bluuebunny/crossref_metadata_2025 huggingface dataset:
Two Muscle-Specific and Direct Transcriptional Targets of DAF-16/FOXO Activated by Reduced Insulin/IGF-1 Signaling
Authors: Wu Shifei , Li Yan , Roy Charline , Wang Ying , Mulcahy Ben , Li William , Calarco John , Hung Wesley , Zhen Mei
Published: December 2022

C. elegansinsulin/insulin-like growth factor 1 signaling (IIS) affects diverse physiological processes through the DAF-16/FOXO transcription factor. Despite its presence in all somatic cells, DAF-16’s physiological effects, such as modulation of dauer formation, synapse maturation, axon regeneration, and adult longevity, exhibit prevalent tissue-specificity as well as tissue crosstalk. This implies that tissue-specific DAF-16 transcriptional programs contribute to the functional diversity of IIS. To further examine this possibility, we sought to identify tissue-specific and direct transcriptional targets of DAF-16 in muscle cells. Following FACS-sorting to enrich mature muscle cells from young adult animals, we compared the muscle transcriptomes under high and low IIS states, with and without DAF-16. We further analyzed and compared the DAF-16 docking sites in muscle and intestine cells from published datasets. These analyses revealed 14 potential muscle-specific DAF-16 transcriptional targets, among which we validated two that are strongly and specifically activated by DAF-16 in muscles: a secreted protein C54F6.5 and a calcium-binding protein CEX-1/Calexcitin. Both genes exhibit DAF-16-independent non-muscle expression, explaining their low rank or absence from the current DAF-16 target lists generated by multiple independent whole-animal microarray or mRNA-sequencing analyses. These results support the notion of tissue-specific DAF-16 transcriptional programs and highlight the importance of verifying FOXO targets in a cell-type-specific manner.
Inhibiting POLQ-mediated alternative NHEJ enhances CRISPR/Cas9 mediated precise genome editing in CHO cells
Authors: Wang Chuanjie , Wang Ming , Zhang Mengmeng , Wang Yao , Li Xinying , Liu Chenghua , Fan Rongrong , Zheng Yuanqiang , Shen Beifen , Sun Zhaolin , Wang Jing , Feng Jiannan
Published: December 2022

CRISPR/Cas9 mediated precise gene editing requires homology-directed repair (HDR), which occurs less frequently than non-homologous end-joining (NHEJ) including the canonical NHEJ and alternative NHEJ (Alt-EJ) in mammalian cells, especially in CHO cells that inherent resist HDR. To solve the above hurdle, here we for the first time show that knockout the DNA polymerase θ (POLθ), which is essential for Alt-EJ, significantly increases the knock-in efficiency by nearly forty-fold in CHO cells via eGFP reporter system and does not affect the normal growth and proliferation of cells. Meanwhile, even when transfecting simple circular, without negative element homologous template DNA donor and CRISPR/Cas9 plasmid to two different genomic sites, the knock-in rate of 4kb donor integration can still reach a mean of over 80% (29/36) and 2.7% (1/36) of the selected cell colonies inPOLQ-/-CHO cells, however, no positive knock-in cell colonies was obtained in wild-type CHO cells which respectively selected 62 cell colonies and 36 cell colonies. Furthermore, we show thatPOLQpromotes random integration in CHO cells. Finally, RNA-sequence analysis reveals not significant altered DNA repair, metabolism, apoptosis, and cell cycle inPOLQ-/-cells. These findings open a new target genePOLQto overcome bottlenecks of the precision genome editing.
Evaluation of the Efficacy of the Hypocretin/orexin Receptor Agonists TAK-925 and ARN-776 in NarcolepticOrexin/tTA; TetO-DTAMice
Authors: Sun Yu , Ranjan Alok , Tisdale Ryan , Ma Shun-Chieh , Park Sunmee , Haire Meghan , Heu Jasmine , Morairty Stephen R. , Wang Xiaoyu , Rosenbaum Daniel M. , Williams Noelle S. , De Brabander Jef K. , Kilduff Thomas S.
Published: December 2022

The sleep disorder Narcolepsy, a hypocretin deficiency disorder thought to be due to degeneration of hypothalamic hypocretin/orexin neurons, is currently treated symptomatically. We evaluated the efficacy of two small molecule hypocretin/orexin receptor-2 (HCRTR2) agonists in narcoleptic maleorexin/tTA; TetO-DTAmice. TAK- 925 (1-10 mg/kg, s.c.) and ARN-776 (1-10 mg/kg, i.p.) were injected 15 min before dark onset in a repeated measures design. EEG, EMG, subcutaneous temperature (Tsc) and activity were recorded by telemetry; recordings for the first 6-h of the dark period were scored for sleep/wake and cataplexy. At all doses tested, TAK-925 and ARN-776 caused continuous wakefulness and eliminated sleep for the first hour. Both TAK-925 and ARN-776 caused dose-related delays in NREM sleep onset. All doses of TAK-925 and all but the lowest dose of ARN-776 eliminated cataplexy during the first hour after treatment; the anti-cataplectic effect of TAK-925 persisted into the 2ndhour for the highest dose. TAK-925 and ARN-776 also reduced the cumulative amount of cataplexy during the 6-h post-dosing period. The acute increase in wakefulness produced by both HCRTR2 agonists was characterized by increased spectral power in the gamma EEG band. Although neither compound provoked a NREM sleep rebound, both compounds affected NREM EEG during the 2ndhour post-dosing. TAK-925 and ARN-776 also increased gross motor activity, running wheel activity and Tsc, suggesting that the wake-promoting and sleep-suppressing activities of these compounds could be a consequence of hyperactivity. Nonetheless, the anti-cataplectic activity of TAK-925 and ARN-776 is encouraging for the development of HcrtR2 agonists.
FGF2 and BMP4 influence on FGFR2 dynamics during the segregation of epiblast and primitive endoderm cells in the pre-implantation mouse embryo
Authors: Goissis Marcelo D. , Bradshaw Brian , Posfai Eszter , Rossant Janet
Published: December 2022

Specification of the epiblast (EPI) and primitive endoderm (PE) in the mouse embryo involves FGF signaling through the RAS/MAP kinase pathway. FGFR1 and FGFR2 are thought to mediate this signaling in the inner cell mass (ICM) of the mouse blastocyst. In this study, we verified the dynamics of FGFR2 expression through a green fluorescent protein reporter mouse line (FGFR2-eGFP). We observed that FGFR2-eGFP is present in the late 8-cell stage; however, it is absent or reduced in the ICM of early blastocysts. We then correlated GFP expression with GATA6 and NANOG after immunostaining. We detected that GFP is weakly correlated with GATA6 in early blastocysts, but this correlation quickly increases as the blastocyst develops. The correlation between GFP and NANOG decreases throughout blastocyst development. Treatment with FGF from the morula stage onwards did not affect FGFR2-eGFP presence in the ICM of early blastocysts; however, late blastocysts presented FGFR2-eGFP in all cells of the ICM. BMP treatment positively influenced FGFR2-eGFP expression and reduced the number of NANOG-positive cells in late blastocysts. In conclusion, FGFR2 is not strongly associated with PE precursors in the early blastocyst, but it is highly correlated with PE cells as blastocyst development progresses, consistent with the proposed role for FGF in maintenance rather than initiating the PE lineage.
Observation of the dynamic changes in the urinary proteome in rats during immunization
Authors: Wang Yunlong , Gao Youhe
Published: December 2022

Objective

Changes in the immune system in the urine proteome were observed by injecting bovine serum albumin and aluminum hydroxide adjuvant into rats.

Methods

In this study, bovine serum albumin and aluminum hydroxide adjuvant were injected into rat thigh muscle, urine was collected, differential proteins were identified by liquid chromatography—mass spectrometry (LC—MSMS/MS), and biological pathways of differential proteins were analyzed by IPA software to observe the changes in the immune system as evidenced by rat urinary proteins.

Results

Fifteen rats were intramuscularly injected with normal saline, aluminum hydroxide adjuvant, bovine serum albumin, aluminum hydroxide adjuvant, and bovine serum albumin (BSA) mixture to construct the models of the control, adjuvant, BSA, and mixed groups. Upon comparing the different proteins between different groups to obtain the relevant biological pathways, it was found that adjuvants can be observed in urine to help bovine serum albumin stimulate the immune system to respond earlier. It was also observed in urine that the mixed group successively stimulated immune-related pathways, such as the inflammatory response, T-cell activation, antigen-presenting cell-related pathways, and B-cell-related pathways.

Discussion

We can observe changes in the immune system from the urine proteome in the early stage, providing some new clues and a basis for future research on the immune system and accelerating vaccine research and development.
Genetically encoded multimeric tags for intracellular protein localisation in cryo-EM
Authors: Fung Herman KH , Hayashi Yuki , Salo Veijo T , Babenko Anastasiia , Zagoriy Ievgeniia , Brunner Andreas , Ellenberg Jan , Müller Christoph W , Cuylen-Haering Sara , Mahamid Julia
Published: December 2022

Cryo-electron tomography is a powerful label-free tool for visualizing biomolecules in their native cellular context at molecular resolution. However, the precise localisation of biomolecules of interest in the tomographic volumes is challenging. Here, we present a tagging strategy for intracellular protein localisation based on genetically encoded multimeric particles (GEMs). We show the applicability of drug-controlled GEM labelling of endogenous proteins in cryo-electron tomography and cryo-correlative fluorescence imaging in human cells.
Effects of aging on successful object encoding: Enhanced semantic representations compensate for impaired visual representations
Authors: Naspi Loris , Stensholt Charlotte , Karlsson Anna E , Monge Zachary A , Cabeza Roberto
Published: December 2022

Whereas episodic memory and visual processing decline substantially with healthy aging, semantic knowledge is generally spared. There is evidence that older adults can take advantage of their spared semantic knowledge to support their performance in episodic memory and visual tasks. Here, we used fMRI combined with representational similarity analyses (RSA) to examine how visual and semantic representations stored during encoding predict subsequent object memory. Young and older adults encoded images of objects during fMRI scanning and recalled these images while rating the vividness of their memories. After scanning, participants discriminated between studied images and similar lures. RSA based on a deep convolutional neural network and normative concept feature data was used to link patterns of neural activity during encoding to visual and semantic representations. The quality of visual representations was reduced in older adults, consistent with dedifferentiation, whereas the quality of semantic representations was enhanced in older adults, consistent with hyperdifferentiation. Despite dedifferentiation, visual representations stored in early visual cortex predicted later recall with high vividness in both young and older adults, with no age-related differences. In contrast, semantic representations in lingual and fusiform gyrus were associated with better subsequent object picture recall in older but not in young adults. This finding is consistent with evidence that older adults rely on semantic knowledge to compensate for cognitive deficits. Taken together, the results suggest that the age-related neural dedifferentiation for visual information in posterior regions might be partly counteracted by a boost on semantic representations in more anterior areas.

Significance Statement

Previous research has shown that healthy aging tends to impair memory for individual events, visual processing, and other cognitive abilities but not semantic knowledge. We investigated the effects of aging on the quality of the information stored in the brain when viewing common objects and on how this information enables subsequent memory for these objects. Using fMRI combined with modeling of the stimuli, we found that visual information was degraded in older adults, but it was sufficient to support subsequent memory. In contrast, semantic information supported subsequent memory only in older adults. This is the first direct neuroscience evidence that older adults take advantage of spared semantic representations to boost their memory for individual events.
Abstraction of reward context facilitates relative reward coding in neural populations of the anterior cingulate cortex
Authors: Chien Jonathan M. , Wallis Joni D. , Rich Erin L.
Published: December 2022

The anterior cingulate cortex (ACC) is believed to be involved in many cognitive processes, including linking goals to actions and tracking decision-relevant contextual information. ACC neurons robustly encode expected outcomes, but how this relates to putative functions of ACC remains unknown. Here, we approach this question from the perspective of population codes by analyzing neural spiking data in the ventral and dorsal banks of the ACC in monkeys trained to perform a stimulus-motor mapping task. We found that neural populations favor a representational geometry that emphasizes contextual information, while facilitating the independent, abstract representation of multiple task-relevant variables. In addition, trial outcomes were primarily encoded relative to task context, suggesting that the population structures we observe could be a mechanism allowing feedback to be interpreted in a context-dependent manner. Together, our results point to a prominent role for ACC in context-setting and relative interpretation of outcomes, facilitated by abstract, or “untangled,” representations of task variables.

Author Summary

The ability to interpret events in light of the current context is a critical facet of higher-order cognition. The anterior cingulate cortex is suggested to be important for tracking information about current contexts, while alternate views hold that its function is more related to the motor system and linking goals to appropriate motor responses. Here, we evaluated these two possibilities by recording anterior cingulate neurons from monkeys performing a stimulus-motor mapping task in which compound cues both defined the current reward context and instructed appropriate motor responses. By analyzing geometric properties of neural population activity, we found that the ACC prioritized context information, representing it as a dominant, abstract concept. Ensuing trial outcomes were then coded relative to these contexts, suggesting an important role for these representations in context-dependent evaluation. Such mechanisms may be critical for the abstract reasoning and generalization characteristic of biological intelligence.
PYPE: A Python pipeline for phenome-wide association (PheWAS) and mendelian randomization in investigator-driven phenotypes and genotypes of biobank data
Authors: Dalal Taykhoom , Patel Chirag J.
Published: December 2022

Motivation

Phenome-wide association studies (PheWASs) serve as a way of documenting the relationship between genotypes and multiple phenotypes, helping to uncover new and unexplored genotype-phenotype associations (known as pleiotropy). Secondly, Mendelian Randomization (MR) can be harnessed to make causal statements about a pair of phenotypes (e.g., does one phenotype cause the other?) by comparing the genetic architecture of the phenotypes in question. Thus, approaches that automate both PheWAS and MR can enhance biobank scale analyses, circumventing the need for multiple bespoke tools for each task by providing a comprehensive, end-to-end pipeline to drive scientific discovery.

Results

We present PYPE, a Python pipeline for running, visualizing, and interpreting PheWAS. Our pipeline allows the researcher to input genotype or phenotype files from the UK Biobank (UKBB) and automatically estimate associations between the chosen independent variables and the phenotypes. PYPE also provides a variety of visualization options including Manhattan and volcano plots and can be used to identify nearby genes and functional consequences of the significant associations. PYPE additionally provides the user with the ability to run Mendelian Randomization (MR) under a variety of causal effect modeling scenarios (e.g., Inverse Variance Weighted Regression, Egger Regression, and Weighted Median Estimation) to identify possible causal relationships between phenotypes.

Availability and Implementation

PYPE is a free, open-source project developed entirely in Python and can be found athttps://github.com/TaykhoomDalal/pype. PYPE is published under the Apache 2.0 license and supporting documentation can be found at the aforementioned link.

Contact

Chirag_Patel@hms.harvard.edu
Bulk and Mosaic Deletions ofEgfrReveal Regionally Defined Gliogenesis in the Developing Mouse Forebrain
Authors: Zhang Xuying , Xiao Guanxi , Johnson Caroline , Cai Yuheng , Horowitz Zachary K. , Mennicke Christine , Coffey Robert , Haider Mansoor , Threadgill David , Eliscu Rebecca , Oldham Michael C. , Greenbaum Alon , Ghashghaei H. Troy
Published: December 2022

The Epidermal growth factor receptor (EGFR) plays a role in cell proliferation and differentiation during healthy development and tumor growth, however its requirement for brain development remains unclear. Here we used a conditional mouse allele forEgfrto examine its contributions to perinatal forebrain development at the tissue level. Subtractive bulk ventral and dorsal forebrain deletions ofEgfruncovered significant and permanent decreases in oligodendrogenesis and myelination in the cortex and corpus callosum. Additionally, an increase in astrogenesis or reactive astrocytes in effected regions was evident in response to cortical scarring. Sparse deletion using Mosaic Analysis with Double Markers (MADM) surprisingly revealed a regional requirement for EGFR in rostrodorsal, but not ventrocaudal glial lineages including both astrocytes and oligodendrocytes. The EGFR-independent ventral glial progenitors may compensate for the missing EGFR-dependent dorsal glia in the bulkEgfr-deleted forebrain, potentially exposing a regenerative population of gliogenic progenitors in the mouse forebrain.
Spatial omics representation and functional tissue module inference using graph Fourier transform
Authors: Chang Yuzhou , Liu Jixin , Ma Anjun , Jiang Sizun , Krull Jordan , Yeo Yao Yu , Liu Yang , Rodig Scott J. , Barouch Dan H. , Fan Rong , Xu Dong , Nolan Garry , Li Zihai , Liu Bingqiang , Ma Qin
Published: December 2022

Tissue module (TM) is a spatially organized tissue region and executes specialized biological functions, recurring and varying at different tissue sites. However, the computational identification of TMs poses challenges due to their convoluted biological functions, poorly-defined molecular features, and varying spatially organized patterns. Here, we present a hypothesis-free graph Fourier transform model, SpaGFT, to represent spatially organized features using the Fourier coefficients, leading to an accurate representation of spatially variable genes and proteins and the characterization of TM at a fast computational speed. We implemented sequencing-based and imaging-based spatial transcriptomics, spatial-CITE-seq, and spatial proteomics to identify spatially variable genes and proteins, define TM identities, and infer convoluted functions among TMs in mouse brains and human lymph nodes. We collected a human tonsil sample and performed CODEX to accurately demonstrate molecular and cellular variability within the secondary follicle structure. The superior accuracy, scalability, and interpretability of SpaGFT indicate that it is an effective representation of spatially-resolved omics data and an essential tool for bringing new insights into molecular tissue biology.
Regime type and Data Manipulation: Evidence from the COVID-19 Pandemic
Authors: Wigley Simon
Published: December 2022

Autocratic and democratic leaders have an incentive to misreport data that may reveal policy failure. However, it is easier for autocratic leaders to fabricate data because they are not subject to scrutiny from media, opposition parties, and civil society. This suggests that autocratic governments are more likely to manipulate policy-relevant statistics than democratic governments. It is inherently difficult to test that claim because researchers typically do not have access to data from sources other than the government. The COVID-19 pandemic represents a unique opportunity to examine the relationship between regime type and data manipulation because of its widespread impact, as well as the ability to compare reported with excess deaths and test for statistical anomalies in reported data. Based on regressions for undercounting and statistical irregularities that take into account unintentional mismeasurement, I find that autocratic governments are more likely to deliberately under-report the impact of COVID-19 than their democratic counterparts.
Distinct stem-like cell populations facilitate functional regeneration of theCladonemamedusa tentacle
Authors: Fujita Sosuke , Takahashi Mako , Kumano Gaku , Kuranaga Erina , Miura Masayuki , Nakajima Yu-ichiro
Published: December 2022

Blastema formation is a crucial process that provides a cellular source for regenerating tissues and organs. While bilaterians have diversified blastema formation methods, its mechanisms in non-bilaterians remain poorly understood. Cnidarian jellyfish, or medusae, represent early-branching metazoans that exhibit complex morphology and possess defined appendage structures highlighted by tentacles with stinging cells (nematocytes). Here we investigate the mechanisms of tentacle regeneration, using the hydrozoan jellyfishCladonema pacificum. We show that proliferative cells accumulate at the tentacle amputation site and form a blastema composed of cells with stem cell morphology. Lineage tracing experiments indicate that repair-specific proliferative cells in the blastema are distinct from resident stem cells. We further demonstrate that resident stem cells control nematogenesis and tentacle elongation during both homeostasis and regeneration as homeostatic stem cells, while repair-specific proliferative cells preferentially differentiate into epithelial cells in the newly formed tentacle, analogous to lineage-restricted stem/progenitor cells observed in salamander limbs. Taken together, our findings reveal a regeneration mechanism that utilizes both resident homeostatic stem cells and repair-specific proliferative cells, which in conjunction efficiently enable functional appendage regeneration, and provide novel insight into the diversification of blastema formation across animal evolution.
The genetic basis of traits associated with the evolution of serpentine endemism in monkeyflowers
Authors: Toll Katherine , Willis John H.
Published: December 2022

The floras on chemically and physically challenging soils, such as gypsum, shale, and serpentine, are characterized by narrowly endemic species. These edaphic endemics often have widespread close relatives that are not restricted to specific soil types. The evolution of edaphic endemics may be facilitated or constrained by genetic correlations among traits contributing to adaptation and reproductive isolation across soil boundaries. The yellow monkeyflowers in theMimulus guttatusspecies complex are an ideal system in which to examine these evolutionary patterns. To determine the genetic basis of adaptive and prezygotic isolating traits, we performed genetic mapping experiments with F2 hybrids derived from a cross between a serpentine endemic,M. nudatus, and its close relativeM. guttatus. Plants occurring on serpentine soils have repeatedly evolved short statures and small leaves, suggesting that these traits are adaptive, andM. nudatusshows all these characteristics compared toM. guttatus. Previous research demonstrated that flower size and life history differences between these species contribute to prezygotic reproductive isolation between them. Few large effect and many small effect loci contribute to interspecific divergence in life history, floral and leaf traits, and a history of directional selection contributed to trait divergence. Loci contributing to adaptive traits and prezygotic reproductive isolation overlap, and their allelic effects are largely in the direction of species divergence. These loci contain promising candidate genes regulating flowering time and plant organ size. Together our results suggest that genetic correlations among traits facilitated the evolution of edaphic adaptation and speciation in this species pair.
COVID-19 Outbreak Control Strategies and their Impact on the Provision of Essential Health Services in Ghana: An Explanatory-Sequential Study
Authors: Dwomoh Duah , Yeboah Isaac , Ndejjo Rawlance , Kabwama Steven Ndugwa , Aheto Justice Moses , Liu Anne , Lazenby Siobhan , Ohemeng Fidelia , Takyi Sylvia Akpene , Issah Ibrahim , Bawuah Serwaa Akoto , Wanyenze Rhoda K. , Fobil Julius
Published: December 2022

Background

The COVID-19 pandemic has led to substantial interruptions in critical health services, with 90% of countries reporting interruptions in routine vaccinations, maternal health care and chronic disease management. The use of non-pharmaceutical interventions (NPIs) such as lockdowns and self-isolation had implications on the provision of essential health services (EHS). We investigated exemplary COVID-19 outbreak control strategies and explored the extent to which the adoption of these NPIs affected the provision of EHS including immunization coverage and facility-based deliveries. Finally, we document core health system strategies and practices adopted to maintain EHS during the early phase of the pandemic.

Methods

This study used an explanatory sequential study design. First, we utilized data from routine health management information systems to quantify the impact of the pandemic on the provision of EHS using interrupted time series models. Second, we explored exemplary strategies and health system initiatives that were adopted to prevent the spread of COVID-19 infections while maintaining the provision of EHS using in-depth interviews with key informants including policymakers and healthcare providers.

Results

The COVID-19 pandemic and the interventions that were implemented disrupted the provision of EHS. In the first month of the COVID-19 pandemic, Oral Polio and pentavalent vaccination coverage reduced by 15.2% [95% CI = −22.61, −7.87, p<0.001] and 12.4% [95% CI = 17.68, −7.13; p<0.001] respectively. The exemplary strategies adopted in maintaining the provision of EHS while also responding to the spread of infections include the development of new policy guidelines that were disseminated with modified service delivery models, new treatment and prevention guidelines, healthcare workforce capacity building on outbreak control strategies, the use of telemedicine and medical drones to provide EHS and facilitate rapid testing of suspected cases.

Conclusion

The implementation of different NPIs during the peak phase of the pandemic disrupted the provision of EHS. However, the Ministry of Health leveraged the resilient health system and deployed efficient, all-inclusive, and integrated infectious disease management and infection prevention control strategies to maintain the provision of EHS while responding to the spread of infections.
Pholcodine consumption increases the risk of perioperative anaphylaxis to neuromuscular blocking agents: the ALPHO case-control study
Authors: Mertes Paul Michel , Petitpain Nadine , Tacquard Charles , Delpuech Marion , Baumann Cédric , Malinovsky Jean Marc , Longrois Dan , Gouel-Cheron Aurélie , Quang Diane Le , Demoly Pascal , Guéant Jean Louis , Gillet Pierre
Published: December 2022

Background

Neuromuscular blocking agents (NMBAs) are the leading cause of perioperative anaphylaxis (POA), most reactions being IgE mediated. Allergic sensitization induced by environmental exposure to other quaternary ammonium-containing compounds, such as pholcodine, has been suggested. The aim of this study was to assess the relationship between pholcodine exposure and NMBA-related POA.

Methods

ALPHO is a multicentre case-control study, comparing pholcodine exposure within a year before anaesthesia between patients with NMBA-related POA (cases) and control patients with uneventful anaesthesia. Each case was matched to two controls by age, sex, type of NMBA, geographic area, and season. Pholcodine exposure was assessed by a self-administered questionnaire and pharmaceutical history retrieved from pharmacy records. The diagnostic values of anti-pholcodine and anti-quaternary ammonium specific IgE (sIgE) were also evaluated.

Results

Overall, 167 cases were matched with 334 controls. NMBA-related POA was significantly associated with pholcodine consumption (OR =4.2; CI95% 2.3-7.0) and occupational exposure to quaternary ammoniums (OR = 6.1; CI95% 2.7-13.6). Anti-pholcodine and anti-quaternary ammonium sIgEs had a high negative predictive value (99.9%) but a very low positive predictive value (< 3%) for identifying NMBA-related POA.

Conclusion

Patients exposed to pholcodine 12 months prior to NMBA exposure have a significantly higher risk of a NMBA-related POA. The low positive predictive values of pholcodine and quaternary ammonium sIgEs precludes their use to identify a population with a high risk of NMBA-related POA. The strong association of NMBA-related POA with occupational exposure suggests that other environmental factors may also lead to sensitization to NMBAs.
Genomic characterization of respiratory syncytial virus 2022-2023 outbreak in Washington State, USA
Authors: Goya Stephanie , Sereewit Jaydee , Pfalmer Daniel , Nguyen Tien V. , Mohamed Bakhash Shah A. K. , Sobolik Elizabeth B. , Greninger Alexander L.
Published: December 2022

Mitigation measures against the COVID-19 pandemic affected the RSV seasonality and led to an unexpectedly high number of RSV cases in Washington State since October 2022. Here we describe the RSV genomic characteristics and evolutionary relationship of 2022 outbreak compared to the previous RSV outbreaks in the region and globally.
The COVID-19 pandemic and its prolonged impacts on food prices, food consumption and diet quality in sub-Saharan Africa
Authors: Ismail Abbas , Madzorera Isabel , Apraku Edward A. , Tinkasimile Amani , Dasmane Dielbeogo , Zabre Pascal , Ourohire Millogo , Assefa Nega , Chukwu Angela , Workneh Firehiwot , Mapendo Frank , Lankoande Bruno , Hemler Elena , Wang Dongqing , Abubakari Sulemana W. , Asante Kwaku P. , Baernighausen Till , Killewo Japhet , Oduola Ayoade , Sie Ali , Soura Abdramane , Vuai Said , Smith Emily , Berhane Yemane , Fawzi Wafaie W.
Published: December 2022

Background

Sub-Saharan Africa faces prolonged COVID-19 related impacts on economic activity, livelihoods, nutrition, and food security, with recovery slowed down by lagging vaccination progress.

Objective

This study investigated the economic impacts of COVID-19 on food prices, consumption and dietary quality in Burkina Faso, Ethiopia, Ghana, Nigeria, and Tanzania.

Methods

We conducted a repeated cross-sectional study and used a mobile platform to collect data. Data collected from round 1 (July-November, 2020) and round 2 (July-December, 2021) were considered. We assessed participants’ dietary intake of 20 food groups over the previous seven days. The study’s primary outcome was the Prime Diet Quality Score (PDQS), with higher scores indicating better dietary quality. We used linear regression and generalized estimating equations to assess factors associated with diet quality during COVID-19.

Results

Most of the respondents were male and the mean age (±SD) was 42.4 (±12.5) years. Mean PDQS (±SD) was low at 19.1 (±3.8) before COVID-19, 18.6(±3.4) in Round 1, and 19.4(±3.8) in Round 2. A majority of respondents (80%) reported higher than expected prices for all food groups during the pandemic. Secondary education or higher (estimate: 0.73, 95% CI: 0.32, 1.15), older age (estimate: 30-39 years: 0.77, 95% CI: 0.35, 1.19, or 40 years or older: 0.72, 95% CI: 0.30, 1.13), and medium wealth status (estimate: 0.48, 95% CI: 0.14, 0.81) were associated with higher PDQS. Farmers and casual laborers (estimate: -0.60, 95% CI: -1.11, - 0.09), lower crop production (estimate: -0.87, 95% CI: -1.28, -0.46) and not engaged in farming (estimate: -1.38, 95% CI: -1.74, -1.02) associated with lower PDQS.

Conclusion

Diet quality which had declined early in the pandemic had started to improve. However, consumption of healthy diets remained low, and food prices remained high. Efforts should continue to improve diet quality for sustained nutrition recovery through mitigation measures, including social protection.
Live-attenuated pediatric parainfluenza vaccine expressing 6P-stabilized SARS-CoV-2 spike protein is protective against SARS-CoV-2 variants in hamsters
Authors: Liu Xueqiao , Park Hong-Su , Matsuoka Yumiko , Santos Celia , Yang Lijuan , Luongo Cindy , Moore Ian N. , Johnson Reed F. , Garza Nicole L. , Zhang Peng , Lusso Paolo , Best Sonja M. , Buchholz Ursula J. , Nouën Cyril Le
Published: December 2022

The pediatric live-attenuated bovine/human parainfluenza virus type 3 (B/HPIV3)-vectored vaccine expressing the prefusion-stabilized SARS-CoV-2 spike (S) protein (B/HPIV3/S-2P) was previously evaluatedin vitroand in hamsters. To improve its immunogenicity, we generated B/HPIV3/S-6P, expressing S further stabilized with 6 proline mutations (S-6P). Intranasal immunization of hamsters with B/HPIV3/S-6P reproducibly elicited significantly higher serum anti-S IgA/IgG titers than B/HPIV3/S-2P; hamster sera efficiently neutralized variants of concern (VoCs), including Omicron variants. B/HPIV3/S-2P and B/HPIV3/S-6P immunization protected hamsters against weight loss and lung inflammation following SARS-CoV-2 challenge with the vaccine-matched strain WA1/2020 or VoCs B.1.1.7/Alpha or B.1.351/Beta and induced near-sterilizing immunity. Three weeks post-challenge, B/HPIV3/S-2P- and B/HPIV3/S-6P-immunized hamsters exhibited a robust anamnestic serum antibody response with increased neutralizing potency to VoCs, including Omicron sublineages. B/HPIV3/S-6P primed for stronger anamnestic antibody responses after challenge with WA1/2020 than B/HPIV3/S-2P. B/HPIV3/S-6P will be evaluated as an intranasal vaccine to protect infants against both HPIV3 and SARS-CoV-2.

AUTHOR SUMMARY

SARS-CoV-2 infects and causes disease in all age groups. While injectable SARS-CoV-2 vaccines are effective against severe COVID-19, they do not fully prevent SARS-CoV-2 replication and transmission. This study describes the preclinical comparison in hamsters of B/HPIV3/S-2P and B/HPIV3/S-6P, live-attenuated pediatric vector vaccine candidates expressing the “2P” prefusion stabilized version of the SARS-CoV-2 spike protein, or the further-stabilized “6P” version. B/HPIV3/S-6P induced significantly stronger anti-S serum IgA and IgG responses than B/HPIV3/S-2P. A single intranasal immunization with B/HPIV3/S-6P elicited broad systemic antibody responses in hamsters that efficiently neutralized the vaccine-matched isolate as well as variants of concern, including Omicron. B/HPIV3/S-6P immunization induced near-complete airway protection against the vaccine-matched SARS-CoV-2 isolate as well as two variants. Furthermore, following SARS-CoV-2 challenge, immunized hamsters exhibited strong anamnestic serum antibody responses. Based on these data, B/HPIV3/S-6P will be further evaluated in a phase I study.
Pan-cancer transcriptomic analysis reveals a tissue-specific loss of identity
Authors: dos Santos Gabriel Arantes , Chatsirisupachai Kasit , Avelar Roberto A. , de Magalhães João Pedro
Published: December 2022

Understanding changes in cell identity in cancer and ageing is of great importance. In this work, we analyzed how gene expression changes in human tissues are associated with tissue specificity during cancer and ageing using transcriptome data from TCGA and GTEx. We found a loss of cell identity during ageing in around 40% of tissues. In cancer, we observed a pattern of downregulation of genes specific to the tissue of origin of the tumor for most cancer types. Moreover, we observed an activation of genes not usually expressed in a tissue as well as an upregulation of genes specific to other tissues in cancer. These patterns in cancer were associated with patient survival. The age of the patient, however, does not influence these patterns. Thus, we identified a moderate but statistically significant pattern of loss of cell identity in ageing, and a clear pattern in cancer, where during tumorigenesis, cells express genes specific to other organs while suppressing the expression of genes from their original tissue. The loss of cellular identity observed in cancer is associated with prognosis and is not influenced by age, suggesting that it is a crucial stage in carcinogenesis.
Reanalysis of mtDNA mutations of human primordial germ cells (PGCs) reveals NUMT contamination and suggests that selection in PGCs may be positive
Authors: Fleischmann Zoë , Cote-L’Heureux Auden , Franco Melissa , Oreshkov Sergey , Annis Sofia , Khrapko Mark , Aidlen Dylan , Popadin Konstantin , Woods Dori C. , Tilly Jonathan L. , Khrapko Konstantin
Published: December 2022

The resilience of the mitochondrial genome (mtDNA) to a high mutational pressure depends, in part, on negative purifying selection in the germline. A paradigm in the field has been that such selection, at least in part, takes place in primordial germ cells (PGCs). Specifically, Floros et al. (Nature Cell Biology20: 144–51) reported an increase in the synonymity of mtDNA mutations (a sign of purifying selection) between pooled early-stage and late-stage PGCs. We re-analyzed Floros’ et al. pooled PGC data and noticed that their mutational dataset was significantly contaminated with single nucleotide variants (SNVs) derived from a nuclear sequence of mtDNA origin (NUMT) located on chromosome 5. Contamination was caused by co-amplification of the NUMT sequence by cross-specific PCR primers. Importantly,when we removed NUMT-derived SNVs, the evidence of purifying selection was abolished. In addition to pooled PGCs, Floros et al. reported the analysis ofsinglelate-stage PGCs, which were amplified with different sets of PCR primers that cannot amplify the NUMT sequence. Accordingly, we found no NUMT-derived SNVs among single PGCs mutations. Interestingly, single PGC mutations show adecreaseof synonymity with increased intracellular mutant fraction. This pattern is incompatible with predominantly negative selection. This suggests that germline selection of mtDNA mutations is a complex phenomenon and that the part of this process that takes place in PGCs may be predominantly positive. However counterintuitive, positive germline selection of detrimental mtDNA mutations has been reported previously and potentially may be evolutionarily advantageous.
Unraveling the role of non-coding rare variants in epilepsy
Authors: Girard Alexandre , Moreau Claudia , Michaud Jacques , Minassian Berge , Cossette Patrick , Girard Simon L.
Published: December 2022

Importance

Despite the use of very large cohorts, the discovery of new variants has leveled off in recent years in epilepsy studies and consequently, most of the heritability is still unexplained. Rare non-coding variants have been largely ignored in studies on epilepsy, although non-coding single nucleotide variants can have a significant impact on gene expression.

Objective

To determine if rare non-coding deleterious variants are associated with epilepsy.

Design

This is a case-control study made possible by the CENet cohort.

Setting

This was initially a multicenter study (families and trios), although the sequencing was processed at the same facility and for the present case-control study, only unrelated individuals were drawn.

Participants

Patients used in this study are affected either by genetic generalized epilepsy (GGE), non-acquired focal epilepsy (NAFE) or are called ‘mixed’ (phenotype that differs from other affected relatives). Controls are unaffected parents from developmental and epileptic encephalopathy trios.

Main Outcomes and Measures

To assess the functional impact of non-coding variants, ExPecto, a deep learning algorithm was used. A binomial logistic regression was performed to compare the burden of rare non-coding deleterious variants between cases and controls.

Results

We had access to WGS from 123 GGE, 112 NAFE and 12 mixed for a total of 247 patients, as well as 377 controls. Rare non-coding highly deleterious variants were associated with GGE (OR 2.74; 95% CI 1.20-6.22), but not with NAFE (OR 0.85; 95% CI 0.27-2.67) or all epilepsy cases (OR 1.54; 95% CI 0.77-3.11) when compared with controls.

Conclusion and Relevance

In this study we showed that rare non-coding deleterious variants are associated with epilepsy, specifically with GGE. Larger WGS epilepsy cohort will be needed to investigate those effects at a greater resolution. Nevertheless, we demonstrated the importance of studying non-coding regions in epilepsy, a disease where new discoveries are scarce, and a high proportion of the heritability is yet to be explained.

Key points

Question

Are non-coding single nucleotide variants (SNV) associated with epilepsy?

Findings

In this study we showed that patients with generalized genetic epilepsy (GGE) had significantly more rare non-coding deleterious variants than controls and non-acquired focal epilepsy (NAFE) patients. The study included 247 epilepsy patients and 377 controls who were sequenced for the whole genome.

Meaning

Rare non-coding SNV are associated with epilepsy, more specifically with GGE.
A novel mechanistic framework for precise sequence replacement using reverse transcriptase and diverse CRISPR-Cas systems
Authors: Bill Kim Y. , Pierce Elizabeth B. , Brown Michael , Peterson Brenda A. , Sanford Derek , Fear Justin , Nicholl David , San Pedro Ellyce , Reynolds Grace M. , Hunt Joanne E. , Schwark David G. , Jali Sathya , Graham Nathaniel , Cesarz Zoe , Chapman Tracey A. Lincoln , Watts Joseph M. , Hummel Aaron W.
Published: December 2022

CRISPR/Cas systems coupled with reverse transcriptase (RT), such as the recently described Prime editing, allow for site-specific replacement of DNA sequences. Despite widespread testing of Prime editing, it is currently only compatible with type II CRISPR/Cas proteins such asStreptococcus pyogenesandStaphylococcus aureusCas9. Enabling RT compatibility with other CRISPR/Cas domains, such as type V enzymes with orthogonal protospacer adjacent motif specificities and smaller protein size would expand the range of edits that can be made in therapeutic and industrial applications. We achieve this with a novel mode of DNA editing at CRISPR-targeted sites that reverse transcribes the edit into the target strand DNA (e.g., the complement of the PAM-containing strand), rather than the non-target strand DNA, as in Prime editing. We term this technologyRNA encodedDNAreplacement ofalleleswith CRISPR (hereafter, REDRAW). We show that REDRAW extends the utility of RT-mediated editing beyond type II to include multiple type V CRISPR domains. REDRAW features a broad (8-10 bases) targeting window, at which all types of substitutions, insertions and deletions are possible. REDRAW combines the advantages of type V CRISPR domains with the extensive range of genetic variation enabled by RT-mediated, templated sequence replacement strategies.
Paternalism as a long-term strategy of a management control system
Authors: Cohanier Bruno , Baker Charles Richard
Published: December 2022

Purpose

The purpose of this paper is to trace the evolution of paternalism as a long-term component of a management control system (MCS) in a multi-national business enterprise.

Design/methodology/approach

The authors used a historical methodology involving the collection and evaluation of both primary and secondary data. Annual reports of Michelin (2009–2021) were also analysed to trace the evolution of the MCS towards corporate social responsibility (CSR).

Findings

This research traces the evolution of Michelin's Paternalistic MCS from “Traditional Paternalism” to “Welfare Paternalism”, “Managerial Paternalism” and “Libertarian Paternalism” thereby leading the way to CSR. The findings indicate that the evolution of the MCS revealed “Managerial Paternalism” as a specific type of paternalism and an important component of the “Personnel and Cultural Controls” (Merchant and Van der Stede, 2018, p. 95) at Michelin.

Research limitations/implications

Many multi-national companies began as family-owned and controlled firms (e.g. Ford, Toyota, Fiat, Renault, Tata) and they often employed paternalistic MCSs during their early development (Newby, 1977; Perrot, 1979; Colli, 2003). Such MCSs have been seen as being anachronistic and are often abandoned as the family-owned enterprise grows into a multi-national company (Casson and Cox, 1993; McKinlay et al., 2010). The research challenges this assertion and demonstrates how aspects of a paternalistic MCS can survive in a multi-national business enterprise.

Practical implications

With respect to practical implications, this research shows that paternalism can still be a component of an MCS in a multi-national enterprise.

Originality/value

Using a historical approach, this research addresses a gap in the prior literature regarding the variations and persistence of paternalism in companies. In the case of Michelin, the authors investigate the evolution of its paternalistic MCS from a traditional form to an emphasis on CSR.
Pre-construction duration of public-private partnership projects: evidence from China
Authors: Wang Cong , Liu Henry , Sing Michael C.P. , Wu Jin
Published: December 2022

Purpose

Pre-construction of a project comprises stages that are pivotal for the procurement performance. It is defined as the duration from the project's initiation to construction. However, Private Public Partnerships (PPPs) have been subjected to a long pre-construction, thereby leading to an inefficient development process. Therefore, the purpose of this paper is to pay attention to the influencing factors elongating the pre-construction duration.

Design/methodology/approach

Based on data of 5,677 PPP projects between 2009 and 2021 in China, the authors adopt the Accelerated Failure Time (AFT) model in duration analysis to empirically analyze the following underlying dynamics determining the duration of PPP pre-construction stages: (1) policy uncertainty; (2) corruption; and (3) procurement method selection. To observe the influencing paths more specifically, the authors divided the pre-construction duration into the pre-tendering period and tendering period and regressed them separately.

Findings

The results indicate that the pre-construction duration is significantly prolonged with increased policy uncertainty and corruption degree as well as the use of tendering methods. Meanwhile, the above factors have a greater impact on the pre-tendering period than the tendering period.

Originality/value

The contribution of this study is twofold: (1) theoretically, this paper provides new evidence on the impact of PPP policy uncertainty, corruption and procurement method selection on the pre-construction duration. It complements empirical studies on the factors elongating the time efficiency of PPPs projects. (2) In practice, it provides a specific path for the government to improve the time efficiency of PPPs.