bluuebunny/crossref_metadata_2025 huggingface dataset:
Horizontal gene transfer of a key translation protein has shaped the polyproline proteome
Authors: Brewer Tess E. , Wagner Andreas
Published: October 2023

Prolines take longer than other amino acids to be incorporated into nascent proteins and cause ribosomes to stall during translation. This phenomenon occurs in all domains of life and is exacerbated at polyproline motifs. Such stalling can be eased by elongation factor P (EFP) in bacteria. We discovered a potential connection between horizontally transferred EFP variants and genomic signs of EFP dysfunction. Horizontal transfer of theefpgene has occurred several times throughout the bacterial tree of life, and such transfer events are associated with the loss of otherwise highly conserved polyproline motifs. In this study, we pinpoint cases of horizontal EFP transfer among a diverse set of bacterial genomes and examine the consequences of these events on genome evolution in the phyla Thermotogota and Planctomycetes. In these phyla, horizontal EFP transfer is not only associated with the loss of conserved polyproline motifs, but also with the loss of entire polyproline motif containing proteins, whose expression is likely dependent on EFP. In particular, three proteases (Lon, ClpC, and FtsH) and three tRNA synthetases (ValS, IleS1, IleS2) appear highly sensitive to EFP transfer. The conserved polyproline motifs within these proteins all reside within, or in close proximity to ATP binding regions, some of which have been shown to be crucial to their function. Our work shows that the horizontal transfer of EFP has left genomic traces that persist to this day. It also implies that the process of ‘domesticating’ a horizontally transferredefpgene can perturb the overall function of EFP.
Sealing the deal – Antarctic fur seals’ active hunting tactics to capture small evasive prey revealed by miniature sonar tags
Authors: Chevallay Mathilde , Guinet Christophe , Goulet-Tran Didier , Jeanniard du Dot Tiphaine
Published: October 2023

Fine-scale interactions between predators and their prey are key factors determining both predators’ hunting efficiency and prey survival. The ability to adopt hunting tactics that minimise the risk of triggering an escape reaction from the prey is crucial for an efficient foraging, and is contingent to detection capabilities and locomotor performances of both predators and prey. In this study, we aimed at describing fine-scale predator-prey interactions in female Antarctic fur seals (Arctocephalus gazella,AFS hereafter), a small pinniped foraging on evasive prey. Our objectives were (1) to describe characteristics of prey targeted by female AFS to assess prey selection in this species; (2) to estimate the timing of prey detection by AFS and prey reaction to the AFS approach, and (3) to describe AFS hunting tactics, i.e. fine-scale AFS posture and swimming activity during prey capture events.In fine, we seek to better understand AFS’s efficiency at exploiting their small prey. To do so, we used data recorded by a newly developed sonar tag that combines active acoustics with ultra-high resolution movement sensors to study simultaneously the fine-scale behaviour of both AFS and prey during predator-prey interactions. We analysed more than 1200 prey capture events in eight female AFS and showed that AFS and their prey detect each other at the same time, i.e. 1-2 seconds before the strike, forcing AFS to display reactive fast-moving chases to capture their prey. Prey detection was consistently followed by bursts of accelerations from AFS, which lasted longer for evasive prey. We suggest that the ability of AFS to perform bursts of accelerations may allow them to target evasive prey. This active hunting tactics is likely very energy-consuming but might be compensated by the consumption of highly nutritious prey.
DNA metabarcoding reveals limited consumption of livestock and black rhinoceros by spotted hyenas in a prey-rich environment
Authors: Dheer Arjun , Danabalan Renita , Pellizzone Antonia , Davidian Eve , Naman Philemon , Mazzoni Camila , Höner Oliver P.
Published: October 2023

The diet of large carnivores is of great interest to conservation managers, as it can reveal the extent of human-carnivore conflict and the impact of carnivores on species of high conservation priority. Metabarcoding of environmental DNA can identify species and is often more reliable in doing so than observational or morphological methods. Metabarcoding is particularly powerful at detecting elusive and rare species and has therefore become a widely applied tool in biodiversity research. Here, we used DNA metabarcoding of fecal samples to determine the diet of spotted hyenas in the Ngorongoro Crater, a protected area in Northern Tanzania surrounded by areas co-inhabited by pastoralists. We assessed which species hyenas preferably consumed over a 24-year period and how frequently they consumed pastoralist livestock and black rhinoceros, a species of high economic value and conservation priority. We further estimated the effects of three key socio-demographic variables – age, social rank, and sex – on the propensity of hyenas to consume livestock. We detected DNA from 20 species in 371 hyena feces. Hyenas preferably consumed blue wildebeest and Grant’s gazelle. Among the detected species were five domestic species and one wild species that lived in the pastoralist-inhabited areas but not the Crater. This shows that resident Crater hyenas undertake foraging trips to areas surrounding the Crater. DNA of domestic species however was rarely detected (4.1% of 434 detections), and predominantly in feces of old hyenas. This suggests that Crater hyenas rarely consume livestock and that livestock is mostly consumed by hyenas less capable of hunting fleet-footed and powerful wild prey. No DNA of black rhinoceros was detected in any of the samples, suggesting that Crater hyenas do not frequently consume rhinoceros. Our findings suggest that the impact of Crater hyenas on livestock and wildlife of high conservation priority is limited. Our study highlights the potential of DNA metabarcoding to assess the extent of human-carnivore conflict and to guide evidence-based conservation efforts to promote coexistence of carnivores, humans and species of high conservation priority.
Introducing Isotòpia: a stable isotope database for Classical Antiquity
Authors: Formichella Giulia , Soncin Silvia , Lubritto Carmine , Tafuri Mary Anne , Fernandes Ricardo , Cocozza Carlo
Published: October 2023

We present Isotòpia, an open-access database compiling over 36,000 stable isotope measurements (δ13C, δ15N, δ18O, δ34S,87Sr/86Sr,206Pb/204Pb,207Pb/204Pb,208Pb/204Pb,207Pb/206Pb, and208Pb/206Pb) on human, animal, and plant bioarchaeological remains dating to Classical Antiquity (approximately 800 BCE - 500 CE). These were recovered from different European regions, particularly from the Mediterranean. Isotòpia provides a comprehensive characterisation of the isotopic data, encompassing various historical, archaeological, biological, and environmental variables. Isotòpia is a resource for meta-analytical research of past human activities and paleoenvironments. The database highlights data gaps in isotopic classical archaeology, such as the limited number of isotopic measurements available for plants and animals, limited number of studies on spatial mobility, and spatial heterogeneity of isotopic research. As such, we emphasise the necessity to address and fill these gaps in order to unlock the reuse potential of this database.
GAS6 and AXL promote insulin resistance by rewiring insulin signaling and increasing insulin receptor trafficking to endosomes
Authors: Schott Céline , Germain Amélie , Lacombe Julie , Pata Monica , Faubert Denis , Boulais Jonathan , Carmeliet Peter , Côté Jean-François , Ferron Mathieu
Published: October 2023

Growth-arrest specific 6 (GAS6) is a secreted protein that acts as a ligand for TAM receptors (TYRO3, AXL and MERTK). In humans, GAS6 circulating levels and genetic variations inGAS6are associated with hyperglycemia and increased risk of type 2 diabetes. However, the mechanisms by which GAS6 influences glucose metabolism are not understood. Here, we show thatGas6deficiency in mice increases insulin sensitivity and protects from diet-induced insulin resistance. Conversely, increasing GAS6 circulating levels is sufficient to reduce insulin sensitivityin vivo. GAS6 inhibits the activation of the insulin receptor (IR) and reduces insulin response in muscle cells in vitro and in vivo. Mechanistically, AXL and IR fom a complex, while GAS6 reprograms signaling pathways downstream of IR. This results in increased IR endocytosis following insulin treatment. This study contributes to a better understanding of the cellular and molecular mechanisms by which GAS6 and AXL influence insulin sensitivity.

ARTICLE HIGHLIGHTS

GAS6 deficient mice are characterized by improved glucose tolerance, increased insulin sensitivity and are protected from diet-induced insulin resistance.

The GAS6 receptor AXL is expressed in muscle cells and forms a complex with the insulin receptor.

GAS6 reprograms insulin signaling by modulating the phosphorylation of proteins implicated in endocytosis, vesicle-mediated transport, and membrane trafficking.

AXL and GAS6 promotes insulin receptor endocytosis following insulin treatment.
A FLASH model of radiolytic oxygen depletion and reactive oxygen species for differential tumor and normal-tissue response
Authors: Ma Jiangjun , Gao Hao , Shen Xing , Bai Xuemin , Tang Min
Published: October 2023

Objective

FLASH-RT can potentially improve the sparing of normal tissues while preserving the tumoricidal efficiency, owing to the radiation with ultra-high dose rate. However, the FLASH mechanism remains to be solved. A popular FLASH model is based on radiolytic oxygen depletion (ROD), which explains for radiation protection of normal tissues under FLASH-RT. However, ROD does not explain the preservation of tumoricidal efficiency for tumors. This work will develop a ROS+ROD FLASH model that can explain the differential tumor and normal-tissue response.

Approach

The new FLASH model utilizes reactive oxygen species (ROS) in addition to ROD, and takes into account that ROS level decreases during FLASH-RT. Specifically, the differential-equation model takes into account that the basic ROS level is lower during FLASH-RT and the degeneration rates of ROS are different in tumor cells and healthy cells. Based on this ROS+ROD FLASH model, the surviving fractions of tumor and normal cells are respectively compared between conventional radiotherapy (CONV-RT) and FLASH-RT.

Main results

While ROD alone does not distinguish the response of tumors and normal tissues to FLASH-RT, the proposed new FLASH model based on ROD and ROS successfully explained the differential response of tumors and normal tissues to FLASH-RT, i.e., the preserved tumoricidal capability, which cannot be explained by ROD alone, and the extra normal-tissue protection owing to the ultra-high dose rate.

Significance

Since the ROS level decreases slower in tumors than in normal tissues, during FLASH-RT, ROS decreases more in normal tissue, thus can get more protection. By incorporating ROS in addition to ROD, the new FLASH model can not only recover all results by previous FLASH model with ROD alone, but also explain the differential response: preserved lethality of FLASH-RT to tumors and improved protection to normal tissues.
Global risk of selection and spread ofPlasmodium falciparumhistidine-rich protein 2 and 3 gene deletions
Authors: Watson Oliver J. , Tran Thu Nguyen-Anh , Zupko Robert J , Symons Tasmin , Thomson Rebecca , Visser Theodoor , Rumisha Susan , Dzianach Paulina A , Hathaway Nicholas , Kim Isaac , Juliano Jonathan J. , Bailey Jeffrey A. , Slater Hannah , Okell Lucy , Gething Peter , Ghani Azra , Boni Maciej F , Parr Jonathan B. , Cunningham Jane
Published: October 2023

In the thirteen years since the first report ofpfhrp2-deleted parasites in 2010, the World Health Organization (WHO) has found that 40 of 47 countries surveyed worldwide have reportedpfhrp2/3gene deletions. Due to a high prevalence ofpfhrp2/3deletions causing false-negative HRP2 RDTs, in the last five years, Eritrea, Djibouti and Ethiopia have switched or started switching to using alternative RDTs, that target pan-specific-pLDH orP. falciparumspecific-pLDH alone of in combination with HRP2. However, manufacturing of alternative RDTs has not been brought to scale and there are no WHO prequalified combination tests that use Pf-pLDH instead of HRP2 forP. falciparumdetection. For these reasons, the continued spread ofpfhrp2/3deletions represents a growing public health crisis that threatens efforts to control and eliminateP. falciparummalaria. National malaria control programmes, their implementing partners and test developers desperately seekpfhrp2/3deletion data that can inform their immediate and future resource allocation. In response, we use a mathematical modelling approach to evaluate the global risk posed bypfhrp2/3deletions and explore scenarios for how deletions will continue to spread in Africa. We incorporate current best estimates of the prevalence ofpfhrp2/3deletions and conduct a literature review to estimate model parameters known to impact the selection ofpfhrp2/3deletions for each malaria endemic country. We identify 20 countries worldwide to prioritise for surveillance and future deployment of alternative RDT, based on quickly selecting forpfhrp2/3deletions once established. In scenarios designed to explore the continued spread of deletions in Africa, we identify 10 high threat countries that are most at risk of deletions both spreading to and subsequently being rapidly selected for. If HRP2-based RDTs continue to be relied on for malaria case management, we predict that the major route forpfhrp2deletions to spread is south out from the current hotspot in the Horn of Africa, moving through East Africa over the next 20 years. We explore the variation in modelled timelines through an extensive parameter sensitivity analysis and despite wide uncertainties, we identify three countries that have not yet switched RDTs (Senegal, Zambia and Kenya) that are robustly identified as high risk forpfhrp2/3deletions. These results provide a refined and updated prediction model for the emergence ofpfhrp2/3deletions in an effort to help guidepfhrp2/3policy and prioritise future surveillance efforts and innovation.
Genotype prediction of 336,463 samples from public expression data
Authors: Razi Afrooz , Lo Christopher C. , Wang Siruo , Leek Jeffrey T. , Hansen Kasper D.
Published: October 2023

Tens of thousands of RNA-sequencing experiments comprising hundreds of thousands of individual samples have now been performed. These data represent a broad range of experimental conditions, sequencing technologies, and hypotheses under study. The Recount project has aggregated and uniformly processed hundreds of thousands of publicly available RNA-seq samples. Most of these samples only include RNA expression measurements; genotype data for these same samples would enable a wide range of analyses including variant prioritization, eQTL analysis, and studies of allele specific expression. Here, we developed a statistical model based on the existing reference and alternative read counts from the RNA-seq experiments available through Recount3 to predict genotypes at autosomal biallelic loci in coding regions. We demonstrate the accuracy of our model using large-scale studies that measured both gene expression and genotype genome-wide. We show that our predictive model is highly accurate with 99.5% overall accuracy, 99.6% major allele accuracy, and 90.4% minor allele accuracy. Our model is robust to tissue and study effects, provided the coverage is high enough. We applied this model to genotype all the samples in Recount3 and provide the largest ready-to-use expression repository containing genotype information. We illustrate that the predicted genotype from RNA-seq data is sufficient to unravel the underlying population structure of samples in Recount3 using Principal Component Analysis.
KCC2 Enhancers Normalize Reflex Responses and Improve Locomotor Function after Chronic Spinal Cord Injury
Authors: Bilchak Jadwiga N. , Caron Guillaume , Danner Simon M. , Côté Marie-Pascale
Published: October 2023

Within a year after a spinal cord injury (SCI), 75% of individuals develop spasticity. While normal movement relies on the ability to adjust reflexes appropriately, and on reciprocal inhibition of antagonistic muscles, spastic individuals display hyperactive spinal reflexes and involuntary muscle co-contractions. Current anti-spastic medications can suppress uncontrolled movements, but by acting on GABAergic signalling, these medications lead to severe side-effects and weakened muscle force, making them incompatible with activity-based therapies. We have previously shown that pharmacologically enhancing activity of KCC2, a chloride cotransporter, reduces signs of spasticity in anesthetized chronic SCI rats. Here, we examine the effect of enhancing KCC2 in awake animals, using a battery of tests to assess multiple reflex pathways required for normal movement as well as locomotor function. Sprague-Dawley rats were implanted with chronic EMG electrodes bilaterally in ankle flexor and ankle extensor muscles and received a complete spinal transection at T12. Four weeks following SCI, the stretch reflex, the non-nociceptive cutaneous reflex pathway, the flexor withdrawal reflex, and the crossed-extensor reflex pathway as well as locomotor function were evaluated before and after receiving the KCC2 enhancer, CLP290. Our results show that enhancing KCC2 activity normalizes reflex responses in multiple pathways and reduces muscle co-contraction without weakening motor output, thereby improving stepping ability. This work reveals the substantial potential for KCC2 enhancers as a novel antispastic treatment.
Physiological and transcriptomic characterization of cold acclimation in endodormant grapevine under different temperature regimes
Authors: Wang Hongrui , Kovaleski Al P. , Londo Jason P.
Published: October 2023

It is essential for the survival of grapevines in cool climate viticultural regions that vines properly acclimate in the late fall and early winter and develop freezing tolerance. Climate change-associated abnormities in temperature during the dormant season, including oscillations between extreme cold and prolonged warmth, impacts cold acclimation and threatens the sustainability of the grape and wine industry. We conducted two experiments in controlled environment to investigate the impacts of different temperature regimes on cold acclimation ability in endodormant grapevine buds through a combination of freezing tolerance based physiological and RNA-seq based transcriptomic monitoring. Results show that the freezing tolerance of buds was not altered from field levels when exposed to stable temperatures ranging from 2 °C to 22 °C but was enhanced when exposed to temperature cycling (7±5 °C). We also characterized the transcriptomic response of endodormant buds to high and low temperatures and the potential genetic control for the maintenance of endodormancy. Several pathways that were previously reported to be responsive or functional during cold acclimation, such as theICE-CBF-CORcascade, were not observed to play a role in the enhancement of freezing tolerance or the sensing of different temperatures, indicating our current understanding of the genetic control of cold acclimation remains a challenge when generalizing across plant species and phenological stages.
Simultaneous whole-head electrophysiological recordings using EEG and OPM-MEG
Authors: Seedat Zelekha A. , Pier Kelly St , Holmes Niall , Rea Molly , Al-Hilaly Layla , Tierney Tim M. , Pardington Rosemarie , Mullinger Karen J. , Cross J. Helen , Boto Elena , Brookes Matthew J.
Published: October 2023

Electroencephalography (EEG) and magnetoencephalography (MEG) non-invasively measure human brain electrophysiology. They differ in nature; MEG offers better performance (higher spatial precision) whilst EEG (a wearable platform) is more practical. They are also complementary, with studies showing that concurrent MEG/EEG provides advantages over either modality alone, and consequently clinical guidelines for MEG in epilepsy recommend simultaneous acquisition of EEG. In recent years, new instrumentation – optically pumped magnetometers (OPMs) – has had a significant impact on MEG, offering improved performance, lifespan compliance, and wearable sensors. Nevertheless, the ability to carry out simultaneous EEG/OPM-MEG remains critical. Here, we investigated whether simultaneous, wearable, whole-head EEG and OPM-MEG measurably degrades signal quality in either modality. We employed two tasks: a motor task known to modulate beta oscillations, and an eyes-open/eyes-closed task known to modulate alpha oscillations. In both, we characterised the performance of EEG alone, MEG alone, and concurrent EEG/OPM-MEG. Our results show that the SNR of the beta response was very similar, regardless of whether modalities were used individually or concurrently. Likewise, our alpha band recordings demonstrated that signal contrast was stable, regardless of the concurrent recording. These results combined suggest that there are no fundamental barriers to simultaneous wearable EEG/OPM-MEG, and consequently this technique is ripe for neuroscientific and clinical adoption. This will be particularly important in the clinical sphere where a direct comparison between simultaneous EEG and OPM-MEG recordings will facilitate interpretation of OPM-MEG data in patients.
Proportion of cancer cases and deaths attributable to potentially modifiable risk factors in Peru prior to the COVID-19 pandemic
Authors: De La Cruz-Vargas Jhony A. , Ramos Willy , Chanduví Willer , Correa-López Lucy E. , Guerrero Nadia , Loayza-Castro Joan , Tami-Maury Irene M. , Venegas Diego
Published: October 2023

OBJECTIVE

To estimate the fraction of cancer cases and deaths attributable to potentially modifiable risk factors in Peru in 2018, prior to the COVID-19 pandemic.

MATERIAL AND METHODS

An ecological study was carried out using the prevalence of exposure of the Peruvian population to modifiable risk factors for cancer, relative risk of each risk factor, and number of cancer cases and deaths in 2018 as inputs. We used the Parkin formula with a Montecarlo statistical simulation model to calculate the population attributable fraction (PAF) and confidence intervals. The number of new cancer cases and deaths attributable to each risk factor was calculated by multiplying the number of cases and deaths in each sex by the PAF of each risk factor.

RESULTS

38.4% of new cases (34.4% in men and 41.8% in women) and 43.2% of deaths by cancer in Peru (43.1% in men and 43.2% in women) were attributable to modifiable risk factors. The number of cancers attributable was 25,591 (10,616 in men and 14,975 in women) and the number of deaths attributable to cancer was 14,922 (6,996 in men and 7,926 in women). The modifiable risk factors that caused a greater number of cases and deaths were HPV infection (4563 cases, 2410 deaths), current tobacco use (3387 cases, 2198 deaths), and Helicobacter pylori infection (2686 cases, 1874 deaths). The oncogenic infections made up the group of risk factors that presented a greater PAF (16.6% for cases, 19.1% for deaths) followed by other unhealthy lifestyle factors (14.1% for cases, 16.5% for deaths), tobacco (7.2% for cases, 7.3% for deaths) and ultraviolet radiation (0.5% for cases, 0.3% for deaths).

CONCLUSION

Prior to the COVID-19 pandemic, a proportion of 38.4% of cancer cases and 43.2% of cancer deaths in Peru during 2018 were attributable to modifiable risk factors. Most preventable cancer cases and deaths are linked to oncogenic infections, primarily caused by HPV and Helicobacter pylori.
Environmentally persistent free radicals in household dust: the seasonal and longitudinal trends
Authors: Vilcins Dwan , Dangal Prakash , Lomnicki Slawomir , Cormier Stephania , Lee Wen Ray , Sly Peter D
Published: October 2023

Objective

Epidemiological links between air pollution and adverse health outcomes are strong, but the mechanism(s) remain obscure. A newly recognised combustion by-product, environmentally persistent free radicals (EPFRs), may be the missing link. EPFRs persist for extended periods of time in the environment, however very little is known about the presence of EPFRs inside homes where prolonged exposure is likely to occur. The objective of this study is to explore the presence of EPFRs in household dust and ascertain if EPFR concentration is stable across time and season.

Material and methods

The ORChID/ELLF cohort is a longitudinal birth cohort (n=82) with dust samples collected from the family vacuum cleaner at multiple time points. EPFR characteristics were assessed with electron paramagnetic resonance. Our team developed an algorithm to estimate oxygen-weighted concentration and impact score for risk of adverse health outcomes. Kruskal-Wallis rank sum test and Fisher’s exact tests were used to assess seasonal differences. A simple mixed-effects linear regression, with random intercepts on participant ID, was employed for longitudinal analysis of EPFR concentration in households that did not move.

Results

83 participants returned 238 dust samples. EPFRs were measured in virtually all samples. EPFR concentration was stable across visits, when controlling for season and ambient air pollution (p=0.05), Oxygen-weighted EPFRs were also stable. There was a seasonal trend, with concentration (p=<0.01), oxygen weighted concentration (p=<0.01) and g factor (p=0.05) all significantly lower in summer months.

Conclusion

Our results indicate that the concentration of EPFRs in household dust are stable across time in households that did not move, but the oxygen-centred radicals are more sensitive to changes. These findings suggest that exposure to EPFRs occurs in the home and may be a significant place for exposure to highly biologically reactive EPFRs.
Altered Platelet-Megakaryocyte Endocytosis and Trafficking of Albumin and Fibrinogen inRUNX1Haplodeficiency
Authors: Carpio-Cano Fabiola Del , Mao Guangfen , Goldfinger Lawrence E. , Wurtzel Jeremy , Guan Liying , Alam Afaque Mohammad , Lee Kiwon , Poncz Mortimer E. , Rao A. Koneti
Published: October 2023

Platelet α-granules have numerous proteins, some synthesized by megakaryocytes (MK) and others not synthesized but incorporated by endocytosis, an incompletely understood process in platelets/MK. GermlineRUNX1haplodeficiency, referred to as familial platelet defect with predisposition to myeloid malignancies (FPDMM), is associated with thrombocytopenia, platelet dysfunction and granule deficiencies. In previous studies, we found that platelet albumin, fibrinogen and IgG levels were decreased in a FPDMM patient. We now show that platelet endocytosis of fluorescent-labeled albumin, fibrinogen and IgG is decreased in the patient and his daughter with FPDMM. In megakaryocytic human erythroleukemia (HEL) cells, siRNARUNX1knockdown (KD) increased uptake of these proteins over 24 hours compared to control cells, with increases in caveolin-1 and flotillin-1 (two independent regulators of clathrin-independent endocytosis), LAMP2 (a lysosomal marker), RAB11 (a marker of recycling endosomes) and IFITM3. Caveolin-1 downregulation in RUNX1-deficient HEL cells abrogated the increased uptake of albumin, but not fibrinogen. Albumin, but not fibrinogen, partially colocalized with caveolin-1.RUNX1knockdown increased colocalization of albumin with flotillin and of fibrinogen with RAB11 suggesting altered trafficking of both. The increased albumin and fibrinogen uptake and levels of caveolin-1, flotillin-1, LAMP2 and IFITM3 were recapitulated by shRNARUNX1knockdown in CD34+-derived MK. These studies provide the first evidence that inRUNX1-haplodeficiency platelet endocytosis of albumin and fibrinogen is impaired and that megakaryocytes have enhanced endocytosis with defective trafficking leading to loss of these proteins by distinct mechanisms. They provide new insights into mechanisms governing endocytosis and α-granule deficiencies inRUNX1-haplodeficiency.

Key points

Platelet content and endocytosis of α-granule proteins, albumin, fibrinogen and IgG, are decreased in germline RUNX1 haplodeficiency.

InRUNX1-deficient HEL cells and primary MK endocytosis is enhanced with defective trafficking leading to decreased protein levels.
Comparative Immune profiling in Pancreatic Ductal Adenocarcinoma Progression Among South African patients
Authors: Elebo Nnenna , Abdel-Shafy Ebtesam A. , Omoshoro-Jones Jones A.O. , Nsingwane Zanele , Hussein Ahmed A.A. , Smith Martin , Candy Geoffrey , Cacciatore Stefano , Fru Pascaline , Nweke Ekene Emmanuel
Published: October 2023

Introduction

Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive cancer with a 5-year survival rate of only 11%. PDAC is characterized by an immunosuppressive microenvironment; thus, there have been multiple attempts to target it, although with little success. A better understanding of the immune landscape in PDAC is required to help elucidate the roles of these cells for effective targeting. This study investigated the expression of circulating key immune cell markers in South African PDAC patients.

Method

Blood samples were obtained from a total of 34 PDAC patients consisting of 22 resectable (RPC), 8 locally advanced (LAPC) and 4 metastatic (MPC), 6 Chronic Pancreatitis (CP), and 6 healthy volunteers (HC). Immunophenotyping, real-time polymerase chain reactions (PCR), enzyme-linked immunosorbent assay (Elisa), and reactive oxygen species (ROS) assays were conducted. Statistical analysis was conducted in R (version 3.6.1) and Wilcoxon and Kruskal-Wallis rank-sum tests were used to compare between groups. Kaplan-Meier analysis and Spearman’s rank test were used for survival and correlation analyses, respectively.

Results

Granulocyte and neutrophil levels were significantly elevated while lymphocytes decreased with PDAC severity. The total percentages of CD4+, CD8+, and CD3+CD4-CD8-T-cells increased across the group. Of note are the reduction of CD16+NKTs across the RPC (p= 0.002), LAPC (p= 0.01), and MPC (p= 0.017) groups when compared to HC. Both NK (p= 0.0047) and NKTs (p= 0.0027) increased in RPC but decreased in both LAPC and MPC when compared to HC. Although there was no statistical correlation or differences observed when comparing the PDAC groups with the control groups, RPC had the highest foldchange for bothCD4(11.75 ± 44.31) andCD3(30.47 ± 75.01) while the LAPC group had the highest fold change forCD8(3.86 ± 7.35) andCD16(51.69 ± 108.9) genes compared to MPC. The inflammatory status of PDAC was assessed by DEPPD levels of serum which were elevated in RPC (p= 0.003) and LAPC (p= 0.008) but decreased in MPC (p= 0.025), compared to the HC group. ROS was shown to be positively correlated with GlycA (R=0.45,p= 0.00096).

Conclusion

The expression of these immune cell markers observed in this pilot study provides insight into their potential roles in tumour progression in the patient group and suggests their potential utility in the development of immunotherapeutic strategies.
Identifying and ranking novel independent features for cardiovascular disease prediction in people with type 2 diabetes
Authors: Dziopa K , Chaturvedi N , Asselbergs F W , Schmidt A F
Published: October 2023

Background

CVD prediction models do not perform well in people with diabetes. We therefore aimed to identify novel predictors for six facets of CVD, (including coronary heart disease (CHD), Ischemic stroke, heart failure (HF), and atrial fibrillation (AF)) in people with T2DM.

Methods

Analyses were conducted using the UK biobank and were stratified on history of CVD and of T2DM: 459,142 participants without diabetes or a history of CVD, 14,610 with diabetes but without CVD, and 4,432 with diabetes and a history of CVD. Replication was performed using a 20% hold-out set, ranking features on their permuted c-statistic.

Results

Out of the 600+ candidate features, we identified a subset of replicated features, ranging between 32 for CHD in people with diabetes to 184 for CVD+HF+AF in people without diabetes. Classical CVD risk factors (e.g. parental or maternal history of heart disease, or blood pressure) were relatively highly ranked for people without diabetes. The top predictors in the people with diabetes without a CVD history included: cystatin C, self-reported health satisfaction, biochemical measures of ill health (e.g. plasma albumin). For people with diabetes and a history of CVD top features were: self-reported ill health, and blood cell counts measurements (e.g. red cell distribution width). We additionally identified risk factors unique to people with diabetes, consisting of information on dietary patterns, mental health and biochemistry measures. Consideration of these novel features improved risk classification, for example per 1000 people with diabetes 133 CVD and 165 HF cases appropriately received a higher risk.

Conclusion

Through data-driven feature selection we identified a substantial number of features relevant for prediction of cardiovascular risk in people with diabetes, the majority of which related to non-classical risk factors such as mental health, general illness markers, and kidney disease.
A mechanical circuit in End4p coordinates force transmission during clathrin-mediated endocytosis
Authors: Ren Yuan , Yang Jie , Fujita Barbara , Zhang Yongli , Berro Julien
Published: October 2023

Mechanical forces are transmitted from the actin cytoskeleton to the membrane during clathrin-mediated endocytosis (CME) in the fission yeastSchizosaccharomyces pombe. The onset and termination of force transmission is tightly regulated temporally during different stages of CME, and spatially over the surface of the invaginated membrane. How force transmission is regulated and coordinated at the molecular scale is unclear. An adaptor protein in CME, End4p, directly transmits force by binding to both the membrane (through ANTH domain) and F-actin (through THATCH domain). We show that 8pN is required for stable binding between THATCH and F-actin. We also report the discovery and characterization of a new domain on End4p, which we named Rend (Rdomain inEnd4p), that resembles R12 of talin. Membrane localization of Rend primes the binding of THATCH to F-actin, and force-induced unfolding of Rend at 15pN terminates the transmission of force during CME. We show that the mechanical properties (mechanical stability, unfolding length, hysteresis) of Rend and THATCH are tuned to form an auto-regulated circuit for the initiation, transmission and termination of force between the actin cytoskeleton and membrane. Shorting the circuit leads to permanent End4p association with the membrane or with F-actin, or failure to enter the force transmission cycle. Mathematical modeling of force transmission through Rend-THATCH connection shows that input force from F-actin is buffered to a narrow range towards the membrane. The mechanical circuit by Rend and THATCH may be conserved and coopted evolutionarily in cell adhesion complexes.
SenPred: A single-cell RNA sequencing-based machine learning pipeline to classify senescent cells for the detection of anin vivosenescent cell burden
Authors: Hughes Bethany K. , Davis Andrew , Milligan Deborah , Wallis Ryan , Philpott Michael P. , Wainwright Linda J. , Gunn David A. , Bishop Cleo L.
Published: October 2023

Senescence classification is an acknowledged challenge within the field, as markers are cell-type and context dependent. Currently, multiple morphological and immunofluorescence markers are required for senescent cell identification. However, emerging scRNA-seq datasets have enabled increased understanding of the heterogeneity of senescence. Here we present SenPred, a machine-learning pipeline which can identify senescence based on single-cell transcriptomics. Using scRNA-seq of both 2D and 3D deeply senescent fibroblasts, the model predicts intra-experimental and inter-experimental fibroblast senescence to a high degree of accuracy (>99% true positives). We position this as a proof-of-concept study, with the goal of building a holistic model to detect multiple senescent subtypes. Importantly, utilising scRNA-seq datasets from deeply senescent fibroblasts grown in 3D refines our ML model leading to improved detection of senescent cellsin vivo.This has allowed for detection of anin vivosenescent cell burden, which could have broader implications for the treatment of age-related morbidities.
TheNRC0gene cluster of sensor and helper NLR immune receptors is functionally conserved across asterid plants
Authors: Sakai Toshiyuki , Martinez-Anaya Claudia , Contreras Mauricio P , Kamoun Sophien , Wu Chih-Hang , Adachi Hiroaki
Published: October 2023

NLR (nucleotide-binding domain and leucine-rich repeat-containing) proteins can form complex receptor networks to confer innate immunity. NRCs are phylogenetically related nodes that function downstream of a massively expanded network of disease resistance proteins that protect against multiple plant pathogens. Here, we used phylogenomic methods to reconstruct the macroevolution of the NRC family. One of the NRCs, we termedNRC0, is the only family member shared across asterid plants, leading us to investigate its evolutionary history and genetic organization. In several asterid species,NRC0is genetically clustered to other NLRs that are phylogenetically related to NRC-dependent disease resistance genes. This prompted us to hypothesize that the ancestral state of the NRC network is an NLR helper-sensor gene cluster that was present early during asterid evolution. We validated this hypothesis by demonstrating that NRC0 is essential for the hypersensitive cell death induced by its genetically linked sensor NLR partners in four divergent asterid species: tomato, wild sweet potato, coffee and carrot. In addition, activation of a sensor NLR leads to high-order complex formation of its genetically linked NRC0 similar to other NRCs. Our findings map out contrasting evolutionary dynamics in the macroevolution of the NRC network over the last 125 million years from a functionally conserved NLR gene cluster to a massive genetically dispersed network.

One-sentence summary

NRC0gene cluster is functionally conserved across divergent asterid species and predates the massively expanded NRC network.
KIF1C, an RNA transporting kinesin-3, undergoes liquid-liquid phase separation through its C-terminal disordered domain
Authors: Geng Qi , Keya Jakia Jannat , Hotta Takashi , Verhey Kristen J
Published: October 2023

The spatial distribution of mRNA is critical for local control of protein production. Recent studies have identified the kinesin-3 family member KIF1C as an RNA transporter. However, it is not clear how KIF1C interacts with RNA molecules. Here, we show that KIF1C’s C-terminal tail domain is an intrinsically disordered region (IDR) containing a prion-like domain (PLD) that is unique compared to the C-terminal tails of other kinesin family members. In cells, KIF1C constructs undergo reversible formation of dynamic puncta that display physical properties of liquid condensates and incorporate RNA molecules in a sequence-selective manner. The IDR is necessary and sufficient for driving liquid-liquid phase separation (LLPS) but the condensate properties can be modulated by adjacent coiled-coil segments. The purified KIF1C IDR domain undergoes LLPSin vitroat near-endogenous nM concentrations in a salt-dependent manner. Deletion of the IDR abolished the ability of KIF1C to undergo LLPS and disrupted the distribution of mRNA cargoes to the cell periphery. Our work thus uncovers an intrinsic correlation between the LLPS activity of KIF1C and its role as an RNA transporter. In addition, as the first kinesin motor reported to undergo LLPS, our work reveals a previously uncharacterized mode of motor-cargo interaction that extends our understanding of the behavior of cytoskeletal motor proteins.
Genome-wide chromatin interaction profiling reveals a vital role of super-enhancers and rearrangements in host enhancer contacts during BmNPV infection
Authors: Zhao Shudi , Li Yuedong , Chen Guanping , Wang Xingyang , Chen Nan , Wu Xiaofeng
Published: October 2023

As influential regulatory elements in the genome, enhancers control gene expression under specific cellular conditions, and such connections are dynamic under different conditions. However, because of the lack of a genome-wide enhancer–gene connection map, the roles and regulatory pattern of enhancers were poorly investigated in insects, and the dynamic changes of enhancer contacts and functions under different conditions remain elusive. Here, combining Hi-C, ATAC-seq, and H3K27ac ChIP-seq data, we generate the genome-wide enhancer–gene map of silkworm and identify super-enhancers with a role in regulating the expression of vital genes related to cell state maintenance through a sophisticated interaction network. Additionally, a radical attenuation of chromatin interactions is found after infection ofBombyx morinucleopolyhedrovirus (BmNPV), the main pathogen of silkworm, which directly rearranges the enhancer contacts. Such a rearrangement disturbs the intrinsic enhancer–gene connections in several antiviral genes, resulting in reduced expression of these genes, which accelerates viral infection. Overall, our results reveal the regulatory role of super-enhancers and shed new light on the mechanisms and dynamic changes of the genome-wide enhancer regulatory network.
Adherence to care and treatment review policy and impact on length of stay
Authors: Jones Lucy Jade , Woodrow Ceri
Published: October 2023

Purpose

The purpose of this clinical audit was to review the adherence to the 2017 care and treatment review policy across two NHS assessment and treatment units. Care and treatment reviews should be offered to people with an intellectual disability and/or autism who are at risk of admission into a mental health hospital.

Design/methodology/approach

Admission and discharge data was collected across two assessment and treatment units between January 2019 and December 2022. Adherence to the care and treatment review policy was also reviewed as was length of inpatient stay. A retrospective evaluation was conducted. Triangulation of data was collected via the trusts’ electronic patient record system and NHS analytics team. Descriptive statistics, Mann–Whitney U test and a one-way ANOVA with post hoc tests were used in the analysis.

Findings

An increase in behaviours of challenge and deterioration of mental health were the main reasons for admission. Forty-nine percent (30) of those admitted to the assessment and treatment units accessed a care and treatment review. Care and treatment reviews were more frequently provided for individuals experiencing longer inpatient stays.

Originality/value

There is limited evidence relating to outcomes and impact of care and treatment reviews. Further research is required to explore effectiveness of care and treatment reviews to understand benefits and appropriately prioritise resource.
Evaluating global data policies around non-personal data on social and public good
Authors: Verma Asmita , Gurtoo Anjula
Published: October 2023

Purpose

The paper aims to review rules and policy guidelines worldwide around non-personal data (NPD) and evaluate the policies on criteria that allow for the use of data for economic and social good. A review related to diverse policy approaches of various countries remains a research gap, and hence the analysis in the paper is designed with the intention of developing a research framework and providing policy gaps for further exploration.

Design/methodology/approach

A systematic review of academic and non-academic literature on theoretical foundations, applications of NPD for economic and social good and NPD policies and regulations was conducted to identify the evaluation criteria. A total of 32 dimensions got identified for evaluation. As second step, content analysis was used for evaluation. A total of 13 documents from 6 countries and 1 geographical region were identified for evaluation. The documents were evaluated based on the 32 dimensions spread across 5 domains that facilitate data access and sharing for economic and societal benefit.

Findings

The analysis highlights three distinct emerging perspectives on data exchange: most policy and regulatory documents acknowledge the importance of identifying different types of NPD and accordingly describing the distinct roles and responsibilities of data actors for leveraging the data; the policy and regulatory frameworks clearly focus on increasing business opportunities, data sharing cooperation and innovation; and findings also demonstrate certain gaps in the policy frameworks such as a more comprehensive discussion on data access and sharing mechanisms, particularly data sandboxes and open data, and concrete norms and rigorous standards regarding accountability, transparency, ownership and confidentiality. Furthermore, policies and regulations may include appropriate incentive structures for data providers and users to ensure unhindered and sustainable access to data for the common good.

Originality/value

To the best of the authors’ knowledge, this paper represents one of the first research contributions evaluating global data policies focused on NPD in the context of its increasing use as a public good. The paper first identifies evaluation criteria for the analysis on public and social good, and, thus, provides a conceptual framework for future research. Additionally, the analysis identifies the broad domains of policy analysis on social and public good for data economics.
Effect of applied electric and magnetic fields on surface roughness in minimum quantity lubrication turning using Fe3O4 nano-ferrofluid
Authors: Khodabandeh Alireza , Abootorabi Mohammad Mahdi
Published: October 2023

Purpose

First, the effect of magnetic field intensity and nano-ferrofluid concentrations on surface roughness was evaluated in magnetic minimum quantity lubrication (MMQL). Then, the effect of lubricant flow rate and nozzle position on surface roughness was investigated in MQL, MMQL, electrostatic MQL (EMQL) and electromagnetic MQL (EMMQL).

Design/methodology/approach

This study examined the performance of MQL under magnetic and electric fields in turning AISI 304 stainless steel in terms of surface roughness and compared the results with those obtained from wet cutting and MQL turning operations. To prepare the nano-ferrofluid used in different states of MQL, Fe3O4 nanoparticles were added to the base fluid.

Findings

The results showed that the surface roughness under the EMMQL technique decreased by 36% and 49.4% on average compared with wet and MQL techniques, respectively. The lubrication technique affected the surface roughness by 90.2%, whereas it was 8.3% for the lubricant flow rate. EMQL and EMMQL techniques had no significant difference in their effects on surface roughness. In the innovative MMQL technique, the nano-ferrofluid concentration of 6% and magnetic field intensity of 93 G resulted in lower surface roughness of the workpiece relative to other counterparts.

Originality/value

Examining previously published studies showed that using nano-ferrofluids under a magnetic field for cooling purposes in machining processes have less considered by researchers. This study applies an innovative method of lubrication under the concurrent effect of magnetic and electric fields, called EMMQL, to improve the efficiency of MQL in machining hard-to-cut materials. For comprehensively inspecting the newly presented method, the effects of several parameters, including the nano-ferrofluid concentration, magnetic field intensity, lubricant flow rate and position of lubricant spray nozzle, on the surface roughness of workpiece in turning of AISI 304 stainless steel are investigated.