bluuebunny/crossref_metadata_2025 huggingface dataset:
High-power, gigahertz repetition frequency self-mode-locked Ho:GdVO4 laser resonantly pumped by a Tm-doped fiber laser
Authors: Kang Panqiang , Zhang Xinlu , Jing Xiaofan , Shen Changchang , Huang Jinjer , Wang Yulei , Lu Zhiwei
Published: March 2024

A self-mode-locked Ho:GdVO4 laser with the GHz pulse repetition frequency oscillation near 2.06 µm was demonstrated for the first time to our knowledge. The output performances of the self-mode-locked Ho:GdVO4 laser were investigated for a few output coupler transmittances at the pulse repetition frequency of 1.89 GHz. At the incident pump power of 8.12 W, the maximum average output power was as high as 2.28 W, corresponding to the slope efficiency and optical-to-optical efficiency of 36.3% and 28.1%, respectively. This is the maximum average output for the 2 µm self-mode-locked solid-state laser with a GHz pulse repetition frequency. This work provides a new way for generating an efficient and a high-power ultrafast pulse laser with a GHz repetition frequency in the 2 µm wave band.
Engineering of Cas12a nuclease variants with enhanced genome-editing specificity
Authors: Chen Peng , Zhou Jin , Liu Huan , Zhou Erchi , He Boxiao , Wu Yankang , Wang Hongjian , Sun Zaiqiao , Paek Chonil , Lei Jun , Chen Yongshun , Zhang Xinghua , Yin Lei
Published: March 2024

The clustered regularly interspaced short palindromic repeat (CRISPR)-Cas12a system is a powerful tool in gene editing; however, crRNA-DNA mismatches might induce unwanted cleavage events, especially at the distal end of the PAM. To minimize this limitation, we engineered a hyper fidelity AsCas12a variant carrying the mutations S186A/R301A/T315A/Q1014A/K414A (termed HyperFi-As) by modifying amino acid residues interacting with the target DNA and crRNA strand. HyperFi-As retains on-target activities comparable to wild-type AsCas12a (AsCas12aWT) in human cells. We demonstrated that HyperFi-As has dramatically reduced off-target effects in human cells, and HyperFi-As possessed notably a lower tolerance to mismatch at the position of the PAM-distal region compared with the wild type. Further, a modified single-molecule DNA unzipping assay at proper constant force was applied to evaluate the stability and transient stages of the CRISPR/Cas ribonucleoprotein (RNP) complex. Multiple states were sensitively detected during the disassembly of the DNA-Cas12a-crRNA complexes. On off-target DNA substrates, the HyperFi-As-crRNA was harder to maintain the R-loop complex state compared to the AsCas12aWT, which could explain exactly why the HyperFi-As has low off-targeting effects in human cells. Our findings provide a novel version of AsCas12a variant with low off-target effects, especially capable of dealing with the high off-targeting in the distal region from the PAM. An insight into how the AsCas12a variant behaves at off-target sites was also revealed at the single-molecule level and the unzipping assay to evaluate multiple states of CRISPR/Cas RNP complexes might be greatly helpful for a deep understanding of how CRISPR/Cas behaves and how to engineer it in future.
An analytically tractable, age-structured model of the impact of vector control on mosquito-transmitted infections
Authors: Davis Emma L. , Hollingsworth T. Déirdre , Keeling Matt J.
Published: March 2024

Vector control is a vital tool utilised by malaria control and elimination programmes worldwide, and as such it is important that we can accurately quantify the expected public health impact of these methods. There are very few previous models that consider vector-control-induced changes in the age-structure of the vector population and the resulting impact on transmission. We analytically derive the steady-state solution of a novel age-structured deterministic compartmental model describing the mosquito feeding cycle, with mosquito age represented discretely by parity—the number of cycles (or successful bloodmeals) completed. Our key model output comprises an explicit, analytically tractable solution that can be used to directly quantify key transmission statistics, such as the effective reproductive ratio under control, Rc, and investigate the age-structured impact of vector control. Application of this model reinforces current knowledge that adult-acting interventions, such as indoor residual spraying of insecticides (IRS) or long-lasting insecticidal nets (LLINs), can be highly effective at reducing transmission, due to the dual effects of repelling and killing mosquitoes. We also demonstrate how larval measures can be implemented in addition to adult-acting measures to reduce Rc and mitigate the impact of waning insecticidal efficacy, as well as how mid-ranges of LLIN coverage are likely to experience the largest effect of reduced net integrity on transmission. We conclude that whilst well-maintained adult-acting vector control measures are substantially more effective than larval-based interventions, incorporating larval control in existing LLIN or IRS programmes could substantially reduce transmission and help mitigate any waning effects of adult-acting measures.
Unlocking ensemble ecosystem modelling for large and complex networks
Authors: Vollert Sarah A. , Drovandi Christopher , Adams Matthew P.
Published: March 2024

The potential effects of conservation actions on threatened species can be predicted using ensemble ecosystem models by forecasting populations with and without intervention. These model ensembles commonly assume stable coexistence of species in the absence of available data. However, existing ensemble-generation methods become computationally inefficient as the size of the ecosystem network increases, preventing larger networks from being studied. We present a novel sequential Monte Carlo sampling approach for ensemble generation that is orders of magnitude faster than existing approaches. We demonstrate that the methods produce equivalent parameter inferences, model predictions, and tightly constrained parameter combinations using a novel sensitivity analysis method. For one case study, we demonstrate a speed-up from 108 days to 6 hours, while maintaining equivalent ensembles. Additionally, we demonstrate how to identify the parameter combinations that strongly drive feasibility and stability, drawing ecological insight from the ensembles. Now, for the first time, larger and more realistic networks can be practically simulated and analysed.
A fatty acid anabolic pathway in specialized-cells sustains a remote signal that controls egg activation in Drosophila
Authors: Poidevin Mickael , Mazuras Nicolas , Bontonou Gwénaëlle , Delamotte Pierre , Denis Béatrice , Devilliers Maëlle , Akiki Perla , Petit Delphine , de Luca Laura , Soulie Priscilla , Gillet Cynthia , Wicker-Thomas Claude , Montagne Jacques
Published: March 2024

Egg activation, representing the critical oocyte-to-embryo transition, provokes meiosis completion, modification of the vitelline membrane to prevent polyspermy, and translation of maternally provided mRNAs. This transition is triggered by a calcium signal induced by spermatozoon fertilization in most animal species, but not in insects. In Drosophila melanogaster, mature oocytes remain arrested at metaphase-I of meiosis and the calcium-dependent activation occurs while the oocyte moves through the genital tract. Here, we discovered that the oenocytes of fruitfly females are required for egg activation. Oenocytes, cells specialized in lipid-metabolism, are located beneath the abdominal cuticle. In adult flies, they synthesize the fatty acids (FAs) that are the precursors of cuticular hydrocarbons (CHCs), including pheromones. The oenocyte-targeted knockdown of a set of FA-anabolic enzymes, involved in very-long-chain fatty acid (VLCFA) synthesis, leads to a defect in egg activation. Given that some but not all of the identified enzymes are required for CHC/pheromone biogenesis, this putative VLCFA-dependent remote control may rely on an as-yet unidentified CHC or may function in parallel to CHC biogenesis. Additionally, we discovered that the most posterior ventral oenocyte cluster is in close proximity to the uterus. Since oocytes dissected from females deficient in this FA-anabolic pathway can be activated in vitro, this regulatory loop likely operates upstream of the calcium trigger. To our knowledge, our findings provide the first evidence that a physiological extra-genital signal remotely controls egg activation. Moreover, our study highlights a potential metabolic link between pheromone-mediated partner recognition and egg activation.
INSIDER: Interpretable sparse matrix decomposition for RNA expression data analysis
Authors: Zhao Kai , Huang Sen , Lin Cuichan , Sham Pak Chung , So Hon-Cheong , Lin Zhixiang
Published: March 2024

RNA sequencing (RNA-Seq) is widely used to capture transcriptome dynamics across tissues, biological entities, and conditions. Currently, few or no methods can handle multiple biological variables (e.g., tissues/ phenotypes) and their interactions simultaneously, while also achieving dimension reduction (DR).

We propose INSIDER, a general and flexible statistical framework based on matrix factorization, which is freely available at https://github.com/kai0511/insider. INSIDER decomposes variation from different biological variables and their interactions into a shared low-rank latent space. Particularly, it introduces the elastic net penalty to induce sparsity while considering the grouping effects of genes. It can achieve DR of high-dimensional data (of > = 3 dimensions), as opposed to conventional methods (e.g., PCA/NMF) which generally only handle 2D data (e.g., sample × expression). Besides, it enables computing ’adjusted’ expression profiles for specific biological variables while controlling variation from other variables. INSIDER is computationally efficient and accommodates missing data. INSIDER also performed similarly or outperformed a close competing method, SDA, as shown in simulations and can handle complex missing data in RNA-Seq data. Moreover, unlike SDA, it can be used when the data cannot be structured into a tensor. Lastly, we demonstrate its usefulness via real data analysis, including clustering donors for disease subtyping, revealing neuro-development trajectory using the BrainSpan data, and uncovering biological processes contributing to variables of interest (e.g., disease status and tissue) and their interactions.
A qualitative analysis of community health worker perspectives on the implementation of the preconception and pregnancy phases of the Bukhali randomised controlled trial
Authors: Soepnel Larske M. , Norris Shane A. , Mabetha Khuthala , Motlhatlhedi Molebogeng , Nkosi Nokuthula , Lye Stephen , Draper Catherine E.
Published: March 2024

Community health workers (CHWs) play an important role in health systems in low- and middle-income countries, including South Africa. Bukhali is a CHW-delivered intervention as part of a randomised controlled trial, to improve the health trajectories of young women in Soweto, South Africa. This study aimed to qualitatively explore factors influencing implementation of the preconception and pregnancy phases of Bukhali, from the perspective of the CHWs (Health Helpers, HHs) delivering the intervention. As part of the Bukhali trial process evaluation, three focus group discussions were conducted with the 13 HHs employed by the trial. A thematic approach was used to analyse the data, drawing on elements of a reflexive thematic and codebook approach. The following six themes were developed, representing factors impacting implementation of the HH roles: interaction with the existing public healthcare sector; participant perceptions of health; health literacy and language barriers; participants’ socioeconomic constraints; family, partner, and community views of trial components; and the HH-participant relationship. HHs reported uses of several trial-based tools to overcome implementation challenges, increasing their ability to implement their roles as planned. The relationship of trust between the HH and participants seemed to function as one important mechanism for impact. The findings supported a number of adaptations to the implementation of Bukhali, such as intensified trial-based follow-up of referrals that do not receive management at clinics, continued HH training and community engagement parallel to trial implementation, with an increased emphasis on health-related stigma and education. HH perspectives on intervention implementation highlighted adaptations across three broad strategic areas: navigating and bridging healthcare systems, adaptability to individual participant needs, and navigating stigma around disease. These findings provide recommendations for the next phases of Bukhali, for other CHW-delivered preconception and pregnancy trials, and for the strengthening of CHW roles in clinical settings with similar implementation challenges.

Trial registration: Pan African Clinical Trials Registry; PACTR201903750173871, Registered March 27, 2019.
Mechanisms of active diffusion of vesicular stomatitis virus inclusion bodies and cellular early endosomes in the cytoplasm of mammalian cells
Authors: Moran Steven J. , Oglietti Ryan , Smith Kathleen C. , Macosko Jed C. , Holzwarth George , Lyles Douglas S.
Published: March 2024

Viral and cellular particles too large to freely diffuse have two different types of mobility in the eukaryotic cell cytoplasm: directed motion mediated by motor proteins moving along cytoskeletal elements with the particle as its load, and motion in random directions mediated by motor proteins interconnecting cytoskeletal elements. The latter motion is referred to as “active diffusion.” Mechanisms of directed motion have been extensively studied compared to mechanisms of active diffusion, despite the observation that active diffusion is more common for many viral and cellular particles. Our previous research showed that active diffusion of vesicular stomatitis virus (VSV) ribonucleoproteins (RNPs) in the cytoplasm consists of hopping between traps and that actin filaments and myosin II motors are components of the hop-trap mechanism. This raises the question whether similar mechanisms mediate random motion of larger particles with different physical and biological properties. Live-cell fluorescence imaging and a variational Bayesian analysis used in pattern recognition and machine learning were used to determine the molecular mechanisms of random motion of VSV inclusion bodies and cellular early endosomes. VSV inclusion bodies are membraneless cellular compartments that are the major sites of viral RNA synthesis, and early endosomes are representative of cellular membrane-bound organelles. Like VSV RNPs, inclusion bodies and early endosomes moved from one trapped state to another, but the distance between states was inconsistent with hopping between traps, indicating that the apparent state-to-state movement is mediated by trap movement. Like VSV RNPs, treatment with the actin filament depolymerizing inhibitor latrunculin A increased VSV inclusion body mobility by increasing the size of the traps. In contrast neither treatment with latrunculin A nor depolymerization of microtubules by nocodazole treatment affected the size of traps that confine early endosome mobility, indicating that intermediate filaments are likely major trap components for these cellular organelles.
Unravelling the link between SARS-CoV-2 mutation frequencies, patient comorbidities, and structural dynamics
Authors: Azzeri Amirah , Mohamed Nurul Azmawati , Wan Rosli Saarah Huurieyah , Abdul Samat Muttaqillah Najihan , Rashid Zetti Zainol , Mohamad Jamali Muhamad Arif , Md Zoqratt Muhammad Zarul Hanifah , Mohammad Nasir Muhammad Azamuddeen , Ranjit Singh Harpreet Kaur , Azmi Liyana
Published: March 2024

Genomic surveillance is crucial for tracking emergence and spread of novel variants of pathogens, such as SARS-CoV-2, to inform public health interventions and to enforce control measures. However, in some settings especially in low- and middle- income counties, where sequencing platforms are limited, only certain patients get to be selected for sequencing surveillance. Here, we show that patients with multiple comorbidities potentially harbour SARS-CoV-2 with higher mutation rates and thus deserve more attention for genomic surveillance. The relationship between the patient comorbidities, and type of amino acid mutations was assessed. Correlation analysis showed that there was a significant tendency for mutations to occur within the ORF1a region for patients with higher number of comorbidities. Frequency analysis of the amino acid substitution within ORF1a showed that nsp3 P822L of the PLpro protease was one of the highest occurring mutations. Using molecular dynamics, we simulated that the P822L mutation in PLpro represents a system with lower Root Mean Square Deviation (RMSD) fluctuations, and consistent Radius of gyration (Rg), Solvent Accessible Surface Area (SASA) values—indicate a much stabler protein than the wildtype. The outcome of this study will help determine the relationship between the clinical status of a patient and the mutations of the infecting SARS-CoV-2 virus.
Deep learning in public health: Comparative predictive models for COVID-19 case forecasting
Authors: Tariq Muhammad Usman , Ismail Shuhaida Binti
Published: March 2024

The COVID-19 pandemic has had a significant impact on both the United Arab Emirates (UAE) and Malaysia, emphasizing the importance of developing accurate and reliable forecasting mechanisms to guide public health responses and policies. In this study, we compared several cutting-edge deep learning models, including Long Short-Term Memory (LSTM), bidirectional LSTM, Convolutional Neural Networks (CNN), hybrid CNN-LSTM, Multilayer Perceptron’s, and Recurrent Neural Networks (RNN), to project COVID-19 cases in the aforementioned regions. These models were calibrated and evaluated using a comprehensive dataset that includes confirmed case counts, demographic data, and relevant socioeconomic factors. To enhance the performance of these models, Bayesian optimization techniques were employed. Subsequently, the models were re-evaluated to compare their effectiveness. Analytic approaches, both predictive and retrospective in nature, were used to interpret the data. Our primary objective was to determine the most effective model for predicting COVID-19 cases in the United Arab Emirates (UAE) and Malaysia. The findings indicate that the selected deep learning algorithms were proficient in forecasting COVID-19 cases, although their efficacy varied across different models. After a thorough evaluation, the model architectures most suitable for the specific conditions in the UAE and Malaysia were identified. Our study contributes significantly to the ongoing efforts to combat the COVID-19 pandemic, providing crucial insights into the application of sophisticated deep learning algorithms for the precise and timely forecasting of COVID-19 cases. These insights hold substantial value for shaping public health strategies, enabling authorities to develop targeted and evidence-based interventions to manage the virus spread and its impact on the populations of the UAE and Malaysia. The study confirms the usefulness of deep learning methodologies in efficiently processing complex datasets and generating reliable projections, a skill of great importance in healthcare and professional settings.
The beneficial effect of Allium Cepa bulb extract on reproduction of rats; A two-generation study on fecundity and sex hormones
Authors: Suri Sadia , Khan Saira Saeed , Naeem Sadaf , Nisa Zeb Un , Alam Nausheen , Majeed Saba , Kumar Suresh , Khan Rafeeq Alam
Published: March 2024

Allium Cepa Linn. (Onions) has extensively been used in traditional medicine, is one of the important Allium species regularly used in our daily diet, and has been the source of robust phenolic compounds. The current study is intended to evaluate the fecundity-enhancing effect of A. Cepa on the reproductive performance of two successive generations of rats; F0 and F1. A. Cepa extract was initially tested for in vitro antioxidant assay via DPPH and ROS, followed by in vivo toxicity testing. In the fecundity assessment, eighteen pairs of male and female rats (n = 36, 1:1, F0 generation) were divided into three groups and dosed with 75mg/kg and 150 mg/kg daily of A. Cepa extract and saline respectively, up to pre-cohabitation, cohabitation, gestation and lactation period. The reproductive performance, including body weight, live birth index, fertility index, and litter size, was assessed. Various parameters like Hematological, Hormonal (FSH, LH, Testosterone, estradiol), antioxidant markers (SOD, Glutathione peroxidase) and lipid profile of F0 and F1 generations were assessed with evaluation of histopathology of male and female organs. Ethanolic extract of A. Cepa showed the greatest antioxidant potential in DPPH and ROS methods. The continued exposure of the F0 and F1 generations to A. Cepa extract did not affect body weight, fertility index, litter size, and survival index. However, semen pH, sperm motility, sperm count, sperm viability, and semen volume were significantly improved in both generations. We have found pronounced fecundity outcomes in both genders of F0 and F1 generations with A. Cepa 150mg/kg/day extract as compared to control. Results showed that A. Cepa significantly increased (P < 0.05) hemoglobin, follicular stimulating hormone (FSH), luteinizing hormone (LH), plasma testosterone and glutathione peroxidase activities, while total lipid, LDL, and cholesterol were significantly decreased (P < 0.05) in both generations. Histology of both generations of animals reveals enhanced spermatogenesis and enhanced folliculogenesis with improved architecture. Altogether, the present results suggest that A. Cepa extract improved fecundity in both male and female rats by improving hormonal activities and oxidative stress.
Relative income concerns and smoking behaviour: The role of unobserved heterogeneity
Authors: Akay Alpaslan , Caner Asena
Published: March 2024

Status or relative concerns (as in the idiom ‘keeping up with the Joneses’) can lead to negative feelings such as stress and anxiety. One key question is whether these concerns relate to daily smoking behaviour. The conjecture is that status concerns and the accompanying stress and anxiety might be associated with a higher likelihood of smoking and a higher number of cigarettes smoked, generating a higher instant physical reward and reducing the stress and anxiety. The literature aiming to identify this relationship focuses mostly on a single cross section of individuals, ignoring potential differences in unobserved characteristics of smokers and non-smokers (e.g., genetic factors, personality differences, parental smoking during childhood). This paper investigates the role of unobserved individual characteristics on this relationship, which has not been done in previous studies. Using a long panel data of smoking information in Germany and a variety of panel data model specifications, we show that there is no statistically significant association between relative income concerns and the likelihood of smoking or the number of cigarettes smoked among the overall population. We find a positive and significant relationship only among people who smoked at least one cigarette in the past. A 10% appreciation in the income of comparable other individuals relates to about 3.5 more cigarettes per month among these people. Importantly, failing to allow for the unobserved influences of smoking leads to three times larger estimates than when using models with unobserved factors correlating to the income and smoking behaviour. The results are robust with respect to alternative assumptions and specifications where we use different functional forms of unobserved heterogeneity, definitions of relative concerns, incomes, and reference groups.
Deaths and cardiopulmonary events following colorectal cancer screening—A systematic review with meta-analyses
Authors: Martiny Frederik Handberg Juul , Bie Anne Katrine Lykke , Jauernik Christian Patrick , Rahbek Or Joseph , Nielsen Sigrid Brisson , Gram Emma Grundtvig , Kindt Isabella , Siersma Volkert , Bang Christine Winther , Brodersen John Brandt
Published: March 2024

Background

Colorectal cancer screening programmes (CRCSPs) are implemented worldwide despite recent evidence indicating more physical harm occurring during CRCSPs than previously thought. Therefore, we aimed to review the evidence on physical harms associated with endoscopic diagnostic procedures during CRCSPs and, when possible, to quantify the risk of the most serious types of physical harm during CRCSPs, i.e. deaths and cardiopulmonary events (CPEs).

Methods

Systematic review with descriptive statistics and random-effects meta-analyses of studies investigating physical harms following CRCSPs. We conducted a systematic search in the literature and assessed the risk of bias and the certainty of the evidence.

Results

We included 134 studies for review, reporting findings from 151 unique populations when accounting for multiple screening interventions per study. Physical harm can be categorized into 17 types of harm. The evidence was very heterogeneous with inadequate measurement and reporting of harms. The risk of bias was serious or critical in 95% of assessments of deaths and CPEs, and the certainty of the evidence was very low in all analyses. The risk of death was assessed for 57 populations with large variation across studies. Meta-analyses indicated that 3 to 23 deaths occur during CRCSPs per 100,000 people screened. Cardiopulmonary events were assessed for 55 populations. Despite our efforts to subcategorize CPEs into 17 distinct subtypes, 41% of CPE assessments were too poorly measured or reported to allow quantification. We found a tendency towards lower estimates of deaths and CPEs in studies with a critical risk of bias.

Discussion

Deaths and CPEs during CRCSPs are rare, yet they do occur during CRCSPs. We believe that our findings are conservative due to the heterogeneity and low quality of the evidence. A standardized system for the measurement and reporting of the harms of screening is warranted.

Trial registration

PROSPERO Registration numberCRD42017058844.
Street-wise dog testing: Feasibility and reliability of a behavioural test battery for free-ranging dogs in their natural habitat
Authors: Capitain Svenja , Cimarelli Giulia , Blenkuš Urša , Range Friederike , Marshall-Pescini Sarah
Published: March 2024

Behavioural scientists are increasingly recognizing the need to conduct experiments in the wild to achieve a comprehensive understanding of their species’ behaviour. For domestic dogs (Canis familiaris), such progress has been slow. While the life in human households is often regarded as dogs’ natural habitat, this classification disregards most of the global dog population. The value of experimentally testing free-ranging dogs’ cognition and behaviour is increasingly being recognized, but no comprehensive test batteries have been conducted on those populations so far, leaving the feasibility and reliability of such endeavours unknown. This study is the starting point to fill this gap by pioneering and validating an elaborate behavioural test battery on street-living dogs. Therein, six common temperament tests (human-/conspecific-directed sociability, neophobia, tractability) and dog-human communication paradigms (pointing, inaccessible object) were adapted to the street conditions. We evaluated the feasibility of the test battery, the coding reliability of the measures, and investigated their temporal consistency in a retest of the same individuals six weeks later (test-retest reliability). The test battery proved feasible with most dogs participating in all subtests, and it showed satisfactory inter- and intra-rater reliability (0.84 and 0.93 respectively), providing evidence that complex behavioural tests can be conducted even in highly variable street conditions. Retesting revealed that some behaviours could be captured reliably across time, especially when the subtest was particularly engaging (e.g., human approach, point following). In contrast, the low retest reliability for subtests relying on sustained novelty and behaviours that were highly susceptible to disturbances (e.g., gazing) reflects the difficulties of street dog testing, including standardisation in disturbance-prone environments, ecology-dependent adaptation of methods, and intrinsic differences between pet and free-ranging dogs. With some adaptations, this test battery can be valuable in investigating cognition and behavioural profiles in such an understudied population as free-ranging dogs.
Estimating household contact matrices structure from easily collectable metadata
Authors: Dall’Amico Lorenzo , Kleynhans Jackie , Gauvin Laetitia , Tizzoni Michele , Ozella Laura , Makhasi Mvuyo , Wolter Nicole , Language Brigitte , Wagner Ryan G. , Cohen Cheryl , Tempia Stefano , Cattuto Ciro
Published: March 2024

Contact matrices are a commonly adopted data representation, used to develop compartmental models for epidemic spreading, accounting for the contact heterogeneities across age groups. Their estimation, however, is generally time and effort consuming and model-driven strategies to quantify the contacts are often needed. In this article we focus on household contact matrices, describing the contacts among the members of a family and develop a parametric model to describe them. This model combines demographic and easily quantifiable survey-based data and is tested on high resolution proximity data collected in two sites in South Africa. Given its simplicity and interpretability, we expect our method to be easily applied to other contexts as well and we identify relevant questions that need to be addressed during the data collection procedure.
A semi-automated and high-throughput approach for the detection of honey bee viruses in bee samples
Authors: Nikulin Sofia Levin , Hesketh-Best Poppy J. , Mckeown Dean A. , Spivak Marla , Schroeder Declan C.
Published: March 2024

Deformed wing virus (DWV) was first detected in dead honey bees in 1982 but has been in honey bees for at least 300 years. Due to its high prevalence and virulence, they have been linked with the ongoing decline in honey bee populations worldwide. A rapid, simple, semi-automated, high-throughput, and cost-effective method of screening colonies for viruses would benefit bee research and the beekeeping industry. Here we describe a semi-automated approach that combines an RNA-grade liquid homogenizer followed by magnetic bead capture for total virus nucleic acid extraction. We compare it to the more commonly applied nucleic acid column-based purification method and use qPCR plus Oxford Nanopore Technologies sequencing to evaluate the accuracy of analytical results for both methods. Our results showed high reproducibility and accuracy for both approaches. The semi-automated method described here allows for faster screening of viral loads in units of 96 samples at a time. We developed this method to monitor viral loads in honey bee colonies, but it could be easily applied for any PCR or genomic-based screening assays.
The polyglutamine domain is the primary driver of seeding in huntingtin aggregation
Authors: Skeens Adam , Siriwardhana Chathuranga , Massinople Sophia E. , Wunder Michelle M. , Ellis Zachary L. , Keith Kaitlyn M. , Girman Tyler , Frey Shelli L. , Legleiter Justin
Published: March 2024

Huntington’s Disease (HD) is a fatal, neurodegenerative disease caused by aggregation of the huntingtin protein (htt) with an expanded polyglutamine (polyQ) domain into amyloid fibrils. Htt aggregation is modified by flanking sequences surrounding the polyQ domain as well as the binding of htt to lipid membranes. Upon fibrillization, htt fibrils are able to template the aggregation of monomers into fibrils in a phenomenon known as seeding, and this process appears to play a critical role in cell-to-cell spread of HD. Here, exposure of C. elegans expressing a nonpathogenic N-terminal htt fragment (15-repeat glutamine residues) to preformed htt-exon1 fibrils induced inclusion formation and resulted in decreased viability in a dose dependent manner, demonstrating that seeding can induce toxic aggregation of nonpathogenic forms of htt. To better understand this seeding process, the impact of flanking sequences adjacent to the polyQ stretch, polyQ length, and the presence of model lipid membranes on htt seeding was investigated. Htt seeding readily occurred across polyQ lengths and was independent of flanking sequence, suggesting that the structured polyQ domain within fibrils is the key contributor to the seeding phenomenon. However, the addition of lipid vesicles modified seeding efficiency in a manner suggesting that seeding primarily occurs in bulk solution and not at the membrane interface. In addition, fibrils formed in the presence of lipid membranes displayed similar seeding efficiencies. Collectively, this suggests that the polyQ domain that forms the amyloid fibril core is the main driver of seeding in htt aggregation.
Therapeutic potential of salidroside in preserving rat cochlea organ of corti from gentamicin-induced injury through modulation of NRF2 signaling and GSK3β/NF-κB pathway
Authors: Zhang Yan , Yu Shuyuan , Guo Xinyi , Wang Luoying , Yu Ling , Wang Ping
Published: March 2024

Salidroside (SAL) is a phenol glycoside compound found in plants of the Rhodiola genus which has natural antioxidant and free radical scavenging properties. SAL are able to protect against manganese-induced ototoxicity. However, the molecular mechanism by which SAL reduces levels of reactive oxygen species (ROS) is unclear. Here, we established an in vitro gentamicin (GM) ototoxicity model to observe the protective effect of SAL on GM-induced hair cells (HC) damage. Cochlear explants of postnatal day 4 rats were obtained and randomly divided into six groups: two model groups (treatment with 0.2 mM or 0.4 mM GM for 24 h); two 400 μmol/L SAL-pretreated groups pretreatment with SAL for 3 h followed by GM treatment (0.2 mM or 0.4 mM) for 24 h; 400 μmol/L SAL group (treatment with SAL for 24 h); control group (normal cultured cochlear explants). The protective effects of SAL on GM-induced HC damage, and on mRNA and protein levels of antioxidant enzymes were observed. HC loss occurred after 24 h of GM treatment. Pretreatment with SAL significantly reduced GM-induced OHC loss. In cochlear tissues, mRNA and protein levels of NRF2 and HO-1 were enhanced in the GM alone group compared with the SAL pretreatment GM treatment group. SAL may protect against GM-induced ototoxicity by regulating the antioxidant defense system of cochlear tissues; SAL can activate NRF2/HO-1 signaling, inhibit NF-κB activation, activate AKT, and increase inhibitory phosphorylation of GSK3β to decrease GSK3 activity, all of which exert antioxidant effects.
Intensity scaling of conventional brain magnetic resonance images avoiding cerebral reference regions: A systematic review
Authors: Wiltgen Tun , Voon Cuici , Van Leemput Koen , Wiestler Benedikt , Mühlau Mark
Published: March 2024

Background

Conventional brain magnetic resonance imaging (MRI) produces image intensities that have an arbitrary scale, hampering quantification. Intensity scaling aims to overcome this shortfall. As neurodegenerative and inflammatory disorders may affect all brain compartments, reference regions within the brain may be misleading. Here we summarize approaches for intensity scaling of conventional T1-weighted (w) and T2w brain MRI avoiding reference regions within the brain.

Methods

Literature was searched in the databases of Scopus, PubMed, and Web of Science. We included only studies that avoided reference regions within the brain for intensity scaling and provided validating evidence, which we divided into four categories: 1) comparative variance reduction, 2) comparative correlation with clinical parameters, 3) relation to quantitative imaging, or 4) relation to histology.

Results

Of the 3825 studies screened, 24 fulfilled the inclusion criteria. Three studies used scaled T1w images, 2 scaled T2w images, and 21 T1w/T2w-ratio calculation (with double counts). A robust reduction in variance was reported. Twenty studies investigated the relation of scaled intensities to different types of quantitative imaging. Statistically significant correlations with clinical or demographic data were reported in 8 studies. Four studies reporting the relation to histology gave no clear picture of the main signal driver of conventional T1w and T2w MRI sequences.

Conclusions

T1w/T2w-ratio calculation was applied most often. Variance reduction and correlations with other measures suggest a biologically meaningful signal harmonization. However, there are open methodological questions and uncertainty on its biological underpinning. Validation evidence on other scaling methods is even sparser.
Field-based molecular detection of Batrachochytrium dendrobatidis in critically endangered Atelopus toads and aquatic habitats in Ecuador
Authors: Riascos-Flores Lenin R. , Bonilla Julio , Naranjo-Briceño Leopoldo , Apunte-Ramos Katherine , Reyes-Ortega Grace C. , Cabrera Marcela , Cáceres-Andrade José F. , Carrera-Gonzalez Andrea , Yánez-Galarza Jomira K. , Siavichay Pesántez Fausto , Oyagata-Cachimuel Luis A. , Goethals Peter , Celi Jorge , Van der Heyden Christine , Ortega-Andrade H. Mauricio
Published: March 2024

Batrachochytrium dendrobatidis (Bd) is a lethal fungal species that parasitizes vertebrates and is associated with the worldwide decline of amphibian populations. The development of sensitive, rapid detection methods, particularly DNA-based techniques, is critical for effective management strategies. This study evaluates the efficacy of DNA extraction and a portable PCR device in a mountable field laboratory setup for detecting Bd near the habitats of three critically endangered Atelopus toad species in Ecuador. We collected skin swabs from Atelopus balios, A. nanay, and A. bomolochos, and environmental DNA (eDNA) samples from streams in Andean and coastal regions of Ecuador. For eDNA, a comparison was made with duplicates of the samples that were processed in the field and in a standard university laboratory. Our findings revealed Bd detection in eDNA and swabs from 6 of 12 water samples and 10 of 12 amphibian swab samples. The eDNA results obtained in the field laboratory were concordant with those obtained under campus laboratory conditions. These findings highlight the potential of field DNA-based monitoring techniques for detecting Bd in amphibian populations and their aquatic habitats, particularly in remote areas. Furthermore, this research aligns with the National Action Plan for the Conservation of Ecuadorian Amphibians and contributes to the global effort to control this invasive and deadly fungus.
Mathematical modeling and control of lung cancer with IL2 cytokine and anti-PD-L1 inhibitor effects for low immune individuals
Authors: Ahmad Aqeel , Kulachi Muhammad Owais , Farman Muhammad , Junjua Moin-ud-Din , Bilal Riaz Muhammad , Riaz Sidra
Published: March 2024

Mathematical formulations are crucial in understanding the dynamics of disease spread within a community. The aim of this work is to examine that the Lung Cancer detection and treatment by introducing IL2 and anti-PD-L1 inhibitor for low immune individuals. Mathematical model is developed with the created hypothesis to increase immune system by antibody cell’s and Fractal-Fractional operator (FFO) is used to turn the model into a fractional order model. A newly developed system TCDIL2Z is examined both qualitatively and quantitatively in order to determine its stable position. The boundedness, positivity and uniqueness of the developed system are examined to ensure reliable bounded findings, which are essential properties of epidemic models. The global derivative is demonstrated to verify the positivity with linear growth and Lipschitz conditions are employed to identify the rate of effects in each sub-compartment. The system is investigated for global stability using Lyapunov first derivative functions to assess the overall impact of IL2 and anti-PD-L1 inhibitor for low immune individuals. Fractal fractional operator is used to derive reliable solution using Mittag-Leffler kernel. In fractal-fractional operators, fractal represents the dimensions of the spread of the disease and fractional represents the fractional ordered derivative operator. We use combine operators to see real behavior of spread as well as control of lung cancer with different dimensions and continuous monitoring. Simulations are conducted to observe the symptomatic and asymptomatic effects of Lung Cancer disease to verify the relationship of IL2, anti-PD-L1 inhibitor and immune system. Also identify the real situation of the control for lung cancer disease after detection and treatment by introducing IL2 cytokine and anti-PD-L1 inhibitor which helps to generate anti-cancer cells of the patients. Such type of investigation will be useful to investigate the spread of disease as well as helpful in developing control strategies from our justified outcomes.
Spatio-Temporal analysis of exports of cultural products and their affecting factors for spatial distribution
Authors: Qie Xingjia
Published: March 2024

Cultural products constitute a significant portion of global trade, and understanding their export patterns can shed light on economic trends, trade dynamics, and market opportunities. This study conducted the spatio-temporal analysis of exports of cultural products, exploring the relationship between various influencing factors and their impact on the spatial distribution of these exports. Leveraging a diverse dataset encompassing 55 BRI countries for the period of 2005–2022, this research employs advanced spatial analysis techniques, including spatial autocorrelation and spatial regression models, to examine the spatial patterns and determinants of exports if cultural product exports. Moreover, this study delves into the multifaceted determinants affecting the spatial distribution of these exports. The findings of this study reveal significant spatio-temporal variations in the exports of cultural products. Spatial autocorrelation analysis indicates the presence of spatial clustering, suggesting that regions with high cultural product exports tend to be geographically close to each other. The spatial regression models further identify several key factors like economic development, productive capacities, cultural tourism, information development and human capital influence the spatial distribution of these exports. The findings of the study reveal that there is strong spatial relationship for exports of cultural products in BRI countries. The findings of this research contribute valuable insights for policymakers, businesses, and stakeholders regarding a deeper comprehension of the driving forces behind the spatial distribution of these cultural products, facilitating informed decision-making processes to optimize strategies for promoting and sustaining the trade of cultural products in an increasingly interconnected world.
Deep learning-based fully automated grading system for dry eye disease severity
Authors: Kim Seonghwan , Park Daseul , Shin Youmin , Kim Mee Kum , Jeon Hyun Sun , Kim Young-Gon , Yoon Chang Ho
Published: March 2024

There is an increasing need for an objective grading system to evaluate the severity of dry eye disease (DED). In this study, a fully automated deep learning-based system for the assessment of DED severity was developed. Corneal fluorescein staining (CFS) images of DED patients from one hospital for system development (n = 1400) and from another hospital for external validation (n = 94) were collected. Three experts graded the CFS images using NEI scale, and the median value was used as ground truth. The system was developed in three steps: (1) corneal segmentation, (2) CFS candidate region classification, and (3) estimation of NEI grades by CFS density map generation. Also, two images taken on different days in 50 eyes (100 images) were compared to evaluate the probability of improvement or deterioration. The Dice coefficient of the segmentation model was 0.962. The correlation between the system and the ground truth data was 0.868 (p<0.001) and 0.863 (p<0.001) for the internal and external validation datasets, respectively. The agreement rate for improvement or deterioration was 88% (44/50). The fully automated deep learning-based grading system for DED severity can evaluate the CFS score with high accuracy and thus may have potential for clinical application.
JUN mRNA translation regulation is mediated by multiple 5’ UTR and start codon features
Authors: González-Sánchez Angélica M. , Castellanos-Silva Eimy A. , Díaz-Figueroa Gabriela , Cate Jamie H. D.
Published: March 2024

Regulation of mRNA translation by eukaryotic initiation factors (eIFs) is crucial for cell survival. In humans, eIF3 stimulates translation of the JUN mRNA which encodes the transcription factor JUN, an oncogenic transcription factor involved in cell cycle progression, apoptosis, and cell proliferation. Previous studies revealed that eIF3 activates translation of the JUN mRNA by interacting with a stem loop in the 5′ untranslated region (5′ UTR) and with the 5′ -7-methylguanosine cap structure. In addition to its interaction site with eIF3, the JUN 5′ UTR is nearly one kilobase in length, and has a high degree of secondary structure, high GC content, and an upstream start codon (uAUG). This motivated us to explore the complexity of JUN mRNA translation regulation in human cells. Here we find that JUN translation is regulated in a sequence and structure-dependent manner in regions adjacent to the eIF3-interacting site in the JUN 5′ UTR. Furthermore, we identify contributions of an additional initiation factor, eIF4A, in JUN regulation. We show that enhancing the interaction of eIF4A with JUN by using the compound Rocaglamide A (RocA) represses JUN translation. We also find that both the upstream AUG (uAUG) and the main AUG (mAUG) contribute to JUN translation and that they are conserved throughout vertebrates. Our results reveal additional layers of regulation for JUN translation and show the potential of JUN as a model transcript for understanding multiple interacting modes of translation regulation.
A person-centred care transition support for people with stroke/TIA: A study protocol for effect and process evaluation using a non-randomised controlled design
Authors: Lindblom Sebastian , Flink Maria , von Koch Lena , Tistad Malin , Stenberg Una , Elf Marie , Carlsson Axel C. , Laska Ann Charlotte , Ytterberg Charlotte
Published: March 2024

Introduction

Care transitions following a stroke call for integrated care approaches to reduce death and disability. The proposed research described in this study protocol aims to evaluate the effectiveness of a person-centred multicomponent care transition support and the process in terms of contextual moderators, implementation aspects and mechanisms of impact.

Methods

A non-randomized controlled trial design will be used. The intervention includes person-centred dialogue intended to permeate all patient-provider communication, various pedagogical modes of information, a person-centred care and rehabilitation plan, and a bridging e-meeting to prepare patients for homecoming. Patients with stroke or TIA who are to be discharged from the participating hospitals to home and referred to a neurorehabilitation team for continued rehabilitation will be included. Follow-ups will be conducted at one week, 3 months and 12 months. Data will be collected on the primary outcome of perceived quality of the care transition, and on the secondary outcomes of health literacy, medication adherence, and perceived person-centeredness. Data for process evaluation will be collected through semi-structured interviews, focus groups, participatory observations, and the Normalisation Measure Development Questionnaire.

Discussion

The study will provide insights on implementation, mechanisms of impact, contextual moderators, and effectiveness of a care transition support, targeting a poorly functioning part of the care trajectory for people with stroke and TIA.

Clinical trial registration

ClinicalTrials.gov Identifier: NCT05646589.