bluuebunny/crossref_metadata_2025 huggingface dataset:
GenTB: A user-friendly genome-based predictor for tuberculosis resistance powered by machine learning
Authors: Gröschel Matthias I , Owens Martin , Freschi Luca , Vargas Roger , Marin Maximilian G , Phelan Jody , Iqbal Zamin , Dixit Avika , Farhat Maha R
Published: March 2021

Introduction

Multidrug-resistantMycobacterium tuberculosis(Mtb) is a significant global public health threat. Genotypic resistance prediction fromMtbDNA sequences offers an alternative to laboratory-based drug-susceptibility testing. User-friendly and accurate resistance prediction tools are needed to enable public health and clinical practitioners to rapidly diagnose resistance and inform treatment regimens.

Methods

We present Translational Genomics platform for Tuberculosis (GenTB), a web-based application to predict antibiotic resistance from next-generation sequence data. The user can choose between two potential predictors, a Random Forest (RF) classifier and a Wide and Deep Neural Network (WDNN) to predict phenotypic resistance to 13 and 10 anti-tuberculosis drugs, respectively. We benchmark GenTB’s predictive performance along with leading TB resistance prediction tools (Mykrobe and TB-Profiler) using a ground truth dataset of 20,408 isolates with laboratory-based drug susceptibility data.

Results

All four tools reliably predicted resistance to first-line tuberculosis drugs but had varying performance for second-line drugs. The mean sensitivities for GenTB-RF and GenTB-WDNN across the nine shared drugs was 77.6% (95% CI 76.6 - 78.5%) and 75.4% (95% CI 74.5 - 76.4%) respectively, and marginally higher than the sensitivities of TB-Profiler at 74.4% (95% CI 73.4 - 75.3%) and Mykrobe at 71.9% (95% CI 70.9 - 72.9%). The higher sensitivities were at an expense of ≤1.5% lower specificity: Mykrobe 97.6% (95% CI 97.5 - 97.7%), TB-Profiler 96.9% (95% CI 96.7 to 97.0%), GenTB-WDNN 96.2% (95% CI 96.0 to 96.4%), and GenTB-RF 96.1% (95% CI 96.0 to 96.3%). Genotypic resistance sensitivity was 11% and 9% lower for isoniazid and rifampicin respectively, on isolates sequenced at low depth (<10x across 95% of the genome) emphasizing the need to quality control input sequence data before prediction. We discuss differences between tools in reporting results to the user including variants underlying the resistance calls and any novel or indeterminate variants

Conclusion

GenTB is an easy-to-use online tool to rapidly and accurately predict resistance to anti-tuberculosis drugs. GenTB can be accessed online athttps://gentb.hms.harvard.edu, and the source code is available athttps://github.com/farhat-lab/gentb-site.
MQuad enables clonal substructure discovery using single cell mitochondrial variants
Authors: Kwok Aaron Wing Cheung , Qiao Chen , Huang Rongting , Sham Mai-Har , Ho Joshua W. K. , Huang Yuanhua
Published: March 2021

Mitochondrial mutations are increasingly recognised as informative endogenous genetic markers that can be used to reconstruct cellular clonal structure using single-cell RNA or DNA sequencing data. However, there is a lack of effective computational methods to identify informative mtDNA variants in noisy and sparse single-cell sequencing data. Here we present an open source computational tool MQuad that accurately calls clonally informative mtDNA variants in a population of single cells, and an analysis suite for complete clonality inference, based on single cell RNA or DNA sequencing data. Through a variety of simulated and experimental single cell sequencing data, we showed that MQuad can identify mitochondrial variants with both high sensitivity and specificity, outperforming existing methods by a large extent. Furthermore, we demonstrated its wide applicability in different single cell sequencing protocols, particularly in complementing single-nucleotide and copy-number variations to extract finer clonal resolution. MQuad is a Python package available viahttps://github.com/single-cell-genetics/MQuad.
Small RNA-sequencing for Analysis of Circulating miRNAs: Benchmark Study
Authors: Androvic Peter , Benesova Sarka , Rohlova Eva , Kubista Mikael , Valihrach Lukas
Published: March 2021

Small RNA-sequencing (RNA-Seq) is being increasingly used for profiling of circulating microRNAs (miRNAs), a new group of promising biomarkers. Unfortunately, small RNA-Seq protocols are prone to biases limiting quantification accuracy, which motivated development of several novel methods. Here, we present comparison of all small RNA-Seq library preparation approaches that are commercially available for quantification of miRNAs in biofluids. Using synthetic and human plasma samples, we compared performance of traditional two-adaptor ligation protocols (Lexogen, Norgen) as well as methods using randomized adaptors (NEXTflex), polyadenylation (SMARTer), circularization (RealSeq), capture probes (EdgeSeq) or unique molecular identifiers, UMIs (QIAseq). Globally, there was no single protocol outperforming others across all metrics. We documented limited overlap of measured miRNA profiles between methods largely owing to protocol-specific biases. We found that methods designed to minimize bias largely differ in their performance and we identified contributing factors. We found that usage of UMIs has rather negligible effect and if designed incorrectly can even introduce spurious results. Together, these results identify strengths and weaknesses of current methods and provide guidelines for applications of small RNA-Seq in biomarker research.
Analysis of half a billion datapoints across ten machine-learning algorithms identify key determinants of insulin gene transcription
Authors: Wong Wilson K.M. , Thorat Vinod , Joglekar Mugdha V. , Dong Charlotte X. , Lee Hugo , Chew Yi Vee , Bhave Adwait , Hawthorne Wayne J. , Engin Feyza , Pant Aniruddha , Dalgaard Louise T. , Bapat Sharda , Hardikar Anandwardhan A.
Published: March 2021

Machine learning (ML)-workflows enable unprejudiced/robust evaluation of complex datasets. Here, we analyzed over 490,000,000 data points to compare 10 different ML-workflows in a large (N=11,652) training dataset of human pancreatic single-cell (sc-)transcriptomes to identify genes associated with the presence or absence of insulin transcript(s). Prediction accuracy/sensitivity of each ML-workflow were tested in a separate validation dataset (N=2,913). Ensemble ML-workflows, in particular Random Forest ML-algorithm delivered high predictive power (AUC=0.83) and sensitivity (0.98), compared to other algorithms. The transcripts identified through these analyses also demonstrated significant correlation with insulin in bulk RNA-seq data from human islets. The top-10 features, (includingIAPP, ADCYAP1, LDHAandSST) common to the three Ensemble ML-workflows were significantly dysregulated in scRNA-seq datasets from Ire-1αβ-/-mice that demonstrate dedifferentiation of pancreatic β-cells in a model of type 1 diabetes (T1D) and in pancreatic single cells from individuals with type 2 Diabetes (T2D). Our findings provide direct comparison of ML-workflows in big data analyses, identify key determinants of insulin transcription and provide workflows for future analyses.
Prohibit, protect, or adapt? The changing role of volunteers in palliative and hospice care services during the COVID-19 pandemic. A multinational survey (CovPall)
Authors: Walshe Catherine , Garner Ian , Dunleavy Lesley , Preston Nancy , Bradshaw Andy , Cripps Rachel L , Bajwah Sabrina , Sleeman Katherine E , Hocaoglu Mevhibe , Maddocks Matthew , Murtagh Fliss EM , Oluyase Adejoke O , Fraser Lorna K , Higginson Irene J
Published: March 2021

Background

Volunteers are common within palliative care services, and provide support that enhances care quality. The support they provided, and any role changes, during the COVID-19 pandemic are unknown.

Aims

To understand volunteer deployment and activities within palliative care services, and to identify what may affect any changes in volunteer service provision, during the COVID-19 pandemic.

Methods

Multi-national online survey disseminated via key stakeholders to specialist palliative care services, completed by lead clinicians. Data collected on volunteer roles, deployment, and changes in volunteer engagement. Analysis included descriptive statistics, a multivariable logistic regression, and analysis of free-text comments using a content analysis approach.

Results

458 respondents: 277 UK, 85 rest of Europe, and 95 rest of the world. 68.5% indicated volunteer use pre-COVID-19. These were across a number of roles (from 458): direct patient/family facing support (58.7%), indirect support (e.g. driving) (52.0%), back office (48.5%) and fundraising (45.6%). 11% had volunteers with COVID-19. Of those responding to a question on change in volunteer deployment (328 of 458) most (256/328, 78%) indicated less or much less use of volunteers. Less use of volunteers was associated with being an in-patient hospice, (OR=0.15, 95%CI = 0.07-0.3 p<.001). This reduction in volunteers was felt to protect potentially vulnerable volunteers and with policy changes preventing volunteers from supporting services. However, adapting was also seen where new roles were created, or existing roles pivoted to provide virtual support.

Discussion and conclusion

Volunteers were mostly prevented from supporting many forms of palliative care, particularly in in-patient hospices, which may have quality and safety implications given their previously central roles. Volunteer re-deployment plans are needed that take a more considered approach, using volunteers more flexibly to enhance care while ensuring safe working practices. Consideration needs to be given to widening the volunteer base away from those who may be considered to be most vulnerable to COVID-19.
Transcription initiation at a consensus bacterial promoter proceeds via a “bind-unwind-load-and-lock” mechanism
Authors: Mazumder Abhishek , Ebright Richard H , Kapanidis Achillefs N
Published: March 2021

Transcription initiation starts with unwinding of promoter DNA by RNA polymerase (RNAP) to form a catalytically competent RNAP-promoter complex (RPO). Despite extensive study, the mechanism of promoter unwinding has remained unclear, in part due to the transient nature of intermediates on path to RPo. Here, using single-molecule unwinding-induced fluorescence enhancement to monitor promoter unwinding, and single-molecule fluorescence resonance energy transfer to monitor RNAP clamp conformation, we analyze RPo formation at a consensus bacterial core promoter. We find that the RNAP clamp is closed during promoter binding, remains closed during promoter unwinding, and then closes further, locking the unwound DNA in the RNAP active-centre cleft. Our work defines a new, “bind-unwind-load-and-lock,” model for the series of conformational changes occurring during promoter unwinding at a consensus bacterial promoter and provides the tools needed to examine the process in other organisms and at other promoters.

Significance statement

Transcription initiation, the first step and most important step in gene expression for all organisms, involves unwinding of promoter DNA by RNA polymerase (RNAP) to form an open complex (RPo); this step also underpins transcriptional regulation and serves as an antibiotic target. Despite decades of research, the mechanism of promoter DNA unwinding has remained unresolved. Here, we solve this puzzle by using single-molecule fluorescence to directly monitor conformational changes in the promoter DNA and RNAP in real time during RPo formation. We show that RPo forms via a “bind-unwind-load-and-lock” mechanism, where the promoter unwinds outside the RNAP cleft, the unwound template DNA loads into the cleft, and RNAP “locks” the template DNA in place by closing the RNAP clamp module.
Mismatch between bird species sensitivity and the protection of intact habitats across the Americas
Authors: Cazalis Victor , Barnes Megan D. , Johnston Alison , Watson James E.M. , Şekercioğlu Cagan H. , Rodrigues Ana S.L.
Published: March 2021

Protected areas, the most prevalent international policy mechanism for biodiversity conservation, are highly heterogeneous in their effectiveness at buffering ecosystems and species’ habitats from human pressure. Protected areas with intense human pressure cannot protect species that are highly sensitive to human activities. Here, we use 60 million bird observations from the eBird citizen science platform to estimate the sensitivity to human pressure of each bird species breeding in the Americas (Nearctic and Neotropical regions). We find that high-sensitivity species, while found in all ecoregions, are concentrated in the tropical biomes. Ecoregions with large proportions of high-sensitivity species do not have more intact protected habitat, resulting in a low coverage of intact protected habitat for many high-sensitivity species. What is more, 139 high-sensitivity species have little or no intact protected habitat within their distributions while being threatened with extinction. Finally, we show that protected area intactness is decreasing faster in ecoregions with many high-sensitivity species. Our results highlight a major mismatch between species conservation needs and the coverage of intact protected habitats, and will likely hamper the long-term effectiveness of protected areas at retaining species. We highlight ecoregions where the protection and management of intact habitats, complemented by the restoration of degraded ones, is urgently needed to avoid extinctions.
Preliminary report on SARS-CoV-2 Spike mutation T478K
Authors: Di Giacomo Simone , Mercatelli Daniele , Rakhimov Amir , Giorgi Federico M.
Published: March 2021

Several SARS-CoV-2 variants have emerged, posing a renewed threat to COVID-19 containment and to vaccine and drug efficacy. In this study, we analyzed more than 1,000,000 SARS-CoV-2 genomic sequences deposited up to April 27, 2021 on the GISAID public repository, and identified a novel T478K mutation located on the SARS-CoV-2 Spike protein. The mutation is structurally located in the region of interaction with human receptor ACE2 and was detected in 11,435 distinct cases. We show that T478K has appeared and risen in frequency since January 2021, predominantly in Mexico and USA, but we could also detect it in several European countries.
Electron transfer parameters for Methemoglobin formation in mutant Hemoglobin α-chains
Authors: Dixit Vaibhav A. , Blumberger Jochen , Vyas Shivam Kumar
Published: March 2021

Hemoglobin mediated transport of dioxygen (O2) critically depends on the stability of the reduced (Fe2+) form of the Heme cofactors. Some protein mutations stabilize oxidized (Fe3+) state (Methemoglobin, Hb M) causing methemoglobinemia and can be lethal above 30 %. Majority of the analyses of factors influencing Hb oxidation are retrospective and give insights only for inner sphere mutations of Heme (His58, His87). Herein, we report the first all atom MD simulations on redox states and calculations of the Marcus ET parameters for the α-chain Hb oxidation and reduction rates for Hb M. The Hb (wild type), and most of the studied α-chain variants maintain globin structure except the Hb M Iwate (H87Y). Using linear response approximation we calculated average energy gaps (<ΔE>), total (λ), protein (λprot), solvent (λsolv) reorganization energies, and redox potentials (E°), and oxidation free energies (ΔG°). The total λ ranges from 0.685 – 0.730 eV in agreement with literature on Hb and similar Heme proteins. The mutants forming Hb M tend to lower theE° and thus stabilize the oxidized (Fe3+) state (e.g. the Hb Miyagi variant with K61E mutation). Solvent reorganization (λsolv73 – 96 %) makes major contributions to λ, while protein reorganization (λprot) accounts for 27 – 30 % except for the Miyagi and J-Buda variants (λprot∼ 4 %). Analysis of Heme-solvent H-bonding interactions among variants provide insights into the role of Lys61 residue in stabilizing Fe2+state and ET parameters. The ET parameters provide valuable insights into the Hb oxidation to Hb M in agreement with the experimental data. Thus our methodology explains the effect of mutations on the structure, stability and Hb oxidation, and has potential for the prediction of methemoglobinemia.
Paraburkholderia edwiniiprotectsAspergillussp. from phenazines by acting as a toxin sponge
Authors: Dahlstrom Kurt M. , Newman Dianne K.
Published: March 2021

Many environmentally and clinically important fungi are sensitive to toxic, bacterially-produced, redox-active molecules called phenazines. Despite being vulnerable to phenazine-assault, fungi inhabit microbial communities that contain phenazine producers. Because many fungi cannot withstand phenazine challenge, but some bacterial species can, we hypothesized that bacterial partners may protect fungi in phenazine-replete environments. In the first soil sample we collected, we co-isolated several such physically associated pairings. We discovered the novel speciesParaburkholderia edwiniiand demonstrated it can protect a co-isolatedAspergillusspecies from phenazine-1-carboxylic acid (PCA) by sequestering it, acting as a toxin sponge; in turn, it also gains protection. When challenged with PCA,P. edwiniichanges its morphology, forming aggregates within the growing fungal colony. Further, the fungal partner triggersP. edwiniito sequester PCA and maintains conditions that limit PCA toxicity by promoting an anoxic and highly reducing environment. A mutagenic screen revealed this program depends on the stress-inducible transcriptional repressor HrcA. We show that one relevant stressor in response to PCA challenge is fungal acidification and that acid stress causesP. edwiniito behave as though the fungus were present. Finally, we reveal this phenomenon as widespread amongParaburkholderiawith moderate specificity among bacterial and fungal partners, including plant and human pathogens. Our discovery suggests a common mechanism by which fungi can gain access to phenazine-replete environments, and provides a tractable model system for its study. These results have implications for how rhizosphere microbial communities as well as plant and human infection sites are policed for fungal membership.
Predictors of zoonotic potential in helminths
Authors: Majewska Ania A. , Huang Tao , Han Barbara , Drake John M.
Published: March 2021

Helminths are parasites that cause disease at considerable cost to public health and present a risk for emergence as novel human infections. Although recent research has elucidated characteristics conferring a propensity to emergence in other parasite groups (e.g. viruses), the understanding of factors associated with zoonotic potential in helminths remains poor. We applied an investigator-directed learning algorithm to a global dataset of mammal helminth traits to identify factors contributing to spillover of helminths from wild animal hosts into humans. We characterized parasite traits that distinguish between zoonotic and non-zoonotic species with greater than 88% accuracy. Results suggest that helminth traits relating to transmission (e.g. definitive and intermediate hosts) and geography (e.g. distribution) are more important to predicting zoonotic species than morphological or epidemiological traits. Whether or not a helminth causes infection in companion animals (cats and dogs) is the most important predictor of propensity to cause human infection. Finally, we identified helminth species with high modeled propensity to cause zoonosis (over 70%) that have not previously been deemed to be of risk. This work highlights the importance of prioritizing studies on the transmission of helminths that infect pets and points to the risks incurred by close associations with these animals.
A TBP-independent mechanism for RNA Polymerase II transcription
Authors: Kwan James Z.J. , Nguyen Thomas F. , Budzyński Marek A. , Cui Jieying , Price Rachel M. , Teves Sheila S.
Published: March 2021

Transcription by RNA Polymerase II (Pol II) is initiated by the hierarchical assembly of the Pre-Initiation Complex onto promoter DNA. Decades ofin vitroand yeast research have shown that the TATA-box binding protein (TBP) is essential to Pol II initiation by triggering the binding of other general transcription factors, and ensuring proper Pol II loading. Here, we report instead that acute depletion of TBP in mouse embryonic stem cells (mESCs) has no global effect on ongoing Pol II transcription. Surprisingly, Pol II transcriptional induction through the Heat Shock Response or cellular differentiation also occurs normally in the absence of TBP. In contrast, acute TBP depletion severely impairs initiation by RNA Polymerase III. Lastly, we show that a metazoan-specific paralog of TBP is expressed in mESCs and that it binds to promoter regions of active Pol II genes even in the absence of TBP. Taken together, our findings reveal an unexplored TBP-independent process in mESCs that points to a diversity in Pol II transcription initiation mechanisms.
Endocervical regulatory T cells are associated with decreased genital inflammation and lower HIV target cell abundance
Authors: Ssemaganda Aloysious , Cholette Francois , Perner Michelle , Kambaran Cheli , Adhiambo Wendy , Wambugu Peter M. , Gebrebrhan Henok , Lee Amy , Nuhu Faisal , Mwatelah Ruth S. , Jahan Naima , Omole Tosin E. , Wanjiru Tabitha , Gitau Apollo , Kimani Joshua , McKinnon Lyle R.
Published: March 2021

Regulatory T cells (Tregs) play important roles in tissue homeostasis, but few studies have investigated tissue Tregs in the context of genital inflammation, HIV target cell density, and vaginal microbiota in humans. In women from Nairobi (n=64), the proportion of CD4+ CD25+ CD127lowTregs in the endocervix correlated with those in blood (r=0.31, p=0.01), with a higher Treg frequency observed in the endocervix (median 3.8 vs 2.0%, p<0.0001). Most Tregs expressed FoxP3 in both compartments, and CTLA-4 expression was higher on endocervical Tregs compared to blood (median 50.8 vs 6.0%, p<0.0001). More than half (34/62, 55%) of participants displayed a non-Lactobacillusdominant vaginal microbiota, which was not associated with endocervical Tregs or CD4+ T cell abundance. In a multivariable linear regression, endocervical Treg proportions were inversely associated with the number of elevated pro-inflammatory cytokines (p=0.03). Inverse Treg associations were also observed for specific cytokines including IL-1β, G-CSF, Eotaxin, IL-1RA, IL-8, and MIP-1 β. Higher endocervical Treg proportions were associated with lower abundance of endocervical CD4+ T cells (0.30 log10CD4+ T cells per log10Treg, p=0.00028), with a similar trend for Th17 cells (p=0.09). Selectively increasing endocervical Tregs may represent a pathway to reduce genital tract inflammation in women.
An improved assembly of theAlbugo candidaAc2V genome reveals the expansion of the “CCG” class of effectors
Authors: Furzer Oliver J. , Cevik Volkan , Fairhead Sebastian , Bailey Kate , Redkar Amey , Schudoma Christian , MacLean Dan , Holub Eric B. , Jones Jonathan D.G.
Published: March 2021

Albugo candidais an obligate oomycete pathogen that infects many plants in the Brassicaceae family. We re-sequenced the genome of isolate Ac2V using PacBio long reads and constructed an assembly augmented by Illumina reads. The Ac2VPB genome assembly is 10% larger and more contiguous compared to a previous version. Our annotation of the new assembly, aided by RNASeq information, revealed a dramatic 250% expansion (40 to 110) in the CHxC effector class, which we redefined as “CCG” based on motif analysis. This class of effectors consist of arrays of phylogenetically related paralogs residing in gene sparse regions, and shows signatures of positive selection and presence/absence polymorphism. This work provides a resource that allows the dissection of the genomic components underlyingA. candidaadaptation and particularly the role of CCG effectors in virulence and avirulence on different hosts.
Critical contribution of 3’ non-seed base pairing to thein vivofunction of the evolutionarily conservedlet-7amicroRNA
Authors: Duan Ye , Veksler-Lublinsky Isana , Ambros Victor
Published: March 2021

Base-pairing of the seed region (g2-g8) is essential for microRNA targeting, however, thein vivofunction of the 3’ non-seed region (g9-g22) are less well understood. Here we report the first systematic investigation of thein vivoroles of 3’ non-seed nucleotides in microRNAlet-7a,whose entire g9-g22 region is conserved among bilaterians. We found that the 3’ non-seed sequence functionally distinguisheslet-7afrom its family paralogs. The complete pairing of g11-g16 is essential forlet-7ato fully repress multiple key targets, including evolutionarily conservedlin-41,daf-12andhbl-1. Nucleotides at g17-g22 are less critical but may compensate for mismatches in the g11-g16 region. Interestingly, the 3’ non-seed pairing oflet-7acan be critically required with certain minimal complementarity for sites with perfect seed pairing. These results provide evidence that the specific configurations of both seed and 3’ non-seed base-pairing can critically influence microRNA-mediated gene regulationin vivo.
Gene expression in the developing nemertean brain indicates convergent evolution of complex brains in Spiralia
Authors: Gąsiorowski Ludwik , Børve Aina , Cherneva Irina A. , Orús-Alcalde Andrea , Hejnol Andreas
Published: March 2021

Background

Nemertea is a clade of worm-like animals, which belongs to a larger animal group called Spiralia (together with e.g. annelids, flatworms and mollusks). Many of the nemertean species possess a complex central nervous system (CNS) with a prominent brain, and elaborated chemosensory and neuroglandular cerebral organs, which have been suggested as homologues to the annelid mushroom bodies. In order to understand the developmental and evolutionary origins of complex nemertean brain, we investigated details of neuroanatomy and gene expression in the brain and cerebral organs of the juveniles of nemerteanLineus ruber.

Results

In the hatched juveniles the CNS is already composed of all major elements present in the adults, including the brain (with dorsal and ventral lobes), paired longitudinal lateral nerve cords and an unpaired dorsal nerve cord. The TEM investigation of the juvenile cerebral organ revealed that the structure is already composed of several distinct cell types present also in the adults. We further investigated the expression of twelve transcription factors commonly used as brain and cell type markers in bilaterian brains, including genes specific for annelid mushroom bodies. The expression of the investigated genes in the brain is region-specific and divides the entire organ into several molecularly distinct areas, partially overlapping with the morphological compartments. Additionally, we detected expression of mushroom body specific genes in the developing cerebral organs.

Conclusions

At the moment of hatching, the juveniles ofL. ruberalready have a similar neuroarchitecture as adult worms, which suggests that further neural development is mostly related with increase in the size but not in complexity. Comparison in the gene expression betweenL. ruberand the annelidPlatynereis dumeriliiand other spiralians, indicates that the complex brains present in those two species evolved convergently by independent expansion of non-homologues regions of the simpler brain present in their common ancestor. The similarities in gene expression in mushroom bodies and cerebral organs might be a result of the convergent recruitment of the same genes into patterning of non-homologues organs or the results of more complicated evolutionary processes, in which conserved and novel cell types contribute to the non-homologues structures.
Dual control exerted by dopamine in blood-progenitor cell cycle regulation inDrosophila
Authors: Kapoor Ankita , Padmavathi A. , Mukherjee Tina
Published: March 2021

InDrosophila, definitive hematopoiesis occurs in a specialized organ termed “lymph gland”, where multi-potent stem-like blood progenitor cells reside and their homeostasis is central to growth of this organ. Recent findings have implicated a reliance on neurotransmitters in progenitor development and function however, our understanding of these molecules is still limited. Here, we extend our analysis and show that blood-progenitors are self-sufficient in synthesizing dopamine, a well-established neurotransmitter and have modules for its sensing through receptor and uptake via, transporter. Modulating their expression in progenitor cells affects lymph gland growth. Progenitor cell cycle analysis revealed an unexpected requirement for intracellular dopamine in the progression of early progenitors from S to G2 phase of the cell cycle, while activation of dopamine-receptor later in development regulated progression from G2 to entry into mitosis. The dual capacity in which dopamine operates, both intra-cellular and extra-cellular, controls lymph gland growth. These data highlight a novel and non-canonical use of dopamine as a proliferative cue by the myeloid-progenitor system and reveals a functional requirement for intracellular dopamine in cell-cycle progression.
Alpha-synuclein alters the faecal viromes of rats in a gut-initiated model of Parkinson’s disease
Authors: Stockdale S. R. , Draper L. A. , O’Donovan S. M. , Barton W. , O’Sullivan O. , Volpicelli-Daley L. A. , Sullivan A. M. , O’Neill C. , Hill C.
Published: March 2021

Parkinson’s disease (PD) is a chronic neurological disorder associated with the misfolding of alpha-synuclein (α-syn) into Lewy body aggregates within nerve cells that contribute to their neurodegeneration. Recent evidence suggests α-syn aggregation may begin in the gut and travel to the brain along the vagus nerve, with microbes a potential trigger initiating the misfolding of α-syn. However, changes in the gut virome in response to α-syn alterations have not been investigated. In this study, we show longitudinal changes in the faecal virome of rats administered either monomeric or preformed fibrils (PFF) of α-syn directly into their enteric nervous system. Differential changes in rat viromes were observed when comparing monomeric and PFF α-syn. The virome β-diversity changes after α-syn treatment were compounded by the addition of LPS as an adjunct. Changes in the diversity of rat faecal viromes were observed after one month and did not resolve within the study’s five month observational period. Overall, these results suggest that microbiome alterations associated with PD may, partially, be reactive to host α-syn associated changes.
Distal and proximal cis-regulatory elements sense X-chromosomal dosage and developmental state at theXistlocus
Authors: Gjaltema Rutger A.F. , Schwämmle Till , Kautz Pauline , Robson Michael , Schöpflin Robert , Lustig Liat Ravid , Brandenburg Lennart , Dunkel Ilona , Vechiatto Carolina , Ntini Evgenia , Mutzel Verena , Schmiedel Vera , Marsico Annalisa , Mundlos Stefan , Schulz Edda G.
Published: March 2021

Developmental genes such asXist, the master regulator of X-chromosome inactivation (XCI), are controlled by complexcis-regulatory landscapes, which decode multiple signals to establish specific spatio-temporal expression patterns.Xistintegrates information on X-chromosomal dosage and developmental stage to trigger XCI at the primed pluripotent state in females only. Through a pooled CRISPR interference screen in differentiating mouse embryonic stem cells, we identify functional enhancer elements ofXistduring the onset of random XCI. By quantifying how enhancer activity is modulated by X-dosage and differentiation, we find that X-dosage controls the promoter-proximal region in a binary switch-like manner. By contrast, differentiation cues activate a series of distal elements and bring them into closer spatial proximity of theXistpromoter. The strongest distal element is part of an enhancer cluster ∼200 kb upstream of theXistgene which is associated with a previously unannotatedXist-enhancing regulatory transcript, we namedXert. Developmental cues and X-dosage are thus decoded by distinct regulatory regions, which cooperate to ensure female-specificXistupregulation at the correct developmental time. Our study is the first step to disentangle how multiple, functionally distinct regulatory regions interact to generate complex expression patterns in mammals.
An investigation into decision-making and delivery activities following design-led events in collaborative planning
Authors: AlWaer Husam , Rintoul Susan , Cooper Ian
Published: March 2021

Purpose

This paper is concerned with what should happen after design-led events have been held to promote co-decision-making, between professionals and local stakeholders, in collaborative planning of the built environment. Rather than being standalone, such events form one single step in a multi-stage collaborative planning process. What comes before and after them has to be acknowledged as important to their effective contribution to collaborative planning. This paper aims to make a case for giving more attention to the post-event stages of collaborative planning, to ensure that the involvement of the public produces real and tangible benefits.

Design/methodology/approach

Content analysis of both academic and grey literatures was undertaken to examine emerging advice on how to conduct decision-making, the implementation of outputs and the delivery of desired outcomes, after design-led events. A critical review of the post-event decision-making and delivery activities is offered, which aims to add to the current academic literature on the deployment of design-led events. An attempt is made to sketch out the characteristics of post-event stages, drawn from the literature and collated specific examples of collaborative planning investigated in Scotland.

Findings

Three key factors are identified as affecting the successful implementation of decisions reached at design-led events: (1) a shared follow-on plan, (2) an agreed action programme for delivering this and (3) a properly constituted and resourced delivery vehicle that can monitor and evaluate progress. A research agenda to address questions raised but left unanswered is suggested dealing with how the decision-making and delivery activities following design-led events in collaborative planning might be improved.

Originality/value

A research agenda to address questions raised but left unanswered is suggested dealing with how the decision-making and delivery activities following design-led events in collaborative planning might be improved.
How relationship quality, autonomous work motivation and socialization experience influence the adjustment of self-initiated expatriates in China
Authors: Jannesari Milad T. , Sullivan Sherry E.
Published: March 2021

Purpose

The continued expansion of organizations outside China's planned economy due to the Belt-and-Road Initiative (BRI) is expected to increase recruitment of self-initiated expatriates (SIEs). Drawing on social capital, motivation and socialization theories, this study examines the experiences of SIEs in China, which is considered one of the most difficult locations for foreigners to work. While previous research has focused on the impact of individual characteristics on adjustment, this study explores the interplay among relationship quality (trust and shared vision), autonomous work motivation, socialization experience and adjustment.

Design/methodology/approach

Based on the developed theoretical framework, hypotheses are proposed and tested using data collected by surveying 274 SIEs in China.

Findings

Relationship quality with host country nationals (HCNs) was positively associated with adjustment, and autonomous work motivation fully mediated this relationship. Socialization experience moderated the association between relationship quality and autonomous work motivation. Specifically, SIEs' socialization experience strengthened the associations of trust and shared vision with autonomous work motivation. However, socialization experiences failed to moderate the mediated effects of trust and shared vision on adjustment via autonomous work motivation.

Originality/value

This study answers repeated calls for more research on SIEs' adjustment and SIEs working in non-Western countries, especially China. The findings underscore the importance of studying SIE-HCN work relationships and the theoretical value of autonomous work motivation as an underlying mechanism by which the quality of an SIE's relationship with an HCN colleague influences adjustment.
Reverse mentoring, job crafting and work-outcomes: the mediating role of work engagement
Authors: Garg Neha , Murphy Wendy , Singh Pankaj
Published: March 2021

Purpose

Reverse mentoring and job crafting are innovative, employee-driven job resources that can lead to positive organizational outcomes. The purpose of this paper is to explore the role of work engagement in mediating the association of these resources with work performance and work withdrawal behavior.

Design/methodology/approach

Hypotheses were tested using structural equation modeling on data obtained from 369 software developers in India.

Findings

Findings demonstrate that reverse mentoring and job crafting are positively related to work engagement, which, in turn, increase performance and decreases work withdrawal behaviors. Work engagement partially mediates the association of job crafting with both outcomes. In contrast, work engagement fully mediates the relationship between reverse mentoring and withdrawal behavior and partially mediates the relationship between reverse mentoring and work performance.

Research limitations/implications

This study is a cross-sectional, survey design in the understudied technical industry in India, which may limit generalizability. However, the authors also connect the previously unrelated literatures on reverse mentoring and work engagement and develop a scale for use in future reverse mentoring studies.

Practical implications

This study provides evidence to support practitioners in implementing resources for reverse mentoring and job crafting to increase work engagement among employees and subsequent positive outcomes.

Originality/value

Organizations can support reverse mentoring and job crafting as cost effective employee development tools. The research focuses on the mentors, who tend to be the less experienced and younger counterparts in a reverse mentoring pair and a critical part of the workforce for the growing IT industry.
Quality assurance in the domestic third-party arrangement in Australia
Authors: Shah Mahsood , Lim Choon Boey
Published: March 2021

Purpose

Third-party arrangements where a university offers its degrees in collaboration with another institution are not a new phenomenon, particularly when the third-party arrangements occur in the form of a cross-border education (or widely known as transnational education). Drawing on a critical review of the literature available on quality assurance of domestic third-party arrangements and through the use of interviews with the sessional teaching staff, the paper offers theoretical as well as practical views on the domestic third-party arrangement and seeks to inform key stakeholders in the academic management of such collaboration.

Design/methodology/approach

The study was undertaken with 40 sessional academics who are involved in teaching postgraduate courses at several third-party education providers and universities with metropolitan campuses in Australia. Focus group interviews were conducted with 8–10 participants in each group. The qualitative study included seven open-ended questions. Each focus group interview was between 45–60 minutes.

Findings

The study found 11 universities in Australia offering courses in third-party arrangement with a focus on international students. Online third-party arrangement is also gaining momentum. The study found the following areas that require attention: induction and professional development, quality assurance arrangements, maintenance of standards, adequacy of resources and infrastructure and risk related to academic quality.

Research limitations/implications

Limited study has been conducted on third-party arrangements where a university, usually located far from the city vicinity, works in a collaborative mode with another institution, primarily a private institution, to offer degrees at metropolitan city areas in the same country. Further research is needed with a large number of participants.

Originality/value

The study is undertaken for the first time in Australia. No research has been undertaken on the growth and quality assurance of a third-party arrangement in Australia and other developed countries. The study involves the engagement of the sessional academic staff.
Innovations in self care and close care made during COVID 19 pandemic: a narrative review
Authors: Øvretveit John
Published: March 2021

Purpose

Previously, health self-care and informal or “close-care” for family and friends were receiving increasing attention, but became more important during the COVID-2019 pandemic. Sometimes, this was because formal services became less physically accessible to patients and were overburdened by patients ill with COVID-2019. The purpose of this paper is to give an overview of this phenomenon and consider the implications for clinical governance.

Design/methodology/approach

A five-step search and narrative review method were used, and case examples were selected to illustrate some of these developments.

Findings

Examples discovered and described include innovations in websites, social media support groups, systems for matching volunteers to people needing of help, computer and mobile phone applications, digital devices and virtual health rooms run by peer volunteers to help others to learn and use digital technologies.

Originality/value

In response to their health self-care needs not being met, some patients and carers and their associations developed new digital technologies or adapted existing ones. This use and their innovation separate from health care have been largely unreported in the scientific and professional literature. This is the first review of grey literature and other reports of this growing phenomena.
Economic policy uncertainty and stock liquidity: evidence from China
Authors: Zhang Liguang , Chen Wanyi , Hu Ning
Published: March 2021

Purpose

The main purpose of this study is to examine whether economic policy uncertainty affects the stock liquidity. Furthermore, this study explores the influencing factors, transmission mechanism and solution path between economic policy uncertainty and the stock liquidity.

Design/methodology/approach

A data set comprising 97,729 firm-quarter observations of Chinese firms with A-shares listed on the Shenzhen and Shanghai stock exchanges was selected, China's economic policy uncertainty was measured by using the China Economic Policy Uncertainty Index and the impact of economic policy uncertainty on the stock liquidity over the period 2004–2017 was empirically tested. The empirical analysis was based on ordinary least square regression model, and mediation and moderation effect models were used in the further analysis.

Findings

The empirical results show that the higher the economic policy uncertainty, the lower the stock liquidity, which is more significant in firms with an opaque information environment, less investor attention and weak risk resistance ability. The authors argue that the transmission mechanism can be explained by the quality of information disclosure and investor sentiment. Moreover, the negative impact of economic policy uncertainty on the stock liquidity can be mitigated by increasing voluntary disclosures.

Originality/value

This study enriches the literature on factors affecting the stock liquidity from the perspective of macroeconomic policy and provides a reference for policymakers to formulate relevant measures to improve the stock liquidity in emerging markets.
Building health system responsiveness to noncommunicable diseases for Gweru District adults, Zimbabwe: a case study
Authors: Muzvondiwa Blender , Batterham Roy
Published: March 2021

Purpose

Gweru District, Zimbabwe faces a major challenge of noncommunicable diseases (NCDs). Globally, health systems have not responded successfully to problems in prevention and management of NCDs. Despite numerous initiatives, reorienting health services has been slow in many countries. Gweru District has similar challenges. The purpose of this paper is to explore what the health systems in Zimbabwe have done, and are doing to respond to increasing numbers of NCD cases in adults in the nation, especially in the district of Gweru

Design/methodology/approach

The study employed a descriptive narrative review of the academic and grey literature, supplemented by semi-structured key informant interviews with 14 health care staff and 30 adults living with a disease or caring for an adult with a disease in Gweru District.

Findings

Respondents identified many limitations to the response in Gweru. Respondents said that screening and diagnosis cease to be helpful when it is difficult securing medications. Nearly all community respondents reported not understanding why they are not freed of the diseases, showing poor understanding of NCDs. The escalating costs and scarcity of medications have led people to lose trust in services. Government and NGO activities include diagnosis and screening, provision of health education and some medication. Health personnel mentioned gaps in transport, medication shortages, poor equipment and poor community engagement. Suggestions include: training of nurses for a greater role in screening and management of NCDs, greater resourcing, outreach activities/satellite clinics and better integration of diverse NCD policies.

Originality/value

This research offers an understanding of NCD strategies and their limitations from the bottom-up, lived experience perspective of local health care workers and community members.