bluuebunny/crossref_metadata_2025 huggingface dataset:
tRNA modifications inform tissue specific mRNA translation and codon optimization
Authors: Ando Daisuke , Rashad Sherif , Begley Thomas J , Endo Hidenori , Aoki Masashi , Dedon Peter C , Niizuma Kuniyasu
Published: October 2023

The tRNA epitranscriptome has been recognized as an important player in mRNA translation regulation. Our knowledge of the role of tRNA epitranscriptome in fine-tuning translation codon decoding at tissue or cell levels remains incomplete. Here, we analyzed seven tissues from mice for the expression of tRNA modifications and mature tRNAs as well as mRNA translation and codon decoding. Our analysis revealed distinct enrichment patterns of tRNA modifications in tissues. Queuosine (Q) tRNA modification was most enriched in the brain compared to other tissues, while mitochondrial tRNA modifications and tRNA expression was highest in the heart. Using three different metrics for codon analysis; isoacceptors frequencies, total codon frequencies, and A-site pausing, we revealed a strong bias towards A/T ending codons in most tissues except for the brain. Using this observation, we synthesized, and deliveredin vivo, codon mutated EGFP for Q-codons, where the C-ending Q-codons were replaced with U-ending codons. The protein levels of mutant EGFP were downregulated in liver, which is poor in Q, when NAC codons were exchanged for NAU codons, while in brain EGFP levels did not change. This data shows that understanding tRNA modifications enrichments across tissues is not only essential for understanding codon decoding and bias, but it can also be utilized for optimizing gene and mRNA therapeutics to be more tissue, cell, or condition specific.
“He stepped on my belly” An exploration of Intimate Partner Violence Experience and Coping Strategies among Pregnant Women in Southwestern-Uganda
Authors: Katushabe Eve , Ndinawe JohnBosco , Editor Abeneitwe , Agnes Katusiime , Nakidde Gladys , Asiimwe John Baptist , Batwala Vincent
Published: October 2023

Intimate Partner Violence (IPV) associated with pregnancy remains a challenge globally and in the Ugandan context. However, literature on IPV experiences, support seeking and coping strategies during pregnancy remains limited in Uganda. This study explored the pregnant women’s IPV experiences, support seeking and coping strategies in Southwestern Uganda. Pregnant women with IPV experience during the index pregnancy were purposively approached for in-depth interviews and saturation of data was reached at 25 respondents. Data was analyzed inductively using thematic analysis.

Women voiced experiences of IPV that included partners: spending nights away from home without any communication, refusal of accompaniment for antenatal care contacts, uncomfortable sexual intercourse positions, forced sexual intercourse, being slapped, punched, and kicked, failure to pay bills like rent, children’s school fees, transport money to seek medical care and food. Women preferred sharing IPV experiences with their biological mothers to midwives or any other person and some kept it to themselves. The main support given by their support systems was encouraging the victims to try and maintain their marriage and keeping quiet when the partner starts quarreling. Women coped by confiding in their relatives, keeping silent, self-consolation, tolerance of the perpetrator since they financially depended on them, distracting bad thoughts through thinking about good things like friends, self-blame and praying to God. Pregnant women did not understand the role of midwives in IPV nor did the midwives’ inquire about the IPV experience during Antenatal care contacts.

The findings of this study point to the need for the Health system to incorporate a user friendly IPV screening tool onto the ANC card to enhance routine IPV screening by midwives and recruit counselors and peer supporters to assist midwives in providing individualized psychological support.
Competing risks multi-state model for time-to-event data analysis of HIV/AIDS: A retrospective cohort national datasets, Ethiopia
Authors: Kumsa Tsegaye Hailu , Mulu Andargachew , Mihret Adane , Asfaw Zeytu G.
Published: October 2023

Introduction

When HIV/AIDS patients die from opportunistic infections that cause death to happen more quickly, competing dangers are present. The objective of the current study was to estimate the probability of HIV/AIDS patients dying from competing illnesses such as tuberculosis, diarrhea, other opportunistic infections, and unidentified infections.

Methods

All regional states, including the administrative cities of Addis Abeba and Dire Dawa, a retrospective cohort research was carried out between November 2019 to March 2020. There were 39590 HIV-positive individuals considered. We used competing risk models with a time-to-death horizon of 1212 for the total number of HIV-positive people. A competing event was thought to be death from various causes.

Results

Out of the total 1212 deaths, 542(44.7%) died competing with other opportunistic infection (TE-Esophageal Candidiasis, TO-oral, CT-CNS Toxoplasmosis, CM-Crypotococcal Meningitis…), 421 (34.7%) died due to tuberculosis and the remaining death were unknown/Not specified infection 222(18.3%) and diarrhea 27(2.2%). Rates of mortality caused by tuberculosis, competing with other opportunistic infection, diarrhea and unknown/Not specified were 3.5, 4.5, 0.2 and 1.8 per 1000 person-months, respectively. Responding to combined Antiretroviral Treatment (cART) 6 months after initiation, receiving Pneumocystis Pneumonia (PCP) prophylaxis, and higher CD4 count at diagnosis reduced the hazard of tuberculosis, other opportunistic infection and unknown and diarrhea causes of death. However, older age, late HIV.AIDS diagnosis, and the last HIV/AIDS WHO clinical stages increased the hazard of tuberculosis and other opportunistic disease mortality. Additionally, male gender, older age and last HIV clinical stages increased the mortality HIV/AIDS patients.

Conclusion

The findings of this study demonstrated that TB, an opportunistic infection, was the primary cause of death in HIV/AIDS patients, despite the presence of several competing risks, such as diarrhea, other infections, and an undetermined or unclear cause. It’s important to use effective techniques to quickly detect those who have HIV or AIDS and provide them with care and treatment to increase their chances of surviving.
The experiences and impact of the COVID-19 pandemic on Young Carers: practice implications and planning for future health emergencies
Authors: Hayes D , Fancourt D , Burton A
Published: October 2023

Background

Young Carers faced significant challenges brought on by the COVID-19 pandemic. We explored the impact of the pandemic and associated restrictions on mental health, wellbeing and access to support in Young Carers in the United Kingdom (UK) to understand how to improve services, as well as support this population in future health emergencies.

Method

We conducted 22 qualitative semi-structured interviews from May to November 2021, with 14 Young Carers and 8 staff working in organisations that supported them. Interviews took place remotely over video or telephone call, discussing topics such as experiences of the pandemic on their health, wellbeing and caring responsibilities. We used reflexive thematic analysis to analyse interview transcripts.

Results

We identified 4 overarching themes pertaining to the impact of the pandemic and associated restrictions on mental health, wellbeing, and access to support in Young Carers in the UK: 1) challenges to following the guidelines, 2) changes to and loss of routine, 3) changes in provision of informal and formal support and 4) better understanding of inner resilience and goals. Many participants struggled with their mental health and wellbeing as a result of pandemic related restrictions, impacting on support structures for themselves, as well as the individual cared for. However, positive impacts pertained to additional support from local authority and third sector organisations.

Conclusions

Our findings highlight some of the changes that affected Young Carers during the COVID-19 pandemic. The impact of changes to routine and a reduction in pre-pandemic support were the greatest concerns reported by participants in this study. The additional support provided by local authority and third sector organisations during social restrictions suggests such organisations could play a greater role in supporting this population going forward, and that schools and Governments may wish to put in additional strategies and provisions to protect this population in the future.
Large-Scale Analysis Reveals Racial Disparities in the Prevalence of ADHD and Conduct Disorders
Authors: Shalaby Noha , Sengupta Sourav , Williams Jamal B.
Published: October 2023

Objective

The primary purpose of this study is to highlight trends in the prevalence of Attention Deficit/Hyperactivity Disorders (ADHD) and Conduct Disorders (CD) between non-Hispanic White and non-Hispanic Black populations and identify potential diagnostic disparities between these groups.

Methods

De-identified electronic health record data on the TriNetX platform of patients diagnosed with ADHD, CD, or both between January 2013 and May 2023 from 50 healthcare organizations in the US were used to investigate racial and sex disparities in the prevalence of ADHD and CD diagnoses.

Results

With a cohort of 849,281 ADHD patients and 157,597 CD patients, non-Hispanic Whites were ∼26% more likely to receive ADHD diagnosis and ∼61% less likely to be diagnosed with CD than non-Hispanic Blacks. The mean age of diagnosis of ADHD was over 8 years higher for White patients than for Black patients, with a disproportionately higher number of White patients diagnosed in adulthood, compared to a comparatively negligible number of Blacks diagnosed with ADHD in the same age group. Additionally, Black females were the cohort least likely to be diagnosed with ADHD, while White females were the cohort least likely to be diagnosed with CD.

Conclusions

Race disparities exist between Black and White populations, and sex disparities exist within each population. More information is needed to determine contributors to these differences, although implicit biases and systemic racism may be key contributing factors. Presenting evidence and increasing awareness of culturally relevant diagnoses can reduce unconscious bias and move toward more informed and objective psychiatric evaluations.
Self-supervised deep representation learning of a foundation transformer model enabling efficient ECG-based assessment of cardiac and coronary function with limited labels
Authors: Moody Jonathan B. , Poitrasson-Rivière Alexis , Renaud Jennifer M. , Hagio Tomoe , Alahdab Fares , Al-Mallah Mouaz H. , Vanderver Michael D. , Ficaro Edward P. , Murthy Venkatesh L.
Published: October 2023

Background:Although deep learning methods have shown great promise for identification of structural and functional cardiac abnormalities using electrocardiographic data, these methods are data hungry, posing a challenge for critically important tasks where ground truth labels are relatively scarce. Impaired coronary microvascular and vasomotor function is difficult to identify with standard clinical methods of cardiovascular testing such as coronary angiography and noninvasive single photon emission tomography (SPECT) myocardial perfusion imaging (MPI). Gold standard data from positron emission tomography (PET) are gaining emphasis in clinical guidelines but are expensive and only available in relatively limited centers. We hypothesized that signals embedded within resting and stress electrocardiograms (ECGs) identify individuals with microvascular and vasomotor dysfunction.Methods:We developed and pretrained a self-supervised foundation vision transformer model using a large database of unlabeled ECG waveforms (N=800,035). We then fine-tuned the foundation model for two clinical tasks: the difficult problem of identifying patients with impaired myocardial flow reserve (AI-MFR), and the relatively easier problem of detecting impaired LVEF (AI-LVEF). A second ECG database was labeled with task-specific annotations derived from quantitative PET MPI (N=4167). Diagnostic accuracy of AI predictions was tested in a holdout set of patients undergoing PET MPI (N=1031). Prognostic evaluation was performed in the PET holdout cohort, as well as independent cohorts of patients undergoing pharmacologic or exercise stress SPECT MPI (N=6635).Results:The diagnostic accuracy of AI-MFR with SSL pretraining increased significantly compared tode novosupervised training (AUROC, sensitivity, specificity: 0.758, 70.1%, 69.4% vs. 0.632, 66.1%, 57.3%,p< 0.0001). SSL pretraining also produced a smaller increase in AI-LVEF accuracy (AUROC, sensitivity, specificity: 0.946, 89.4%, 85.9% vs. 0.918, 87.6%, 82.5%,p< 0.02). Abnormal AI-MFR was found to be significantly associated with mortality risk in all three test cohorts (Hazard Ratio (HR) 2.61 [95% CI 1.83, 3.71],p< 0.0001, PET cohort; HR 2.30 [2.03, 2.61],p< 0.0001, pharmacologic stress SPECT cohort; HR 3.76 [2.36, 5.99],p< 0.0001, exercise stress SPECT cohort).Conclusion:SSL pretraining of a vision transformer foundation model enabled identification of signals predictive of impaired MFR, a hallmark of microvascular and vasomotor dysfunction, and impaired LV function in resting and stress ECG waveforms. These signals are powerful predictors of prognosis in patients undergoing routine noninvasive stress testing and could enable more efficient diagnosis and management of these common conditions.
Conversions between noise exposure metrics 24-hour Leq, Ldn, and Lden: the impact of diurnal local bus traffic patterns on population annoyance in the United States
Authors: Seto Edmund , Huang Ching-Hsuan
Published: October 2023

Noise during evening and nighttime hours tends to be associated with high annoyance, which is reflected in the use of community noise exposure metrics, such as the Ldnand Lden, that include penalties during these hours. Transportation noise sources may exhibit distinct diurnal patterns, but the impact of these patterns on different noise metrics has not been thoroughly evaluated, especially within the United States. In this study, we utilized General Transit Feed Specification (GTFS) data from 24 major cities in the U.S. to quantify diurnal traffic patterns for local buses, and the impact of these patterns on differences in noise metrics, such as LDay, LEvening, LNight, Ldn, and Lden, compared to the 24-hour LAeq24, Using mathematical conversions between the noise metrics, we found on average across the cities that the Ldnwas between 2.8 to 3.6 dB higher than the LAeq24, and the Ldenwas also 3.6 to 3.8 dB higher than the LAeq24for noise from local buses. This increase was mainly due to noise during daytime (LDay) that was higher than the 24-hour average noise, and dB penalties added to the Ldnand Ldenmetrics, which compensate for less bus traffic during evening and nighttime hours. We discuss the relevance of these conversions and the observed differences between the 24-hour LAeq24and the Ldnand Lden, which are used for health impact assessments of high annoyance, on public transportation planning.
Immunological variables and tumor types influence one-year survival probability in cancer patients: A comprehensive analysis using logistic regression and decision tree models
Authors: Malizia Alvaro López
Published: October 2023

The present study aimed to explore immunological variables associated with survival, TP53 gene expression, and primary diagnosis in patients with cancer. Based on these variables, logistic regression and decision tree models (lightGBM) were used to model the probability of one-year survival of patients following their initial diagnosis. Logistic regression revealed the significance of primary diagnosis categories such as Malignant Melanoma, Ovarian Cancer, and Glioblastoma as predictor variables. For the classification model, in addition to these tumor types, variables related to the immune system were also found to be important, including tumor cell percentage, stromal cell percentage, lymphocytes, and necrotic cells. In addition, unsupervised classification techniques were employed to explore the numerical dataset. For this methodology, the best clustering cohesion was observed with two groups determined using different algorithms. The clusters generated by k-means and DBSCAN exhibited differences in the proportion of infiltrating lymphocytes, neutrophils, and monocytes.
Engineered yeast cells simulating CD19+ cancers to control CAR T cell activation
Authors: Deichmann Marcus , Schiesaro Giovanni , Ramanathan Keerthana , Zeeberg Katrine , Koefoed Nanna M. T. , Ormhøj Maria , Friis Rasmus U. W. , Gill Ryan T. , Hadrup Sine R. , Jensen Emil D. , Jensen Michael K.
Published: October 2023

Chimeric antigen receptor (CAR) T cells have become an established immunotherapy and show promising results for the treatment of hematological cancers. However, modulation of surface levels of the targeted antigen in cancer cells affects the quality and safety of CAR T cell therapy. Here we present theSyntheticCellularAdvancedSignalAdapter (SCASA) system, based on successful engineering of yeast to simulate cancer cells with tunable surface-antigen densities, as a tool for controlled activation of CAR T cell responses and assessment of antigen density effects. Specifically, we demonstrate I) controllable antigen-densities of CD19 on yeast using G protein-coupled receptors (GPCRs), II) a customizable system allowing choice of signal input and modular pathway engineering for precise fine-tuning of the output, III) synthetic cell-cell communication with CAR T cells and the application of CD19-displaying yeast in the characterization of CAR designs, and IV) more efficient and robust activational control of clinically-derived CAR T cells in comparison to the NALM6 cancer cell line. Based on this yeast-based antigen-presenting cell system, we envision efficient assessment of how varying antigen densities in cancer cells affect CAR T cell responses and ultimately support development of safer and better quality of personalized cancer therapies.
PredictingPseudomonas aeruginosadrug resistance using artificial intelligence and clinical MALDI-TOF mass spectra
Authors: Nguyen Hoai-An , Peleg Anton Y. , Song Jiangning , Antony Bhavna , Webb Geoffrey I. , Wisniewski Jessica A. , Blakeway Luke V. , Badoordeen Gnei Z. , Theegala Ravali , Zisis Helen , Dowe David L. , Macesic Nenad
Published: October 2023

Matrix-assisted laser desorption/ionization–time of flight mass spectrometry (MALDI-TOF MS) is widely used in clinical microbiology laboratories for bacterial identification but its use for prediction of antimicrobial resistance (AMR) remains limited. Here, we used MALDI-TOF MS with artificial intelligence (AI) approaches to successfully predict AMR inPseudomonas aeruginosa, a priority pathogen with complex AMR mechanisms. The highest performance was achieved for modern β-lactam/β-lactamase inhibitor drugs, namely ceftazidime/avibactam and ceftolozane/tazobactam, with area under the receiver operating characteristic curve (AUROC) of 0.86 and 0.87, respectively. As part of this work, we developed dynamic binning, a feature engineering technique that effectively reduces the high-dimensional feature set and has wide-ranging applicability to MALDI-TOF MS data. Compared to conventional methods, our approach yielded superior performance in 10 of 11 antimicrobials. Moreover, we showcase the efficacy of transfer learning in enhancing the performance for 7 of 11 antimicrobials. By assessing the contribution of features to the model’s prediction, we identified proteins that may contribute to AMR mechanisms. Our findings demonstrate the potential of combining AI with MALDI-TOF MS as a rapid AMR diagnostic tool forPseudomonas aeruginosa.
Molecular regulation of PPARγ/RXRα signaling by the novel cofactor ZFP407
Authors: Charrier Alyssa , Ockunzzi Jeremiah , Ghanta Siddharth V. , Buchner David A.
Published: October 2023

Cofactors interacting with PPARγ can regulate adipogenesis and adipocyte metabolism by modulating the transcriptional activity and selectivity of PPARγ signaling. ZFP407 was previously demonstrated to regulate PPARγ target genes such asGLUT4, and its overexpression improved glucose homeostasis in mice. Here, using a series of molecular assays, including protein-interaction studies, mutagenesis, and ChIP-seq, ZFP407 was found to interact with the PPARγ/RXRα protein complex in the nucleus of adipocytes. Consistent with this observation, ZFP407 DNA binding sites significantly overlapped with PPARγ sites, with more than half of ZFP407 binding sites overlapping with PPARγ DNA binding sites. Transcription factor binding motifs enriched in these overlapping sites included GFY-Staf, ELF1, ETS, ELK1, and ELK4, which regulate key functions within adipocytes. Site-directed mutagenesis of frequent PPARγ phosphorylation or SUMOylation sites did not prevent its regulation by ZFP407, while mutagenesis of ZFP407 regions necessary for RXR and PPARγ binding abrogated any impact of ZFP407 on PPARγ activity. These data suggest that ZFP407 controls the activity of PPARγ, but does so independently of post-translational modifications, likely by direct binding, establishing ZFP407 as a newly identified PPARγ cofactor. In addition, ZFP407 was also found to bind to DNA in regions that did not overlap with PPARγ. These DNA binding sites were more significantly enriched for the transcription factor binding motifs of GFY and ZNF143, which may contribute to the non-PPARγ dependent functions of ZFP407 in adipocytes and other cell types.
Dysregulated neuroimmune interactions and sustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids
Authors: Boreland Andrew J. , Stillitano Alessandro C. , Lin Hsin-Ching , Abbo Yara , Hart Ronald P. , Jiang Peng , Pang Zhiping P. , Rabson Arnold B.
Published: October 2023

Human immunodeficiency virus type-1 (HIV-1) associated neurocognitive disorder (HAND) affects up to half of HIV-1 positive patients with long term neurological consequences, including dementia. There are no effective therapeutics for HAND because the pathophysiology of HIV-1 induced glial and neuronal functional deficits in humans remains enigmatic. To bridge this knowledge gap, we established a model simulating HIV-1 infection in the central nervous system using human induced pluripotent stem cell (iPSC) derived microglia combined with sliced neocortical organoids. Upon incubation with two replication-competent macrophage-tropic HIV-1 strains (JRFL and YU2), we observed that microglia not only became productively infected but also exhibited inflammatory activation. RNA sequencing revealed a significant and sustained activation of type I interferon signaling pathways. Incorporating microglia into sliced neocortical organoids extended the effects of aberrant type I interferon signaling in a human neural context. Collectively, our results illuminate the role of persistent type I interferon signaling in HIV-1 infected microglial in a human neural model, suggesting its potential significance in the pathogenesis of HAND.

Highlights of the work

HIV-1 productively infects iPSC-derived microglia and triggers inflammatory activation.

HIV-1 infection of microglia results in sustained type I interferon signaling.

Microglia infected by HIV-1 incorporate into sliced neocortical organoids with persistent type I interferon signaling and disease risk gene expression.
The intracellular domain of the epilepsy-related protein PCDH19 regulates spine density in cortical neurons
Authors: Newbold Sylvia A , Fox Ian WJ , Llinares-Benadero Cristina , Fabra-Beser Jaime , Stebleva Elizaveta , Gil-Sanz Cristina , Martinez-Garay Isabel
Published: October 2023

Mutations in the X-linked cell adhesion molecule Protocadherin 19 (PCDH19) lead to epilepsy with cognitive impairment in heterozygous females and post-zygotic mosaic males. A complete absence of functional protein does not elicit symptoms, indicating a complex physiopathology and a dependence on cellular mosaicism. It is believed that mosaic expression of PCDH19 on neuronal membranes leads to defective cell-cell communication in the brain, but whether further roles beyond cell adhesion are critical for PCDH19 function in the cortex is currently unknown. Here, we characterize the proteolytic processing of PCDH19 in mouse cortical-like embryonic stem cell derived neurons and cortical lysates and show that its intracellular domain interacts with importins to be transported into the nucleus. RNAseq analysis of neurons derived from an engineered mouse embryonic stem cell line further indicates that the intracellular domain of PCDH19 leads to broad changes in the transcriptional landscape that are related to neuronal differentiation processes. Finally, we usein uteroelectroporation to provide the firstin vivodata about the role of this cleaved intracellular domain in upper layer cortical neurons, where it reduces spine density without affecting overall dendritic morphology. Because processing is activity dependent, our results suggest that PCDH19 could act as an activity sensor in a synapse to nucleus signaling pathway involved in synaptic homeostasis.
Streptococcus pyogenesCas9 ribonucleoprotein delivery for efficient, rapid and marker-free gene editing inTrypanosomaandLeishmania
Authors: Corinne Asencio , Perrine Hervé , Pauline Morand , Quentin Oliveres , Alexandra Morel Chloé , Valérie Prouzet-Mauleon , Marc Biran , Sarah Monic , Mélanie Bonhivers , Roy Robinson Derrick , Marc Ouellette , Loïc Rivière , Frédéric Bringaud , Emmanuel Tetaud
Published: October 2023

Kinetoplastids are unicellular eukaryotic flagellated parasites found in a wide range of hosts within the animal and plant kingdoms. They are known to be responsible in humans for African sleeping sickness (Trypanosoma brucei), Chagas disease (Trypanosoma cruzi), and various forms of leishmaniasis (Leishmaniaspp.), as well as several animal diseases with important economic impact (African trypanosomes, includingT. congolense). Understanding the biology of these parasites necessarily implies the ability to manipulate their genomes. In this study, we demonstrate that transfection of a ribonucleoprotein complex, composed of recombinantStreptococcus pyogenesCas9 (SpCas9) and anin vitro-synthesized guide RNA, results in rapid and efficient genetic modifications of trypanosomatids, in marker-free conditions. This approach was successfully developed to inactivate, delete and mutate candidate genes in various stages of the life cycle ofT. bruceiandT. congolense, andLeishmaniapromastigotes. The functionality ofSpCas9 in these parasites now provides, to the research community working on these parasites, a rapid and efficient method of genome editing, without requiring plasmid construction and selection by antibiotics. Importantly, this approach is adaptable to any wild-type parasite, including field isolates.
Incorporation of collagen intoPseudomonas aeruginosaandStaphylococcus aureusbiofilms impedes phagocytosis by neutrophils
Authors: Zhou Xuening , Wells Marilyn J. , Gordon Vernita D.
Published: October 2023

Biofilms are communities of microbes embedded in a matrix of extracellular polymeric substances (EPS). Matrix components can be produced by biofilm organisms and can also originate from the environment and then be incorporated into the biofilm. For example, we have recently shown that collagen, a host-produced protein that is abundant in many different infection sites, can be taken up into the biofilm matrix, altering biofilm mechanics. The biofilm matrix protects bacteria from clearance by the immune system, and some of that protection likely arises from the mechanical properties of the biofilm.

Pseudomonas aeruginosaandStaphylococcus aureusare common human pathogens notable for forming biofilm infections in anatomical sites rich in collagen. Here, we show that the incorporation of Type I collagen intoP. aeruginosaandS. aureusbiofilms significantly hinders phagocytosis of biofilm bacteria by human neutrophils. However, enzymatic treatment with collagenase, which breaks down collagen, can partly or entirely negate the protective effect of collagen and restore the ability of neutrophils to engulf biofilm bacteria. From these findings, we suggest that enzymatic degradation of host materials may be a potential way to compromise biofilm infections and enhance the efficacy of the host immune response without promoting antibiotic resistance. Such an approach might be beneficial both in cases where the infecting species is known and also in cases wherein biofilm components are not readily known, such as multispecies infections or infections by unknown species.
SCFcyclin F- EXO1 axis controls cell cycle dependent execution of double strand break repair
Authors: Yang Hongbin , Fouad Shahd , Smith Paul , Bae Eun Young , Ji Yu , Ess Ava Van , Buffa Francesca M , Fisher Roman , Vendrell Iolanda , Kessler Benedikt M , D’Angiolella Vincenzo
Published: October 2023

Ubiquitination is a crucial post-translational modification required for the proper repair of DNA double-strand breaks (DSBs) induced by ionising radiation (IR). DSBs are mainly repaired through homologous recombination (HR) when template DNA is present and non-homologous end joining (NHEJ) in its absence. Additionally, microhomology-mediated end joining (MMEJ) and single strand annealing (SSA) provide back-up DSBs repair pathways. However, the mechanisms controlling their use remain poorly understood. By employing a high-resolution CRISPR screen of the ubiquitin system after IR, we systematically uncover genes required for cell survival and elucidate a critical role of the E3 ubiquitin ligase SCFcyclinFin cell cycle-dependent DSB repair. We show that SCFcyclinF-mediated EXO1 degradation prevents DNA end resection in mitosis, allowing MMEJ to take place. Moreover, we identify a conserved cyclin F recognition motif, distinct from the one used by other cyclins, with broad implications in cyclin specificity for cell cycle control.
Spatial control of the APC/C ensures the rapid degradation of Cyclin B1
Authors: Cirillo Luca , Young Rose , Veerapathiran Sapthaswaran , Roberti Annalisa , Martin Molly , Abubacar Azzah , Perosa Camilla , Coates Catherine , Muhammad Reyhan , Roumeliotis Theodoros I. , Choudhary Jyoti S. , Alfieri Claudio , Pines Jonathon
Published: October 2023

The proper control of mitosis depends on the ubiquitin-mediated degradation of the right mitotic regulator at the right time. This is under the control of the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase that is regulated by the Spindle Assembly Checkpoint (SAC). The Checkpoint prevents the APC/C from recognizing Cyclin B1, the essential anaphase and cytokinesis inhibitor, until all chromosomes are attached to the spindle. Once chromosomes are attached, Cyclin B1 is rapidly degraded to enable chromosome segregation and cytokinesis. We have a good understanding of how the SAC inhibits the APC/C, but relatively little is known about how the APC/C recognises Cyclin B1 as soon as the SAC is turned off. Here, by combining live cell imaging,in vitroreconstitution, biochemistry, and structural analysis by cryo-electron microscopy, we provide evidence that the rapid recognition of Cyclin B1 in metaphase requires spatial regulation of the APC/C. Using fluorescence cross correlation spectroscopy, we find that Cyclin B1 and the APC/C primarily interact at the mitotic apparatus. We further show that this is because Cyclin B1, like the APC/C, binds to nucleosomes, and identify an ‘arginine-anchor’ in the N-terminus as necessary and sufficient for binding to the nucleosome. Mutating the nucleosome binding motif on Cyclin B1 reduces its interaction with APC/C and delays its degradation, and cells with the mutant, non-nucleosome-binding Cyclin B1 become aneuploid, demonstrating the physiological relevance of our findings. Together, our data demonstrate that mitotic chromosomes constitute a platform to promote the efficient interaction between Cyclin B1 and APC/C and ensure the timely degradation of Cyclin B1 and genomic stability.
Activation of the mitochondrial unfolded protein response regulates the formation of stress granules
Authors: Lopez-Nieto Marta , Sun Zhaozhi , Relton Emily , Safakli Rahme , Freibaum Brian D. , Taylor J Paul , Ruggieri Alessia , Smyrnias Ioannis , Locker Nicolas
Published: October 2023

To rapidly adapt to harmful changes to their environment, cells activate the integrated stress response (ISR). This results in an adaptive transcriptional and translational rewiring, and the formation of biomolecular condensates named stress granules (SGs), to resolve stress. In addition to this first line of defence, the mitochondrial unfolded protein response (UPRmt) activates a specific transcriptional programme to maintain mitochondrial homeostasis. We present evidence that SGs and UPRmtpathways are intertwined and communicate. UPRmtinduction results in eIF2α phosphorylation and the initial and transient formation of SGs, which subsequently disassemble. The induction of GADD34 during late UPRmtprotects cells from prolonged stress by impairing further assembly of SGs. Furthermore, mitochondrial functions and cellular survival are enhanced during UPRmtactivation when SGs are absent, suggesting that UPRmt-induced SGs have an adverse effect on mitochondrial homeostasis. These findings point to a novel crosstalk between SGs and the UPRmtthat may contribute to restoring mitochondrial functions under stressful conditions.

Summary statement

We describe a novel crosstalk between the mitochondrial unfolded protein response and the integrated stress response involving stress granules that protects cells from further stress.
Identification and characterization of intermediate states in mammalian neural crest cell epithelial to mesenchymal transition and delamination
Authors: Zhao Ruonan , Moore Emma L. , Gogol Madelaine M , Unruh Jay R. , Yu Zulin , Scott Allison , Wang Yan , Rajendran Naresh Kumar , Trainor Paul A.
Published: October 2023

Epithelial to mesenchymal transition (EMT) is a cellular process that converts epithelial cells to mesenchymal cells with migratory potential in both developmental and pathological processes. Although originally considered a binary event, EMT in cancer progression involves intermediate states between a fully epithelial and a fully mesenchymal phenotype, which are characterized by distinct combinations of epithelial and mesenchymal markers. This phenomenon has been termed epithelial to mesenchymal plasticity (EMP), however, the intermediate states remain poorly described and it’s unclear whether they exist during developmental EMT. Neural crest cells (NCC) are an embryonic progenitor cell population that gives rise to numerous cell types and tissues in vertebrates, and their formation is a classic example of developmental EMT. An important feature of NCC development is their delamination from the neuroepithelium via EMT, following which NCC migrate throughout the embryo and undergo differentiation. NCC delamination shares similar changes in cellular state and structure with cancer cell invasion. However, whether intermediate states also exist during NCC EMT and delamination remains unknown. Through single cell RNA sequencing, we identified intermediate NCC states based on their transcriptional signature and then spatially defined their locations in situ in the dorsolateral neuroepithelium. Our results illustrate the progressive transcriptional and spatial transitions from premigratory to migratory cranial NCC during EMT and delamination. Of note gene expression and trajectory analysis indicate that distinct intermediate populations of NCC delaminate in either S phase or G2/M phase of the cell cycle, and the importance of cell cycle regulation in facilitating mammalian cranial NCC delamination was confirmed through cell cycle inhibition studies. Additionally, transcriptional knockdown revealed a functional role for the intermediate stage markerDlc1in regulating NCC delamination and migration. Overall, our work identifying and characterizing the intermediate cellular states, processes, and molecular signals that regulate mammalian NCC EMT and delamination furthers our understanding of developmental EMP and may provide new insights into mechanisms regulating pathological EMP.
Single-cell transcriptome and metagenome profiling reveals the genetic basis of rumen functions and convergent developmental patterns in ruminants
Authors: Deng Juan , Liu Ya-Jing , Wei Wen-Tian , Huang Qi-Xuan , Zhao Li-Ping , Luo Ling-Yun , Zhu Qi , Zhang Lin , Chen Yuan , Ren Yan-Ling , Jia Shan-Gang , Lin Yu-Luan , Yang Ji , Lv Feng-Hua , Zhang Hong-Ping , Li Feng-E , Li Li , Li Meng-Hua
Published: October 2023

The rumen undergoes developmental changes during maturation. To characterize this understudied dynamic process, we profiled single-cell transcriptomes of about 308,000 cells from the rumen tissues of sheep and goats at 17 time points. We built comprehensive transcriptome and metagenome atlases from early embryonic to rumination stages, and recapitulated histomorphometric and transcriptional features of the rumen, revealing key transitional signatures associated with the development of ruminal cells, microbiota, and core transcriptional regulatory networks. In addition, we identified and validated potential cross-talk between host cells and microbiomes and revealed their roles in modulating the spatiotemporal expression of key genes in ruminal cells. Cross-species analyses revealed convergent developmental patterns of cellular heterogeneity, gene expression, and cell–cell and microbiome–cell interactions. Finally, we uncovered how the interactions can act upon the symbiotic rumen system to modify the processes of fermentation, fiber digestion, and immune defense. These results significantly enhance understanding of the genetic basis of the unique roles of rumen.
A transferable quantum mechanical energy model for intermolecular interactions using a single empirical parameter
Authors: Spackman Peter R. , Spackman Mark A. , Gale Julian D.
Published: October 2023

The calculation of intermolecular interactions in molecular crystals using model energies provides a unified route to understanding the complex interplay of driving forces in crystallization, elastic properties and more. Presented here is a new single-parameter interaction energy model (CE-1p), extending the previous CrystalExplorer energy model and calibrated using density functional theory (DFT) calculations at the ωB97M-V/def2-QZVP level over 1157 intermolecular interactions from 147 crystal structures. The new model incorporates an improved treatment of dispersion interactions and polarizabilities using the exchange-hole dipole model (XDM), along with the use of effective core potentials (ECPs), facilitating application to molecules containing elements across the periodic table (from H to Rn). This new model is validated against high-level reference data with outstanding performance, comparable to state-of-the-art DFT methods for molecular crystal lattice energies over the X23 set (mean absolute deviation 3.6 kJ mol−1) and for intermolecular interactions in the S66x8 benchmark set (root mean-square deviation 3.3 kJ mol−1). The performance of this model is further examined compared to the GFN2-xTB tight-binding model, providing recommendations for the evaluation of intermolecular interactions in molecular crystal systems.
Designing aerodynamic devices for UAV – lessons learned
Authors: Mieloszyk Jacek , Tarnowski Andrzej , Goetzendorf-Grabowski Tomasz
Published: October 2023

Purpose

Designing new aircraft that are state-of-the-art and beyond always requires the development of new technologies. This paper aims to present lessons learned while designing, building and testing new UAVs in the configuration of the flying wing. The UAV contains a number of aerodynamic devices that are not obvious solutions and use the latest manufacturing technology achievements, such as 3D printing.

Design/methodology/approach

The design solutions were applied on an airworthy aircraft and checked during test flights. The process was first conducted on the smaller UAV, and based on the test outcomes, improvements were made and then applied on the larger version of the UAV, where they were verified.

Findings

A number of practical findings were identified. For example, the use of 3D printing technology for manufacturing integrated pressure ports, investigation of the adverse yaw effect on the flying wing configuration and the effectiveness of winglet rudders in producing yawing moment.

Practical implications

All designed devices were tested in practice on the flying aircraft. It allowed for improved aircraft performance and handling characteristics. Several of the technologies used improved the speed and quality of aerodynamic device design and manufacturing, which also influences the reliability of the aircraft.

Originality/value

The paper presents how 3D printing technology can be utilized for manufacturing of aerodynamic devices. Specially developed techniques for control surface design, which can affect adverse yaw problem and aircraft handling characteristics, were described.
Collaborative technology in a hybrid learning context: exploring feeling at ease and perceived learning among college students
Authors: Hopkins Matt , Lin Meng-Hsien , Nariswari Angeline
Published: October 2023

Purpose

This study explores collaborative technology's effectiveness in facilitating learning in a hybrid (synchronous face-to-face and asynchronous virtual) context. In particular, the study explores the critical role of students' feeling-at-ease, including its drivers and impact on their perception of the technology.

Design/methodology/approach

The study included a classroom intervention in which a collaborative technology, i.e. VoiceThread, was implemented in a hybrid learning context. Online surveys, which included quantitative and qualitative components, were administered at the start and end of the semester to capture student perceptions and experiences with the technology.

Findings

Students who felt more at ease assessed the collaborative technology more positively. While extraversion was marginally associated with initial feeling at ease, technology anxiety was not. When using the technology to post content, students who felt more at ease preferred using audio or video over text. Students' perception of the importance of technology in facilitating their learning was a key mediator in the relationship between feeling less at ease and future intention to use the collaborative technology.

Originality/value

The paper investigates the implementation of a collaborative technology in a hybrid learning context, highlighting the critical role of feeling at ease in impacting its acceptance.
Refugees and asylum seekers in informal and precarious jobs: early labour market insertion from the perspectives of professionals and volunteers
Authors: Dimitriadis Iraklis
Published: October 2023

Purpose

This article aims to explore the engagement of refugees and asylum seekers (RAS) in informal and precarious jobs from a civil society actors' perspective. Despite a burgeoning literature on refugee integration and a focus on institutional integration programmes, little is known about the early insertion of RAS into informal and precarious employment as an alternative to subsidised integration programmes, when these are available.

Design/methodology/approach

This article draws on rich qualitative data collected through in-depth interviews with social workers, volunteers and other professionals supporting migrants.

Findings

Data analysis shows that migrants' insertion in informal jobs and their rejection of integration programmes may be the result of people's need to access financial capital to cover actual and future needs. Although such an engagement may be criticised for hampering RAS’ integration, it can be seen as an important source of agency against insecurity surrounding one's legal status.

Originality/value

This article highlights the importance of legal status precarity in shaping informal workers' agency and perceptions of them, opening up a debate on the relevance of informal work in terms of long-term integration and future migration trajectories.
Multiple interaction strategies for mobile robots based on improved dynamic window approach in unknown dynamic environments
Authors: He Li , Zhang Shuai , Zhang Heng , Yuan Liang
Published: October 2023

Purpose

The purpose of this paper is to solve the problem that mobile robots are still based on reactive collision avoidance in unknown dynamic environments leading to a lack of interaction with obstacles and limiting the comprehensive performance of mobile robots. A dynamic window approach with multiple interaction strategies (DWA-MIS) is proposed to solve this problem.

Design/methodology/approach

The algorithm firstly classifies the moving obstacle movement intention, based on which a rule function is designed to incorporate positive incentives to motivate the robot to make correct avoidance actions. Then, the evaluation mechanism is improved by considering the time cost and future information of the environment to increase the motion states. Finally, the optimal objective function is designed based on genetic algorithm to adapt to different environments with time-varying multiparameter optimization.

Findings

Faced with obstacles in different states, the mobile robot can choose a suitable interaction strategy, which solves the limitations of the original DWA evaluation function and avoids the defects of reactive collision avoidance. Simulation results show that the algorithm can efficiently adapt to unknown dynamic environments, has less path length and iterations and has a high comprehensive performance.

Originality/value

A DWA-MIS is proposed, which increases the interaction capability between mobile robots and obstacles by improving the evaluation function mechanism and broadens the navigation strategy of DWA at a lower computational cost. After real machine verification, the algorithm has a high comprehensive performance based on real environment and provides a new idea for local path planning methods.
Does a conduct disorder factor increment the capacity of the Youth Psychopathic Traits Inventory-Short to predict criminal recidivism?
Authors: Pechorro Pedro , Gomide Paula , DeLisi Matt , Simões Mário
Published: October 2023

Purpose

Recent developments in the psychometric assessment of youth psychopathic traits suggest that the inclusion of a conduct disorder (CD) factor to the traditional three factors of the psychopathy construct may improve the incremental validity of these measures. The purpose of the current study is to examine whether the addition of a CD factor incrementally improves the ability of the Youth Psychopathic Traits Inventory Short version (YPI-S) to predict criminal recidivism.

Design/methodology/approach

A longitudinal quantitative research design was used with a sample detained male youth (N = 214, Mage = 16.4 years, SDage = 1.3 years).

Findings

Results using the area under the curve analysis suggest that the inclusion of a CD factor slightly improves the capacity of the YPI-S to predict one-year general criminal recidivism, but it does not significantly increase its capacity to predict violent criminal recidivism. Results also indicate that a CD scale outperforms the YPI-S, even with an additional CD factor included, in terms of predicting one-year general and violent recidivism.

Practical implications

Self-reported youth psychopathic trait measures, even those that include a CD factor as a fourth factor, should be used with caution when the aim is to predict youth criminal recidivism.

Originality/value

To the best of the authors’ knowledge, this is the first study using a self-reported youth psychopathic traits measure with a CD factor to examine youth criminal recidivism.