bluuebunny/crossref_metadata_2025 huggingface dataset:
Dietary fat promotes antibiotic-induced Clostridioides difficile mortality in mice
Authors: Hazleton Keith Z. , Martin Casey G. , Orlicky David J , Arnolds Kathleen L. , Nusbacher Nichole M. , Moreno-Huizar Nancy , Armstrong Michael , Reisdorph Nichole , Lozupone Catherine A.
Published: November 2019

Clostridioides difficile infection (CDI), is the leading cause of hospital-acquired diarrhea and emerging evidence has linked dietary components with CDI pathogenesis, suggesting that dietary modulation may be an effective strategy for prevention. Here, we show that mice fed a high-fat/low-fiber “Western type” diet (WD) had dramatically increased mortality in a murine model of antibiotic-induced CDI compared to a low-fat/low-fiber (LF/LF) diet and standard mouse chow controls. We found that the WD had a pro- C. difficile bile acid composition that was driven in part by higher levels of primary bile acids that are produced to digest fat, and a lower level of secondary bile acids that are produced by the gut microbiome. This lack of secondary bile acids was associated with a greater disturbance to the gut microbiome with antibiotics in both the WD and LF/LF diet compared to mouse chow. Mice fed the WD also had the highest level of toxin TcdA just prior to the onset of mortality, but not of TcdB or increased inflammation. These findings indicate that dietary intervention to decrease fat may complement previously proposed dietary intervention strategies to prevent CDI in high-risk individuals.

One Sentence Summary

A high-fat/low-fiber Western type diet promoted mortality in a mouse model of antibiotic-induced C. difficile infection compared to a low-fat/low-fiber diet and chow diet, suggesting that lower dietary fat may be an effective strategy for preventing C. difficile pathology.
Structural robustness affects the engineerability of aminoacyl-tRNA synthetases for genetic code expansion
Authors: Grasso Katherine T. , Yeo Megan Jin Rae , Hillenbrand Christen M. , Ficaretta Elise D. , Italia James S. , Huang Rachel L. , Chatterjee Abhishek
Published: November 2019

The ability to engineer the substrate specificity of natural aminoacyl-tRNA synthetase/tRNA pairs facilitates the site-specific incorporation of noncanonical amino acids (ncAAs) into proteins. The Methanocaldococcus jannaschii derived tyrosyl-tRNA synthetase (MjTyrRS)/tRNA pair has been engineered to incorporate numerous ncAAs into protein expressed in bacteria. However, it cannot be used in eukaryotic cells due to cross-reactivity with its host counterparts. The E. coli derived tyrosyl-tRNA synthetase (EcTyrRS)/tRNA pair offers a suitable alternative to this end, but a much smaller subset of ncAAs has been genetically encoded using this pair. Here we report that this discrepancy, at least partly, stems from the lower structural robustness of EcTyrRS relative to MjTyrRS. We show that engineered TyrRS mutants in general exhibit significantly lower thermostability relative to their wild-type counterparts. Derived from a thermophilic archaeon, MjTyrRS is a remarkably sturdy protein and tolerates extensive active site engineering without a catastrophic loss of stability at physiological temperature. In contrast, EcTyrRS exhibits significantly lower thermostability, rendering some of its engineered mutants insufficiently stable at physiological temperature. Our observations identify the structural robustness of an aaRS as an important factor that significantly influences how extensively it can be engineered. To overcome this limitation, we have further developed chimeras between EcTyrRS and its homolog from a thermophilic bacteria, which offer an optimal balance between thermostability and activity. We show that the chimeric bacterial TyrRSs show enhanced tolerance for destabilizing active site mutations, providing a potentially more engineerable platform for genetic code expansion.
Understory light quality affects leaf pigments and leaf phenology in different plant functional types
Authors: Brelsford CC , Trasser M , Paris T , Hartikainen SM , Robson TM
Published: November 2019

Understory plant species take on different functional strategies, whereby some exploit periods of available light in springtime before the canopy closes, and others also benefit from sunlight later in autumn when the canopy opens again. These strategies involve understory species coordinating phenological events to pre-empt canopy leaf out and to extend their growing season beyond canopy leaf senescence, meanwhile accumulating photo-protective pigments which mitigate periods of high-light exposure. Canopy closure brings shade to the understory, but also causes drastic changes in light quality. Whilst many experiments manipulating spectral quality have revealed understory plant responses to the changing R:FR ratio in shade, effect of the blue and UV regions have been examined very little. We installed filters attenuating short wavelength regions of the solar spectrum in a forest understory in southern Finland, creating the following treatments: a transparent control filter, and filters attenuating UV radiation < 350 nm, all UV radiation, and both UV and blue light. In eight understory species, representing different plant functional types, we repeatedly assessed leaf optical properties to obtain epidermal flavonol and anthocyanin contents from leaf emergence in spring to leaf senescence in autumn, during both 2017 and 2018. Flavonols responded more to seasonal changes in light quality in relatively light-demanding species than in shade-tolerant and wintergreen species; and were particularly responsive to blue light. However, anthocyanins were largely unaffected by our filter treatments, suggesting that other cues such as cold temperatures govern their seasonal variation. UV radiation only accelerated leaf senescence inAcer platanoidesseedlings, but blue light accelerated leaf senescence in all species measured apart fromQuercus robur. In summary, seasonal changes in understory solar radiation in the blue and UV regions affected leaf pigments and leaf phenology; particularly for more light-demanding species. An increase in canopy duration under climate change will extend the period of shade in the understory, with consequences for the spectral cues available to understory plants. The resultant reduction in blue and UV radiation in shade, could delay leaf senescence in the understory even further.
Phylodynamics of sunflower chlorotic mottle virus, a re-emerging pathosystem
Authors: Mederos Dariel Cabrera , Torres Carolina , Bejerman Nicolás , Trucco Verónica , Lenardon Sergio , Mora Michel Leiva , Giolitti Fabián
Published: November 2019

Distribution and epidemiological patterns of sunflower chlorotic mottle virus (SCMoV) in sunflower (Helianthus annuusL.) growing areas in Argentina were studied from 2006 to 2017. The virus was detected exclusively in the Pampas region (Entre Ríos, Santa Fe, Córdoba, La Pampa and Buenos Aires provinces). Phylodynamic analyses performed using the coat protein gene of SCMoV isolates from sunflower and weeds dated the most recent common ancestor (MRCA) back to 1887 (HPD95% = 1572-1971), which coincides with the dates of sunflower introduction in Argentina. The MRCA was located in the south of Buenos Aires province and was associated with sunflower host (posterior probability for the ancestral host, ppah= 0.98). The Bayesian phylodynamic analyses revealed the dispersal patterns of SCMoV, suggesting a link between natural host diversity, crop displacement by human activities and virus spread.
Ytterbium-doped fibre femtosecond laser offers robust design with deep and precise microsurgery
Authors: Harreguy MB , Marfil V , Gabel CV , Chung SH , Haspel G
Published: November 2019

Laser microsurgery is a powerful tool for neurobiology used to ablate cells and sever neurites in-vivo. We compare a relatively new laser source to two well-established designs. Rare-earth-doped mode-locked fibre laser that produce high power pulsed radiation recently gained popularity for industrial uses. Such systems are manufactured at high standards of robustness and low maintenance requirements typical of solid-state lasers. We demonstrate that an Ytterbium-doped fibre femtosecond laser is comparable in precision to other femtosecond lasers, but with added reliability. It is more precise and can lesion deeper in tissue than a solid-state nanosecond laser. These advantages are not specific to the model system ablated for our demonstration, namely neurites in the nematode C. elegans, but are applicable to other systems and transparent tissue where a precise submicron resolution dissection is required.
Genome-wide DNA methylation analysis of heavy cannabis exposure in a New Zealand longitudinal cohort
Authors: Osborne Amy J. , Pearson John F. , Noble Alexandra J. , Gemmell Neil J. , Horwood L. John , Boden Joseph M. , Benton Miles , Macartney-Coxson Donia P. , Kennedy Martin A.
Published: November 2019

Cannabis use is of increasing public health interest globally. Here we examined the effect of cannabis use, with and without tobacco, on genome-wide DNA methylation in a longitudinal birth cohort (Christchurch Health and Development Study). We found the most differentially methylated sites in cannabis with tobacco users were in the AHRR and F2RL3 genes, replicating previous studies on the effects of tobacco. Cannabis-only users had no evidence of differential methylation in these genes, or at any other loci at the epigenomewide significance level (P<10−7). However, there were 521 sites differentially methylated at P<0.001 which were enriched for genes involved in cardiomyopathy and neuronal signalling. Further, the most differentially methylated loci were associated with genes with reported roles in brain function (e.g. TMEM190, MUC3L, CDC20 and SP9). We conclude that the effects of cannabis use on the mature human blood methylome differ from, and are less pronounced than, the effects of tobacco use, and that larger sample sizes are required to investigate this further.
Independent evolution of cutaneous lymphoma subclones in different microenvironments of the skin
Authors: Iyer Aishwarya , Hennessey Dylan , O’Keefe Sandra , Patterson Jordan , Wang Weiwei , Wong Gane Ka-Shu , Gniadecki Robert
Published: November 2019

Mycosis fungoides (MF) is the most common, yet incurable, cutaneous T-cell lymphoma. We have recently shown that the disease is initiated by hematogenous seeding the skin with clonotypically diverse neoplastic T-cells which proliferate accumulating numerous mutations and produce lesions of high intratumoral heterogeneity (ITH). A characteristic but a poorly studied feature of MF is epidermotropism, the tendency to infiltrate skin epithelial layer (epidermis) in addition to the vascularized dermis. By sequencing the exomes of the microdissected clusters of lymphoma cells from the epidermis and the dermis, we found that those microenvironments harbored different malignant clonotypes and exhibited different patterns of driver gene mutation. Phylogenetic relationships between cancer subclones witnessed to the independent mutational evolution in the epidermis and dermis. Thus, the invasion of MF to different skin layers does not occur by gradual infiltration of the expanding tumor mass, but is caused by separate seeding processes with different malignant clones that develop independently of one another via a neutral, branched evolution. In conclusion, tissue microenvironments shape the subclonal architecture in MF leading to “ecological heterogeneity” which contributes to the total ITH. Since ITH adversely affects cancer prognosis, targeting the microenvironment may present therapeutic opportunities in MF and other cancers.
CTP synthase forms cytoophidia in archaea
Authors: Zhou Shuang , Xiang Hua , Liu Ji-Long
Published: November 2019

CTP synthase (CTPS) is an important metabolic enzyme that catalyzes the rate-limiting reaction of de novo synthesis of the nucleotide CTP. Since 2010, a series of studies have demonstrated that CTPS can form filamentous structures termed cytoophidia in bacteria and eukaryotes. However, it remains unknown whether cytoophidia exist in archaea, the third domain of life. UsingHaloarcula hispanicaas a model system, here we demonstrate that CTPS forms distinct intracellular compartments in archaeal cells. Under stimulated emission depletion (STED) microscopy, we find that some HhCTPS compartments have elongated filamentous structures, resembling cytoophidia in bacteria and eukaryotes. WhenHaloarculacells are cultured in low-salt medium, the occurrence of cytoophidia increases dramatically. Moreover, overexpression of CTPS or glutamine analog treatment promotes cytoophidium assembly inH. hispanica.Our study reveals that CTPS forms cytoophidia in all three domains of life, suggesting that this is an ancient property of CTPS.
Grid pattern development, distortions and topological defects may depend on distributed anchoring
Authors: Mørreaunet Maria , Hägglund Martin
Published: November 2019

The firing pattern of grid cells in rats has been shown to exhibit elastic distortions that compresses and shears the pattern and suggests that the grid is locally anchored. Anchoring points may need to be learned to account for different environments. We recorded grid cells in animals encountering a novel environment. The grid pattern was not stable but moved between the first few sessions predicted by the animals running behavior. Using a learning continuous attractor network model, we show that learning distributed anchoring points may lead to such grid field movement as well as previously observed shearing and compression distortions. The model further predicted topological defects comprising a pentagonal/heptagonal break in the pattern. Grids recorded in large environments were shown to exhibit such topological defects. Taken together, the final pattern may be a compromise between local network attractor states driven by self-motion signals and distributed anchoring inputs from place cells.
Mathematical modeling of plant cell fate transitions controlled by hormonal signals
Authors: Klawe Filip Z. , Stiehl Thomas , Bastian Peter , Gaillochet Christophe , Lohmann Jan U. , Marciniak-Czochra Anna
Published: November 2019

Coordination of fate transition and cell division is crucial to maintain the plant architecture and to achieve efficient production of plant organs. In this paper, we analysed the stem cell dynamics at the shoot apical meristem (SAM) that is one of the plant stem cells locations. We designed a mathematical model to elucidate the impact of hormonal signaling on the fate transition rates between different zones corresponding to slowly dividing stem cells and fast dividing transit amplifying cells. The model is based on a simplified two-dimensional disc geometry of the SAM and accounts for a continuous displacement towards the periphery of cells produced in the central zone. Coupling growth and hormonal signaling results in a non-linear system of reaction-diffusion equations on a growing domain with the growth velocity depending on the model components. The model is tested by simulating perturbations in the level of key transcription factors that maintain SAM homeostasis. The model provides new insights on how the transcription factor HECATE is integrated in the regulatory network that governs stem cell differentiation.

Plants continuously generate new organs such as leaves, roots and flowers. This process is driven by stem cells which are located in specialized regions, so-called meristems. Dividing stem cells give rise to offspring that, during a process referred to as cell fate transition, become more specialized and give rise to organs. Plant architecture and crop yield crucially depend on the regulation of meristem dynamics. To better understand this regulation, we develop a computational model of the shoot meristem. The model describes the meristem as a two-dimensional disk that can grow and shrink over time, depending on the concentrations of the signalling factors in its interior. This allows studying how the non-linear interaction of multiple transcription factors is linked to cell division and fate-transition. We test the model by simulating perturbations of meristem signals and comparing them to experimental data. The model allows simulating different hypotheses about signal effects. Based on the model we study the specific role of the transcription factor HECATE and provide new insights in its action on cell dynamics and in its interrelation with other known transcription factors in the meristem.
Potpourri: An Epistasis Test Prioritization Algorithm via Diverse SNP Selection
Authors: Caylak Gizem , Tastan Oznur , Cicek A. Ercument
Published: November 2019

Genome-wide association studies explain a fraction of the underlying heritability of genetic diseases. Investigating epistatic interactions between two or more loci help closing this gap. Unfortunately, sheer number of loci combinations to process and hypotheses to test prohibit the process both computationally and statistically. Epistasis test prioritization algorithms rank likely-epistatic SNP pairs to limit the number of tests. Yet, they still suffer from very low precision. It was shown in the literature that selecting SNPs that are individually correlated with the phenotype and also diverse with respect to genomic location, leads to better phenotype prediction due to genetic complementation. Here, we propose that an algorithm that pairs SNPs from such diverse regions and ranks them can improve prediction power. We propose an epistasis test prioritization algorithm which optimizes a submodular set function to select a diverse and complementary set of genomic regions that span the underlying genome. SNP pairs from these regions are then further ranked w.r.t. their co-coverage of the case cohort. We compare our algorithm with the state-of-the-art on three GWAS and show that (i) we substantially improve precision (from 0.003 to 0.652) while maintaining the significance of selected pairs, (ii) decrease the number of tests by 25 folds, and (iii) decrease the runtime by 4 folds. We also show that promoting SNPs from regulatory/coding regions improves the performance (up to 0.8). Potpourri is available at http:/ciceklab.cs.bilkent.edu.tr/potpourri.
Research of the mechanism on miRNA193 in exosomes promotes cisplatin resistance in esophageal cancer cells
Authors: Shi Shifeng , Huang Xin , Ma Xiao , Zhu Xiaoyan , Zhang Qinxian
Published: November 2019

Purpose

Chemotherapy resistance of esophageal cancer is a key factor affecting the postoperative treatment of esophageal cancer. Among the media that transmit signals between cells, the exosomes secreted by tumor cells mediate information transmission between tumor cells, which can make sensitive cells obtain resistance. Although some cellular exosomes play an important role in tumor’s acquired drug resistance, the related action mechanism is still not explored specifically.

Methods

To elucidate this process, we constructed a cisplatin-resistant esophageal cancer cell line, and proved that exosomes conferring cellular resistance in esophageal cancer can promote cisplatin resistance in sensitive cells. Through high-throughput sequencing analysis of the exosome and of cells after stimulation by exosomes, we determined that the miRNA193 in exosomes conferring cellular resistance played a key role in sensitive cells acquiring resistance to cisplatin. In vitro experiments showed that miRNA193 can regulate the cell cycle of esophageal cancer cells and inhibit apoptosis, so that sensitive cells can acquire resistance to cisplatin. An in vivo experiment proved that miRNA193 can promote tumor proliferation through the exosomes, and provide sensitive cells with slight resistance to cisplatin.

Results

Small RNA sequencing of exosomes showed that exosomes in drug-resistant cells have 189 up-regulated and 304 down-regulated miRNAs; transcriptome results showed that drug-resistant cells treated with drug-resistant cellular exosomes have 3446 high-expression and 1709 low-expression genes; correlation analysis showed that drug-resistant cellular exosomes mainly affect the drug resistance of sensitive cells through paths such as cytokine–cytokine receptor interaction, and the VEGF and Jak-STAT signaling pathways; miRNA193, one of the high-expression miRNAs in drug-resistant cellular exosomes, can promote drug resistance by removing cisplatin’s inhibition of the cell cycle of sensitive cells.

Conclusion

Sensitive cells can become resistant to cisplatin through acquired drug-resistant cellular exosomes, and miRNA193 can make tumor cells acquire cisplatin resistance by regulating the cell cycle.
Role ofTrypanosoma cruzinucleoside diphosphate kinase 1 in DNA-damage responses
Authors: Reigada Chantal , Sayé Melisa , Di Girolamo Fabio , Valera-Vera Edward A. , Pereira Claudio A. , Miranda Mariana R.
Published: November 2019

NME23/NDPK proteins are well conserved proteins found in all living organism. Besides their catalytic activity of nucleoside diphosphate kinase (NDPK) they are considered multifunctional, which were first characterized as non-metastatic proteins in mammalian cells. Later, increasing evidences placed NME/NDPK as proteins involved in DNA stability such as gene regulation and DNA-repair. TcNDPK1 is the canonical NDPK isoform present in the parasiteTrypanosoma cruzi, orthologous to NME23-H1/H2 which has been shown to have in vitro nuclease activity and DNA-binding properties. In the present study we investigate the role of TcNDPK1 in DNA-damage responses using heterologous gene expression systems and over-expression in epimastigote cells. We found that different strains of bacteria, WT andndk-mutants, expressing the enzyme decreased about 5 fold and 18 fold the spontaneous mutation rate, respectively. In addition, yeasts lacking the endogenous geneYNK1(YNK1-) and expressing TcNDPK1, were significantly more resistant to different concentrations of hydrogen peroxide and were less sensible to UV radiation than controls. Parasites over-expressing TcNDPK1 were able to withstand different genotoxic stresses caused by hydrogen peroxide, phleomycin and hidroxyurea. In addition, under oxidative damage, TcNDPK1 over-expressing parasites presented lesser genomic damage and augmented levels of poly(ADP)ribose and poly(ADP)ribose polymerase, an enzyme involved in DNA repair. These results strongly suggest that TcNDPK1 is involved in the maintenance of parasite genomic-DNA integrity, thus, giving rise to a novel function.
Human Bocavirus Prevalence In Children With Acute Gastroenteritis From Rural Communities In The Northen Region Of South Africa
Authors: Rikhotso Mpumelelo Casper , Khumela Ronewa , Kabue Jean Pierre , Traoré Afsatou Ndama , Potgieter Natasha
Published: November 2019

BACKGROUND

Acute gastroenteritis (AGE) is a leading cause of morbidity and mortality in young children worldwide. Human Bocavirus (HBoV) is an emerging virus globally associated with diarrhea. The aim of this study was to demonstrate the prevalence of HBoV genotypes in children (≤5 years) from rural communities in South Africa (SA) suffering from AGE.

MATERIAL AND METHOD

A total of 141 fecal samples of children ≤5 years with acute gastroenteritis (AGE) were collected from rural Primary Health Care facilities in the Vhembe district of SA between June 2017 and July 2018. Clinical symptoms and demographic data were also recorded. A total of 102 (72%) were outpatients and 39 (28%) were hospitalized patients. Human Bocavirus (HBoV) genotypes were determined using Real-Time Multiplex PCR. DNA extracts of positive samples were confirmed by conventional PCR targeting the NS1 gene. Co-infection with other enteric viruses were determined in HBoV positive samples using Real-Time PCR.

RESULTS

HBoV was detected in 8 (5.7%) children with AGE. Children were in the age group between 1-24 months. HBoV1 and HBoV3 genotypes were each detected in 3 (37.5%) stool samples and HBoV2 in 2 (25%) stool samples. Co-infection with other enteric viruses included Rotavirus (37.5%); Adenovirus (37.5%); Norovirus (25%) and Astrovirus (12.5%).

CONCLUSION

HBoV infections could be seen as a potential emerging diarrheal pathogen in South Africa. Further studies are required to understand the role of HBoV infections in children and adults with acute gastroenteritis.

Author summary

Acute gastroenteritis (AGE) is recognized as a major cause for mortality in children ≤5 years of age in Africa and other developing countries. Viruses known to be involved in AGE includes Rotavirus, Norovirus, Astrovirus and Adenovirus and have been reported globally. Recently the Human Bocavirus (HBoV) have been reported in numerous studies globally as a potential cause of diarrhea. In this study, the prevalence and genetic diversity of human Bocavirus in children with AGE from rural communities in Limpopo, South Africa were investigated. In total, 141 stool samples from children ≤ 5 years with AGE were assessed for the presence of HBoV using Real-Time PCR. HBoV were detected in 8 (5.7%) patients and included 3 positive samples for HBoV1 and HBoV3 respectively and 2 positive for HBoV2. No HBoV4 were detected. Among the 8 positive HBoV samples, co-infection with other enteric viruses were found in 7 (87.5%) samples, while mono infection with HBoV alone was detected in 1 (12.5%) patient. HBoV mixed infection with Rotavirus (3/8; 37.5%); Adenovirus (3/8; 37.5%); Norovirus (2/8; 25%) and Astrovirus (1/8; 12.5%) were observed in this study. This study reported for the first time on the prevalence of human Bocavirus in children with AGE from rural communities in South Africa.
Dynamic connectivity maps of pericytes and endothelial cells mediate neurovascular coupling in health and disease
Authors: Kovacs-Oller Tamas , Ivanova Elena , Bianchimano Paola , Sagdullaev Botir T.
Published: November 2019

Functional hyperemia, or matching blood flow to activity, is spatially accurate to direct the oxygen and nutrients to regionally firing neurons. The underlying signaling mechanisms of neurovascular coupling remain unclear, but are critical for brain function and establish the diagnostic power of BOLD-fMRI. Here, we described a mosaic of pericytes, the vasomotor capillary cells in the living retina. We then tested if this symmetric net of pericytes and surrounding neuroglia predicted a connectivity map in response to sensory stimuli. Surprisingly, we found that these connections were not only discriminatory across cell types, but also highly asymmetric spatially. First, pericytes connected predominantly to other neighboring pericytes and endothelial cells, and less to arteriolar smooth muscle cells, and not to surrounding neurons or glia. Second, focal, but not global stimulation evoked a directional vasomotor response by strengthening connections along the feeding vascular branch. This activity required local NO signaling and occurred by means of direct coupling via gap-junctions. By contrast, bath application of NO or diabetes, a common microvascular pathology, not only weakened the vascular signaling but also abolished its directionality. We conclude that the discriminatory nature of neurovascular interactions may thus establish spatial accuracy of blood delivery with the precision of the neuronal receptive field size, and is disrupted early in microvascular disease.

Highlights

Within a structurally symmetric mosaic, pericytes form discriminatory connections

Pericyte connectome tunes with a precision matching a neuronal receptive field

Focal but not global input evokes a vasomotor response by strengthening the gap-junction mediated signaling towards a feeding vascular branch

Disrupted functional connectivity map triggers loss of the functional hyperemia in diabetic neuropathy
Deep Generative Models for 3D Compound Design
Authors: Imrie Fergus , Bradley Anthony R. , van der Schaar Mihaela , Deane Charlotte M.
Published: November 2019

Rational compound design remains a challenging problem for both computational methods and medicinal chemists. Computational generative methods have begun to show promising results for the design problem. However, they have not yet used the power of 3D structural information. We have developed a novel graph-based deep generative model that combines state-of-the-art machine learning techniques with structural knowledge. Our method (“DeLinker”) takes two fragments or partial structures and designs a molecule incorporating both. The generation process is protein context dependent, utilising the relative distance and orientation between the partial structures. This 3D information is vital to successful compound design, and we demonstrate its impact on the generation process and the limitations of omitting such information. In a large scale evaluation, DeLinker designed 60% more molecules with high 3D similarity to the original molecule than a database baseline. When considering the more relevant problem of longer linkers with at least five atoms, the outperformance increased to 200%. We demonstrate the effectiveness and applicability of this approach on a diverse range of design problems: fragment linking, scaffold hopping, and proteolysis targeting chimera (PROTAC) design. As far as we are aware, this is the first molecular generative model to incorporate 3D structural information directly in the design process. Code is available at https://github.com/oxpig/DeLinker.
Differential complex formation via paralogs in the human Sin3 protein interaction network
Authors: Adams Mark K. , Banks Charles A.S. , Thornton Janet L. , Sardiu Mihaela E. , Killer Maxime , Kempf Cassandra G. , Florens Laurence , Washburn Michael P.
Published: November 2019

Despite the continued analysis of HDAC inhibitor efficacy in clinical trials, the heterogeneous nature of the protein complexes they target limits our understanding of the beneficial and off-target effects associated with their application. Among the many HDAC protein complexes found within the cell, Sin3 complexes are conserved from yeast to humans and likely play important roles as regulators of transcriptional activity. The functional attributes of these protein complexes remain poorly characterized in humans. Contributing to the poor definition of Sin3 complex attributes in higher eukaryotes is the presence of two Sin3 scaffolding proteins, SIN3A and SIN3B. Here we show that paralog switching influences the interaction networks of the Sin3 complexes. While SIN3A and SIN3B do have unique interaction network components, we find that SIN3A and SIN3B interact with a common set of proteins. Additionally, our results suggest that SIN3A and SIN3B may possess the capacity to form hetero-oligomeric complexes. While one principal form of SIN3B exists in humans, the analysis of rare SIN3B proteoforms provides insight into the domain organization of SIN3B. Together, these findings shed light on the shared and divergent properties of human Sin3 proteins and highlight the heterogeneous nature of the complexes they organize.
Novel neural signal features permit robust machine-learning of natural tactile- and proprioception-dominated dorsal column nuclei signals
Authors: Loutit Alastair J , Potas Jason R
Published: November 2019

Neural prostheses enable users to effect movement through a variety of actuators by translating brain signals into movement control signals. However, to achieve more natural limb movements from these devices, restoration of somatosensory feedback and advances in neural decoding of motor control-related brain signals are required. We used a machine-learning approach to assess signal features for their capacity to enhance decoding performance of neural signals evoked by natural tactile and proprioceptive somatosensory stimuli, recorded from the surface of the dorsal column nuclei in urethane-anaesthetised rats. We determined signal features that are highly informative for decoding somatosensory stimuli, yet these appear underutilised in neuroprosthetic applications. We found that proprioception-dominated stimuli generalise across animals better than tactile-dominated stimuli, and we demonstrate how information that signal features contribute to neural decoding changes over a time-course of dynamic somatosensory events. These findings may improve neural decoding for various applications including novel neuroprosthetic design.
Enhanced aversive memory retrieval by chemogenetic activation of locus coeruleus norepinephrine neurons
Authors: Fukabori Ryoji , Iguchi Yoshio , Kato Shigeki , Takahashi Kazumi , Eifuku Satoshi , Tsuji Shingo , Hazama Akihiro , Uchigashima Motokazu , Watanabe Masahiko , Mizuma Hiroshi , Cui Yilong , Onoe Hirotaka , Hikishima Keigo , Yasoshima Yasunobu , Osanai Makoto , Inagaki Ryo , Fukunaga Kohji , Nishijo Takuma , Momiyama Toshihiko , Benton Richard , Kobayashi Kazuto
Published: November 2019

The ability to retrieve memory store in response to the environment is essential for animal behavioral adaptation. Norepinephrine (NE)-containing neurons in the brain play a key role in the modulation of synaptic plasticity underlying various processes of memory formation. However, the role of the central NE system in memory retrieval remains unclear. In this study, we developed a neural chemogenetic activation strategy using insect olfactory Ionotropic Receptors (IRs), and used it for selective stimulation of NE neurons in the locus coeruleus (LC) in transgenic mice. Ligand-induced activation of LC NE neurons resulted in enhancement of the retrieval process of conditioned taste aversion, which was mediated through at least partly adrenergic receptors in the amygdala. Pharmacological blockade of LC activity confirmed the facilitative role of these neurons in memory retrieval. Our findings indicate that the LC-amygdalar pathway is required and sufficient for enhancing the recall of taste associative memory.
Strategies of Kenyan firms: a case study of food processing firms in Nairobi
Authors: Wamalwa Herbert , Upadhyaya Radha , Kamau Paul , McCormick Dorothy
Published: November 2019

Purpose

While many studies have discussed the regulatory constraints that hinder industrial development in sub-Saharan Africa, little attention has been paid to the behavior of those firms that succeed despite a challenging business environment. The purpose of this paper is to fill this gap by focusing on specific strategies of a subset of successful industrial firms in Kenya.

Design/methodology/approach

The paper draws on two data sets. First, a quantitative data set based on a survey of food processing firms provides an overall profile of the sub-sector and the strategies employed by successful Kenyan firms. Second, qualitative in-depth case studies unpack the concept of strategy from the perspective of the firm, with the aim of showing the links between vision and strategy and the adaptive nature of firm strategy.

Findings

The quantitative data set reveals that the most important strategies used by agri-processing firms are differentiation strategies (selling at a premium), cost reduction strategies and niche strategies. A second major finding, based on the case study interviews, is that Kenyan firms adopt a combination of strategies to cope with the volatile business environment and grow their market. Furthermore, the qualitative interviews reveal that the vision of the leader is linked to firm strategy and firms follow an adaptive approach to strategy development.

Originality/value

The paper’s original contribution is the conclusion that while the existing typologies of strategy were acknowledged by respondents, their actual strategies were composites resulting from adaptive strategy development. This conclusion was made possible by the paper’s mixed methods approach.
Feasibility of drone integration as last mile delivery
Authors: Ali Sadia Samar , Deka Supriya , Ahmad Zulfiqar , Ahmed Salma , Jaswal Mansingh , Alsulami Hemaid
Published: November 2019

Supplementary materials

Padmanabhan A. 2017 “Civilian drones and India’s regulatory response”. Moushami P. Joshi and Jennifer E. Trock (2016) “India Moving Forward with Unmanned Aircraft Systems Regulations for Civil and Commercial Use” www.lexology.com/library/detail.aspx?g=6d596577-7a4a-4ecc-916e-83c4d37cc90c. www.indrones.com/2017/04/27/drone-industry-india/.Zeimpekis, Vasileios; Ichoua, Soumia; and Minis, Ioannis (2013), Humanitarian and Relief Logistics. Research Issues, Case Studies and Future Trends;Operations Research/Computer Sciences Interfaces Series. Springer Publications, www.springer.com/in/book/9781461470069.

Learning outcomes

The learning outcomes are to illustrate the concept and features of cost-effective and responsive supply chain, to explain the concept of hub and spoke and milk run methods used for delivery, to identify financial, operational and technological risks, to elaborate the importance of social dimension (behavioral dimension) in any technological change in an organization and to understand the concept of management of change in organizations.

Case overview/synopsis

The case deals with a typical challenge of periodical delivery systems, in this case specifically of The Topical, an Indian periodical. The service manager of the company, Sara Jindal, recognized a problem with customer retention. She explored the causes and found that The Topical, a 20-year-old company, was losing its popularity due to the untimely delivery of the magazines. To solve the problem Jindal, tried to gain an understanding of the operational processes and realized that there was no issue in the warehouse regarding inventory control, management or order pickup. However, she found that the magazines were parceled through book post and that there was no tracking policy in the company for the deliveries. Therefore, it was not possible to know whether the magazines got delivered on time. The matter was taken seriously and as a solution, the possibility of integrating drones into the delivery system came up.

Complexity academic level

Undergraduate and Postgraduate students.

Subject code

CSS 9: Operations and Logistics
Prediction of clothing mobility using a musculoskeletal simulator
Authors: Horiba Yosuke , Tokutake Ayumu , Inui S.
Published: November 2019

Purpose

Mobility is one of the important elements in clothing design. The purpose of this paper is to examine the predictability of clothing mobility via musculoskeletal simulation.

Design/methodology/approach

In order to carry out the musculoskeletal simulation considering the influence of clothing, simulation of the dressed state was attempted. This paper simulated the dressed state and measured the motion-related deformation of the clothing to estimate the force applied to the human body based on the material property of the clothing samples. The dressed state was simulated using an external force in the musculoskeletal model.

Findings

When the elbow flexion torque with an elbow supporter was calculated using the above-mentioned method of musculoskeletal simulation, it was confirmed that the lower the stretchability of the sample, the higher the elbow flexion torque. In addition, the sensory evaluation performed under the same condition as that in the simulation showed that the lower the joint torque during the motion, the higher the subjective mobility, and that the higher the joint torque, the lower the subjective mobility. Thus, it is suggested that musculoskeletal simulation of the dressed state can predict the clothing mobility.

Research limitations/implications

However, the method proposed in this paper requires the measurement of the deformation of the clothing to estimate the force applied to the human body. Thus, it is difficult to apply this in the measurement of general clothing that allows enough space between it and the human body, requiring further improvement of the dressed state simulation method.

Originality/value

Because it is difficult to estimate the force applied by the clothing to the human body, only a few studies have performed analysis on the effect of clothing by using musculoskeletal simulation. Conversely, although the force applied by the clothing to the human body needs to be estimated in advance by the measurement of the deformation, the utility of the simulation in clothing design seems to be high because the simulation can estimate clothing mobility and the effects of clothing on muscle activity.
Characteristics of New Zealand dividend omissions and resumptions
Authors: Kraiger Nicholas , Anderson Warwick
Published: November 2019

Purpose

For firms listed on the New Zealand Stock Exchange, which is a relatively thinly traded market, the purpose of this paper is to examine the nature of stock returns associated with a dividend omission announcement when computations specifically address thin trading, and whether specific firm characteristics affect the likelihood and nature of a dividend omission.

Design/methodology/approach

First, event study analysis is used to check if dividend omissions actually do impact share prices in terms of short-term abnormal returns and longer-term cumulative abnormal returns (CARs) in a thinly traded market. Second, binomial logistic regression analysis is used to determine what, if any, company characteristics are associated with the decision to omit a dividend. Third, multinomial logistic regression analysis is employed to determine what firm characteristics are associated with continuing (or ending) a phase of no dividends before a dividend resumption.

Findings

Dividend omissions generate immediate negative abnormal returns, and there is a longer-term persistence of negative CARs. The size and duration of these abnormal returns are smaller, but still significant, when thin-market-specific methodology is employed. With respect to firm characteristic, smaller firms, firms with decreased earnings, a higher level of extraordinary charges, greater leverage and firms with a higher book-to-market value are associated with a greater likelihood of making an omission. With respect to the length of time between an omission and resumption of dividend payments, earnings decreases, a higher book-to-market value, a higher level of extraordinary charges and a decrease in firm debt level become significant.

Originality/value

This paper adds value in two dimensions. First, it considers dividend omissions in three different, but inter-connected ways. Second, the use of multinomial logistic regression to examine an aspect of the non-payment hiatus breaks new ground.
Greenwashing and responsible investment practices: empirical evidence from Zimbabwe
Authors: Olatubosun Posi , Nyazenga Sethi
Published: November 2019

Purpose

This paper aims to explore the nature of responsible investment (RI) practices in Zimbabwe from the point of view of the institutional asset owners by investigating not only how they incorporate the ESG criteria when selecting investee companies but also the elements of greenwashing and impression management.

Design/methodology/approach

Based on semi-structured interviews conducted with Pension Fund Entities, Mutual Funds and Life Assurance companies, the authors used interpretive methodological approach to derive the symbolic RI techniques used.

Findings

This study discovered many symbolic acts of “greenwashing” and impression management as opposed to genuine concerns for ESG issues which are at the core of RI practice. RI is used as not only a systematic risk management instrument but also a symbolic marketing tool due to weak regulatory environment. Contrary to the significantly high public communication on RI, the actual links of the asset owners with the environmental impacts in investee companies is insignificant. The authors also found that there are clear distinctions between how foreign and local firms operating in the local economy engage on ESG matters.

Practical implications

This is likely to have practical implications for stewardship practices in developing jurisdictions where RI practices are puerile.

Originality/value

This paper contributes to the literature on RI dialogue by demonstrating the peculiarity of ESG engagement in a developing economy.
Addressing sustainability information needs along supply chains
Authors: Akhavan Roya Manuela , Zvezdov Dimitar
Published: November 2019

Purpose

Gaining a better understanding of various actors’ information demands and developing suitable approaches to fulfilling them is key in managing sustainability performance in supply chains. Sustainability thereby creates different levels of uncertainty and equivocality. This paper investigates the challenges in managing sustainability information flows along several nodes in the supply chain.

Design/methodology/approach

A multiple case study approach explores the various sustainability information needs along different nodes of supply chains. For this, three automotive triads are investigated, each comprising an original equipment manufacturer, a first-tier supplier and a second-tier supplier.

Findings

The results reveal that fulfilling information demands presents a substantial challenge to each of the three actors, albeit a different one in each case: whereas focal companies seek to figure out what information may be relevant to sustainability performance, their direct suppliers struggle to develop suitable approaches for enabling second-tier suppliers to generate and provide such information.

Practical implications

Depending on the level of uncertainty and equivocality, companies are supported in approaching sustainability information needs by applying individual or collective processing mechanisms. Decisions on such mechanisms and organisational structure can help to allocate resources according to the degree of challenges to achieve a fit between information needs and mechanisms.

Social implications

Reducing uncertainty and equivocality related to sustainability information provides a powerful approach to improving the sustainability performance along supply chains.

Originality/value

Having identified sustainability information challenges, the paper analyses and develops a typology of potentially useful approaches.
Significance of Markers of Monocyte Activation (CD163 and sCD14) and Inflammation (IL‐6) in Patients Admitted for Alcohol Use Disorder Treatment
Authors: García‐Calvo Xavier , Bolao Ferran , Sanvisens Arantza , Zuluaga Paola , Tor Jordi , Muga Robert , Fuster Daniel
Published: November 2019

Background

Monocyte activation and inflammation are prominent features of alcohol‐related liver disease; however, they have not been thoroughly assessed in patients with alcohol use disorder (AUD) without overt liver disease. This study aimed to analyze associations among clinical and laboratory variables and markers of monocyte activation (CD163 and sCD14), and inflammation (interleukin [IL]‐6) among AUD patients.

Methods

We analyzed the aforementioned associations in the highest quartile in 289 patients (77.5% male; median age, 50 years) consecutively admitted for alcohol detoxification in 2 tertiary hospitals in the Barcelona metropolitan area, Spain.

Results

Median alcohol intake was 142 g/d; median glucose, albumin, creatinine, and bilirubin levels (mg/dl), 92, 40, 0.78, and 0.69, respectively; median AST, 41 U/l; median hemoglobin, median corpuscular volume, and platelet count, 14.1 g/dl, 94.8 fL, and 189 × 109/l, respectively; median cholesterol, triglyceride, fibrinogen, and ferritin levels, 187 mg/dl, 109.3 mg/dl, 341 mg/dl, and 177 ng/ml, respectively. In addition, 36.7% patients had an erythrocyte sedimentation rate >20 mm, 32.5% had a C‐reactive protein (CRP) level of >5 mg/l, and 10.9% were hepatitis C virus (HCV)‐positive. Median CD163, sCD14, and IL‐6 levels were 759, 1.68 × 106, and 4.37 pg/ml, respectively. On logistic regression analyses, glucose, AST, bilirubin, hemoglobin levels, and HCV infection (adjusted odds ratio [aORs]: 1.01, 1.02, 3.04, and 9.73, respectively) were associated with CD163. Glucose, AST, triglyceride, and CRP >5 mg/l (aORs: 1.02, 1.01, 1.00, and 3.49, respectively) were associated with sCD14. Alcohol consumption upon admission, MCV, total cholesterol levels, and CRP >5 mg/l (aORs: 0.99, 1.05, 0.99, and 2.56, respectively) were associated with IL‐6.

Conclusions

Monocyte activation and systemic inflammation are associated with higher glucose, liver enzyme, and lipid levels, HCV infections, and CRP of >5 mg/l, thus potentially identifying patients with AUD at high risk of midterm poor outcomes.