasis. Administration of deoxycholate alone (in the absence ofC. scindens) increased the epigenetic mediator JMJD3 and GMPs and provided protection from amebiasis. In conclusion the microbiota was shown to communicate to the bone marrow via microbially-metabolized bile salts to train innate immune memory to provide antigen-nonspecific protection from subsequent infection. This represents a novel mechanism by which the microbiome protects from disease.

One Sentence Summary

Introduction of the human commensal bacteriaClostridium scindensinto the intestinal microbiota epigenetically alters bone marrow and protects from future parasite infection.
Widespread PERK-dependent repression of ER targets in response to ER stress
Authors: Gonen Nir , Sabath Niv , Burge Christopher B. , Shalgi Reut
Published: December 2018

The UPR (Unfolded Protein Response) is a well-orchestrated response to ER protein folding and processing overload, integrating both transcriptional and translational outputs. Its three arms in mammalian cells, the PERK translational response arm, together with the ATF6 and IRE1-XBP1-mediated transcriptional arms, have been thoroughly investigated.

Using ribosome footprint profiling, we performed a deep characterization of gene expression programs involved in the early and late ER stress responses, within WT or PERK -/- Mouse Embryonic Fibroblasts (MEFs). We found that both repression and activation gene expression programs, affecting hundreds of genes, are significantly hampered in the absence of PERK. Specifically, PERK -/- cells do not show global translational inhibition, nor do they specifically activate early gene expression programs upon short exposure to ER stress. Furthermore, while PERK -/- cells do activate/repress late ER-stress response genes, the response is substantially weaker. Importantly, we highlight a widespread PERK-dependent repression gene expression program, consisting of ER targeted proteins, including transmembrane proteins, glycoproteins, and proteins with disulfide bonds. This phenomenon occurs in various different cell types, and has a major translational regulatory component. Moreover, we revealed a novel interplay between PERK and the XBP1-ATF6 arms of the UPR, whereby PERK attenuates the expression of a specific subset of XBP1-ATF6 targets, further illuminating the complexity of the integrated ER stress response.
The accuracy of estimating time to contact in transversal motion and head-on motion
Authors: Daneshi Asieh , Azarnoush Hamed , Towhidkhah Farzad , Tranvouez-Bernardin Delphine , Faubert Jocelyn
Published: December 2018

The ability to estimate precisely the time to contact (TTC) of the objects is necessary for planning actions in dynamic environments. TTC estimation is involved in many everyday activities with different levels of difficulty. Although tracking a ball that moves at a constant speed and estimating the time it reaches a non-moving target can be fairly simple, tracking a fast moving car with inconsistent speeds and estimating the time it reaches another car is rather difficult. In this study, we asked participants to estimate TTC of an object in transversal and head-on motions. The object became invisible shortly after movement initiation. The results demonstrated that TTC estimation for transversal motion is more accurate than for head-on motion. We present a mathematical model to explain why humans are better in estimating TTC for transversal motion than for head-on motion.
A three-dimensional ZnII coordination network based on 5,5′-methylenebis(2,4,6-trimethylisophthalic acid) and 2,7-bis(1H-imidazol-1-yl)fluorene: synthesis, structure and luminescence properties
Authors: Chen Zhen , Sun Yanwen , Liu Zi-an , Wang Ning , Yang Xue , You Xiaomeng , Wang Xiaozhong
Published: December 2018

In recent years, coordination polymers constructed from multidentate carboxylate ligands and N-containing ligands have attracted much attention since these ligands can adopt a rich variety of coordination modes which can lead to crystalline products with intriguing structures and interesting properties. A new coordination polymer, namely poly[[diaqua[μ-2,7-bis(1H-imidazol-1-yl)fluorene-κ2
N
3:N
3′][μ-5,5′-methylenebis(3-carboxy-2,4,6-trimethylbenzoato)-κ2
O
1:O
1′]zinc(II)] hemihydrate], {[Zn(C23H22O8)(C19H14N4)(H2O)2]·0.5H2O}
n
, 1, was prepared by the self-assembly of Zn(NO3)2·6H2O with 5,5′-methylenebis(2,4,6-trimethylisophthalic acid) (H4BTMIPA) and 2,7-bis(1H-imidazol-1-yl)fluorene (BIF) under solvothermal conditions. The structure of 1 was determined by elemental analysis, single-crystal X-ray crystallography, powder X-ray diffraction, IR spectroscopy and thermogravimetric analysis. Each ZnII ion is six-coordinated by two O atoms from two H2BTMIPA2− ligands, by two N atoms from two BIF ligands and by two water molecules, forming a distorted octahedral ZnN2O4 coordination geometry. Adjacent ZnII ions are linked by H2BTMIPA2− ligands and BIF ligands, leading to the formation of a two-dimensional (2D) (4,4)-sql network, and intermolecular hydrogen-bonding interactions connect the 2D layer structure into the three-dimensional (3D) supramolecular structure. Each 2D layer contains two kinds of helices with the same direction, which are opposite in adjacent layers. The luminescence properties of complex 1 in the solid state have also been investigated.
The combination of different open innovations: a longitudinal case study
Authors: Yuan Xiaodong , Li Xiaotao
Published: December 2018

Purpose

The purpose of this paper is to explore how an organization can combine different types of open innovations and what are the key factors that may influence the combination of different open innovations.

Design/methodology/approach

The basic methodology of this paper is the longitudinal inductive analysis within the conceptual framework of the open innovation proposed by Dahlander and Gann (2010). In this case study of Xiaomi Tech Inc., the open innovation combination is investigated through examining 25 new products created between August 2010 and December 2016 in terms of four general types: acquiring, sourcing, selling and revealing open innovation.

Findings

In practice, the combination of different types of open innovations can be realized. A firm may combine different open innovations at three levels: a single product level, a related product cluster level and a company level. In addition, different open innovations can be combined in diverse modes. The purpose of combining different types of open innovations is to overcome the disadvantages of each type and to exploit the advantages of all different types. Many factors may affect a firm’s option of how to combine open innovations. At different development stages, a firm may make and implement corresponding strategic direction based on its innovation capacity and internal resource. For a given strategy, the firm needs to create profits and manage intellectual property in the implementation of open innovations. These factors are interacted each other, rather than isolated.

Originality/value

The findings of this paper are helpful for better understanding how and why an organization can combine different types of open innovations. From a managerial point of view, an organization may combine different types of open innovations to leverage advantages and avoid disadvantages of each certain type of open innovation. An appropriate combination of different open innovations can effectively improve new product development.
Critical perspectives on international pharmaceutical innovation
Authors: Callaghan Christian William
Published: December 2018

Purpose

This paper aims to argue that certain insights offered by Kuhn and Foucault may be of use to those seeking to resist a global paradigm of inequality in access to the outcomes of pharmaceutical development. It is further argued that these relationships are not independent of certain power relationships. This critical review seeks to highlight certain of these power relationships, and to suggest how they might be better managed to ensure more equitable outcomes for those in society that are most vulnerable to innovation failure.

Design/methodology/approach

This research takes the form of a critical review paper, seeking to develop theory though a synthesis of literature.

Findings

Unlike market incentives, it might be the research process itself that is most vulnerable to stakeholder resistance to slow and unequal delivery of life-saving pharmaceutical development. Given that a lack of responsiveness to societal needs can itself be considered unethical, Kuhnian theory predicting pharmaceutical innovation failure is related to what Foucault describes as a system of oppression, whereby power relationships disadvantage those most vulnerable and powerless.

Research limitations/implications

Given the rise of movements like citizen science and participant-led research, as well as new ethical frameworks premised on increasing accountability in science, Foucault’s principles are considered to echo a general trend towards the democratisation of science, and towards increasing the responsiveness of pharmaceutical development to societal needs.

Originality/value

A novel synthesis of literature is undertaken, offering useful theoretical insights into how social actors might contribute to enabling a more responsive system of international healthcare business.
More product, more process: metadata in digital image collections
Authors: Therrell Grace
Published: December 2018

Purpose

The purpose of this paper is to discuss the implications of current theories that advocate for minimal levels of description in digital collections. Specifically, this paper looks at the archival theory of “More Product, Less Process” and its encouragement of collection-level description. The purpose of the study was to analyze how levels of description impact resource retrieval.

Design/methodology/approach

This study analyzed 35 images from a New York Public Library (NYPL) digital collection present on the NYPL website and on Flickr. The methodology was designed to reflect users’ information seeking behavior for image collections. There were two research questions guiding this study: what are the descriptive terms used to describe items in digital collections? and what is the success rate of retrieving resources using assigned descriptive terms?

Findings

The results of this study revealed that the images from the NYPL collection were more difficult to find on the institution’s website as compared with Flickr. These findings suggest that lesser levels of description in digital collections hinder resource retrieval.

Research limitations/implications

These findings suggest that lesser description levels hurt the findability of resources. In the wake of theories such as “More Product, Less Process”, information professionals must find ways to assign metadata to individual materials in digital image collections.

Originality/value

Recent research concerning description levels of digital collections is several years old and focuses mostly on the usefulness of collection-level metadata as a supplement to or substitute for item-level metadata. Few, if any, studies exist that explore the implications of description levels on resource retrievability and findability. This study is also unique in that it discusses these implications in the context of less-is-more theories of archival processing.
Implementation of RFID in university libraries of Bangladesh
Authors: Rahman Md. Habibur , Islam Md. Shiful
Published: December 2018

Purpose

The purpose of this paper is to describe the present status of implementing innovative radio frequency identification (RFID) technology in university libraries of Bangladesh. The main obstacles of implementing this technology among university libraries and ways to overcome the obstacles are also described.

Design/methodology/approach

This study uses both qualitative and quantitative approaches along with review of related literature. The present scenario of RFID implementation status of Bangladesh is shown by a survey with a structured questionnaire and reviewing related literature.

Findings

The findings show that RFID is being used in the university libraries to reduce staff stress, increase efficiency, track and locate items quickly, book drop support at any time, easier circulation, promote self-check-in check-out activities, etc. This study identifies the challenges in libraries of Bangladesh which are lack of adequate funding, unavailability of RFID accessories, lack of skilled manpower, unwillingness, erratic power supply, etc. Also, it suggests some suitable ways such as creating positive impression and attitudes, arrangement of proper training, appointment of skilled manpower and allocation of sufficient budget to overcome the existing challenges of RFID.

Originality/value

The study describes the benefits of RFID technology for libraries, and some recommendations are proposed for extensive use of this technology.
Pakistani prison libraries: an assessment of services and challenges
Authors: Hussain Tauseef , Batool Syeda Hina , Soroya Saira Hanif , Warraich Nosheen Fatima
Published: December 2018

Purpose

The purpose of the paper is to examine the current status of prison libraries, their role, services and collection in Pakistani context. It also attempts to highlight the main problems faced by selected libraries.

Design/methodology/approach

The qualitative research approach was adopted to achieve the study objectives. Data were collected using face-to-face interviews to find out respondents’ views about libraries in prison.

Findings

Findings of the study confirmed that inmates’ library queries are mostly related to the legal matters, and it is quite natural. One of the significant services of the Pakistani prison libraries is to help prisoners in their education. The main role of the library caretaker was to educate and offer rehabilitation programs. Unavailability of library space, lack of professional staff, limited collections, poor budgetary situation and censorship issues are the major challenges that Pakistani prison libraries are facing.

Social implications

The study findings further implicate that open libraries and access to books would promote positivity within society and reduce criminal and immoral acts.

Originality/value

It is the first of its kind and unique study that presents the current situation of prison libraries in the Pakistani context. The study has practical implications for policymakers to give importance to prison libraries in terms of finance, professional staff and the availability of information sources.
Improving outcomes for homeless inpatients in mental health
Authors: Khan Zana , Koehne Sophie , Haine Philip , Dorney-Smith Samantha
Published: December 2018

Purpose

The purpose of this paper is to describe the delivery of the first clinically led, inter-professional Pathway Homeless team in a mental health trust, within the King’s Health Partners hospitals in South London. The Kings Health Partners Pathway Homeless teams have been operating since January 2014 at Guy’s and St Thomas’ (GStT) and Kings College Hospital and expanded to the South London and Maudsley in 2015 as a charitable pilot, now continuing with short-term funding.

Design/methodology/approach

This paper outlines how the team delivered its key aim of improving health and housing outcomes for inpatients. It details the service development and integration within a mental health trust incorporating the experience of its sister teams at Kings and GStT. It goes on to show how the service works across multiple hospital sites and is embedded within the Trust’s management structures.

Findings

Innovations including the transitional arrangements for patients’ post-discharge are described. In the first three years of operation the team saw 237 patients. Improved housing status was achieved in 74 per cent of patients with reduced use of unscheduled care after discharge. Early analysis suggests a statistically significant reduction in bed days and reduced use of unscheduled care.

Originality/value

The paper suggests that this model serves as an example of person centred, value-based health that is focused on improving care and outcomes for homeless inpatients in mental health settings, with the potential to be rolled-out nationally to other mental health Trusts.
Introducing MathQA: a Math-Aware question answering system
Authors: Schubotz Moritz , Scharpf Philipp , Dudhat Kaushal , Nagar Yash , Hamborg Felix , Gipp Bela
Published: December 2018

Purpose

This paper aims to present an open source math-aware Question Answering System based on Ask Platypus.

Design/methodology/approach

The system returns as a single mathematical formula for a natural language question in English or Hindi. These formulae originate from the knowledge-based Wikidata. The authors translate these formulae to computable data by integrating the calculation engine sympy into the system. This way, users can enter numeric values for the variables occurring in the formula. Moreover, the system loads numeric values for constants occurring in the formula from Wikidata.

Findings

In a user study, this system outperformed a commercial computational mathematical knowledge engine by 13 per cent. However, the performance of this system heavily depends on the size and quality of the formula data available in Wikidata. As only a few items in Wikidata contained formulae when the project started, the authors facilitated the import process by suggesting formula edits to Wikidata editors. With the simple heuristic that the first formula is significant for the paper, 80 per cent of the suggestions were correct.

Originality/value

This research was presented at the JCDL17 KDD workshop.