bluuebunny/crossref_metadata_2025 huggingface dataset:
Shiella aurantiaca gen. nov., sp. nov., a novel bacterium isolated from activated sludge, and proposal of Shiellaceae fam. nov.
Authors: Liu Bin , Wan Yingying , Liu Le , Lv Yu , Zhang Qi , Cheng Dan , He Jian , Shen Qirong
Published: November 2023

A novel Gram-stain-negative, long rod-shaped, aerobic, non-motile, non-spore-forming and orange-pigmented bacterium, designated LB-30T, was isolated from activated sludge. Growth was observed at 15–40 °C (optimum 30 °C), pH 6.0–9.0 (optimum 7.0) and salinities of 0–3.0 % (w/v; optimum 2.0 %). LB-30T showed less than 89.9 % sequence similarities to the recognized taxa of the order
Cytophagales
. The results of phylogenetic analysis based on 16S rRNA gene sequences and phylogenomic tree indicated that LB-30T formed a distinct lineage within the order

Cytophagales

. The average amino acid identity (AAI) values between LB-30T and members of the related families Cyclobacteriaceae, Fulvivirgaceae, Roseivirgaceae, Reichenbachiellaceae, Cesiribacteraceae,
Cytophagaceae
and Hymenobacteraceae in the order

Cytophagales

were 50.5–54.6 %. The sole respiratory quinone of LB-31T was menaquinone 7 (MK-7). The major polar lipids were phosphatidylethanolamine, aminolipid and four unidentified lipids. The major fatty acids were iso-C15 : 0, iso-C15 : 1G and iso-C17 : 0 3-OH. The DNA G+C content was 43.8 mol%, calculated from the genome sequence. On the basis of differences in the phenotypic, physiological and biochemical characteristics, and distinct phylogenetic relationships, strain LB-30T is proposed to represent a novel species in a novel genus for which the name Shiella aurantiaca gen. nov., sp. nov is proposed, within a novel family Shiellaceae fam. nov. of the order

Cytophagales

. The type strain is LB-30T (=GDMCC 1.3629T= KCTC 92689T).
Anti-persister efficacy of colistin and meropenem against uropathogenic Escherichia coli is dependent on environmental conditions
Authors: Urbaniec Joanna , Getino Maria , McEwan Tahnee B-D. , Sanderson-Smith Martina L. , McFadden Johnjoe , Hai Faisal , La Ragione Roberto , Hassan Marwa M. , Hingley-Wilson Suzie
Published: November 2023

Antibiotic persistence is a phenomenon observed when genetically susceptible cells survive long-term exposure to antibiotics. These ‘persisters’ are an intrinsic component of bacterial populations and stem from phenotypic heterogeneity. Persistence to antibiotics is a concern for public health globally, as it increases treatment duration and can contribute to treatment failure. Furthermore, there is a growing array of evidence that persistence is a ‘stepping-stone’ for the development of genetic antimicrobial resistance. Urinary tract infections (UTIs) are a major contributor to antibiotic consumption worldwide, and are known to be both persistent (i.e. affecting the host for a prolonged period) and recurring. Currently, in clinical settings, routine laboratory screening of pathogenic isolates does not determine the presence or the frequency of persister cells. Furthermore, the majority of research undertaken on antibiotic persistence has been done on lab-adapted bacterial strains. In the study presented here, we characterized antibiotic persisters in a panel of clinical uropathogenic

Escherichia coli

isolates collected from hospitals in the UK and Australia. We found that a urine-pH mimicking environment not only induces higher levels of antibiotic persistence to meropenem and colistin than standard laboratory growth conditions, but also results in rapid development of transient colistin resistance, regardless of the genetic resistance profile of the isolate. Furthermore, we provide evidence for the presence of multiple virulence factors involved in stress resistance and biofilm formation in the genomes of these isolates, whose activities have been previously shown to contribute to the formation of persister cells.
Broad-spectrum of non-serious adverse events following COVID-19 vaccination: A population-based cohort study in Seoul, South Korea
Authors: Suh Jee Hyun , Kim Hong Jin , Kim Min-Ho , Choi Myeong Geun , Chun Eun Mi
Published: November 2023

Much of the current literature on the adverse effects occurring after the coronavirus disease-2019 (COVID-19) vaccination focused on serious adverse events (AEs). Consequently, the non-serious AEs have yet to be comprehensively elucidated. This study aims to investigate the incidence rate and risk of non-serious AEs including gynecological, hematological, dermatological, ophthalmological, otologic, and dental problems following the COVID-19 vaccination. We conducted a population-based cohort study was conducted with the National Health Insurance Service (NHIS) database in Seoul, South Korea. The cumulative incidence rate (cIR) per 10,000 population, Odds ratio, and Hazard ratio (HR) with a 95% Confidence Interval (CI) were measured to assess the non-serious AEs, as reported by the Vaccine Adverse Event Reporting Center, after COVID-19 vaccination. The cIR of non-serious AEs for three months was significantly higher in vaccinated subjects than in non-vaccinated subjects, except for endometriosis. The vaccination significantly increased the risks of all the non-serious AEs except for visual impairment. The risk of inner ear disease showed the highest HRs (HR [95% CI] = 2.37 [2.15-2.60]) among the non-serious AEs following COVID-19 vaccination. Among the vaccinated subjects, heterologous vaccination was associated with the increased risk of most of the non-serious AEs. The three-month risks of incidental non-serious AEs are substantially higher in the COVID-19 vaccinated subjects than in non-vaccinated controls. Our findings suggested that vaccinated subjects with predisposition are potentially vulnerable to the occurrence of broad-spectrum AEs although the COVID-19 vaccines may not be serious.
MetaNorm: Incorporating Meta-analytic Priors into Normalization of NanoString nCounter Data
Authors: Barth Jackson , Yang Yuqiu , Xiao Guanghua , Wang Xinlei
Published: November 2023

Non-informative or diffuse prior distributions are widely employed in Bayesian data analysis to maintain objectivity. However, when meaningful prior information exists and can be identified, using an informative prior distribution to accurately reflect current knowledge may lead to superior outcomes and great efficiency. We propose MetaNorm, a Bayesian algorithm for normalizing NanoString nCounter gene expression data. MetaNorm is based on RCRnorm, a powerful method designed under an integrated series of hierarchical models that allow various sources of error to be explained by different types of probes in the nCounter system. However, a lack of accurate prior information, weak computational efficiency, and instability of estimates that sometimes occur weakens the approach despite its impressive performance. MetaNorm employs priors carefully constructed from a rigorous meta-analysis to leverage information from large public data. Combined with additional algorithmic enhancements, MetaNorm improves RCRnorm by yielding more stable estimation of normalized values, better convergence diagnostics and superior computational efficiency. R Code for replicating the meta-analysis and the normalization function can be found at github.com/jbarth216/MetaNorm.
Microplastics dysregulate innate immunity in the SARS-CoV-2 infected lung
Authors: Bishop Cameron R. , Yan Kexin , Nguyen Wilson , Rawle Daniel J. , Tang Bing , Larcher Thibaut , Suhrbier Andreas
Published: November 2023

Global microplastic (MP) pollution is now well recognized, with humans and animals consuming and inhaling MPs on a daily basis. Herein we described the effects of azide-free, 1 µm polystyrene MP beads co-delivered into lungs with a SARS-CoV-2 omicron BA.5 inoculum using a mouse model of mild COVID-19. Lung virus titres and viral RNA levels were not significantly affected by MPs, with overt clinical or histopathological changes also not observed. However, RNA-Seq of infected lungs revealed that MP exposure suppressed innate immune responses at 2 days post infection (dpi) and increased pro-inflammatory signatures at 6 dpi. The cytokine profile at 6 dpi showed a significant correlation with the ‘cytokine release syndrome’ signature seen in some severe COVID-19 patients. This study adds to a growing body of literature suggesting that MPs can dysregulate inflammation in specific disease settings.

Graphical Abstract

HIGHLIGHTS

A single inoculation of microplastics dysregulated SARS-CoV-2 lung inflammation

At the peak of SARS-CoV-2 infection microplastics decreased early innate responses

Later post infection microplastics promoted a “cytokine release syndrome” signature

A key mechanism may involve the inhibition of the phagocytosis of infected cells

Azide-free microplastics were used, with no elevated ROS responses identified

Postulated mechanisms whereby microplastics might decrease the proinflammatory responses 2 days after SARS-CoV-2 infection, yet promote the proinflammatory ‘cytokine release syndrome’ signature at 6 days post infection.
Causal Associations of Sleep Apnea with Alzheimer’s Disease and Cardiovascular Disease: a Bidirectional Mendelian Randomization Analysis
Authors: Cavaillès Clémence , Andrews Shea J. , Leng Yue , Chatterjee Aadrita , Daghlas Iyas , Yaffe Kristine
Published: November 2023

Background

Sleep apnea (SA) has been linked to an increased risk of dementia in numerous observational studies; whether this is driven by neurodegenerative, vascular or other mechanisms is not clear. We sought to examine the bidirectional causal relationships between SA, Alzheimer’s disease (AD), coronary artery disease (CAD), and ischemic stroke using Mendelian randomization (MR).

Methods

Using summary statistics from four recent, large genome-wide association studies of SA (n=523,366), AD (n=64,437), CAD (n=1,165,690), and stroke (n=1,308,460), we conducted bidirectional two-sample MR analyses. Our primary analytic method was fixed-effects inverse variance weighted MR; diagnostics tests and sensitivity analyses were conducted to verify the robustness of the results.

Results

We identified a significant causal effect of SA on the risk of CAD (odds ratio (ORIVW) =1.35 per log-odds increase in SA liability, 95% confidence interval (CI) =1.25-1.47) and stroke (ORIVW=1.13, 95% CI =1.01-1.25). These associations were somewhat attenuated after excluding single-nucleotide polymorphisms associated with body mass index (BMI) (ORIVW=1.26, 95% CI =1.15-1.39 for CAD risk; ORIVW=1.08, 95% CI =0.96-1.22 for stroke risk). SA was not causally associated with a higher risk of AD (ORIVW=1.14, 95% CI =0.91-1.43). We did not find causal effects of AD, CAD, or stroke on risk of SA.

Conclusions

These results suggest that SA increased the risk of CAD, and the identified causal association with stroke risk may be confounded by BMI. Moreover, no causal effect of SA on AD risk was found. Future studies are warranted to investigate cardiovascular pathways between sleep disorders, including SA, and dementia.
Prospects and Challenges for Graphene Drums As Sensors Of Individual Bacteria
Authors: Rosłoń I.E. , Japaridze A. , Naarden L. , Smeets L. , Dekker C. , van Belkum A. , Steeneken P.G. , Alijani F.
Published: November 2023

Graphene-drum-enabled nanomotion detection can play an important role in probing life at the nanoscale. By combining micro- and nanomechanical systems with optics, nanomotion sensors bridge the gap between mechanics and cellular biophysics. They have allowed investigation of processes involved in metabolism, growth, and structural organisation of a large variety of microorganisms, ranging from yeasts to bacterial cells. Using graphene drums, these processes can now be resolved at the single-cell level. In this perspective, we discuss the key achievements of nanomotion spectroscopy, and peek forward into the prospects for application of this single-cell technology in clinical settings. Furthermore, we discuss the steps required for implementation and look into applications beyond microbial sensing.
Seasonal Human Coronaviruses OC43, 229E, and NL63 Induce Cell Surface Modulation of Entry Receptors and Display Host Cell-Specific Viral Replication Kinetics
Authors: Siragam Vinayakumar , Maltseva Mariam , Castonguay Nicolas , Galipeau Yannick , Srinivasan Mrudhula Madapuji , Soto Justino Hernandez , Dankar Samar , Langlois Marc-André
Published: November 2023

The emergence of the COVID-19 pandemic prompted increased interest in seasonal human coronaviruses. 229E, OC43, NL63 and HKU1 are endemic seasonal coronaviruses that cause the common cold and are associated with generally mild respiratory symptoms. In this study, we identified cell lines that exhibited cytopathic effects (CPE) upon infection by three of these coronaviruses and characterized their viral replication kinetics and the effect of infection on host surface receptor expression. We found that NL63 produced CPE in LLC-MK2 cells, while OC43 produced CPE in MRC-5, HCT-8 and WI-38 cell lines, while 229E produced CPE in MRC-5 and WI-38 by day 3 post-infection. We observed a sharp increase in nucleocapsid and spike viral RNA (vRNA) from day 3 to day 5 post-infection for all viruses, however the abundance and the proportion of vRNAs copies measured in the supernatants and cell lysates of infected cells varied considerably depending on the virus-host cell pair. Importantly, we observed modulation of coronavirus entry and attachment receptors upon infection. Infection with 229E and OC43 led to a downregulation of CD13 and GD3, respectively. In contrast, infection with NL63, and also with OC43, lead to an increase in ACE2 expression. Attempts to block entry of NL63 using either soluble ACE2 or anti-ACE2 monoclonal antibodies demonstrated the potential of these strategies to greatly reduce infection. Overall, our results enable a better understanding of seasonal coronaviruses infection kinetics in permissive cell lines, and reveal entry receptor modulation that may have implications in facilitating co-infections with multiple coronaviruses in humans.

IMPORTANCE

Seasonal human coronavirus are an important cause of the common cold associated with generally mild upper respiratory tract infections that can result in respiratory complications for some individuals. There are no vaccines available for these viruses, with only limited antiviral therapeutic options to treat the most severe cases. A better understanding of how these viruses interact with host cells is essential to identify new strategies to prevent infection-related complications. By analyzing viral replication kinetics in different permissive cell lines, we find that cell-dependent host factors influence how viral genes are expressed and virus particles released. We also analyzed entry receptor expression on infected cells and found that these can be up or down modulated depending on the infecting coronavirus. Our findings raise concerns over the possibility of infection enhancement upon co-infection by some coronaviruses, which may facilitate genetic recombination and the emergence of new variants and strains.
Human coronavirus OC43 infection remodels Connexin 43 mediated gap junction intercellular communicationin vitro
Authors: Karmakar Souvik , Sarma Jayasri Das
Published: November 2023

β-coronaviruses cause acute infection in the upper respiratory tract, resulting in various symptoms and clinical manifestations. OC43 is a human β-coronavirus that induces mild clinical symptoms and can be safely studied in the BSL2 laboratory. Due to its low risk, OC43 can be a valuable and accessible model for understanding β-coronavirus pathogenesis. One potential target for limiting virus infectivity could be gap junction-mediated communication. This study aims to unveil the status of cell-to-cell communications through gap junctions in human β-coronavirus infection. Infection with OC43 leads to reduced expression of Cx43 in A549, a lung epithelial carcinoma cell line. Infection with this virus also showed a significant ER and oxidative stress increase. Internal localization of Cx43 is observed post OC43 infection in the ERGIC region, which impairs the gap junction communication between two adjacent cells, confirmed by Lucifer yellow dye transfer assay. It also affects hemichannel formation, as depicted by the EtBr uptake assay. Altogether, these results suggest that several physiological changes accompany OC43 infection in A549 cells and can be considered an appropriate model system for understanding the differences in gap junction communication post-viral infections. This model system can provide valuable insights for developing therapies against human β-coronavirus infections.

Importance

The enduring impact of the recent SARS-CoV-2 pandemic underscores the importance of studying human β-coronaviruses, advancing our preparedness for future coronavirus infections. Due to SARS-CoV-2 being highly infectious, another human β-coronavirus OC43 can be considered as an experimental model. One of the crucial pathways that can be considered is gap junction communication, as it is vital for cellular homeostasis. Our study seeks to understand the change in Cx43-mediated cell-to-cell communication during human β-coronavirus OC43 infection.In vitrostudies showed the downregulation of the gap junction protein Cx43 and the upregulation of endoplasmic reticulum and oxidative stress markers post-OC43 infection. Furthermore, OC43 infection causes impairment of functional hemichannel and gap junction formation. Overall, this current study infers that OC43 infection reshapes intercellular communication, suggesting that this pathway may be a promising target for designing highly effective therapeutics against human coronaviruses by regulating Cx43 expression.
A global study of the geographic range size of epiphytes
Authors: Svahnström Vida J. , Lughadha Eimear Nic , Forest Félix , Leão Tarciso C.C.
Published: November 2023

Epiphytes have long been considered to have larger geographic range sizes than terrestrial plants, yet evidence for this claim comes from studies at restricted geographic and taxonomic scales and is contrary to that of some recent studies. We examined if epiphytes have larger or smaller range sizes than terrestrial plants and tested if epiphytism is a likely driver of differences in range size globally across angiosperms. We integrated global datasets on angiosperm taxonomy, distribution, and lifeform to calculate three range size metrics. We tested if there were significant differences in mean range size between epiphytes and terrestrial plants across angiosperms and within epiphyte-rich families using ordinary and phylogenetic regression models. On average, epiphytes have larger range sizes than closely related terrestrial species, supporting the hypothesis that epiphytism favours dispersal into larger areas. However, species in families where epiphytism is prevalent tend to have small range sizes regardless of their lifeform. A high proportion of epiphytes and their close relatives are rare or have vulnerably small range sizes, yet epiphytism per se does not cause rarity. Evolutionary histories and shared traits of epiphyte-rich lineages likely underlie the observed rarity and small ranges.
PROTACable is an Integrative Computational Pipeline of 3-D Modeling and Deep Learning to Automate the De Novo Design of PROTACs
Authors: Mslati Hazem , Gentile Francesco , Pandey Mohit , Ban Fuqiang , Cherkasov Artem
Published: November 2023

Proteolysis-targeting chimeras (PROTACs) that engages two biological targets at once is a promising technology in degrading clinically relevant protein targets. Since factors that influence the biological activities of PROTACs are more complex than those of a small molecule drug, we explored a combination of computational chemistry and deep learning strategies to forecast PROTAC activity and enable automated design. A new method named PROTACable was developed for de novo design of PROTACs, which includes a robust 3-D modeling workflow to model PROTAC ternary complexes using a library of E3 ligase and linker and an SE(3)-equivariant graph transformer network to predict the activity of newly designed PROTACs. PROTACable is available athttps://github.com/giaguaro/PROTACable/.
Cellular zinc status alters chromatin accessibility and binding of transcription factor p53 to genomic sites
Authors: Damon Leah J. , Ocampo Daniel , Sanford Lynn , Jones Taylor , Allen Mary A. , Dowell Robin D. , Palmer Amy E.
Published: November 2023

Zinc (Zn2+) is an essential metal required by approximately 2500 proteins. Nearly half of these proteins act on DNA, including > 850 human transcription factors, polymerases, DNA damage response factors, and proteins involved in chromatin architecture. How these proteins acquire their essential Zn2+cofactor and whether they are sensitive to changes in the labile Zn2+pool in cells remain open questions. Here, we examine how changes in the labile Zn2+pool affect chromatin accessibility and transcription factor binding to DNA. We observed both increases and decreases in accessibility in different chromatin regions via ATAC-seq upon treating MCF10A cells with elevated Zn2+or the Zn2+-specific chelator tris(2-pyridylmethyl)amine (TPA). Transcription factor enrichment analysis was used to correlate changes in chromatin accessibility with transcription factor motifs, revealing 477 transcription factor motifs that were differentially enriched upon Zn2+perturbation. 186 of these transcription factor motifs were enriched in Zn2+and depleted in TPA, and the majority correspond to Zn2+finger transcription factors. We selected TP53 as a candidate to examine how changes in motif enrichment correlate with changes in transcription factor occupancy by ChIP-qPCR. Using publicly available ChIP-seq and nascent transcription datasets, we narrowed the 50,000+ ATAC-seq peaks to 2164 TP53 targets and subsequently selected 6 high-probability TP53 binding sites for testing. ChIP-qPCR revealed that for 5 of the 6 targets, TP53 binding correlates with the local accessibility determined by ATAC-seq. These results demonstrate that changes in labile zinc directly alter chromatin accessibility and transcription factor binding to DNA.
Gain of function inlinc-133compensates fordaf-18/PTENloss and rescues survival
Authors: Huang Wei , Dai Fangzhou , Zhang Lu , Yin Xue , Qu Zhi , Zheng Shanqing
Published: November 2023

DAF-18, homology of PTEN, possess tumor suppressor activity. Loss ofdaf-18causes cell growth in L1 diapauseC. elegansis well studied; however, the reason why survival is dramatically shortened is not well elaborated. We found thatlinc-133gain of function can fully restore the shortened survival caused bydaf-18loss. When lipid phosphatase activity of DAF-18 is defective, thelinc-133gain of function interacts with 14-3-3 proteins to obstruct DAF-16 translocation from the nucleus to the cytoplasm. However, the dysfunction of protein phosphatase activity of DAF-18 caused high levels of aggregated proteins. Thelinc-133gain of function can induce HSP chaperones to select and process the aggregated proteins for degradation through ubiquitination. Our work demonstrates that protein homeostasis controlled by the protein phosphatase activity of DAF-18 is the main factor affecting survival and identifies a new function of thelinc-133gene, which can compensate for the loss ofdaf-18.
Epigenetic age acceleration is related to cognition and cognitive decline in the Elderly: Results of the Austrian Stroke Prevention Study
Authors: Gampawar Piyush , Kumar Veeranki Sai Pavan , Petrovic Katja-Elisabeth , Schmidt Reinhold , Schmidt Helena
Published: November 2023

Epigenetic clocks, an estimate of biological age based on DNA methylation (DNAmAge) are gaining prominence as potential markers of brain ageing. However, consensus is lacking as the repertoire of DNAmAges expands, particularly concerning their ability to predict age-related cognitive changes. In our cohort of 785 elderly, we examined 11 DNAmAges, evaluating their associations with brain ageing in cross-sectional and longitudinal settings. Our results highlighted DNAmAges as strong predictors of cognitive change compared to baseline cognition, albeit varying performance across cognitive domains. DunedinPACE excelled in predicting baseline cognition, while Zhang’s clocks and principal component-based PhenoAge (PCPheno) performed best in predicting cognitive decline. DNAmAges elucidated substantial cognitive variability, matching or surpassing the predictive power of vascular risk factors and ApoE4 genotypes. Notably, in ApoE4 carriers, Zhang’s clock and PCPheno exhibited significantly larger effects, explaining over five times the variability in memory decline compared to non-carriers.
ALifelikeguided journey through the pathophysiology of pulmonary hypertension - from measured metabolites to the mechanism of action of drugs
Authors: Weinstein Nathan , Carlsen Jørn , Schulz Sebastian , Stapleton Timothy , Henriksen Hanne Hee , Travnik Evelyn , Johansson Pär Ingemar
Published: November 2023

Abstract

Pulmonary hypertension (PH) is a pathological condition that affects approximately 1% of the population. The prognosis for many patients is poor, even after treatment. Our knowledge about the pathophysiological mechanisms that cause or are involved in the progression of PH is incomplete. Additionally, the mechanism of action of many drugs used to treat pulmonary hypertension, including sotatercept, requires elucidation. Using our graph-powered knowledge mining softwareLifelikein combination with a very small patient metabolite data set, we demonstrate how we derive detailed mechanistic hypotheses on the mechanisms of PH pathophysiology and clinical drugs. In PH patients, the concentration of hypoxanthine, 12(S)-HETE, glutamic acid, and sphingosine 1 phosphate is significantly higher, while the concentration of L-arginine and L-histidine is lower than in healthy controls. Using the graph-based data analysis, gene ontology, and semantic association capabilities ofLifelike, led us to connect the differentially expressed metabolites with G-protein signaling and SRC. Then, we associated SRC with IL6 signaling. Subsequently, we found associations that connect SRC, and IL6 to Activin and BMP signaling. Lastly, we analyzed the mechanisms of action of several existing and novel pharmacological treatments for PH.Lifelikeelucidated the interplay between G-protein, interleukin 6, activin, and BMP signaling. Those pathways regulate hallmark pathophysiological processes of PH, including vasoconstriction, endothelial barrier function, cell proliferation, and apoptosis. The results highlight the importance of SRC, ERK1, AKT, and MLC activity in PH. The molecular pathways affected by existing and novel treatments for PH also converge on these molecules. Importantly, sotatercept affects SRC, ERK1, AKT, and MLC simultaneously. The present study shows the power of mining knowledge graphs usingLifelike’s diverse set of data analytics functionalities for developing knowledge-driven hypotheses on PH pathophysiological and drug mechanisms and their interactions. We believe thatLifelikeand our presented approach will be valuable for future mechanistic studies of PH, other diseases, and drugs.
The role of systemic therapies in current and emerging opportunities for de-intensification in melanoma: a scoping review protocol
Authors: Soon Jennifer A , Franchini Fanny , Ijzerman Maarten , McArthur Grant A
Published: November 2023

Objective

The purpose of this scoping review is to identify the role of systemic therapies in current and emerging opportunities to de-intensify systemic treatment of cutaneous melanoma. It will also seek to comment on the proportion of studies that include patient-reported outcomes and quality of life measures.

Introduction

With healthcare costs rising, focus is shifting towards maximising health outcomes per dollar. One approach to optimising value is through de-intensification, which is the rationalisation of routine treatment without compromising patient outcomes. Since 2013, successful clinical trials of high-cost immune checkpoint, BRAF and MEK inhibition have led to these drugs becoming ubiquitous in melanoma management. Pipeline therapies such as relatlimab and Tumour Infiltrating Lymphocyte (TIL) therapy are expected to have a similar or even greater cost. We hypothesize that neoadjuvant and response-directed strategies will be identified as well as the emerging potential of prognostic and predictive tools.

Inclusion criteria

This review aims to include studies of adult patients with cutaneous melanoma that report on de-escalation or de-intensification of internationally accepted standard-of-care systemic therapies or the use of systemic therapies to de-intensify subsequent surgery or radiotherapy. Systemic treatment across any stage of disease will be considered. A full-text English-language version must be available for a study to be eligible.

Methods

A systematic search strategy has been developed for MEDLINE, EMBASE and PubMed from 1 January 2013 to 30 June 2023. Additional texts will be sourced from grey literature, Google Scholar and reference scanning. Two authors will screen abstracts and full texts facilitated by the Covidence software. Disagreements will be resolved by consensus or a third reviewer. The first author (JS) will perform data extraction whilst a second author (FF) will review a random selection of papers to ensure consistent interpretation. De-intensification strategies will be categorised by concept, potential impact on resource utilisation and patient outcomes, and strength of evidence. Data will be synthesised qualitatively and quantitatively. Results will be reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR).

The results of this scoping review will directly inform a melanoma consumer and clinician survey exploring their perspectives on de-intensification strategies.
Association Between Major Depressive Disorder and the Development of Cerebral Small Vessel Disease: A Mendelian Randomization Study
Authors: Lu Ting , Luo Lijun , Yang Jie , Li Yueying , Chen Daiyi , Sun Haiyang , Liao Huijuan , Zhao Wen , Ren Zhixuan , Xu Yan , Yu Shiyao , Cheng Xiao , Sun Jingbo
Published: November 2023

Background

Although observational studies indicate a complex, bidirectional association between major depressive disorder (MDD) and cerebral small vessel disease (CSVD), the results are frequently inconsistent. This study investigated the potential correlation of MDD with both CSVD clinical outcomes and imaging markers, utilizing a bidirectional Mendelian randomization (MR) study design.

Methods

Instrumental variables for both MDD and CSVD were extracted from the latest or most extensive genome-wide association study (GWAS) data available for each phenotype. Clinical outcomes and imaging markers of CSVD were defined using several parameters. The inverse variance weighting (IVW) method with additional sensitivity and heterogeneity analyses was used. Furthermore, a separate GWAS for depression was used to validate our significant findings.

Results

In the forward MR analyses, the genetically predicted risk of MDD was positively associated with two CSVD phenotypes showing microscopic white matter (WM) damage: mean diffusivity (IVW OR = 2.191, 95 % CI 1.226 to 3.917, p = 0.008) and WM-enlarged perivascular space (OR = 1.053 95 % CI 1.006 to 1.101, p = 0.026). The use of an independent database for depression yielded no significant risk of depression associated with these two CSVD traits. Furthermore, reverse MR analyses showed no evidence of reverse causality between MDD and an altered CSVD risk.

Conclusions

This study utilizing MR imaging findings supports a substantial causal association between MDD and CSVD-related indicators of impaired WM microstructure. It is necessary to exercise caution when extending these results to individuals with depression.
PREDICTING LEVEL OF COMPLIANCE WITH INFECTION PREVENTION AND CONTROL PRACTICES AMONG HEALTHCARE WORKERS IN SOUTHERN NIGERIA USING ORDINAL LOGISTIC REGRESSION MODEL
Authors: Onyeloili Maureen C
Published: November 2023

Introduction

Adherence to infection prevention and control guidelines is critical to improving the quality of hospital care based on their efficacy in reducing the occurrence of infections that compromise patients’ outcomes. However, the impact of predictors on IPC compliance among healthcare workers has not been adequately reported.

Objectives

This study aims to demonstrate the utility of the Ordinal Logistic regression model in identifying the impact of personal and organizational characteristics on health workers’ level of compliance with infection prevention and control at the University of Port Harcourt Teaching Hospital.

Methods

A cross-sectional study design using a self-administered questionnaire was adopted. A sample of 235 respondents was chosen using a proportionate stratified random sampling method. We analyzed data using descriptive statistics and the ordinal Logistic regression model.

Result

The study result shows that IPC compliance among Health workers in UPTH is high, 77%. Predictors of compliance were found to be age group 35-45years (AOR= 7.679, CI= 1.214 -48.577), training (AOR=0.401, CI: 0.189, 0.849), knowledge, (AOR= 0.45, CI: 0.207, 0.978), management support (AOR=0.45, CI 0.16, 0.968) as they were found to be statistically significant with the level of compliance with infection prevention and control.

Conclusion

There is relatively high Compliance with Infection Prevention and Control; this can be further improved through improved management commitment and increased surveillance of health workers.

KEY MESSAGE

What is already known on this topic: Several studies conducted have reported various factors affecting compliance with infection prevention and control among healthcare workers.

What this study adds:The impact of the predictors on IPC compliance among healthcare workers has not been adequately reported. Hence, there is a methodology gap in the literature. The findings of this study gave insight and quantified the contribution of each predictor to Infection Prevention and Control compliance level, thus, deploying epidemiological and statistical methodology in Infection Prevention and Control studies.

How this study might affect research, practice or policy:The study provides information that serves as a proactive guide on resource allocation and areas of improvement in the Infection Prevention and Control Compliance program for program evaluators, facility managers, health agencies, stakeholders, and other policymakers. It provides researchers with guidance on adopting epidemiological methodology in conducting evidence-based studies.
Nurses’ Satisfaction with and Demand for the National Cancer Patient Home-Care Pilot Program
Authors: Kim Jung Ha , Lee Jang Won , Kim Jung Yoon , Hong Yong Eun , Jang Sol Bi , Lee Woo Jeong , Oh Kyung Hee , Kim Young Ae
Published: November 2023

In December 2021, the “National Cancer Patient Home-Care Pilot Program” was launched in South Korea. However, there were medical institutions with low participation and where services were not provided. Therefore, this study aimed to investigate the progress of, satisfaction with, and needs of nurses’ regarding a pilot program for home care of cancer patients with a stoma. Data were collected through a survey administered to nurses from November 13, 2022, to January 19, 2023; a total of 207 nurses responded. After excluding non-answers, 196 nurses were included in the final study population. The questionnaire sought information on the characteristics of the respondent, status of management of stoma patients, status of the home-care pilot program, satisfaction with the program, and needs of the nurses. The data were analyzed using descriptive statistics. A total of 196 nurses participated in the survey, of whom 42 nurses (21.4%) participated in the home-care pilot program. Thirty-five nurses (85.4 %) were satisfied with the home-care pilot program. Thirty nurses (71.4%) reported that implementation of home care had to be expanded and standards of care improved. To vitalize and expand the pilot program for home care for cancer patients with a stoma, better medical services must be provided by improving the medical fee standard. This will enable more patients and medical institutions to participate in the pilot program.
The potassium channel subunit KV1.8 (Kcna10) is essential for the distinctive outwardly rectifying conductances of type I and II vestibular hair cells
Authors: Martin Hannah R , Lysakowski Anna , Eatock Ruth Anne
Published: November 2023

In amniotes, head motions and tilt are detected by two types of vestibular hair cells (HCs) with strikingly different morphology and physiology. Mature type I HCs express an unusual potassium conductance, gK,L, that activates negative to resting potential, conferring very negative resting potentials and low input resistances. These properties distinguish type I HCs from type II HCs in the same vestibular epithelia and from all other HCs. Following unsatisfactory efforts to identify the unusual gK,L channels, clues emerged pointing to KV1.8 (KCNA10) subunits of the Shaker voltage-gated K channel family. With whole-cell recordings from hair cells in utricles of KV1.8-null mice and their wildtype and heterozygote littermates, we show that KV1.8 is necessary for gK,L. Unexpectedly, KV1.8 is also required for the KV conductances of utricular type II HCs: a fast-inactivating A conductance and delayed rectifier that activate positive to resting potential. The distinct properties of the three KV1.8-dependent conductances may reflect different mixing with other KV subunits that are reported to be differentially expressed in type I and II HCs. In HCs of both types, residual outwardly rectifying conductances include KV7 (KCNQ) channels. Current clamp records show that KV1.8-null type II HCs have more electrical resonance and that, in both cell types, KV1.8-dependent conductances speed up and and dampen responses. gK,L's properties may enhance non-quantal transmission onto calyceal afferent terminals, another type I-specific attribute. Such mechanisms to enhance the speed of receptor potentials and afferent transmission may have evolved under pressure from vestibular challenges experienced as vertebrates moved onto land and air.
Benchmarking Machine Learning Methods for Synthetic Lethality Prediction in Cancer
Authors: Feng Yimiao , Long Yahui , Wang He , Ouyang Yang , Li Quan , Wu Min , Zheng Jie
Published: November 2023

Synthetic lethality (SL) is a type of genetic interaction that occurs when defects in two genes cause cell death, while a defect in a single gene does not. Targeting an SL partner of a gene mutated in cancer can selectively kill tumor cells. Traditional wet-lab experiments for SL screening are resource-intensive. Hence, many computational methods have been developed for virtual screening of SL gene pairs. This study benchmarks recent machine learning methods for SL prediction, including three matrix factorization and eight deep learning models. We scrutinize model performance using various data splitting scenarios, negative sample ratios, and negative sampling methods on both classification and ranking tasks to assess the models’ generalizability and robustness. Our benchmark analyzed performance differences among the models and emphasized the importance of data and real-world scenarios. Finally, we suggest future directions to improve machine learning methods for SL discovery in terms of predictive power and interpretability.
Partial resistance to thyroid hormone-induced tachycardia and cardiac hypertrophy in mice lacking thyroid hormone receptor β
Authors: Dore Riccardo , Sentis Sarah Christine , Johann Kornelia , Lopez-Alcantara Nuria , Resch Julia , Moeller Lars Christian , Fuehrer Dagmar , Obermayer Benedikt , Opitz Robert , Mittag Jens
Published: November 2023

Background

Thyroid hormones regulate cardiac functions mainly via direct actions in the heart and binding to the thyroid hormone receptor (TR) isoforms α1 and β. While the role of the most abundantly expressed isoform, TRα1, is widely studied and well characterized, the role of TRβ in regulating heart functions is still poorly understood, primarily due to the accompanying elevation of circulating thyroid hormone in mice lacking TRβ (TRβ-KO). However, their hyperthyroidism is ameliorated at thermoneutrality, which allows studying the role of TRβ without this confounding factor.

Methods

Here we non-invasively monitored heart rate in TRβ-KO mice over several days using radiotelemetry at different housing temperatures (22°C and 30°C), and upon T3 administration in comparison to wildtype animals.

Results

TRβ-KO mice displayed normal average heart rate at both 22°C and 30°C with only minor changes in heart rate frequency distribution, which was confirmed by independent electrocardiogram recordings in freely-moving conscious mice. Parasympathetic nerve activity was, however, impaired in TRβ-KO mice at 22°C, and only partly rescued at 30°C. As expected, oral treatment with pharmacological doses of T3 at 30°C led to tachycardia in wildtypes, accompanied by broader heart rate frequency distribution and increased heart weight, while TRβ-KO mice showed blunted tachycardia, as well as resistance to changes in heart rate frequency distribution and heart weight. At the molecular level, these observations were paralleled by a blunted cardiac mRNA induction of several important genes, including the pacemaker channelsHcn2andHcn4, as well asKcna7.

Conclusions

The phenotyping of TRβ-KO mice conducted at thermoneutrality allows novel insights on the role of TRβ in cardiac functions in absence of the usual confounding hyperthyroidism. Even though TRβ is expressed at lower levels than TRα1 in the heart, our findings demonstrate an important role for this isoform in the cardiac response to thyroid hormones.
Building a super-resolution fluorescence cryomicroscope
Authors: Last Mart G. F. , Voortman Lenard M. , Sharp Thomas. H.
Published: November 2023

Correlating super-resolution fluorescence microscopy with cryo-electron tomography is a recent advancement in the field of cryo-electron microscopy that enables targeted, high-resolution imaging of specific biomolecules of interest. Critical to this approach is that the cryo-correlated light and electron microscopy (cryoCLEM) workflow requires samples to be cryogenically fixed prior to imaging, and thus a fluorescence microscope is required that can maintain the cryogenically preserved state of the sample while also being capable of super-resolution imaging. In this report, we outline the blueprint of a microscope that was designed for single molecule localization microscopy of cryosamples, and we describe the rationale behind its design. All specifications, including a detailed 3d model of the entire assembly, are freely available viaccb.lumc.nl/downloads-231.
FluoroTensor: identification and tracking of colocalised molecules and their stoichiometries in multi-colour single molecule imaging via deep learning
Authors: Wills Max F.K. , Alejo Carlos Bueno , Hundt Nikolas , Hudson Andrew J. , Eperon Ian C.
Published: November 2023

The identification of photobleaching steps in single molecule fluorescence imaging is a well-established procedure for analysing the stoichiometries of molecular complexes. Nonetheless, the method is challenging with protein fluorophores because of the high levels of noise, rapid bleaching and very variable signal intensities, all of which complicate methods based on statistical analyses of intensities to identify bleaching steps. It has recently been shown that deep learning by convolutional neural networks can yield an accurate analysis with a relatively short computational time. We describe here an improved use of such an approach that detects bleaching events even in the first time point of observation, and we have included this within an integrated software package incorporating fluorescence spot detection, colocalisation, tracking, FRET and photobleaching step analyses of single molecules or complexes. This package, known as FluoroTensor, is written in Python with a self-explanatory user interface.
Real-Time Structural Biology of DNA and DNA-Protein Complexes on an Optical Microscope
Authors: Szalai Alan M. , Ferrari Giovanni , Richter Lars , Hartmann Jakob , Kesici Merve-Zeynep , Ji Bosong , Coshic Kush , Jaeger Annika , Aksimentiev Aleksei , Tessmer Ingrid , Kamińska Izabela , Vera Andrés M. , Tinnefeld Philip
Published: November 2023

The intricate interplay between DNA and proteins is key for biological functions such as DNA replication, transcription, and repair. To better understand these interactions, it is crucial to develop tools to study DNA-protein complexes with high spatial and temporal resolution. Here, we use the vertical orientation that DNA adopts on graphene and investigate its interactions with proteins via energy transfer from a probe dye to graphene, achieving spatial resolution down to the Ångström scale. We measured the bending angle of DNA induced by adenine tracts, bulges, abasic sites and the binding of Escherichiacoliendonuclease IV with unprecedented precision and millisecond time resolution. Additionally, we observed the translocation of the O6-alkylguanine DNA alkyltransferase along double-stranded DNA, reaching single-base pair resolution and detecting an affinity for adenine tracts. Overall, we foresee that this method will become a widespread tool for the dynamical study of nucleic acid and nucleic acid-protein interactions.
Spatially explicit sampling frameworks to identify regions of increased mosquito abundance
Authors: Kemei Brigid , Ochomo Eric , Ombok Maurice , Midega Janet , Lucas Eric R. , Donnelly Martin J , Sedda Luigi , McDermott Daniel P.
Published: November 2023

Vector control interventions often lack comprehensive information on vector population distribution and dynamics. This knowledge gap poses challenges in targeting interventions effectively, especially in areas with heterogeneous transmission and where complementary vector control tools may be required to achieve sustained impact on disease transmission. In this study, we implemented a spatially explicit sampling framework for improved vector surveillance in coastal Kenya. Our stratified lattice with close pair sampling design aimed to characterise the vector dynamics of the primary malaria-transmitting species in the area and assess the ecotype classification’s effectiveness at identifying clear population patterns. The study collected 3,621 mosquitoes, withAn. funestuss.l. being the most abundant malaria vector. The inclusion of the ecotype classification significantly improved spatial abundance model estimates forAn. gambiaeandCulexspp. Wetlands, topographic wetness index, and proximity to rivers were associated with increased mosquito abundance. Spatial modelling revealed high abundance regions near the Galana-Sabaki River. Our study demonstrates the applicability of a reproducible spatial sampling approach to identify areas with high vector abundance and inform targeted vector control strategies. The study highlights the importance of ecological stratification and a spatial explicit sampling approach for predicting mosquito presence when prior data is limited and underscores the potential for refining future sampling for control efforts.