bluuebunny/crossref_metadata_2025 huggingface dataset:
Universality of Universal Health Coverage: a Scoping Review
Authors: Endalamaw Aklilu , Gilks Charles F , Ambaw Fentie , Assefa Yibeltal
Published: May 2022

Background

Universal health coverage (UHC) is achieved in the primary healthcare pathways. UHC is about population coverage, services coverage and financial protection. Tracer indicators are used to measure the progress towards UHC. There is inadequate evidence that assess the extent of the universality of UHC. Evidence is, therefore, needed to map the existing literature and summarize the issues covered in the dimensions of UHC.

Methods

A systematic search was carried out in the Web of Science and PubMed databases. Hand searches were also conducted to find articles from Google Scholar, the World Bank Library, the World Health Organization Library, the United Nations Digital Library Collections, and Google. Articles on UHC coverage, financial risk protection, quality of care, and inequity were included. A stepwise approach was used to identify and select relevant studies, conduct data charting, collation and summarization, as well as report results. Simple descriptive statistics and narrative synthesis were used to present the findings.

Results

Forty-seven papers were included in the final review. One-fourth of the articles (25.5%) were from the African region and 29.8% were from lower-middle-income countries. More than half of the articles (54.1%) used a quantitative research approach. Of included articles, coverage was assessed by 53.2% of articles; financial risk protection by 27.7%, inequity by 25.5% and quality by 6.4% of the articles as their main research objectives or mentioned in result section. Most (42.5%) of articles investigated health promotion and 2.1% palliation and rehabilitation services. Policy and health care level and cross-cutting barriers were identified in the progress of UHC.

Conclusions

The results of the study showed that majorities of evidence were from Africa’s region. Methodologically, the quantitative approach was a more frequently used research design to investigate UHC. Palliation and rehabilitation health care services need attention in the analysis of the progress towards UHC. The finding of the current evidence is noteworthy to focus on quality and inequity of health services in the future UHC research. Comprehensive evidence is needed to fully understand and progressively realize UHC.
Increased ambulance attendances related to suicide and self-injury in response to the pandemic in Australia
Authors: John James , Synn Ei Phyu , Winata Teresa , Eapen Valsamma , Lin Ping-I
Published: May 2022

Investigating the change in the trend of ambulance service utilization for suicide in response to the COVID-19 pandemic can clarify the impact of the pandemic on acute health services. To determine whether the trends of the ambulance attendances related to self-injury and suicide changes in response to the COVID-19 pandemic. We extracted the data from the National Ambulance Surveillance System in Australia between March 2018 and March 2021 to examine the trajectory of the ambulance attendances related to self-injury and suicide. The results indicate that the number of ambulance attendances related to self-injury, suicidal ideation and suicidal attempt increased immediately during the first quarter since the outbreak and stayed higher over the at least 12 months. Notably, the post-outbreak surge in ambulance attendances associated with these mental health crises did not continue to escalate further. To sum up, the overall increase in ambulance attendances may reflect increased distress in the community, but also signify disruptions of other non-emergency health services. In contrast to recent evidence for the suicide rate being unchanged during the pandemic, our findings provide a different perspective on the impact of the pandemic on mental health services. This warrants a re-assessment of resources for mental health services in the post-COVID era.
Molecular consequences of PQBP1 deficiency, involved in the X-linked Renpenning syndrome
Authors: Courraud Jérémie , Engel Camille , Quartier Angélique , Drouot Nathalie , Houessou Ursula , Plassard Damien , Sorlin Arthur , Brischoux-Boucher Elise , Van Maldergem Lionel , Gouy Evan , Rossi Massimiliano , Edery Patrick , Putoux Audrey , Gilbert-Dussardier Brigitte , Kalscheuer Vera , Mandel Jean-Louis , Piton Amélie
Published: May 2022

Mutations in the PQBP1 gene (polyglutamine-binding protein 1) are responsible for a syndromic X-linked form of intellectual disability (XLID), the Renpenning syndrome. PQBP1 encodes a protein that plays a role in the regulation of gene expression, splicing and mRNA translation. To investigate the consequences of variants in PQBP1, we performed transcriptomic studies in 1) patients’ lymphoblastoid cell lines (LCL) carrying pathogenic variants in PQBP1 and 2) in human neural stem cells (hNSC) knocked-down (KD) for PQBP1. This led to the identification of a hundred dysregulated genes. In particular, we identified an increase in the expression of a non-canonical isoform of another XLID gene, UPF3B. UPF3B plays a crucial role during neurodevelopment by coding for an important actor of the nonsense mRNA mediated decay (NMD) system involved in regulation of protein translation, however, the exact function of the non-canonical isoform,UPF3B_S, is currently unknown. In order to investigate the role of UPF3B_S isoform, we compared the protein interactome of UPF3B_S to the canonical isoform (UPF3B_L). We confirmed that, on the contrary to UPF3B_L, UPF3B_S does not interact with the UPF2/UPF1 complex while it still interacts with exon junction complexes (EJC). However, no notable decrease of NMD pathways was observed in patient’s LCL or in hNSC KD for PQBP1. We identified several additional protein interactors specific to UPF3B_S. Moreover, we used the increase of UPF3B_S mRNA as a molecular marker to test the pathogenicity of variants of unknown clinical significance identified in individuals with ID in PQPB1. We analyzed patients’ LCL mRNA as well as blood mRNA samples and performed complementation studies in HeLa cells by overexpressing Wild-type and mutant PQBP1 cDNA. We showed that all these three approaches were efficient to test the effect of variants, at least for variants affecting the CTD domain of the protein. In conclusion, our study provides information on how PQBP1 deficiency may affect the expression of genes and isoforms, such as UPF3B. This informs about the pathological mechanisms involved in Renpenning syndrome but also allows to propose a functional test for variants of unknown significance identified in PQBP1.
HAPLN1 is a driver for peritoneal carcinomatosis in pancreatic cancer
Authors: Wiedmann Lena , De Angelis Rigotti Francesca , Vaquero-Siguero Nuria , Donato Elisa , Espinet Elisa , Moll Iris , Alsina-Sanchis Elisenda , Mülfarth Ronja , Vacca Margherita , Gerwing Jennifer , Trumpp Andreas , Fischer Andreas , Rodriguez-Vita Juan
Published: May 2022

Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes into the peritoneum, which contributes to poor prognosis. Metastatic spreading is promoted by cancer cell plasticity, yet its regulation by the microenvironment is incompletely understood. Here we show that the presence of hyaluronan and proteoglycan link protein-1 (HAPLN1) in the extracellular matrix enhances tumor cell plasticity and PDAC metastasis. Bioinformatic analysis showed that HAPLN1 expression is enriched in the basal PDAC subtype and associated with worse overall patient survival. In a mouse model for peritoneal carcinomatosis, HAPLN1-induced immunomodulation favored a more permissive microenvironment, which accelerated the peritoneal spread of tumor cells. Mechanistically, HAPLN1, via hyaluronic acid synthesis and signaling, promoted adoption of a highly plastic cancer cell state, facilitating EMT, stemness, invasion and immunomodulation in a paracrine manner. Extracellular HAPLN1 modifies cancer cells as well as fibroblasts, rendering them immunomodulatory. We identify HAPLN1 as a prognostic marker and a driver for peritoneal metastasis in PDAC.
Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity
Authors: Lei Yuanjiu , VanPortfliet Jordyn J. , Chen Yi-Fan , Bryant Joshua D. , Li Ying , Fails Danielle , Torres-Odio Sylvia , Ragan Katherine B. , Deng Jingti , Mohan Armaan , Wang Bing , Brahms Olivia N. , Yates Shawn D. , Spencer Michael , Tong Carl W. , Bosenberg Marcus W. , West Laura Ciaccia , Shadel Gerald S. , Shutt Timothy E. , Upton Jason W. , Li Pingwei , West A. Phillip
Published: May 2022

Mitochondrial DNA (mtDNA) is a potent agonist of the innate immune system; however, the exact immunostimulatory features of mtDNA and the kinetics of mtDNA detection by cytosolic nucleic acid sensors remain poorly defined. Here, we show that mitochondrial genome instability leads to Z-form mtDNA accumulation. Z-DNA Binding Protein 1 (ZBP1) stabilizes Z-form mtDNA and nucleates a cytosolic complex containing cGAS, RIPK1, and RIPK3 to sustain STAT1 phosphorylation and type I interferon (IFN-I) signaling. Increased mitochondrial Z-DNA, ZBP1 expression, and IFN-I responses are observed in cardiomyocytes after exposure to Doxorubicin, a first-line chemotherapeutic agent that induces frequent cardiotoxicity in cancer patients. Strikingly, mice lacking ZBP1 or IFN-I signaling are protected from Doxorubicin-induced cardiotoxicity. Our findings reveal ZBP1 as a cooperative partner for cGAS that sustains IFN-I responses to mitochondrial genome instability and highlight ZBP1 as a potential target in heart failure and other disorders where mtDNA stress contributes to interferon-related pathology.
Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities
Authors: Zhang Yuxiang , Remillard David , Onubogu Ugoma , Karakyriakou Barbara , Asiaban Joshua N. , Ramos Anissa R. , Bowland Kirsten , Bishop Timothy R. , Ott Christopher J. , Janiszewska Michalina , Cravatt Benjamin F. , Erb Michael A.
Published: May 2022

Histone deacetylases (HDACs) have been widely pursued as targets for anti-cancer therapeutics. However, many of these targets are universally essential for cell survival, which may limit the therapeutic window that can be achieved by drug candidates. By examining large collections of CRISPR/Cas9-based essentiality screens, we discovered a genetic interaction between HDAC1 and HDAC2 wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal translocations that occur in diverse solid and hematological malignancies, including neuroblastoma and multiple myeloma. Using genetic deletion or dTAG-mediated degradation, we show that HDAC2 disruption suppresses the growth of HDAC1-deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the degradation of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2/NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Furthermore, we reveal that several of the degraded NuRD complex subunits are dependencies in neuroblastoma and multiple myeloma, providing motivation to develop paralog-selective HDAC1 or HDAC2 degraders. Altogether, we identify HDAC1/2 collateral synthetic lethality as a new therapeutic target and reveal a novel mechanism for exploiting NuRD-associated cancer dependencies.
Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing
Authors: Kessler Nina , Viehmann Susanne F. , Krollmann Calvin , Mai Karola , Kirschner Katharina Maria , Luksch Hella , Kotagiri Prasanti , Böhner Alexander M.C. , Huugen Dennis , de Oliveira Mann Carina C. , Otten Simon , Weiss Stefanie A. I. , Zillinger Thomas , Dobrikova Kristiyana , Jenne Dieter E. , Ablasser Andrea , Bartok Eva , Hartmann Gunther , Hopfner Karl-Peter , Lyons Paul A. , Boor Peter , Rösen-Wolff Angela , Teichmann Lino , Heeringa Peter , Kurts Christian , Garbi Natalio
Published: May 2022

Autoimmune vasculitis is a group of life-threatening diseases, whose underlying pathogenic mechanisms are incompletely understood, hampering development of targeted therapies. Here, we demonstrate that patients suffering from anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) showed increased activity of the DNA sensor cGAS and enhanced IFN-I signature. To identify potential therapeutic targets, we developed a mouse model for pulmonary AAV that mimics severe disease in patients. Immunogenic DNA accumulated during disease onset, triggering cGAS/STING/IRF3-dependent IFN-I release that promoted endothelial damage, pulmonary hemorrhages, and lung dysfunction. Macrophage subsets played dichotomic roles in disease. While recruited monocyte-derived macrophages were major disease drivers by producing most IFN-β, resident alveolar macrophages contributed to tissue homeostasis by clearing red blood cells and limiting infiltration of IFN-β-producing macrophages. Moreover, pharmacological inhibition of STING, IFNAR-I or its downstream JAK/STAT signaling reduced disease severity and accelerated recovery. Our study unveils the importance of STING/IFN-I axis in promoting pulmonary AAV progression and identifies cellular and molecular targets to ameliorate disease outcome.

Graphical abstract

Kessler et al. identify aberrant DNA recognition by cGAS/STING axis and IFN-I production by inflammatory macrophages as a major driver of severe ANCA-associated vasculitis (AAV). Pharmacological interventions blocking this pathway ameliorate disease and accelerate recovery, identifying potential targets for therapeutic intervention in patients.
T Cell-to-Stroma Enrichment (TSE) score: a gene expression metric that predicts response to immune checkpoint inhibitors in patients with urothelial cancer
Authors: Rijnders Maud , Alberto Nakauma-González J. , Robbrecht Debbie G.J. , Gil-Jimenez Alberto , Balcioglu Hayri E. , Oostvogels Astrid A.M. , Aarts Maureen J.B. , Boormans Joost L. , Hamberg Paul , van der Heijden Michiel S. , Szabados Bernadett E. , van Leenders Geert J.L.H. , Mehra Niven , Voortman Jens , Westgeest Hans M. , de Wit Ronald , van der Veldt Astrid A.M. , Debets Reno , Lolkema Martijn P.
Published: May 2022

Immune checkpoint inhibitors (ICIs) improve overall survival in patients with metastatic urothelial cancer (mUC). To identify predictive markers of response, whole-genome DNA (n=70) and RNA-sequencing (n=41) were performed using fresh metastatic biopsies prior to treatment with pembrolizumab. PD-L1 combined positivity score did not, whereas tumor mutational burden and APOBEC mutagenesis modestly predicted response. Using gene expression analysis, we defined the T cell-to-stroma enrichment (TSE) score, a signature-based metric that captures the relative abundance of T cells and stromal cells. Patients with a positive and negative TSE score show progression-free survival rates at 6 months of 67 and 0%, respectively. The TSE score was captured by immunofluorescence in tumor tissue, and validated in two independent ICI-treated cohorts of patients with mUC (IMvigor210) and muscle-invasive UC (ABACUS). In conclusion, the TSE score represents a clinically applicable marker that potentially aids in prospectively selecting patients with mUC for ICI treatment.
Chromatin remodeler Chd7 regulates photoreceptor development and outer segment length
Authors: Krueger Laura A. , Bills Jessica D. , Lim Zun Yi , Skidmore Jennifer M. , Martin Donna M. , Morris Ann C.
Published: May 2022

Mutations in the chromatin remodeling factor CHD7 are the predominant cause of CHARGE syndrome, a congenital disorder that frequently includes ocular coloboma. Although CHD7 is known to be required for proper ocular morphogenesis, its role in retinal development has not been thoroughly investigated. Given that individuals with CHARGE syndrome can experience visual impairment even in the absence of coloboma, a better understanding of CHD7 function in the retina is needed. In this study, we characterized the expression pattern of Chd7 in the developing zebrafish and mouse retina and documented ocular and retinal phenotypes in Chd7 loss-of-function mutants. Zebrafish Chd7 was expressed throughout the retinal neuroepithelium when retinal progenitor cells were actively proliferating, and later in subsets of newly post-mitotic retinal cells. At stages of retinal development when most retinal cell types had terminally differentiated, Chd7 expression remained strong in the ganglion cell layer and in some cells in the inner nuclear layer. Intriguingly, strong expression of Chd7 was also observed in the outer nuclear layer where it was co-expressed with markers of post-mitotic cone and rod photoreceptors. Expression of mouse CHD7 displayed a similar pattern, including expression in the ganglion cells, subsets of inner nuclear layer cells, and in the distal outer nuclear layer as late as P15. Two different mutant chd7 zebrafish lines were characterized for ocular and retinal defects. These mutants displayed microphthalmia, reduced numbers of cone photoreceptors, and truncated rod and cone photoreceptor outer segments. Reduced cone photoreceptor number and abnormal outer segments were also observed in heterozygous Chd7 mutant mice. Taken together, our results in zebrafish and mouse reveal a conserved, previously undescribed role for Chd7 in retinal development and photoreceptor outer segment morphogenesis. Moreover, our work suggests an avenue of future investigation into the pathogenesis of visual system defects in CHARGE syndrome.

Highlights

Chd7 is expressed in both retinal progenitor cells and in differentiated retinal neurons, including post-mitotic rod and cone photoreceptors.

Loss of Chd7 results in a significant decrease in cone photoreceptors in both zebrafish and mouse.

Cone and rod photoreceptor outer segments are truncated in chd7 mutants, suggesting a heretofore unappreciated role for Chd7 in outer segment morphogenesis.
CRISPR-Cas effector specificity and target mismatches determine phage escape outcomes
Authors: Schelling Michael A. , Nguyen Giang T. , Sashital Dipali G.
Published: May 2022

CRISPR-mediated interference relies on complementarity between a guiding CRISPR RNA (crRNA) and target nucleic acids to provide defense against bacteriophage. Phages escape CRISPR-based immunity mainly through mutations in the PAM and seed regions. However, previous specificity studies of Cas effectors, including the class 2 endonuclease Cas12a, have revealed a high degree of tolerance of single mismatches. The effect of this mismatch tolerance has not been extensively studied in the context of phage defense. Here, we tested defense against lambda phage provided by Cas12a-crRNAs containing pre-existing mismatches against the genomic targets in phage DNA. We observe a correlation between Cas12a mismatch tolerance in vitro and phage defense on solid media. However, in liquid media, we find that most pre-existing crRNA mismatches lead to phage escape and lysis, regardless of whether the mismatches ablate Cas12a cleavage in vitro. We used high-throughput sequencing to examine the target regions of phage genomes following CRISPR challenge. Mismatches at all locations in the target accelerated emergence of mutant phage, including mismatches that greatly slowed cleavage in vitro. Mutations arose near the existing mismatch, in some cases resulting in multiple PAM-distal mismatches allowing for phage escape. Similar experiments with Cas9 showed the location of emergent target mutations was unaffected by pre-existing crRNA-target mismatches. Expression of multiple mismatched crRNAs prevented new mutations from arising in multiple targeted locations, allowing Cas12a mismatch tolerance to provide stronger and longer term protection. These results demonstrate that Cas effector mismatch tolerance and existing target mismatches strongly influence phage evolution.
Mitochondrially targeted proximity biotinylation and proteomic analysis in Plasmodium falciparum
Authors: Lamb Ian M. , Rios Kelly T. , Shukla Anurag , Ahiya Avantika I. , Morrisey Joanne , Mell Joshua C. , Lindner Scott E. , Mather Michael W. , Vaidya Akhil B.
Published: May 2022

Despite ongoing efforts to control malaria infection, progress in lowering the number of deaths and infections appears to have stalled. The continued high incidence of malaria infection and mortality is in part due to emergence of parasites resistant to frontline antimalarials. This highlights the need for continued identification of novel protein drug targets. Mitochondrial functions in Plasmodium falciparum, the deadliest species of human malaria parasite, are targets of validated antimalarials including atovaquone and proguanil (Malarone). Thus, there has been great interest in identifying other essential mitochondrial proteins as candidates for novel drug targets. Garnering an increased understanding of the proteomic landscape inside the P. falciparum mitochondrion will also allow us to learn about the basic biology housed within this unique organelle. We employed a proximity biotinylation technique and mass spectrometry to identify novel P. falciparum proteins putatively targeted to the mitochondrion. We fused the leader sequence of a mitochondrially targeted chaperone, Hsp60, to the promiscuous biotin ligase TurboID. Through these experiments, we generated a list of 122 “putative mitochondrial” proteins. To verify whether these proteins were indeed mitochondrial, we chose five candidate proteins of interest for localization studies using ectopic expression and tagging of each full-length protein. This allowed us to localize four candidate proteins of unknown function to the mitochondrion, three of which have previously been assessed to be essential. We suggest that phenotypic characterization of these and other proteins from this list of 122 could be fruitful in understanding the basic mitochondrial biology of these parasites and aid antimalarial drug discovery efforts.
A map of cis-regulatory modules and constituent transcription factor binding sites in 80% of the mouse genome
Authors: Ni Pengyu , Wilson David , Su Zhengchang
Published: May 2022

Mouse is probably the most important model organism to study mammal biology and human diseases. A better understanding of the mouse genome will help understand the human genome, biology and diseases. However, despite the recent progress, characterization of the regulatory sequences in the mouse genome is still far from complete, limiting its use to understand the regulatory sequences in the human genome. Here, by integrating binding peaks in 9,060 transcription factor (TF) ChIP-seq datasets that cover 79.9% of the mouse mappable genome using an efficient pipeline, we were able to partition these binding peak-covered genome regions into a cis-regulatory module (CRM) candidate (CRMC) set and a non-CRMC sets. The CRMCs contain 912,197 putative CRMs and 38,554,729 TF binding sites (TFBSs) islands, covering 55.5% and 24.4% of the mappable genome, respectively. The CRMCs tend to be under strongly evolutionary constraints, indicating that they are likely cis-regulatory; while the non-CRMCs are largely selectively neutral, indicating that they are unlikely cis-regulatory. Based on evolutionary profiles of the genome positions, we further estimated that 63.8% and 27.4% of the mouse genome might code for CRMs and TFBSs, respectively. Validation using experimental data suggests that at least most of the CRMCs are authentic. Thus, this unprecedentedly comprehensive map of CRMs and TFBSs can be a good resource to guide experimental studies of regulatory genomes in mice and humans.
Comprehensive Comparative Genomic revels:Bacteroides fragilisis a reservoir of antibiotic resistance genes in the gut microbiota
Authors: Evanovich Eliane , de Souza Mendonça Mattos Patricia Jeanne , Guerreiro João Farias
Published: May 2022

Bacteroides fragilisare commensal bacteria of the gut microbiota of mammals and may cause severe infection in a susceptible host. Treatment can be cumbersome if multidrug resistant strains are present in the affected tissue. The principal aim of this study was to provide new insights into the genomic properties ofB. fragilisthrough different approaches in comparative genomics. Results revealed that the pan-genome is opened, and an intense exchange of genetic material reinforces this inference. The Don complex, responsible for extraintestinal adaptation, is present in all strains, suggesting a crucial role forB. fragilisadaptation. CRISPR-Cas system is at 76% of the samples, but it apparently has low accuracy against prophage. Multidrug resistance genes are in 80% of strains. Conjugative transposons and integrative and conjugative elements (ICE) are the main spreaders of genes for antimicrobial resistance. We also reported evidence for horizontal gene transfer (HGT) of antimicrobial resistance genes among theB. fragilisstrains and Bacteriodales. At least 398 genes are under positive selection, including genes for antimicrobial resistance and transport of toxins and nutrients.
Dual Palmitoylation of PRCD, a Photoreceptor-Specific Protein Linked to RP, Alters Protein Stability and Subcellular Localization
Authors: Myers Boyden , Sechrest Emily R. , Hamner Gabrielle , Motipally Sree , Murphy Joseph , Kolandaivelu Saravanan
Published: May 2022

Progressive rod-cone degeneration (PRCD) is a photoreceptor outer segment (POS) disc-specific protein essential for maintaining outer segment (OS) structures, while also contributing to rhodopsin packaging densities and distribution in the disc membranes. Previously, we showed PRCD undergoing palmitoylation at the sole cysteine (Cys2), where a mutation is found linked with retinitis pigmentosa (RP) that is crucial for protein stability and trafficking to POS. PRCD has several predicted structural domains with unknown significance, such as the polybasic region (PBR) where an Arg17Cys (R17C) mutation is linked with RP. In this study, we demonstrate that a mutation in the PBR augments additional palmitoyl lipid modification observed through acyl-RAC in the mutant cysteine (R17C). Immunolocalization of transiently expressed R17C protein in hRPE1 cells depicts similar characteristics to wild type (WT); however, a double mutant lacking endogenous palmitoylation at the Cys2 position is comparable to the C2Y protein as both are likely aggregated and mislocalized in the mitochondria. Subretinal injection of C2Y, R17C, and R17C/C2Y mutants followed by electroporation in murine retina exhibit mislocalization in the inner segment compared to WT PRCD. Our results in the R17C mutant show palmitoylation transpires at two different locations. Despite being dually palmitoylated and demonstrating membrane association, the mutation in the PBR affects protein stability and trafficking to the OS. Moreover, palmitoylation within the PBR alone does not compensate for protein stability or trafficking, revealing the PBR domain is indispensable and any defects likely lead to dysregulation of PRCD protein associated with blinding diseases.
Conserved transcriptional programming across sex and species after peripheral nerve injury predicts treatments for neuropathic pain
Authors: Ghazisaeidi Shahrzad , Muley Milind M. , Tu YuShan , Kolahdouzan Mahshad , Sengar Ameet S. , Ramani Arun K. , Brudno Michael , Salter Michael W.
Published: May 2022

Chronic pain is a devastating problem affecting 1 in 5 individuals around the globe, with neuropathic pain the most debilitating and poorly treated type of chronic pain. Advances in transcriptomics and data mining have contributed to cataloging diverse cellular pathways and transcriptomic alterations in response to peripheral nerve injury but have focused on phenomenology and classifying transcriptomic responses. Here, with the goal of identifying new types of pain-relieving agents, we compared transcriptional reprogramming changes in the dorsal spinal cord after peripheral nerve injury cross-sex and cross-species and imputed commonalities, as well as differences in cellular pathways and gene regulation. We identified 93 transcripts in the dorsal horn that were increased by peripheral nerve injury in male and female mice and rats. Following gene ontology and transcription factor analyses, we constructed a pain interactome for the proteins encoded by the differentially expressed genes, discovering new, conserved signaling nodes. We interrogated the interactome with the Drug-Gene database to predict FDA-approved medications that may modulate key nodes within the network. The top hit from the analysis was fostamatinib, the molecular target of which is the non-receptor tyrosine kinase Syk, which our analysis had identified as a key node in the interactome. We found that intrathecally administrating the active metabolite of fostamatinib, R406, significantly reversed pain hypersensitivity in both sexes. Thus, we have identified and shown the efficacy of an agent that could not have been previously predicted to have analgesic properties.

One sentence summary

Unbiased approach to predicting safe therapies for neuropathic pain
Gene expression and RNA splicing explain large proportions of the heritability for complex traits in cattle
Authors: Xiang Ruidong , Fang Lingzhao , Liu Shuli , Macleod Iona M. , Liu Zhiqian , Breen Edmond J. , Gao Yahui , Liu George E. , Tenesa Albert ,   CattleGTEx Consortium, Mason Brett A , Chamberlain Amanda J. , Wray Naomi R. , Goddard Michael E.
Published: May 2022

Many quantitative trait loci (QTL) are located in non-coding genomic regions. Therefore, QTL are assumed to affect gene regulation. Gene expression and RNA splicing are primary steps of transcription so QTL changing gene expression (eQTL) or RNA splicing (sQTL) are expected to significantly contribute to phenotypic variations. Here, we quantify the contribution of eQTL and sQTL detected from 16 tissues (N~5,000) to 37 complex traits of ~120k cattle. Using Bayesian methods, we show that including more regulatory variants in the model explains larger proportions of heritability. Across traits, cis and trans eQTL and sQTL detected from 16 tissues jointly explain ~70% (SE=0.5%) of heritability, 44% more than expected from the same number of random variants, where trans e/sQTL contribute 24% (14% more than expected). Multi-tissue cis and trans e/sQTL also explain 71% (SE=0.3%) of heritability for the metabolome, demonstrating the essential role of proximal and distal regulatory variants in shaping mammalian phenotypes.
DrDimont: Explainable drug response prediction from differential analysis of multi-omics networks
Authors: Hiort Pauline , Hugo Julian , Zeinert Justus , Müller Nataniel , Kashyap Spoorthi , Rajapakse Jagath C. , Azuaje Francisco , Renard Bernhard Y. , Baum Katharina
Published: May 2022

Motivation

While it has been well established that drugs affect and help patients differently, personalized drug response predictions remain challenging. Solutions based on single omics measurements have been proposed, and networks provide means to incorporate molecular interactions into reasoning. However, how to integrate the wealth of information contained in multiple omics layers still poses a complex problem.

Results

We present DrDimont, Drug response prediction from Differential analysis of multi-omics networks. It allows for comparative conclusions between two conditions and translates them into differential drug response predictions. DrDimont focuses on molecular interactions. It establishes condition-specific networks from correlation within an omics layer that are then reduced and combined into heterogeneous, multi-omics molecular networks. A novel semi-local, path-based integration step ensures integrative conclusions. Differential predictions are derived from comparing the condition-specific integrated networks. DrDimont’s predictions are explainable, i.e., molecular differences that are the source of high differential drug scores can be retrieved. We predict differential drug response in breast cancer using transcriptomics, proteomics, phosphosite, and metabolomics measurements and contrast estrogen receptor positive and receptor negative patients. DrDimont performs better than drug prediction based on differential protein expression or PageRank when evaluating it on ground truth data from cancer cell lines. We find proteomic and phosphosite layers to carry most information for distinguishing drug response.

Availability

DrDimont is available on CRAN: https://cran.r-project.org/package=DrDimont.

Contact

katharina.baum@hpi.de
Within-individual changes reveal increasing social selectivity with age in rhesus macaques
Authors: Siracusa Erin R. , Negron-Del Valle Josué E. , Phillips Daniel , Platt Michael L. , Higham James P. , Snyder-Mackler Noah , Brent Lauren J. N.
Published: May 2022

Accumulating evidence in humans and other mammals suggests older individuals tend to have smaller social networks. Uncovering the cause of these declines is important as it can inform how changes in social relationships with age might affect health and fitness in later life. Smaller social networks might be detrimental, but may also be the result of greater selectivity in partner choice, reflecting an adaptive solution to physical or physiological limitations imposed by age. While greater selectivity with age has been shown in humans, the extent to which active ‘social selectivity’ within an individual’s lifetime occurs across the animal kingdom remains an open question. Using 8 years of longitudinal data from a population of free-ranging rhesus macaques we provide the first evidence in a non-human animal for within-individual increases in social selectivity with age. Going beyond previous cross-sectional studies, our within-individual analyses revealed that adult female macaques actively reduced the size of their networks as they aged and focused on partners previously linked to fitness benefits, including kin and partners to whom they were strongly and consistently connected earlier in life. Females spent similar amounts of time socializing as they aged, suggesting that network shrinkage does not result from lack of motivation or ability to engage. Furthermore, females remained attractive companions and were not isolated by withdrawal of social partners. Taken together, our results provide rare empirical evidence for social selectivity in non-humans, suggesting patterns of social aging in humans may be deeply rooted in primate evolution and may have adaptive value.

Significance statement

The narrowing of social networks and prioritization of meaningful relationships with age is commonly observed in humans. Determining whether social selectivity is exhibited by other animals remains critical to furthering our understanding of the evolution of late-life changes in sociality. Here we test key predictions from the social selectivity hypothesis and demonstrate that female rhesus macaques show within-individual changes in sociality with age that resemble the human social aging phenotype. Our use of longitudinal data to track how individuals change their social behavior within their lifetimes offers the most conclusive evidence to date that social selectivity is not a phenomenon unique to humans and therefore might have deeper evolutionary underpinnings.
Multiomic deep delve of synthesis and secretion processes in a model peptidergic system
Authors: Bárez-López Soledad , Mecawi André S. , Bryan Natasha , Gillard Benjamin T. , Pauza Audrys G. , Murphy David , Greenwood Michael P.
Published: May 2022

The cell bodies of hypothalamic magnocellular neurones are densely packed in the hypothalamic supraoptic nucleus (SON) whereas their axons project to the anatomically discrete posterior pituitary gland. We have taken advantage of this unique anatomical structure to establish proteome and phosphoproteome dynamics in neuronal cell bodies and axonal terminals in response to physiological stimulation. We have found that proteome and phosphoproteome responses are very different between somatic and axonal neuronal compartments, indicating the need of each cell domain to differentially adapt. In particular, changes in the phosphoproteome in the cell body are involved in the reorganisation of the cytoskeleton and in axonal terminals the regulation of synaptic and secretory processes. We have identified that prohormone precursors including vasopressin and oxytocin are phosphorylated in axonal terminals and become hyperphosphorylated following stimulation. By multi-omic integration of transcriptome and proteomic data we identify changes to proteins present in afferent inputs to this nucleus.

Graphical abstract
Spontaneous Variations in Arousal Modulate Subsequent Visual Processing and Local Field Potential Dynamics in the Ferret during Quiet Wakefulness
Authors: Klaver Lianne M.F. , Brinkhof Lotte P. , Sikkens Tom , Casado-Román Lorena , Williams Alex G. , van Mourik-Donga Laura , Mejías Jorge F. , Pennartz Cyriel M.A. , Bosman Conrado A.
Published: May 2022

Behavioral states affect neuronal responses throughout the cortex and influence visual processing. Quiet wakefulness (QW) is a behavioral state during which subjects are quiescent, but awake and connected to the environment. Here, we examined the effects of pre-stimulus arousal variability on post-stimulus neural activity in primary visual cortex (V1) and posterior parietal cortex (PPc) in awake ferrets, using the pupil diameter as an indicator of arousal. We observed that during low arousal, low- frequency power increases during visual stimulation, and that the peak alpha frequency shifted depending on the arousal state. High arousal increased gamma power as well as low-frequency inter- and intra-areal coherence. Using a simplified model of laminar circuits, we show that this connectivity pattern is compatible with feedback signals targeting infragranular layers in area PPc and supragranular layers in V1. Neurons in V1 displayed higher firing rates at their preferred orientations on high-arousal trials. Broad-spiking cells in V1 entrained to high-frequency oscillations (>80 Hz), whereas narrow-spiking neurons phase-locked to low (12-18 Hz) and high-frequency (>80 Hz) rhythms. These results indicate that the variability and sensitivity of post-stimulus cortical responses and coherence depend on the pre-stimulus behavioral state and account for the neuronal response variability observed during repeated stimulation.
Probabilistic fatigue life prediction of an aero-engine turbine shaft
Authors: Wu Jun , Huang Hong-Zhong , Li Yan-Feng , Bai Song , Yu Ao-Di
Published: May 2022

Purpose

Aero-engine components endure combined high and low cycle fatigue (CCF) loading during service, which has attracted more research attention in recent years. This study aims to construct a new framework for the prediction of probabilistic fatigue life and reliability evaluation of an aero-engine turbine shaft under CCF loading if considering the material uncertainty.

Design/methodology/approach

To study the CCF failure of the aero-engine turbine shaft, a CCF test is carried out. An improved damage accumulation model is first introduced to predict the CCF life and present high prediction accuracy in the CCF loading situation based on the test. Then, the probabilistic fatigue life of the turbine shaft is predicted based on the finite element analysis and Monte Carlo analysis, where the material uncertainty is taken into account. At last, the reliability evaluation of the turbine shaft is conducted by stress-strength interference models based on an improved damage accumulation model.

Findings

The results indicate that predictions agree well with the tested data. The improved damage accumulation model can accurately predict the CCF life because of interaction damage between low cycle fatigue loading and high cycle fatigue loading. As a result, a framework is available for accurate probabilistic fatigue life prediction and reliability evaluation.

Practical implications

The proposed framework and the presented testing in this study show high efficiency on probabilistic CCF fatigue life prediction and can provide technical support for fatigue optimization of the turbine shaft.

Originality/value

The novelty of this work is that CCF loading and material uncertainty are considered in probabilistic fatigue life prediction.
Effect of varied spray drying parameters on physicochemical, micrometric and microstructural characteristics of pear powder employing response surface approach
Authors: Gani Gousia , Naik Haroon , Amin Tawheed , Jan Nusrat , Hussain Syed Zameer , Bashir Omar , Jabeen Abida
Published: May 2022

Purpose

Currently, there is a great demand for those food products that are easy to prepare or ready for direct consumption. Making pear fruit/juice available round the year is desirous owing to pears' high-nutritional value and specific pleasant taste. Pear is, however, a seasonal fruit and under ambient conditions has a limited shelf life rendering it available as fresh fruit for a specific period.

Design/methodology/approach

The study aimed to optimize the spray drying process parameters using response surface methodology for the development of pear juice powder. The process variables included the inlet air temperature of 140–210°C, maltodextrin levels of 4–25%, atomization speed of 11,400–28,000 rpm, feed flow rate of 180–630 mL/hr, and feed total soluble solids (TSS) of 13–30°Brix. The dependent responses were powder yield, solubility, antioxidant activity {% 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging capacity}, dispersibility, hygroscopicity and particle density.

Findings

Among independent variables, inlet air temperature showed a predominant effect. The optimum processing conditions for the development of pear juice powder with optimum quality were 163.02°C inlet air temperature, 13.50% maltodextrin, 28,000 rpm atomization speed, 390.94 mL/h feed flow rate, and 25.5°Brix feed TSS. Under these optimum conditions, pear powder with desirable properties could be produced. The experimental and predicted values were found to be in agreement, indicating the suitability of the model in predicting optimizing responses of pear powder. Glass transition temperature of pear powder was found to be 36.60 ± 0.40°C, which is much higher than that of ambient temperature, suggesting better shelf stability.

Originality/value

The processing of pear fruit has resulted in the increased demand for pear juice powder in both domestic and international markets as a primer of new food products. The optimum conditions obtained in the current study could provide a new insight to the food industry in developing spray-dried pear powder of optimum quality. This can open up a new horizon in the field of food industry for the common masses of Jammu and Kashmir, India.
Applications of Industry 4.0 digital technologies towards a construction circular economy: gap analysis and conceptual framework
Authors: Elghaish Faris , Matarneh Sandra T. , Edwards David John , Pour Rahimian Farzad , El-Gohary Hatem , Ejohwomu Obuks
Published: May 2022

Purpose

This paper aims to explore the emerging relationship between Industry 4.0 (I4.0) digital technologies (e.g. blockchain, Internet of Things (IoT) and artificial intelligence (AI)) and the construction industry’s gradual transition into a circular economy (CE) system to foster the adoption of circular economy in the construction industry.

Design/methodology/approach

A critical and thematic analysis conducted on 115 scientific papers reveals a noticeable growth in adopting digital technologies to leverage a CE system. Moreover, a conceptual framework is developed to show the interrelationship between different I4.0 technologies to foster the implantation of CE in the construction industry.

Findings

Most of the existing bodies of research provide conceptual solutions rather than developing workable applications and the future of smart cities. Moreover, the coalescence of different technologies is highly recommended to enable tracking of building assets’ and components’ (e.g. fixtures and fittings and structural components) performance, which enables users to optimize the salvage value of components reusing or recycling them just in time and extending assets’ operating lifetime. Finally, circular supply chain management must be adopted for both new and existing buildings to realise the industry's CE ambitions. Hence, further applied research is required to foster CE adoption for existing cities and infrastructure that connects them.

Originality/value

This paper investigates the interrelationships between most emerging digital technologies and circular economy and concludes with the development of a conceptual digital ecosystem to integrate IoT, blockchain and AI into the operation of assets to direct future practical research applications
Assessment framework for workforce agility in higher education institutions
Authors: Menon Shalini , Suresh M.
Published: May 2022

Purpose

The higher education sector has been lately facing new challenges. The ease and speed with which the workforce adapts to these changes determine their agility level. This study attempts to develop a conceptual model to measure workforce agility in higher education.

Design/methodology/approach

An extensive literature review revealed limited research on workforce agility assessment. This study addresses the research gap by developing a workforce agility assessment framework and testing the model in a higher education institution (HEI). The study applied the fuzzy logic method for the assessment.

Findings

The computed value of the fuzzy-workforce agility index (3.72, 5.27, 6.86) indicates that the HEI chosen for the assessment is Agile. The fuzzy performance importance index helped identify the six-weak attributes that require immediate attention and improvement.

Practical implications

The proposed framework would help the institution's management understand the current agility level of their workforce and take corrective actions to improve the identified weak attributes.

Originality/value

The study has contributed to the literature of workforce agility assessment by creating a conceptual model for evaluating workforce agility in higher education. This model can be applied to any HEI.