bluuebunny/crossref_metadata_2025 huggingface dataset:
Elucidating the molecular determinants for binding modes of a third-generation HIV-1 integrase strand transfer inhibitor: Importance of side chain and solvent reorganization
Authors: Sun Qinfang , Biswas Avik , Lyumkis Dmitry , Levy Ronald , Deng Nanjie
Published: December 2023

The first and second-generation clinically used HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) are key components of antiretroviral therapy (ART), which work by blocking the integration step in the HIV-1 replication cycle that is catalyzed by a nucleoprotein assembly called an intasome. However, resistance to even the latest clinically used INSTIs is beginning to emerge. Developmental third-generation INSTIs, based on naphthyridine scaffold, are promising candidates to combat drug-resistant viral variants. Among these novel INSTIs, compound 4f exhibits two distinct conformations when binding to intasomes from HIV-1 and the closely related prototype foamy virus (PFV), despite the high structural similarity of their INSTI binding pockets. The molecular mechanism and the key active site residues responsible for these differing binding modes in closely related intasomes remain elusive. To unravel the molecular determinants governing the two distinct binding modes, we employ a novel molecular dynamics-based free energy approach that utilizes alchemical pathways to overcome the sampling challenges associated with transitioning between two ligand conformations within crowded environments along physical pathways. The calculated conformational free energies successfully recapitulate the experimentally observed binding mode preferences in the two viral intasomes. Analysis of the simulated structures suggests that the observed binding mode preferences are caused by amino acid residue differences in both the front and the central catalytic sub-pocket of the INSTI binding site in HIV-1 and PFV. Additional free energy calculations on mutants of HIV-1 and PFV revealed that while both sub-pockets contribute to the binding mode selection, the central sub-pocket plays a more important role. These results highlight the importance of both side chain and solvent reorganization, as well as the conformational entropy in determining the ligand binding mode and will help inform the development of more effective INSTIs for combatting drug-resistant viral variants.
MHC-Fine: Fine-tuned AlphaFold for Precise MHC-Peptide Complex Prediction
Authors: Glukhov Ernest , Kalitin Dmytro , Stepanenko Darya , Zhu Yimin , Nguyen Thu , Jones George , Simmerling Carlos , Mitchell Julie C. , Vajda Sandor , Dill Ken A. , Padhorny Dzmitry , Kozakov Dima
Published: December 2023

The precise prediction of Major Histocompatibility Complex (MHC)-peptide complex structures is pivotal for understanding cellular immune responses and advancing vaccine design. In this study, we enhanced AlphaFold’s capabilities by fine-tuning it with a specialized dataset comprised by exclusively high-resolution MHC-peptide crystal structures. This tailored approach aimed to address the generalist nature of AlphaFold’s original training, which, while broad-ranging, lacked the granularity necessary for the high-precision demands of MHC-peptide interaction prediction. A comparative analysis was conducted against the homology-modeling-based method Pandora [13], as well as the AlphaFold multimer model [8]. Our results demonstrate that our fine-tuned model outperforms both in terms of RMSD (median value is 0.65 Å) but also provides enhanced predicted lDDT scores, offering a more reliable assessment of the predicted structures. These advances have substantial implications for computational immunology, potentially accelerating the development of novel therapeutics and vaccines by providing a more precise computational lens through which to view MHC-peptide interactions.
Enhancing Light-Sheet Fluorescence Microscopy Illumination Beams through Deep Design Optimization
Authors: Li Chen , Rai Mani Ratnam , Cai Yuheng , Ghashghaei H. Troy , Greenbaum Alon
Published: December 2023

Light sheet fluorescence microscopy (LSFM) provides the benefit of optical sectioning coupled with rapid acquisition times for imaging of tissue-cleared specimen. This allows for high-resolution 3D imaging of large tissue volumes. Inherently to LSFM, the quality of the imaging heavily relies on the characteristics of the illumination beam, with the notion that the illumination beam only illuminates a thin section that is being imaged. Therefore, substantial efforts are dedicated to identifying slender, non-diffracting beam profiles that can yield uniform and high-contrast images. An ongoing debate concerns the employment of the most optimal illumination beam; Gaussian, Bessel, Airy patterns and/or others. Comparisons among different beam profiles is challenging as their optimization objective is often different. Given that our large imaging datasets (∼0.5TB images per sample) is already analyzed using deep learning models, we envisioned a different approach to this problem by hypothesizing that we can tailor the illumination beam to boost the deep learning models performance. We achieve this by integrating the physical LSFM illumination model after passing through a variable phase mask into the training of a cell detection network. Here we report that the joint optimization continuously updates the phase mask, improving the image quality for better cell detection. Our method’s efficacy is demonstrated through both simulations and experiments, revealing substantial enhancements in imaging quality compared to traditional Gaussian light sheet. We offer valuable insights for designing microscopy systems through a computational approach that exhibits significant potential for advancing optics design that relies on deep learning models for analysis of imaging datasets.
Fitness models provide accurate short-term forecasts of SARS-CoV-2 variant frequency
Authors: Abousamra Eslam , Figgins Marlin D , Bedford Trevor
Published: December 2023

Genomic surveillance of pathogen evolution is essential for public health response, treatment strategies, and vaccine development. In the context of SARS-COV-2, multi- ple models have been developed including Multinomial Logistic Regression (MLR) de- scribing variant frequency growth as well as Fixed Growth Advantage (FGA), Growth Advantage Random Walk (GARW) and Piantham parameterizations describing vari- ant Rt. These models provide estimates of variant fitness and can be used to forecast changes in variant frequency. We introduce a framework for evaluating real-time fore- casts of variant frequencies, and apply this framework to the evolution of SARS-CoV-2 during 2022 in which multiple new viral variants emerged and rapidly spread through the population. We compare models across representative countries with different intensities of genomic surveillance. Retrospective assessment of model accuracy high- lights that most models of variant frequency perform well and are able to produce reasonable forecasts. We find that the simple MLR model provides ∼0.6% median ab- solute error and ∼6% mean absolute error when forecasting 30 days out for countries with robust genomic surveillance. We investigate impacts of sequence quantity and quality across countries on forecast accuracy and conduct systematic downsampling to identify that 1000 sequences per week is fully sufficient for accurate short-term fore- casts. We conclude that fitness models represent a useful prognostic tool for short-term evolutionary forecasting.
Accurate long-read transcript discovery and quantification at single-cell resolution with Isosceles
Authors: Kabza Michal , Ritter Alexander , Byrne Ashley , Sereti Kostianna , Le Daniel , Stephenson William , Sterne-Weiler Timothy
Published: December 2023

Accurate detection and quantification of mRNA isoforms from nanopore long-read sequencing remains challenged by technical noise, particularly in single cells. To address this, we introduce Isosceles, a computational toolkit that outperforms other methods in isoform detection sensitivity and quantification accuracy across single-cell, pseudo-bulk and bulk resolution levels, as demonstrated using synthetic and biologically-derived datasets. Isosceles improves the fidelity of single-cell transcriptome quantification at the isoform-level, and enables flexible downstream analysis. As a case study, we apply Isosceles, uncovering coordinated splicing within and between neuronal differentiation lineages. Isosceles is suitable to be applied in diverse biological systems, facilitating studies of cellular heterogeneity across biomedical research applications.
Increased levels of circulating methylglyoxal have no consequence for cerebral microvascular integrity and cognitive function in young healthy mice
Authors: Berends Eline , Vangrieken Philippe , Amiri Naima , van de Waarenburg Marjo P.H. , Scheijen Jean L.J.M. , Hermes Denise J.H.P. , van Oostenbrugge Robert J. , Schalkwijk Casper G. , Foulquier Sébastien
Published: December 2023

Diabetes and other age-related diseases are associated with an increased risk of cognitive impairment, but the underlying mechanisms remain poorly understood. Methylglyoxal (MGO), a by-product of glycolysis and a major precursor in the formation of advanced glycation end- products (AGEs), is increased in individuals with diabetes and other age-related diseases, and is associated with microvascular dysfunction. We now investigated whether increased levels of circulating MGO can lead to cerebral microvascular dysfunction, blood brain barrier (BBB) dysfunction, and cognitive impairment. Mice were supplemented or not with 50 mM MGO in drinking water for 13 weeks. Plasma and cortical MGO and MGO-derived AGEs were measured with UPLC-MS/MS. Peripheral and cerebral microvascular integrity and inflammation were investigated. Cerebral blood flow and neurovascular coupling were investigated with laser speckle contrast imaging, and cognitive tests were performed. We found a 2-fold increase in plasma MGO and an increase in MGO-derived AGEs in plasma and cortex. Increased plasma MGO did not lead to cerebral microvascular dysfunction, inflammation, nor cognitive decline. This study shows that increased concentrations of plasma MGO are not associated with cerebral microvascular dysfunction and cognitive impairment in healthy mice. Future research should focus on the role of endogenously formed MGO in cognitive impairment.
Interpretable Machine Learning Decodes Soil Microbiome’s Response to Drought Stress
Authors: Hagen Michelle , Dass Rupashree , Westhues Cathy , Blom Jochen , Schultheiss Sebastian J , Patz Sascha
Published: December 2023

Background

Extreme weather events induced by climate change, particularly droughts, have detrimental consequences for crop yields and food security. Concurrently, these conditions provoke substantial changes in the soil metagenome and affect plant health. Early recognition of soil affected by drought enables farmers to implement appropriate agricultural management practices. In this context, interpretable Machine Learning holds immense potential for drought stress classification in the soil metagenome based on marker taxa.

Results

This study demonstrates that the metagenomic approach of Differential Abundance Analysis methods and Machine Learning-based Shapley Additive Explanation values provide similar information. They exhibit their potential as complementary approaches for identifying marker taxa and investigating their enrichment or depletion under drought stress in grass lineages. Additionally, the Random Forest Classifier trained on a diverse range of relative abundance data from the soil metagenome of various plant species achieves a high accuracy of 92.3 % at the genus rank for drought stress prediction. It demonstrates its generalization capacity for the lineages tested.

Conclusions

In the detection of drought stress in the soil metagenome, this study emphasizes the potential of an optimized and generalized location-based ML classifier. By identifying marker taxa, this approach holds promising implications for microbe-assisted plant breeding programs and contributes to the development of sustainable agriculture practices. These findings are crucial for preserving global food security in the face of climate change.
Transfer of disulfide bond formation modules via yeast artificial chromosomes promotes the expression of heterologous proteins inKluyveromyces marxianus
Authors: Wu Pingping , Mo Wenjuan , Tian Tian , Song Kunfeng , Lyu Yilin , Ren Haiyan , Zhou Jungang , Yu Yao , Lu Hong
Published: December 2023

Kluyveromyces marxianusis a food-safe yeast with great potential for producing heterologous proteins. Improving the yield inK. marxianusremains a challenge, while incorporating large-scale functional modules poses a technical obstacle in engineering. To address these issues, linear and circular yeast artificial chromosomes ofK. marxianus(KmYACs) were constructed and loaded with disulfide bond formation modules fromPichia pastorisorK. marxianus. These modules contained up to 7 genes with a maximum size of 15 kb. KmYACs carried telomeres either fromK. marxianusorTetrahymena. KmYACs were transferred successfully intoK. marxianusand stably propagated without affecting the normal growth of the host, regardless of the type of telomeres and configurations of KmYACs. KmYACs increased the overall expressions of disulfide bond formation genes and significantly enhanced the yield of various heterologous proteins. In high-density fermentation, the use of KmYACs resulted in a glucoamylase yield of 16.8 g/L, the highest reported level to date inK. marxianus. Transcriptomic and metabolomic analysis of cells containing KmYACs suggested increased FAD biosynthesis, enhanced flux entering the TCA cycle and a preferred demand for lysine and arginine as features of cells overexpressing heterologous proteins. Consistently, supplementing lysine or arginine further improved the yield. Therefore, KmYAC provides a powerful platform for manipulating large modules with enormous potential for industrial applications and fundamental research. Transferring the disulfide bond formation module via YACs proves to be an efficient strategy for improving the yield of heterologous proteins, and this strategy may be applied to optimize other microbial cell factories.

Impact Statement

In this study, yeast artificial chromosomes ofK. marxianus(KmYACs) were constructed and successfully incorporating modules for large-scale disulfide bond formation. KmYACs were stably propagated inK. marxianuswithout compromising the normal growth of the host, irrespective of the selection of telomeres (eitherTetrahymenaorK. marxianus) and configuration (either linear or circular). KmYACs notably enhanced the expressions of various heterologous proteins, with further yield improvement by supplementing lysine or arginine in the medium. Our findings affirm KmYAC as a robust and versatile platform for transferring large-scale function modules, demonstrating immense potential for both industrial applications and fundamental research.
Histone N-tails modulate sequence-specific positioning of nucleosomes
Authors: Nikitina Tatiana , Guiblet Wilfried M. , Cui Feng , Zhurkin Victor B.
Published: December 2023

The precise mechanisms governing sequence-dependent positioning of nucleosomes on DNA remain unknown in detail. Existing algorithms, taking into account the sequence-dependent deformability of DNA and its interactions with the histone globular domains, predict rotational setting of only 65% of human nucleosomes mappedin vivo. To uncover novel factors responsible for the nucleosome positioning, we analyzed potential involvement of the histone N-tails in this process. To this aim, we reconstituted the H2A/H4 N-tailless nucleosomes on human BRCA1 DNA (∼100 kb) and compared their positions and sequences with those of the wild-type nucleosomes. In the case of H2A tailless nucleosomes, the AT content of DNA sequences is changed locally at superhelical location (SHL) ±4, while maintaining the same rotational setting as their wild-type counterparts. Conversely, the H4 tailless nucleosomes display widespread changes of the AT content near SHL ±1 and SHL ±2, where the H4 N-tails interact with DNA. Furthermore, a substantial number of H4 tailless nucleosomes exhibit rotational setting opposite to that of the wild-type nucleosomes. Thus, our findings strongly suggest that the histone N-tails are operative in selection of nucleosome positions, which may have wide-ranging implications for epigenetic modulation of chromatin states.
TNF-alpha promotes cilia elongation via Mixed Lineage Kinases signaling
Authors: Kumari Amrita , Caliz Amada , Kant Shashi , Vertii Anastassiia
Published: December 2023

The primary cilium is characteristic of most of non-immune cells and acts as an environmental signal transduction sensor. The defects in primary cilium have profound consequences on the developmental program, including the maturation of retinal epithelium. The ciliary length is tightly regulated during ciliogenesis. Additionally, many features of ciliogenesis are shared with an immune synapse formation. While the interaction between the cells within an immune synapse is well-characterized, the impact of inflammatory stresses on ciliogenesis in non-immune cells remains elusive. The current study investigates the outcome of inflammatory stimuli for the primary cilium in human retinal epithelial cells. Here, we report that the exposure of retinal epithelium cells to pro-inflammatory cytokine TNF-alpha elongates cilia in a Mixed-Lineage Kinase (MLK) - dependent manner. In contrast, febrile condition-mimicking heat stress dramatically reduced the number of ciliated cells regardless of TNF-alpha exposure, suggesting distinct but rapid effects of inflammatory stresses on ciliogenesis.
High-throughput ML-guided design of diverse single-domain antibodies against SARS-CoV-2
Authors: Angermueller Christof , Mariet Zelda , Jester Ben , Engelhart Emily , Emerson Ryan , Alipanahi Babak , Lin Charles , Shikany Colleen , Guion Daniel , Nelson Joel , Kelley Mary , McMurray Margot , Shaffer Parker , Cordray Cameron , Halabiya Samer , Mccaw Zachary , Struyvenberg Sarah , Aggarwal Kanchan , Ertel Stacey , Martinez Anissa , Ozarkar Snehal , Hager Kevin , Frumkin Mike , Roberts Jim , Lopez Randolph , Younger David , Colwell Lucy J.
Published: December 2023

Treating rapidly evolving pathogenic diseases such as COVID-19 requires a therapeutic approach that accommodates the emergence of viral variants over time. Our machine learning (ML)-guided sequence design platform combines high-throughput experiments with ML to generate highly diverse single-domain antibodies (VHHs) that bind and neutralize SARS-CoV-1 and SARS-CoV-2. Crucially, the model, trained using binding data against early SARS-CoV variants, accurately captures the relationship between VHH sequence and binding activity across a broad swathe of sequence space. We discover ML-designed VHHs that exhibit considerable cross-reactivity and successfully neutralize targets not seen during training, including the Delta and Omicron BA.1 variants of SARS-CoV-2. Our ML-designed VHHs include thousands of variants 4-15 mutations from the parent sequence with significantly improved activity, demonstrating that ML-guided sequence design can successfully navigate vast regions of sequence space to unlock and future-proof potential therapeutics against rapidly evolving pathogens.
Strategies for the Production and Phenotypic Analysis of Mutations in the Mouse
Authors: Papaioannou Virginia E. , Behringer Richard R.
Published: December 2023

The laboratory mouse is one of the primary model organisms for human biology and genetics. The production and phenotypic analysis of mutations in the mouse has made great strides with targeted mutagenesis in embryonic stem (ES) cells and clustered regularly interspaced short palindromic repeats (CRISPR)–Cas gene editing in preimplantation embryos. Mutations in many genes are now available or can be easily produced. For anyone planning to use mutational analysis for a research program, this article introduces an overall strategy for obtaining or generating a mutation and systematically analyzing the phenotype.
Phenotypic Analysis of Perinatal Lethality in Mice
Authors: Papaioannou Virginia E. , Behringer Richard R.
Published: December 2023

If homozygous mutants are found dead shortly after birth, further analysis of the phenotype will depend on knowing whether death occurred before or after parturition, which marks a major shift in physiological conditions of neonates. This overview provides methods for determining the time of death and discusses possible causes of lethality during this period, including catastrophic morphological abnormalities or developmental delay of some or all organs. Attention is given to specific defects that could result in perinatal death, such as cranial nerve defects, cleft palate, diaphragm defects, and other problems that might not have been relevant during intrauterine development but become critical during the transition to extrauterine existence.
Tissue- and/or Temporal-Specific Mutations in Mice Using Conditional Alleles
Authors: Papaioannou Virginia E. , Behringer Richard R.
Published: December 2023

Although many existing mutations are null alleles, multipurpose conditional alleles that can be used to delete gene function in a tissue- and/or temporal-specific manner are increasingly the alleles of choice. There are two distinct but related advantages: first, early lethal effects of the mutation can be bypassed by leaving the gene intact until later stages in development; second, indirect or secondary effects on an organ of interest can be eliminated by tissue- or organ-specific gene deletion. In this overview, we cover aspects of testing and using conditional alleles to ensure that the desired effect is obtained, including how to test the engineered conditional allele to ensure it functions as planned, and how to test any recombinase mouse strain used, including inducible transgenic or knock-in lines. Finally, we discuss how to use a conditional allele for maximum value in a phenotypic analysis.
Counting Murine Corpora Lutea to Determine the Number of Oocytes Ovulated
Authors: Papaioannou Virginia E. , Behringer Richard R.
Published: December 2023

One can determine if and how many oocytes have been ovulated in a female mouse by counting the number of corpora lutea (CL) on the ovaries during the process of preimplantation embryo collection. A simple method of harvesting the ovaries and observing with a dissecting microscope and top lighting is provided along with a description of how to recognize CL. As the embryos rarely, if ever, cross the uterotubal junction, this provides a measure of the maximum number of embryos expected to be recovered from each oviduct or uterine horn, a number that can be valuable in analyzing early lethal mutations.
Cell Counting Techniques for Preimplantation Mouse Embryos Using Fluorescent DNA Dyes
Authors: Papaioannou Virginia E. , Behringer Richard R.
Published: December 2023

Counting cells in preimplantation embryos by light microscopy is straightforward until morula compaction, when cell boundaries in living embryos become indistinct. An alternative to morphological assessment of cell number is to use fluorescent DNA dyes. This protocol details simple nuclear counting with a single DNA dye (Hoechst) or a more complicated procedure in which differential nuclear counts of the trophectoderm and inner cell mass (ICM) can be made using immunosurgery of the blastocyst and two DNA dyes (Hoechst and propidium iodide).
Orientation of Implanted or Dissected Mouse Embryos for Histological Sectioning
Authors: Papaioannou Virginia E. , Behringer Richard R.
Published: December 2023

Histological analysis is an informative part of any mutational analysis. Interpretation of histological sections is much easier, and comparisons of mutant and wild-type embryos are more reliable if the plane of sectioning is precisely controlled. This protocol provides methods for obtaining sections with reproducible orientation for embryos between E4.5 and E9.5 still in the uterus and for dissected embryos E9.5 and older.
Queen Ndlovu: opening the throttle on her drone business
Authors: Urban Boris , Townsend Stephanie Althea
Published: December 2023

Learning outcomes

After completion of the case study, students will be able to evaluate the journey of launching a business in an emerging market context and judge how opportunities and challenges can be navigated to build sustainable enterprises; assess the relevance of individual attributes and process skills that are necessary for entrepreneurial agency to transform social structures through entrepreneurial action; formulate an argument highlighting the role of the entrepreneurial ecosystem in growing a competitive business in an emerging market context; make an informed decision and critique how accelerators and incubators affect the development of ideas and access to finance in South Africa; and propose various strategic options available for technology entrepreneurs, considering the challenges they face in emerging economies.

Case overview/synopsis

In April 2023, Queen Ndlovu, CEO and founder of QP Drone Tech, a provider of drone business solutions, was considering options to fulfil her original dream of manufacturing drones in South Africa. She had encountered obstacles to achieving the same in 2019, and had decided to focus on providing commercial drone consulting services. However, her dream had not extinguished, and in 2022, she decided to restart her efforts. She found practical support from The Innovation Hub, an incubator that was supporting her business, which enabled her to enhance the prototype of her drone. She then had to think about how she would manufacture drones locally by ensuring she had access to production infrastructure, funding, partners and customers. Would she be able to gain a competitive advantage that would differentiate her from competitors? Or should she reconsider whether she should be manufacturing in the first place, as there are risks and benefits for smaller businesses in this regard.

Complexity academic level

This case is intended for discussion in postgraduate diploma in business and Master of Business Administration courses.

Supplementary material

Teaching notes are available for educators only.

Subject code

CSS 3: Entrepreneurship.
Understanding the determinants of gifting and social sharing in live streaming: a dual-attachment perspective
Authors: Zhang Yan , Sun Yongqiang , Wang Nan
Published: December 2023

Purpose

This study aims to explore the determinants of viewers’ gifting and social sharing behaviours in online streaming from a dual-attachment perspective and to explain how live streaming fosters attachment through a social interaction aspect.

Design/methodology/approach

This study conducted an online survey with 316 valid responses to test the research model. The structural equation modelling approach was applied to assess both the measurement and structural models.

Findings

The results show that both bond-based and identity-based attachments promote gifting and social sharing behaviours. Participation and cognitive communion motivate viewers to establish bond-based attachment, while group interaction among viewer crowds encourages viewers to create identity-based attachment. In addition, group interaction can moderate the relationship between participation and bond-based attachment.

Originality/value

This study is one of the earliest attempts to highlight the significance of viewer crowd and viewer-viewer interaction in promoting viewers’ behaviours in live streaming context. This study also indicates that viewer-viewer interaction can moderate the impact of viewer–streamer interaction, which is among the first to investigate the interaction effects of viewer-viewer interaction and viewer–streamer interaction.
Are Malaysian undergraduates prepared to study online if another MCO exists?
Authors: Soekarno Megawati , Abd Jalil Mohamad Isa , Lada Suddin , Samsu Siti Hajar , Mokthar Mohammad Zulfakhairi , Shariff Abd Kadir Shariff Umar
Published: December 2023

Purpose

The world after the pandemic of Covid-19 is looking at a different environment in teaching and learning and primarily being influenced by general online learning readiness. Perception towards the measurement of online learning readiness would also need to change. This study seeks to determine whether Malaysian undergraduate students are ready to study online if the Movement Control Order (MCO) is reimposed.

Design/methodology/approach

Using an online poll, this study analysed 299 undergraduate students from Malaysia's public and private universities. The collected data were then analysed using SmartPLS software to test the measurement model and structural equation modelling.

Findings

The findings of this study indicate that computer self-efficacy and self-directed learning have a substantially positive link with online learning preparedness among Malaysian undergraduate students.

Research limitations/implications

Findings in this study indicate that universities should draw comprehensive plans to enhance students' readiness in terms of indicators such as technology usage, technology availability, computer and internet efficacy, self-directed learning and attitude. One of the aspects that require change is online communication self-efficacy. Thus, there is a need for improvement, or this would affect undergraduates adversely, especially in the event of future MCO.

Originality/value

The originality of this article lies in the time frame this study was conducted, where cases of coronavirus infection are seen to increase around the world and there is a possibility that movement restrictions will be re-enforced. The findings in this study are expected to give insight to the government in the effort of the national higher education plan. By not undervaluing previous research models, this research model should give a new perspective to the academic literature on online learning among undergraduate students.
Joint maintenance planning and production scheduling optimization model for green environment
Authors: Attia Ahmed M. , Alatwi Ahmad O. , Al Hanbali Ahmad , Alsawafy Omar G.
Published: December 2023

Purpose

This research integrates maintenance planning and production scheduling from a green perspective to reduce the carbon footprint.

Design/methodology/approach

A mixed-integer nonlinear programming (MINLP) model is developed to study the relation between production makespan, energy consumption, maintenance actions and footprint, i.e. service level and sustainability measures. The speed scaling technique is used to control energy consumption, the capping policy is used to control CO2 footprint and preventive maintenance (PM) is used to keep the machine working in healthy conditions.

Findings

It was found that ignoring maintenance activities increases the schedule makespan by more than 21.80%, the total maintenance time required to keep the machine healthy by up to 75.33% and the CO2 footprint by 15%.

Research limitations/implications

The proposed optimization model can simultaneously be used for maintenance planning, job scheduling and footprint minimization. Furthermore, it can be extended to consider other maintenance activities and production configurations, e.g. flow shop or job shop scheduling.

Practical implications

Maintenance planning, production scheduling and greenhouse gas (GHG) emissions are intertwined in the industry. The proposed model enhances the performance of the maintenance and production systems. Furthermore, it shows the value of conducting maintenance activities on the machine's availability and CO2 footprint.

Originality/value

This work contributes to the literature by combining maintenance planning, single-machine scheduling and environmental aspects in an integrated MINLP model. In addition, the model considers several practical features, such as machine-aging rate, speed scaling technique to control emissions, minimal repair (MR) and PM.
Clinical trial: Clinical and endoscopic outcomes with ustekinumab in patients with Crohn's disease: Results from the long‐term extension period of STARDUST
Authors: Peyrin‐Biroulet Laurent , Vermeire Séverine , D'Haens Geert , Panés Julian , Dignass Axel , Magro Fernando , Nazar Maciej , Le Bars Manuela , Lahaye Marjolein , Ni Lioudmila , Bravatà Ivana , Lavie Frederic , Daperno Marco , Lukáš Milan , Armuzzi Alessandro , Löwenberg Mark , Gaya Daniel R. , Danese Silvio
Published: December 2023

Background

STARDUST, a phase 3b randomised trial, compared ustekinumab therapeutic strategies in patients with Crohn's disease (CD) using early endoscopic assessment and treat‐to‐target (T2T) versus standard of care (SoC).

Aim

To assess the efficacy of ustekinumab extended treatment in a long‐term extension (LTE) of up to 104 weeks with dosing adapted according to clinical, biomarker and endoscopy outcomes.

Methods

Adults with moderately‐to‐severely active CD received intravenous ustekinumab approximating 6 mg/kg at Week 0 and subcutaneous ustekinumab 90 mg at Week 8. At Week 16, 440 ≥70‐point responders were randomised to T2T or SoC and 323 entered the LTE. At Week 48, a unified, protocol‐defined ustekinumab dose frequency escalation/de‐escalation was applied based on achieving endoscopic remission and corticosteroid‐free clinical remission. Achieving corticosteroid‐free clinical remission and biomarker remission at consecutive visits determined ustekinumab dosing frequency. Dichotomous variables were analysed using non‐responder imputation.

Results

Among patients who entered the LTE, 7.7%, 48.6% and 43.7% received doses every 4, 8 and 12 weeks, respectively. Ustekinumab dose frequency was escalated in 23.5% and de‐escalated in 19.7%. Endoscopic response and remission rates were 28.9% and 10.73% (all randomised) and 39.3% and 14.6% (patients entering the LTE), respectively, at Week 104. Clinical remissiona rates at week 104 were 50.2% (all randomised) and 68.4% (patients entering the LTE). There were no new safety signals.

Conclusion

STARDUST LTE is the first interventional ustekinumab efficacy study to show a favourable benefit–risk profile with preservation of clinical and endoscopic outcomes through Week 104 using flexible, algorithm‐driven dose adjustment including de‐escalation.
Management of urinary incontinence in females by primary care providers: a systematic review
Authors: Charette Marylène , Pacheco‐Brousseau Lissa , Poitras Stéphane , Ashton Rosalind , McLean Linda
Published: December 2023

Objective

To describe primary care provider (PCP) practices for the assessment and management of females with urinary incontinence (UI), and appraise these practices relative to recommendations made in high‐quality clinical guidelines.

Methods

Studies were searched in four databases (MEDLINE, EMBASE, CINAHL, Web of Science) from their respective inception dates to 6 March 2023. All studies describing UI evaluation and management practices used by PCPs for female patients were eligible. Two reviewers independently selected studies assessed their quality and extracted data. A narrative synthesis of included studies was performed to describe practices. Relevant evaluation and management practices were then compared to recommendations that were consistent across current high‐quality UI guidelines. Pharmacotherapy, referrals, and follow‐ups were reported descriptively only.

Results

A total of 3475 articles were retrieved and, among those, 31 were included in the review. The majority reported a poor–moderate adherence to performing a pelvic examination (reported adherence range: 23–76%; based on eight studies), abdominal examination (0–87%; three studies), pelvic floor muscle assessment (9–36%; two studies), and bladder diary (0–92%; nine studies), while there was high adherence to urine analysis (40–97%; nine studies). For the conservative management of UI, studies revealed a poor–moderate adherence to recommendations for pelvic floor muscle training (5–82%; nine studies), bladder training (2–53%; eight studies) and lifestyle interventions (1–71%; six studies). Regarding pharmacotherapy, PCPs predominantly prescribed antimuscarinics (2–46%; nine studies) and oestrogen (2–77%; seven studies). Lastly, PCPs referred those reporting UI to medical specialists (5–37%; 14 studies). Referrals were generally made <30 days after diagnosis with urologists being the most sought out professional to assess and treat UI.

Conclusion

This review revealed poor–moderate adherence to clinical practice guideline recommendations. While these findings reflect high variability in reporting, the key message is that most aspects of patient care for female UI provided by PCPs needs to improve.
Conceptualizing adverse childhood experiences as a latent factor: Tests of measurement invariance across five racial and ethnic groups
Authors: Jensen Todd M. , Bernard Donte , Lanier Paul
Published: December 2023

Adverse childhood experiences (ACEs) are conventionally measured using a cumulative‐risk index without consideration of distinct measurement properties across racial and ethnic groups. Drawing from the 2018–2020 National Survey of Children's Health (N = 93,759; 48% female; average age: 9.52 years), we assess the measurement invariance of a latent‐factor ACE model across five groups: Hispanic children (14%) and non‐Hispanic White (73%), Black (7%), Asian/Pacific Islander (5%), and American Indian/Alaskan Native (1%) children. Results support configural and full metric invariance across groups. However, several ACE item thresholds differed across groups. Findings highlight the potential utility of a latent factor approach and underscore the need to assess differences across racial and ethnic groups in terms of the optimal conceptualization and measurement of ACEs.
Adequacy of thyroid hormone replacement for people with hypothyroidism in real‐world settings: A systematic review and meta‐analysis of observational studies
Authors: Efthymiadis Agathoklis , Henry Matthew , Spinos Dimitrios , Bourlaki Marianthi , Tsikopoulos Alexandros , Bourazana Angeliki , Bastounis Anastasios , Tsikopoulos Konstantinos
Published: December 2023

Objective

Thyroid hormone under‐replacement and over‐replacement are associated with adverse health outcomes. This systematic review aimed to evaluate the extent of thyroid hormone replacement adequacy for patients with known hypothyroidism in real‐word settings, excluding those receiving thyroid hormone suppressive therapy as thyroid cancer treatment.

Design

Four electronic databases (Embase [Ovid], Medline [Ovid], PubMed and SCOPUS) were searched for published and unpublished observational studies until 12 December 2022. The results of the studies were meta‐analysed to calculate pooled prevalence estimates for thyroid hormone supplementation adequacy, over‐replacement and under‐replacement. Quality assessment of studies was performed using the Joanna‐Briggs appraisal tool for prevalence studies.

Results

Seven studies with a total of 4230 patients were eligible for quantitative synthesis. The pooled prevalence estimates of adequate thyroid replacement, over‐replacement and under‐replacement were 0.55 (95% confidence interval [CI]: 0.49–0.60, p = .001), 0.20 (95% CI: 0.14–0.27, p = .001) and 0.24 (95% CI: 0.13–0.36, p = .001), respectively. Four studies subclassified hypothyroidism and hyperthyroidism into overt and subclinical. The pooled prevalence of overt and subclinical hyperthyroidism was 0.04 (95% CI: 0.00–0.11, p = .01) and 0.17 (95% CI: 0.09–0.27 p = .001), respectively. For overt and subclinical hypothyroidism, the pooled prevalence was 0.02 (95% CI: 0.01–0.03, p = .001) and 0.20 (95% CI: 0.12–0.29, p = .001), respectively.

Conclusions

On average, approximately half of patients with hypothyroidism are only treated to target euthyroidism. In real‐world practice, a significant number of patients are over‐treated or under‐treated, leading to adverse healthcare outcomes. It is imperative that more effective thyroid monitoring strategies be implemented, with an emphasis on primary care thyroid function monitoring, to minimise inappropriate thyroid replacement treatments and optimise healthcare outcomes at a population level.
Chemotherapy reduces long‐term quality of life in recurrence‐free colon cancer survivors (LaTE study)—a nationwide inverse probability of treatment‐weighted registry‐based cohort study and survey
Authors: Malik Yasir G. , Benth Jūratė Šaltytė , Hamre Hanne M. , Færden Arne E. , Ignjatovic Dejan , Schultz Johannes K.
Published: December 2023

Aim

Stage III colon cancer is routinely treated with adjuvant chemotherapy, which causes significant short‐term morbidity. Its effect on long‐term quality of life (QoL) is poorly investigated. The aim of this study was to investigate long‐term QoL after curative treatment for colon cancer and explore the impact of chemotherapy on general and disease‐specific QoL.

Method

All patients aged under 75 years operated on for colon cancer between 30 September 2007 and 1 October 2019 were identified by the Cancer Registry of Norway. Exclusion criteria were distant metastasis, recurrence, dementia and rectal/rectosigmoid cancer operation. The primary outcome measure was Gastrointestinal Quality of Life Index (GIQLI). Secondary outcome measures included the Short Form Health Survey (SF‐36). To achieve balanced groups when assessing differences in outcome measures the analyses were weighted by inverse probability weights based on a multiple logistic regression model with prechosen confounders.

Results

A total of 8627 patients were invited and 3109 responded (36% response rate). After exclusions 3025 patients were included, of whom 1148 (38%) had received adjuvant chemotherapy and 1877 (62%) had surgery alone, with mean follow‐up of 75.5 versus 74.5 months, respectively. The GIQLI differed significantly between the groups [mean 111.0 (SD 18.4) vs. 115.6 (SD 17.8), respectively; mean difference: −4.6 (95% CI −5.9; −3.2); p < 0.001]. Those with the highest neurotoxicity exhibited the lowest GIQLI. The adjuvant chemotherapy group scored significantly lower in six of eight SF‐36 domains compared with the surgery alone group. The main differences were found in social, physical and emotional function.

Conclusion

Long‐term QoL was significantly lower in patients who received adjuvant chemotherapy than in patients who did not. Neurotoxicity was closely related to reduced QoL in these patients. The low response rate limits the generalizability of the results.
BACKLAND: spatially explicit and high‐resolution pollen‐based BACKward LAND‐cover reconstructions
Authors: Plancher Clara , Mazier Florence , Houet Thomas , Gaucherel Cédric
Published: December 2023

Studying the interactions between humans, land‐cover and biodiversity is necessary for the sustainable management of socio‐ecosystems and requires long‐term reconstructions of past landscapes, improving the integration of slow processes. The main source of information on past vegetation is fossil pollen, but pollen data are biased by inter‐taxonomic differential production and dispersal. The landscape reconstruction algorithm (LRA) approach is the most widely used to correct for these biases. The LOVE algorithm (LOcal Vegetation estimates), the second step in the LRA approach, also estimates the spatial extent of the local vegetation reconstruction zone (the relevant source area of pollen, RSAP). While LRA estimates have already been integrated into certain past land‐cover mapping approaches, none have been designed to allow the diachronic reconstruction of a land‐cover mosaic over the long term combining the following points: the direct integration of LOVE estimates as a source of variability in the composition and distribution of pollen taxa, without multiple scenarios, and the integration of spatiotemporal autocorrelation in the taxa distribution between periods. Here, we propose an innovative approach for BACKward LAND‐cover reconstruction (BACKLAND), combining these points and estimating the past land‐cover mosaic within a set of RSAPs. Based on three stages using parsimonious assumptions and easy‐to‐implement probabilistic and statistical tools, this approach requires LOVE estimates of sites close enough to each other for their RSAPs to overlap, botanical data, a digital elevation model and two recent land‐cover maps. Developed and tested on a small study area within the mountain landscape of the Bassiès valley (French Pyrenees), BACKLAND achieved the reconstruction of a past land‐cover map representing eight land‐cover types at a spatial resolution of 20 m with a good level of accuracy. We show in this study the originality of this approach and discuss its potential for palaeoenvironmental studies, historical ecology and the management of socio‐ecosystems.
Does phasic dopamine release cause policy updates?
Authors: Carter Francis , Cossette Marie‐Pierre , Trujillo‐Pisanty Ivan , Pallikaras Vasilios , Breton Yannick‐André , Conover Kent , Caplan Jill , Solis Pavel , Voisard Jacques , Yaksich Alexandra , Shizgal Peter
Published: December 2023

Phasic dopamine activity is believed to both encode reward‐prediction errors (RPEs) and to cause the adaptations that these errors engender. If so, a rat working for optogenetic stimulation of dopamine neurons will repeatedly update its policy and/or action values, thus iteratively increasing its work rate. Here, we challenge this view by demonstrating stable, non‐maximal work rates in the face of repeated optogenetic stimulation of midbrain dopamine neurons. Furthermore, we show that rats learn to discriminate between world states distinguished only by their history of dopamine activation. Comparison of these results to reinforcement learning simulations suggests that the induced dopamine transients acted more as rewards than RPEs. However, pursuit of dopaminergic stimulation drifted upwards over a time scale of days and weeks, despite its stability within trials. To reconcile the results with prior findings, we consider multiple roles for dopamine signalling.
Mechanisms of infantile epileptic spasms syndrome: What have we learned from animal models?
Authors: Ng Andy Cheuk‐Him , Choudhary Anamika , Barrett Karlene T. , Gavrilovici Cezar , Scantlebury Morris H.
Published: December 2023

The devastating developmental and epileptic encephalopathy of infantile epileptic spasms syndrome (IESS) has numerous causes, including, but not limited to, brain injury, metabolic, and genetic conditions. Given the stereotyped electrophysiologic, age‐dependent, and clinical findings, there likely exists one or more final common pathways in the development of IESS. The identity of this final common pathway is unknown, but it may represent a novel therapeutic target for infantile spasms. Previous research on IESS has focused largely on identifying the neuroanatomic substrate using specialized neuroimaging techniques and cerebrospinal fluid analysis in human patients. Over the past three decades, several animal models of IESS were created with an aim to interrogate the underlying pathogenesis of IESS, to identify novel therapeutic targets, and to test various treatments. Each of these models have been successful at recapitulating multiple aspects of the human IESS condition. These animal models have implicated several different molecular pathways in the development of infantile spasms. In this review we outline the progress that has been made thus far using these animal models and discuss future directions to help researchers identify novel treatments for drug‐resistant IESS.