bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcranial magnetic stimulation language mapping analysis revisited: Machine learning classification of 90 patients reveals distinct reorganization pattern in aphasic patients
Authors: Wang Ziqian , Fekonja Lucius , Dreyer Felix , Vajkoczy Peter , Picht Thomas
Published: February 2020

Repetitive TMS (rTMS) allows to non-invasively and transiently disrupt local neuronal functioning. Its potential for mapping of language function is currently explored. Given the inter-individual heterogeneity of tumor impact on the language network and resulting rTMS derived functional mapping, we propose to use machine learning strategies to classify potential patterns of functional reorganization. We retrospectively included 90 patients with left perisylvian glioma tumors, world health organization (WHO) grade II-IV, affecting the language network. All patients underwent navigated rTMS language mappings. The severity of aphasia was assessed preoperatively using the Berlin Aphasia Score (BAS), which is adapted to the Aachener Aphasia Test (AAT). After spatial normalization to MNI 152 of all rTMS spots, we calculated the error rate (ER) in each cortical area by automated anatomical labeling parcellation (AAL) and used support vector machine (SVM) as a classifier for significant areas in relation to aphasia. 29 of 90 (32.2%) patients suffered from aphasia. Univariate analysis revealed 11 perisylvian AVOIs’ ERs (eight left, three right hemispheric) that were significantly higher in the aphasic than non-aphasic group (p < 0.05), depicting a broad, bihemispheric language network. After feeding the significant AVOIs into the SVM model, it showed that additional to age (w = 2.95), the ERs of right Frontal_Inf_Tri (w = 2.06) and left SupraMarginal (w = 2.05) and Parietal_Inf (w= 1.80) contributed more than other features to the model. The model’s sensitivity was 89.7%, the specificity was 82.0%, the overall accuracy was 81.1% and AUC was 88.7%. Our results demonstrate an increased vulnerability of the right inferior frontal gyrus to rTMS in patients suffering from aphasia due to left perisylvian gliomas. This confirms a functional relevant involvement of the right frontal area in relation to aphasia. While age as a feature improved our SVM model the most, the tumor location feature didn’t affect the SVM model. This finding indicates that general tumor induced network disconnection is relevant to aphasia and not necessarily related to specific lesion locations. Additionally, our results emphasize the decreasing potential for neuroplasticity with age.
The Cognitive-Functional Composite is sensitive to clinical progression in early dementia: longitudinal findings from the Catch-Cog study cohort
Authors: Jutten Roos J. , Harrison John E. , Brunner A. , Vreeswijk R. , van Deelen R.A.J. , de Jong Frank Jan , Opmeer Esther M. , Ritchie Craig W. , Aleman André , Scheltens Philip , Sikkes Sietske A.M.
Published: February 2020

Introduction

In an attempt to capture clinically meaningful cognitive decline in early dementia, we developed the Cognitive-Functional Composite (CFC). We investigated the CFC’s sensitivity to decline in comparison to traditional clinical endpoints.

Methods

This longitudinal construct validation study included 148 participants with subjective cognitive decline, mild cognitive impairment or mild dementia. The CFC and traditional tests were administered at baseline, 3, 6 and 12 months. Sensitivity to change was investigated using linear mixed models andr2effect-sizes.

Results

CFC scores declined over time (β=−.16,p<.001), with steepest decline observed in mild Alzheimer’s dementia (β=−.25,p<.001). The CFC showed medium-to-large effect-sizes at succeeding follow-up points (r2=.08–.42), exhibiting greater change than the Clinical Dementia Rating scale (r2=.02–.12). Moreover, change on the CFC was significantly associated with informant reports of cognitive decline (β=.38,p<.001).

Discussion

By showing sensitivity to decline, the CFC could enhance the monitoring of disease progression in dementia research and clinical practice.
Oxytocin enhances the recovery of eye-contact induced autonomic arousal: A treatment mechanism study with placebo-controlled design
Authors: Daniels Nicky , Prinsen Jellina , Soriano Javier R. , Alaerts Kaat
Published: February 2020

The neuropeptide oxytocin (OT) is suggested to exert a pivotal role in a variety of complex human behaviors, including trust, attachment, social perception and fear-regulation. Previous studies have demonstrated that intranasal administration of OT reduces subjective and neuroendocrine stress responses and dampens amygdala reactivity. Moreover, OT has been proposed to modulate activity of the autonomic nervous system.

Here, we conducted a double-blind, placebo-controlled study with 56 men, to investigate whether a single-dose of OT (24 IU) modulates sympathetic autonomic arousal upon live dyadic gaze interactions. To do so, electro-dermal recordings of skin conductance were performed during the engagement of eye contact with a live model in a naturalistic two-person social context.

In accordance to prior research, direct eye gaze elicited a significant enhancement in skin conductance responses, but OT did not specifically enhance or dampen the overall magnitude (amplitude) of the autonomic arousal response. Administration of OT did facilitate the recovery of skin conductance responses back to baseline (increased steepness of recovery slope), indicating a role of OT in restoring homeostatic balance. Notably, the treatment-effect on autonomic recovery was most prominent in participants with low self-reported social responsiveness and high attachment avoidance, indicating that person-dependent factors play a pivotal role in determining OT treatment-responses. Behaviorally, OT significantly reduced self-reported feelings of tension and (at trend-level) worrying about how one presents oneself.

Together, these observations add further evidence to a role of OT in reducing subjective and autonomic stress responses, primarily by facilitating restoration of homeostatic balance after (social) stress-induced perturbation.
Memo1gene expression in kidney and bone is unaffected by dietary mineral load and calciotropic hormones
Authors: Moor Matthias B. , Bonny Olivier
Published: February 2020

Mediator of Cell Motility 1 (MEMO1) is an ubiquitously expressed modulator of cellular responses to growth factors including FGF23 signaling, andMemo1-deficient mice share some phenotypic traits withFgf23- orKlotho-deficient mouse models. Here, we tested whetherMemo1gene expression is regulated by calciotropic hormones or by changing the dietary mineral load.

MLO-Y4 osteocyte-like cells were cultured and treated with 1,25(OH)2-vitamin D3. Wildtype C57BL/6N mice underwent treatments with 1,25(OH)2-vitamin D3, parathyroid hormone (PTH), 17β-estradiol or vehicle. Other cohorts of C57BL/6N mice were fed diets varying in calcium or phosphate content. Expression ofMemo1and control genes was assessed by qPCR.

1,25(OH)2-vitamin D3caused an acute decrease inMemo1transcript levels in vitro, but not in vivo. None of the hormones tested had an influence onMemo1transcripts, whereas the assessed control genes reacted the expected way. Dietary interventions with calcium and phosphate did not affectMemo1transcripts but altered the chosen control genes’ expression.

We observed thatMemo1was not regulated by calciotropic hormones or change in mineral load, suggesting major differences between the regulation and physiological roles ofKlotho, Fgf23andMemo1.
MicroRNA-dependent inhibition of PFN2 orchestrates ERK activation and pluripotent state transitions by regulating endocytosis
Authors: Sangokoya Carolyn , Blelloch Robert
Published: February 2020

Profilin2 (PFN2) is a target of the embryonic stem cell (ESC) enriched miR-290 family of miRNAs and an actin/dynamin binding protein implicated in endocytosis. Here, we show that the miR-290-PFN2 pathway regulates many aspects of ESC biology. In the absence of microRNAs, PFN2 is upregulated in ESCs, with a resulting decrease in endocytosis. Reintroduction of miR-290, knockout of PFN2, or disruption of the PFN2 dynamin interacting domain in miRNA deficient cells reverses the endocytosis defect. The loss of miRNA suppression of PFN2 and associated reduction in endocytosis impairs ERK signaling, which in turn inhibits ESC cell cycle progression and differentiation from a naïve to formative state. Mutagenesis of the single canonical conserved 3’UTR miR-290 binding site of PFN2 in otherwise wild-type cells recapitulates these phenotypes. Together, these findings define an axis of post-transcriptional control, endocytosis, and signal transduction that is essential for ESC self-renewal and differentiation.
Enterococcus faecalismanganese exporter MntE alleviates manganese toxicity and is required for mouse gastrointestinal colonization
Authors: Lam Ling Ning , Wong Jun Jie , Long Chong Kelvin Kian , Kline Kimberly A.
Published: February 2020

Bacterial pathogens encounter a variety of nutritional environments in the human host, including nutrient metal restriction and overload. Uptake of manganese (Mn) is essential forEnterococcus faecalisgrowth and virulence; however, it is not known how this organism prevents Mn toxicity. In this study, we examine the role of the highly conserved MntE transporter inE. faecalisMn homeostasis and virulence. We show that inactivation ofmntEresults in growth restriction in the presence of excess Mn, but not other metals, demonstrating its specific role in Mn detoxification. Upon growth in the presence of excess Mn, anmntEmutant accumulates intracellular Mn, iron (Fe), and magnesium (Mg), supporting a role for MntE in Mn and Fe export, and a role for Mg in offsetting Mn toxicity. Growth of themntEmutant in excess Fe also results in increased levels of intracellular Fe, but not Mn or Mg, providing further support for MntE in Fe efflux. Inactivation ofmntEin the presence of excess iron also results in the upregulation of glycerol catabolic genes and enhanced biofilm growth, and addition of glycerol is sufficient to augment biofilm growth for both themntEmutant and its wild type parental strain, demonstrating that glycerol availability significantly enhances biofilm formation. Finally, we show thatmntEcontributes to infection of the antibiotic-treated mouse gastrointestinal (GI) tract, suggesting thatE. faecalisencounters excess Mn in this niche. Collectively, these findings demonstrate that the manganese exporter MntE plays a crucial role inE. faecalismetal homeostasis and virulence.
Lateral gene transfer drives metabolic flexibility in the anaerobic methane oxidising archaeal familyMethanoperedenaceae
Authors: Leu Andy O. , McIlroy Simon J. , Ye Jun , Parks Donovan H. , Orphan Victoria J. , Tyson Gene W.
Published: February 2020

Anaerobic oxidation of methane (AOM) is an important biological process responsible for controlling the flux of methane into the atmosphere. Members of the archaeal familyMethanoperedenaceae(formerly ANME-2d) have been demonstrated to couple AOM to the reduction of nitrate, iron, and manganese. Here, comparative genomic analysis of 16Methanoperedenaceacemetagenome-assembled genomes (MAGs), recovered from diverse environments, revealed novel respiratory strategies acquired through lateral gene transfer (LGT) events from diverse archaea and bacteria. Comprehensive phylogenetic analyses suggests that LGT has allowed members of theMethanoperedenaceaeto acquire genes for the oxidation of hydrogen and formate, and the reduction of arsenate, selenate and elemental sulfur. Numerous membrane-bound multi-hemectype cytochrome complexes also appear to have been laterally acquired, which may be involved in the direct transfer of electrons to metal oxides, humics and syntrophic partners.

Importance

AOM by microorganisms limits the atmospheric release of the potent greenhouse gas methane and has consequent importance to the global carbon cycle and climate change modelling. While the oxidation of methane coupled to sulphate by consortia of anaerobic methanotrophic (ANME) archaea and bacteria is well documented, several other potential electron acceptors have also been reported to support AOM. In this study we identify a number of novel respiratory strategies that appear to have been laterally acquired by members of theMethanoperedenaceaeas they are absent in related archaea and other ANME lineages. Expanding the known metabolic potential for members of theMethanoperedenaceaeprovides important insight into their ecology and suggests their role in linking methane oxidation to several global biogeochemical cycles.
An integrated model system to gain mechanistic insights into biofilm formation and antimicrobial resistance development inPseudomonas aeruginosaMPAO1
Authors: Varadarajan Adithi R. , Allan Raymond N. , Valentin Jules D. P. , Castañeda Ocampo Olga E. , Somerville Vincent , Pietsch Franziska , Buhmann Matthias T. , West Jonathan , Skipp Paul J. , van der Mei Henny C. , Ren Qun , Schreiber Frank , Webb Jeremy S. , Ahrens Christian H.
Published: February 2020

Pseudomonas aeruginosaMPAO1 is the parental strain of the widely utilized transposon mutant collection for this important clinical pathogen. Here, we validate a model system to identify genes involved in biofilm growth and antibiotic resistance.

Our model employs a genomics-driven workflow to assemble the complete MPAO1 genome, identify unique and conserved genes by comparative genomics with the PAO1 reference strain and missed genes by proteogenomics. Among over 200 unique MPAO1 genes, we identified six general essential genes that were overlooked when mapping public Tn-seq datasets against PAO1, including an antitoxin. Genomic data were integrated with phenotypic data from an experimental workflow using a user-friendly, soft lithography-based microfluidic flow chamber for biofilm growth. Experiments conducted across three laboratories delivered reproducible data onP. aeruginosabiofilms and validated both known and novel genes involved in biofilm growth and antibiotic resistance identified in screens of the mutant collection. Differential protein expression data from planktonic cells versus biofilm confirmed upregulation of candidates known to affect biofilm formation, of structural and secreted proteins of type six secretion systems, and provided proteogenomic evidence for some missed MPAO1 genes. This integrated, broadly applicable model promises to improve the mechanistic understanding of biofilm formation, antimicrobial tolerance and resistance evolution.
A biodiverse package of southwest Asian grain crops facilitated high-elevation agriculture in the central Tien Shan during the mid-third millennium BCE
Authors: Matuzeviciute Giedre Motuzaite , Hermes Taylor R. , Mir-Makhamad Basira , Tabaldiev Kubatbek
Published: February 2020

We report the earliest and the most abundant archaeobotanical assemblage of southwest Asian grain crops from Early Bronze Age Central Asia, recovered from the Chap II site in Kyrgyzstan. The archaeobotanical remains consist of thousands of cultivated grains dating to the mid-late 3rdmillennium BCE. The recovery of cereal chaff, which is rare in archaeobotanical samples from Central Asia, allows for the identification of some crops to species and indicates local cultivation at 2000 m.a.s.l., as crop first spread to the mountains of Central Asia. The site’s inhabitants cultivated two types of free-threshing wheats, glume wheats, and hulled and naked barleys. Highly compact morphotypes of wheat and barley grains represent a special variety of cereals adopted to highland environments. Moreover, glume wheats recovered at Chap II represent their most eastern distribution in Central Asia so far identified. Based on the presence of weed species, we argue that the past environment of Chap II was characterized by an open mountain landscape, where animal grazing likely took place, which may have been further modified by people irrigating agricultural fields. This research suggests that early farmers in the mountains of Central Asia cultivated a high diversity of southwest Asian crops during the initial eastward dispersal of agricultural technologies, which likely played a critical role in shaping montane adaptations and dynamic interaction networks between farming societies across highland and lowland cultivation zones.
Fluctuation, correlation and perturbation-response behavior of nature-made and artificial nanobodies
Authors: Hacisuleyman Aysima , Erman Batu , Erkip Albert , Erman Burak
Published: February 2020

Nanobodies, like other antibodies bind their targets through complementarity determining regions (CDR’s). Improving nanobody-antigen binding affinities by introducing mutations in these CDR’s is critical for biotechnological applications. However, any mutation is expected to introduce changes in the behavior of the protein, such as fluctuations of residues, correlation of fluctuations of residue pairs, response of a residue to perturbation of another. Most importantly, the nanoscale dynamics of the protein may change. In these respects, the problem is similar to the general problem of dynamic allostery, a perturbation at one site affecting the response at another site. Using the Gaussian Network Model of proteins, we show that CDR mutations indeed modify the fluctuation profile and dynamics of the nanobody. Effects are not confined to CDR regions but extend throughout the full structure. We introduce a computational scheme where fluctuations of a residue are perturbed by a force and response amplitude and response time of the remaining residues are determined. Response to a perturbation of a residue shows a synchronous and an asynchronous component. The model is used to quantify the effects of mutation on protein dynamics: highly perturbable residues and highly responsive residues of the nanobody are determined. Residues whose perturbation has no effect on protein behavior may also be determined with the present model. Three known nanobodies produced by nature are used as an illustrative example and their various modifications which we generated by CDR residue mutations are analyzed.
dyngen: a multi-modal simulator for spearheading new single-cell omics analyses
Authors: Cannoodt Robrecht , Saelens Wouter , Deconinck Louise , Saeys Yvan
Published: February 2020

We present dyngen, a novel, multi-modal simulation engine for studying dynamic cellular processes at single-cell resolution. dyngen is more flexible than current single-cell simulation engines, and allows better method development and benchmarking, thereby stimulating development and testing of novel computational methods. We demonstrate its potential for spearheading novel computational methods on three novel applications: aligning cell developmental trajectories, single-cell regulatory network inference and estimation of RNA velocity.
Single-cell sequencing of developing human gut reveals transcriptional links to childhood Crohn’s disease
Authors: Elmentaite Rasa , Ross Alexander , James Kylie R. , Ortmann Daniel , Gomes Tomas , Roberts Kenny , Nayak Komal , Tuck Liz , Bayraktar Omer Ali , Heuschkel Robert , Vallier Ludovic , Teichmann Sarah A. , Zilbauer Matthias
Published: February 2020

Human gut development requires the orchestrated interaction of various differentiating cell types. Here we generate an in-depth single-cell map of the developing human intestine at 6–10 weeks post-conception, a period marked by crypt-villus formation. Our analysis reveals the transcriptional profile of cycling epithelial precursor cells, which are distinct from LGR5-expressing cells. We use computational analyses to show that these cells contribute to differentiated cell subsets directly and indirectly via the generation of LGR5-expressing stem cells and receive signals from the surrounding mesenchymal cells. Furthermore, we draw parallels between the transcriptomes ofex vivotissues andin vitrofetal organoids, revealing the maturation of organoid cultures in a dish. Lastly, we compare scRNAseq profiles from paediatric Crohn’s disease epithelium alongside matched healthy controls to reveal disease associated changes in epithelial composition. Contrasting these with the fetal profiles reveals re-activation of fetal transcription factors in Crohn’s disease epithelium. Our study provides a unique resource, available atwww.gutcellatlas.org, and underscores the importance of unravelling fetal development in understanding disease.
Targeted biomass degradation by the higher termite gut system - integrative omics applied to host and its gut microbiome
Authors: Calusinska Magdalena , Marynowska Martyna , Bertucci Marie , Untereiner Boris , Klimek Dominika , Goux Xavier , Sillam-Dussès David , Gawron Piotr , Halder Rashi , Wilmes Paul , Ferrer Pau , Gerin Patrick , Roisin Yves , Delfosse Philippe
Published: February 2020

Miscanthussp. is regarded as suitable biomass for different biorefinery value chains. However, due to high recalcitrance, its wide use is yet untapped. Termite is the most efficient lignocellulose degrading insect, and its success results from synergistic cooperation with its gut microbiome. Here, we investigated at holobiont level the dynamic adaptation of a higher termiteCortaritermessp. to imposedMiscanthusdiet, with a long-term objective of overcoming lignocellulose recalcitrance. We used an integrative omics approach, comprising amplicon sequencing, metagenomics and metatranscriptomics that we combined with enzymatic characterisation of carbohydrate active enzymes from termite gut Fibrobacteres and Spirochaetae. Adaptation to the new diet was evidenced by reduced gut bacterial diversity and modified gene expression profiles, further suggesting a shift towards utilisation of cellulose and arabinoxylan, two main components ofMiscanthuslignocellulose. Low identity of reconstructed microbial genomes to microbes from closely related termite species, supported the hypothesis of a strong phylogenetic relationship between host and its gut microbiome. Application-wise, this makes each termite gut system an endless source of enzymes that are potentially industrially relevant.

This study provides a framework for better understanding the complex lignocellulose degradation by the higher termite gut system and paves a road towards its future bioprospecting.
The tapejarid pterosaurTupandactylus imperatorfrom Crato Formation and the preservation of cranial integuments
Authors: Campos Hebert Bruno Nascimento , Kischlat Edio-Ernst
Published: February 2020

The group Tapejaridae forms a clade of toothless pterosaurs easily recognized by their premaxillary sagittal crests and particularly large nasoantorbital fenestrae. The tapejarids represent the most representative group of pterosaurs from the Lower Cretaceous Crato Formation of the Araripe Basin (Northeastern Brazil). The holotype of the large tapejaridTupandactylus imperatorCampos and Kellner, 1997 is known by two main slabs from the New Olinda Member of the Crato Formation, however, only one of the slabs containing the sagittally bipartite skull is referred to the holotype ofTupandactylus imperator, remain the counter-slab be properly described. The cotype is fragmented in several broken pieces and presents a significative number of cranial elements. A medial internasal septum completely preserved inside the nasoantorbital fenestra is reported for the first time for pterosaurs. The exceptional preservation of a collagenous septum and other integumentary structures visible in the cotype specimen is extremely rare and supports the concept of the unusual pattern of soft tissue observed in the fossils from the Crato Konservat-Lagerstätte, specially pterosaurs. Herein is presented the description of the cotype ofTupandactylus imperator, in complementation to the previously designated slab of the holotype of this tapejarid species. The occurrence of casques in pterosaurs is supported by comparative anatomy with the bird galliformPauxi(Cracidae). Besides that, it is discussed on the skull with extravagant cranial crests ofTupandactylus imperatorand the significance of the associated soft tissues and other cranial integuments, which indicates an expressive morphological and taxonomic diversity among the tapejarid pterosaurs.
Method for inferring migration routes from phylogenetic trees
Authors: Bermúdez Juanjo
Published: February 2020

Inferring migration routes from a phylogenetic tree is something that has been done since we have phylogenetic trees. The usual method is just human inference, also known as intuition. Here I present a method for automating this task. Applied to phylogenetic trees with thousands of branches it makes possible to see for the first time inferred routes that were previously too complex to estimate.
Distinct error rates for reference and non-reference genotypes estimated by pedigree analysis
Authors: Wang Richard J. , Radivojac Predrag , Hahn Matthew W.
Published: February 2020

Errors in genotype calling can have perverse effects on genetic analyses, confounding association studies and obscuring rare variants. Analyses now routinely incorporate error rates to control for spurious findings. However, reliable estimates of the error rate can be difficult to obtain because of their variance between studies. Most studies also report only a single estimate of the error rate even though genotypes can be miscalled in more than one way. Here, we report a method for estimating the rates at which different types of genotyping errors occur at biallelic loci using pedigree information. Our method identifies potential genotyping errors by exploiting instances where the haplotypic phase has not been faithfully transmitted. The expected frequency of inconsistent phase depends on the combination of genotypes in a pedigree and the probability of miscalling each genotype. We develop a model that uses the differences in these frequencies to estimate rates for different types of genotype error. Simulations show that our method accurately estimates these error rates in a variety of scenarios. We apply this method to a dataset from the whole-genome sequencing of owl monkeys (Aotus nancymaae) in three-generation pedigrees. We find significant differences between estimates for different types of genotyping error, with the most common being homozygous reference sites miscalled as heterozygous and vice versa. The approach we describe is applicable to any set of genotypes where haplotypic phase can reliably be called, and should prove useful in helping to control for false discoveries.
A convNet based multi label microRNA sub cellular location predictor, by incorporating k-mer positional encoding
Authors: Asim Muhammad Nabeel , Dengel Andreas , Ahmed Sheraz
Published: February 2020

MicroRNAs are special RNA sequences containing 22 nucleotides and are capable of regulating almost 60% of highly complex mammalian transcriptome. Presently, there exists very limited approaches capable of visualizing miRNA locations inside cell to reveal the hidden pathways, and mechanisms behind miRNA functionality, transport, and biogenesis. State-of-the-art miRNA sub-cellular location prediction MIRLocatar approach makes use of sequence to sequence model along with pre-train k-mer embeddings. Existing pre-train k-mer embedding generation methodologies focus on the extraction of semantics of k-mers. In RNA sequences, rather than semantics, positional information of nucleotides is more important because distinct positions of four basic nucleotides actually define the functionality of RNA molecules. Considering the dynamicity and importance of nucleotides positions, instead of learning representation on the basis of k-mers semantics, we propose a novel kmerRP2vec feature representation approach that fuses positional information of k-mers to randomly initialized neural k-mer embeddings. Effectiveness of proposed feature representation approach is evaluated with two deep learning based convolutional neural network CNN and recurrent neural network RNN methodologies using 8 evaluation measures. Experimental results on a public benchmark miRNAsubloc dataset prove that proposed kmerRP2vec approach along with a simple CNN model outperforms state-of-the-art MirLocator approach with a significant margin of 18% and 19% in terms of precision and recall.
Formal model of Parkinson’s disease neurons unveils possible causality links in the pathophysiology of the disease
Authors: Nadal Morgane , Schierle Gabriele S. Kaminski , Dikicioglu Duygu
Published: February 2020

Parkinson’s Disease is the second most common neurodegenerative disease after Alzheimer’s disease. Despite extensive research, the initial cause of the disease is still unknown, although substantial advances were made in understanding of its genetics and the cognate neurophysiological mechanisms. Determining the causality relationships and the chronological steps pertaining to Parkinson’s Disease is essential for the discovery of novel drug targets. We developed a systematicin silicomodel based on available data, which puts the possible sequence of events occurring in a neuron during disease onset into light. This is the first ever attempt, to our knowledge, to model comprehensively the primary modifications in the molecular pathways that manifest in compromised neurons from the commencement of the disease to the consequences of its progression. We showed that our proposed disease pathway was relevant for unveiling yet incomplete knowledge on calcium homeostasis in mitochondria, ROS production and α-synuclein misfolding.

Graphical abstract

Highlights

Varying calcium concentration in aging dopaminergic neurons triggers disease onset.

ROS production in the mitochondria potentially causes iron accumulation.

Iron homeostasis dysregulation is linked to α-synuclein aggregation.
The TIM22 complex regulates mitochondrial one-carbon metabolism by mediating the import of Sideroflexins
Authors: Jackson Thomas D. , Hock Daniella , Palmer Catherine S. , Kang Yilin , Fujihara Kenji M. , Clemons Nicholas J. , Thorburn David R. , Stroud David A. , Stojanovski Diana
Published: February 2020

The Acylglycerol Kinase (AGK) is a mitochondrial lipid kinase that contributes to protein biogenesis as a subunit of the TIM22 complex at the inner mitochondrial membrane. Mutations inAGKcause Sengers syndrome, an autosomal recessive condition characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. We undertook proteomic profiling of Sengers patient fibroblasts and an AGKKOcell line to map the proteomic changes that ensue upon AGK dysfunction. This uncovered extensive remodelling of mitochondrial one-carbon metabolism enzymes and showed that inner membrane serine transporters, Sideroflexins (SFXNs), are novel substrates of the TIM22 complex. Deletion ofSFXN1recapitulates the remodelling of one-carbon metabolism observed in Sengers patient cells. Proliferation of cells lacking AGK is perturbed in the absence of exogenous serine and rescuable through addition of formate, highlighting the dysregulation of one carbon metabolism as a key molecular feature in the biology of Sengers syndrome.
Wiskott Aldrich syndrome protein regulates non-selective autophagy and mitochondrial homeostasis in human myeloid cells
Authors: Rivers E , Rai R , Lötscher J , Hollinshead M , Markelj G , Thaventhiran J , Worth A , Cavazza A , Hess C , Bajaj-Elliott M , Thrasher AJ
Published: February 2020

The actin cytoskeletal regulator Wiskott Aldrich syndrome protein (WASp) has been implicated in maintenance of the autophagy-inflammasome axis in innate murine immune cells. Here, we show that WASp deficiency is associated with impaired rapamycin-induced autophagosome formation and trafficking to lysosomes in primary human monocyte-derived macrophages (MDMs). WASp reconstitutionin vitroand in WAS patients following clinical gene therapy restores autophagic flux and is dependent on the actin-related protein complex ARP2/3. Induction of mitochondrial damage with CCCP, as a model of selective autophagy, also reveals a novel ARP2/3-dependent role for WASp in formation of sequestrating actin cages and maintenance of mitochondrial network integrity. Furthermore, mitochondrial respiration is suppressed in WAS patient MDMs and unable to achieve normal maximal activity when stressed, indicating profound intrinsic metabolic dysfunction. Taken together, we provide evidence of new and important roles of human WASp in autophagic processes and immunometabolic regulation, which may mechanistically contribute to the complex WAS immunophenotype.
DNA Content and Ploidy Estimation ofFestuca ovinaAccessions by Flow Cytometry
Authors: Qiu Yinjie , Hamernick Sierra , Ortiz Joan Barreto , Watkins Eric
Published: February 2020

Festuca ovinais a fine fescue that is used as a low-input turfgrass. The ploidy levels ofF. ovinaaccessions held by the USDA National Plant Germplasm System (NPGS) are unknown, limiting the use of the germplasm in breeding programs. The objective of this study was to determine DNA content and estimate ploidy of these 127 accessions. Among the accessions, we identified a wide range of ploidy levels from diploid to octoploid. We also found the accessions with higher ploidy levels usually had larger seed size. These results will be informative to plant breeders and researchers using germplasm from theF. ovinacollection and point to challenges in maintaining polyploid, outcrossing germplasm seed stocks in common nurseries.
Sex-specific crossover rates did not change with parental age inArabidopsis
Authors: Saini Ramswaroop , Singh Amit Kumar , Hyde Geoffrey J. , Baskar Ramamurthy
Published: February 2020

Crossing over, the exchange of DNA between the chromosomes during meiosis, contributes significantly to genetic variation. The rate of crossovers (CO) varies depending upon the taxon, population, age, external conditions, and also, sometimes, between the sexes, a phenomenon called heterochiasmy. In the model plantArabidopsis thaliana, the male rate of crossovers (mCO) is typically nearly double the female rate (fCO). With increasing parental age, it has been reported that the disparity decreases, because fCO rises while mCO remains stable. That finding, however, is based on chromosome-based averaging, and it is unclear whether all parts of the genome respond similarly. We addressed this point by examining how the level of heterochiasmy responded to parental age in eight genomic intervals distributed across the five chromosomes ofArabidopsis. Unlike the previous work, in each of the eight intervals, the level of heterochiasmy did not change with age, that is, the ratio mCO:fCO remained stable. As expected, though, amongst the intervals, the levels of heterochiasmy at any of the four ages examined, did vary. We propose that while the levels of heterochiasmy inArabidopismight decrease with age on a chromosomal basis, as reported earlier, this is not true for all locations within each chromosome. This has practical implications for plant breeding research, a major aim of which is identifying ways to induce local increases in CO rates.
Strategic development of flexible manufacturing facilities
Authors: Madson Katherine M. , Franz Bryan , Molenaar Keith R. , Okudan Kremer Gül
Published: February 2020

Purpose

This article addresses the lack of formal design guidance that supports flexibility within the architectural and engineered systems of manufacturing facilities through the development of a taxonomy and associated terminology.

Design/methodology/approach

This research performed a comparative analysis of 15 manufacturing facilities located both within the United States (73 percent of cases) and internationally (27 percent of cases). These case studies provided details on how and where flexibility was incorporated into the design of a manufacturing facility. Specific consideration was given to the primary design features that enabled a decoupling of the facility from the manufacturing process. These design features were then clustered to identify main design strategies that enable flexibility.

Findings

By grouping the design features together and creating a common vocabulary, three coherent design approaches for flexible facilities were identified, each having a different potential for responding to short-term and long-term changes. These include general purpose, scalable, and dedicated facilities.

Research limitations/implications

By delineating three high-level strategies for early flexible facility design, this research synthesizes a conceptual understanding of flexibility with practical and implementable designs. This synthesis provides an incremental advance to a complex challenge for researchers. It also provides decision support to design teams by aiding in project definition, when flexibility is desirable. This research is primarily limited by the number of cases reviewed. With more cases, additional facility design strategies may be identified.

Practical implications

The findings in this research allow for a basic understanding of how a flexible facility can be designed with only limited or vague information about the product and manufacturing processes contained within. The development of terminology associated with each facility design strategy provides standardization for the discussion and implementation of flexibility early in the design process. In doing so, flexible designs become easier to create and more efficient to implement.

Originality/value

This research provides the first synthesized approach for considering flexible facility design strategies within the manufacturing sector.
Housing attributes affecting buyers in India
Authors: Ghumare Pavan Namdeo , Chauhan Krupesh A. , Yadav Sanjay Kumar M.
Published: February 2020

Purpose

The purpose of this paper is to provide affordable housing to low- and middle-income groups. The gravity of India’s housing affordability problem has led us to study and analyse the attributes hindering affordable housing for economically weaker section (EWS) and low-income group (LIG). The attributes such as viable parameters, economic parameters, location and communication, regulatory, source of finance, construction, services and infrastructure parameters affect the supply and demand of affordable housing in Indian urban areas for EWS and LIG with an annual household income below 2 lakhs.

Design/methodology/approach

The judgement sampling is used amongst housing and planning professionals working in five different sectors, including local authorities, housing developers, housing sectors, town planning and property/affordable housing consultant. The Analytical hierarchy process method of multi-criteria decision-making was used to analyse the data collected.

Findings

A detailed analysis of the data collected reveals that a viable parameter is the most governing attribute in the supply and demand process of developing affordable housing. Major reforms can be implemented at various levels of housing development in the urban area that can help in reducing the affordability gap for EWS/LIG. The suggested approach will be helpful for developers, urban planners and decision makers while designing an affordable housing project.

Originality/value

The model being proposed in this paper seeks for a proficient allotment of policies and assets, to some extent, by remedying the current market distortions and different inconsistencies that negatively influence the incentive structure of the affordable housing section in India. This paper offers a plan for a housing procedure that is applicable to all measurements of housing poverty and the groups that sustain it. In this way, the current study is, to a greater extent, a facilitator, and not an immediate solution of affordable housing.
Critical success factors for campus interaction spaces and services – a systematic literature review
Authors: Jansz Sascha Naomi , van Dijk Terry , Mobach Mark P.
Published: February 2020

Purpose

The purpose of this paper is to create an overview of current literature and identify gaps in what is known about stimulating interaction through spaces and services provided on university campuses.

Design/methodology/approach

The authors used the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement methodology for systematic literature review. In total, 3,616 articles were screened, 31 articles were included. Facility Directors from 13 Dutch Universities were asked to define the search terms related to services.

Findings

Spaces and services were mostly studied separately. The majority of papers (18/31) were based on perceptions (surveys or interviews). The following critical success factors were identified in the literature: geographic proximity, cognitive proximity, scale, transitional spaces, comfort and experience, shared facilities and events, local buzz and networks. These factors are interrelated. The authors present a new relational model, from spaces and services, through interaction to innovation, visualising how the identified papers are related.

Research limitations/implications

The scope of possible findings may have been narrowed because prior relevant studies were rather limited and as a consequence of the search strategy designed to limit the number of unrelated hits. Some knowledge gaps may not have been identified, as only a few mainstream concepts related to the critical success factors were used for comparison. Nevertheless, the literature review provides a reliable overview of current academic knowledge regarding critical success factors for spaces and services that stimulate interaction on campuses.

Originality/value

This paper offers a novel perspective by emphasising the relational chain from interaction to innovation, visualising the large diversity in research fields and summarising the critical success factors in the literature.
Socio-economics and management of Muslim cemeterywaqfusing istibdal and GIS method in Penang state
Authors: Asni Fathullah , Mahamud Mohd Amirul , Sulong Jasni
Published: February 2020

Purpose

The purpose of this paper is to implement the istibdalwaqfconcept using a geographical information system (GIS) for the benefit of socio-economics and Muslim cemeterywaqfmanagement. GIS is a technique that provides clearer, precise and faster access to a location based on actual space data. It attempts to analyze the area that one wishes to develop to establish whether it fulfills the criteria set for istibdal.

Design/methodology/approach

This research was conducted qualitatively. The study begins with the development of the concept of istibdalwaqfand the concept of GIS. The concept was developed by conducting a literature review of books, articles, newspapers, fatwa and circulars related to istibdalwaqfand GIS. After the concept was formed, field studies were conducted on two mosques, namely, Jamek Jelutong Mosque and Masjid Jamek Sungai Nibong because both mosques have gravesites located within their compound. To obtain information on the problems faced by the mosques Jemaah community, researchers have interviewed the Mosque Committee Members and Jemaah Community in both mosques using the unstructured interviewing method. This process is essential in managing both material and spiritual for sustaining socio-economics of the society.

Findings

The results showed that by applying GIS technique could identify new land locations according to the criteria set by istibdal. Additionally, new location environments found through the GIS application can be viewed more clearly and accurately than using the manual method. The findings also revealed that some of the mosque managers and the heirs of thewaqfgrave land were not open-minded in accepting the istibdal concept of the grave that had been allowed by the Syarak until the process of expanding the mosque was affected. The study also found that the maslahah consideration was considered between doing istibdalwaqfand not doing istibdalwaqf, the maslahah of doing istibdalwaqfis greater because general (umum) maslahah should be prioritized compared to the special (khusus) maslahah. In addition, this effort can appreciate the morality and ethics ofwaqfdonors to donate their wealth or properties for benefit of society.

Research limitations/implications

This study only focuses on Muslim cemeterywaqfin Penang Island.

Practical implications

This study is expected to benefit both material and spiritual where Muslim cemetery site can be developed for expanding mosque site and consequently able to accommodate the increasing of Muslim using the mosque.

Originality/value

This study proposes the transformation of the concept of istibdalwaqffrom the traditional methods to modern and advanced methods using the GIS application. The study also demonstrates how the software for solving the real problem can be used, i.e. the problem of a limited mosque space for sharing space with a cemetery in Penang.
Supply chain coordination under nonlinear cap and trade carbon emission function and demand uncertainty
Authors: Heydari Jafar , Mirzajani Zahra
Published: February 2020

Purpose

This paper investigates to find whether it is possible to align the interests of a small and medium manufacturing enterprise (SMME) with its raw material supplier in a manufacturing supply chain (MSC) to achieve a sustainable solution. To this end, current study examines the coordination of an MSC under cap and trade consisting of a raw material supplier and a carbon-emitting SMME confronting a stochastic demand.

Design/methodology/approach

The model is developed under both the decentralized and centralized decision-making scenarios. Under the investigated model, the SMME decides on both production quantity and sustainability level simultaneously. To achieve coordination and align the interests of both MSC members toward sustainable economic development goals, a customized revenue-sharing contract is developed.

Findings

Although the centralized model is profitable for the MSC, it makes a loss for the SMME compared to the decentralized scenario. The revenue-sharing agreement is able to create coordination among the MSC members and optimize profitability and sustainability. The established revenue-sharing guarantees a Pareto-improving situation for both members. Applying the established contract not only reduces shortage occasions but also results in more sustainability levels, which in turn means movement toward attaining sustainable economic development goals.

Originality/value

Unlike previous studies, carbon emission is assumed as a nonlinear decreasing function of the sustainability level which is a more realistic case. In accordance with SMMEs business environments, the market demand is also assumed uncertain. In addition, instead of assuming an investment cost for sustainability, the authors assumed unit production/purchasing costs as functions of product sustainability level.