bluuebunny/crossref_metadata_2025 huggingface dataset:
Intratumoral Delivery of Chlorine Dioxide Exploits its ROS-like Properties: A Novel Paradigm for Effective Cancer Therapy
Authors: Liu Xuewu , Liu Zhaoyang , Liu Xueyan , Liu Shuangning , Zhang Jiao
Published: November 2023

Our study underscores the potential of chlorine dioxide, resembling reactive oxygen species, in promoting tissue regeneration and executing similar functions. Direct intratumoral administration of chlorine dioxide conveniently and sustainably kills cancer cells, without the risk of developing drug resistance. Given that tumors are viewed as non-healing wounds, the regenerative capabilities of chlorine dioxide offer an innovative method to expedite wound healing and enhance patient outcomes in cancer treatment. Compared to traditional methods, chlorine dioxide treatment reduces complications and risks, presenting a safer alternative. Notably, higher concentrations of chlorine dioxide in promoting tumor ablation can particularly demonstrate the potential to disrupt tumor vasculature. We advocate for the intratumoral injection of chlorine dioxide to achieve direct tumor ablation and boost antitumor immunity while minimizing harm to healthy tissues. Although initial findings indicate that chlorine dioxide stimulates an antitumor immune response, further investigation is essential. As oncology advances with the use of immune checkpoint inhibitors, intratumoral chlorine dioxide administration emerges as a promising strategy, potentially extending survival and alleviating treatment burdens. Future research should focus on refining chlorine dioxide protocols, exploring synergistic therapies, and understanding its systemic immune effects, thereby establishing chlorine dioxide’s role in cancer therapy.

Highlights

Chlorine dioxide demonstrates potent ROS-like capabilities for both cancer elimination and tissue regeneration, offering a and effective treatment approach.

Direct intratumoral administration of chlorine dioxide conveniently and sustainably kills cancer cells, without the risk of developing drug resistance.

Chlorine dioxide can enhance tumor ablation potential by disrupting tumor vasculature, contributing to its overall effectiveness.

Chlorine dioxide promotes an immune response against cancer, significantly enhancing its therapeutic effectiveness.

Intratumoral injections of chlorine dioxide represent an innovative and promising strategy for efficacious cancer therapy.
Neural crest mural cells of forebrain meninges harbor innate immune functions during early brain development and exhibit different responses to septic and toxic insults
Authors: Amarante-Silva Diego , Bruet Emmanuel , Gars Rémy , Piechon Margaux , Gorojankina Tatiana , Bignon Jérôme , Creuzet Sophie E.
Published: November 2023

In vertebrates, the cephalic neural crest (CNC), an embryonic multipotent cell population, gives rise to meningeal derivatives, covering and protecting the developing forebrain. In postnatal life, the meninges exert a prime role in developing and maintaining the central nervous system’s homeostasis and help modulate the immune capacities of resident cells and the blood-brain barrier. However, their role in the embryo remains elusive before the formation of brain barriers. Here, we explore whether meningeal CNC-mural cells participate in immunosurveillance during the early stages of embryogenesis. Using primary cultures of E8 chicken forebrain meningeal mural cells, immuno-phenotyping, and flow cytometry analyses, we demonstrated the expression of specific receptors, including TLRs and MHC class II molecules typically expressed in myeloid cells. Our experiments showed that when challenged by bacterial particles, CNC mural cells also have phagocytic capacities. Transcriptomic analysis revealed activation of inflammatory pathways leading to increased expression of myeloid surface markers and the production of cytokines and interleukins in the presence of bacterial particles. Our in vitro assays also show the capacities of mural cells to present and transfer antigen particles and recruit cooperant cells, both locally and at a distance. Moreover, we revealed that pericytes could deploy DNA traps like neutrophils to stop pathogens. We show that mural cells use extracellular DNA shedding against pathogenic conditions and communicate with each other to mobilize cell cooperation. Transcriptomic analyses revealed that exposure to bacterial particles leads to severe impairment of morphogenetic and neuro-developmental pathways and shed light on the possible detrimental effect of bacterial infection on brain development and maturation of cognitive functions. To reinforce the possible link between neurodevelopmental defects and immune activation, we challenged the immune capacities of CNC pericytes after exposure to toxic medication. We used Valproate (VPA), an antiepileptic drug associated with developmental disorders in newborns when administered during pregnancy. We show that VPA injection into chicken embryos triggered exacerbated myeloid traits and DNA trap releases in CNC pericytes. Our studies show that CNC mural cells are professional innate immune cells capable of pathogen recognition and antigen presentation. This notion breaks the prevailing concept that only mesodermal lineage can participate in the innate immune defense. It opens new avenues for elaborating brain-specific immunity before birth, which may have important biomedical implications for neurodevelopmental disorders.
Wearable Disposable Electrotherapy
Authors: FallahRad Mohamad , Chaudhry Zeeshan , Belali Koochesfahani Mojtaba , Bhuiyan Rayyan , Zaman Mahdi , Liu Tiffany , Saha Kisholoy , Diaz Uraga Miguel R , Velarde Osvaldo , Donnery Kyle , Babaev Benjamin , Saw Matthew , Rddad Ayman , Thahsin Myesha , Couzis Alexander , Bikson Marom
Published: November 2023

We design and validate a novel electrotherapy platform without electronic components, using printed abundant, environmentally benign materials. Whereas existing electrotherapy devices use an independent power source and electronics to generate and control stimulation currents, our design eliminates the need for these components. Device production relies only on scalable additive manufacturing and common materials, minimizing cost and environmental impact. The disposable single-use platform (as discreet as adhesive bandages) is activated simply by placement on the body. A prescribed electrotherapy discharge is regulated by a flexible 3D electrochemical architecture tailored to each application by a novel operational theory. The single-dose usability of this platform is a categorical shift from existing approaches with durable equipment that require programming and assembly to disposable electrodes for each use. Our Wearable Disposable Electrotherapy technology can be distributed like pharmacotherapy, with indications spanning neuromodulation of brain disorders, wound healing, transcutaneous drug delivery, bioelectronic medicine, and aesthetics.
Probabilistic ecological risk assessment for deep-sea mining: a Bayesian Network for Chatham Rise, SW Pacific Ocean
Authors: Kaikkonen Laura , Clark Malcolm R. , Leduc Daniel , Nodder Scott D. , Rowden Ashley A. , Bowden David A. , Beaumont Jennifer , Cummings Vonda
Published: November 2023

Increasing interest in seabed resource use in the ocean is introducing new pressures on deep-sea environments, the ecological impacts of which need to be evaluated carefully. The complexity of these ecosystems and the dearth of comprehensive data pose significant challenges to predicting potential impacts. In this study, we demonstrate the use of Bayesian Networks (BNs) as a modelling framework to address these challenges and enhance the development of robust quantitative predictions concerning the effects of human activities on deep-seafloor ecosystems. The approach consists of iterative model building with experts, and quantitative probability estimates of the relative decrease in abundance of different functional groups of benthos following seabed mining. The model is then used to evaluate two alternative seabed mining scenarios to identify the major sources of uncertainty associated with the mining impacts. By establishing causal connections between the pressures associated with potential mining activities and various components of the benthic ecosystem, our model offers an improved comprehension of potential impacts on the seafloor environment. We illustrate this approach using the example of potential phosphorite nodule mining on the Chatham Rise, offshore Aotearoa/New Zealand, SW Pacific Ocean, and examine ways to incorporate knowledge from both empirical data and expert assessments into quantitative risk assessments. We further discuss how ecological risk assessments can be constructed to better inform decision-making, using metrics relevant to both ecology and policy. The findings from this study highlight the valuable insights that BNs can provide in evaluating the potential impacts of human activities. However, continued research and data collection are crucial for refining and ground truthing these models and improving our understanding of the long-term consequences of deep-sea mining and other anthropogenic activities on marine ecosystems. By leveraging such tools, policymakers, researchers, and stakeholders can work together towards human activities in the deep sea that minimise ecological harm and ensure the conservation of these environments.
Cellular Lipids Regulate the Conformational Ensembles of the Disordered Intracellular Loop 3 in β2 Adrenergic Receptor
Authors: Mukhaleva Elizaveta , Yang Tianyi , Sadler Fredrik , Sivaramakrishnan Sivaraj , Ma Ning , Vaidehi Nagarajan
Published: November 2023

The structurally disordered intracellular loops (ICLs) of G protein-coupled receptors (GPCRs) play a critical role in G protein coupling. In our previous work, we used a combination of FRET-based and computational methodologies to show that the third intracellular loop (ICL3) modulates the activity and G protein coupling selectivity in GPCRs. In the current study, we have uncovered the role of several lipid components in modulating the conformational ensemble of ICL3 of the β2-adrenergic receptor (β2AR). Our findings indicate that phosphatidylinositol 4,5-bisphosphate (PIP2) in the inner leaflet of the membrane bilayer acts as a stabilizing anchor for ICL3, opening the intracellular cavity to facilitate G protein coupling. This interaction between PIP2 and ICL3 causes tilting of β2AR within the cellular membrane. Notably, this tilting of the receptor is supported by ganglioside GM3 stabilizing the extracellular loops on the outer leaflet of the bilayer, thereby exerting an allosteric effect on the orthosteric ligand binding pocket. Our results underscore the significance of lipids in modulating GPCR activity, proposing an allosteric mechanism that occurs through the receptor’s orientation within the membrane.
An Efficient Parallel Sketch-based Algorithmic Workflow for Mapping Long Reads
Authors: Rahman Tazin , Bhowmik Oieswarya , Kalyanaraman Ananth
Published: November 2023

1

Long read technologies are continuing to evolve at a rapid pace, with the latest of the high fidelity technologies delivering reads over 10Kbp with high accuracy (99.9%). Classical long read assemblers produce assemblies directly from long reads. Hybrid assembly workflows provide a way to combine partially constructed assemblies (or contigs) with newly sequenced long reads in order to generate improved and near-complete genomic scaffolds. Under either setting, the main computational bottleneck is the step of mapping the long reads—against other long reads or pre-constructed contigs. While many tools implement the mapping step through alignments and overlap computations, alignment-free approaches have the benefit of scaling in performance. Designing a scalable alignment-free mapping tool while maintaining the accuracy of mapping (precision and recall) is a significant challenge. In this paper, we visit the generic problem of mapping long reads to a database of subject sequences, in a fast and accurate manner. More specifically, we present an efficient parallel algorithmic workflow, calledJEM-mapper, that uses a new minimizer-based Jaccard estimator (or JEM) sketch to perform alignment-free mapping of long reads. For implementation and evaluation, we consider two application settings: (i) the hybrid scaffolding setting, where the goal is to map a large collection of long reads to a large collection of partially constructed assemblies or contigs; and (ii) the classical long read assembly setting, where the goal is to map long reads to one another to identify overlapping long reads. Our algorithms and implementations are designed for execution on distributed memory parallel machines. Experimental evaluation shows that our parallel algorithm is highly effective in producing high-quality mapping while significantly improving the time to solution compared to state-of-the-art mapping tools. For instance, in the hybrid setting for a large genomeBetta splendens(≈350Mbpgenome) with 429KHiFi long reads and 98Kcontigs,JEM-mapperproduces a mapping with 99.41% precision and 97.91% recall, while yielding 6.9×speedup over a state-of-the-art mapper.
Measuring technical variability in Illumina DNA methylation microarrays
Authors: Butler Anderson A. , Kras Jason , Chwalek Karolina , Ramos Enrique I. , Bishof Isaac , Vogel David , Vera Daniel L.
Published: November 2023

DNA methylation microarrays have become a widely used tool for investigating epigenetic modifications in various aspects of biomedical research. However, technical variability in methylation data poses challenges for downstream applications such as predictive modeling of health and disease. In this study, we measure the impact of common sources of technical variability in Illumina DNA methylation microarray data, with a specific focus on positional biases inherent within the microarray technology. By utilizing a dataset comprised of multiple, highly similar technical replicates, we identified a chamber number bias, with different chambers of the microarray exhibiting systematic differences in fluorescence intensities and their derived methylation beta values, which are only partially corrected for by existing preprocessing methods, and demonstrate that this positional bias can lead to false positive results during differential methylation testing. Additionally, our investigation identified outliers in low-level fluorescence data which might play a role in contributing to predictive error in computational models of health-relevant traits such as age.
Human Heart Failure Alters Mitochondria and Fiber 3D Structure Triggering Metabolic Shifts
Authors: Vue Zer , Ajayi Peter T. , Neikirk Kit , Murphy Alexandria C. , Prasad Praveena , Jenkins Brenita C. , Vang Larry , Garza-Lopez Edgar , Mungai Margaret , Marshall Andrea G. , Beasley Heather K. , Killion Mason , Parker Remi , Anukodem Josephs , Lavine Kory , Ajijola Olujimi , Mobley Bret C. , Dai Dao-Fu , Exil Vernat , Kirabo Annet , Ru Su Yan , Tomasek Kelsey , Zhang Xiuqi , Wanjalla Celestine , Hubert David L. , Phillips Mark A. , Shao Jian-qiang , McReynolds Melanie R. , Glancy Brian , Hinton Antentor
Published: November 2023

This study, utilizing SBF-SEM, reveals structural alterations in mitochondria and myofibrils in human heart failure (HF). Mitochondria in HF show changes in structure, while myofibrils exhibit increased cross-sectional area and branching. Metabolomic and lipidomic analyses indicate concomitant dysregulation in key pathways. The findings underscore the need for personalized treatments considering individualized structural changes in HF.
Onsager's relations and Ecology
Authors: Choi Jae S , Hansell Roger I. C.
Published: November 2023

There are two complementary approaches to thermodynamics: an empirical, phenomenological representation of macroscopic states and a model-based, statistical-mechanical representation of microscopic states. If only a few energy transformation steps are involved, macroscopic quantities such as energy and entropy can be estimated without ambiguity, and often the associated microscopic states are well characterised. Both approaches have been used to develop and guide many key early ecological ideas. However, most ecosystems are characterized by uncountably many transformations that operate on a wide range of space and time scales. This renders the bounds of such systems ambiguous making both the macroscopic and microscopic approaches a challenge. As such, the implementation of both approaches remain areas ripe for further investigation. In particular, the Onsager reciprocal relations permit simplification of expectations that are yet to be fully understood in an ecological context. Here we begin to take a few first steps in trying to understand the far-reaching ramifications of these thermodynamic relations.
Benchmarking AlphaSC: A Leap in Single-Cell Data Processing
Authors: Vuong Hy , Luu Tam , Nguyen Nhat , Tra Nghia , Nguyen Ha , Nguyen Huy , Truong Thao , Pham Son
Published: November 2023

Abstract

We benchmarked AlphaSC, BioTuring’s GPU-accelerated single-cell analytics package, against other popular tools including Scanpy, Seurat, and RAPIDS. The results demonstrate that AlphaSC operates thousands of times faster than Seurat and Scanpy. Additionally, it surpasses RAPIDS, another GPU-accelerated package from NVIDIA, by an order of magnitude in terms of speed while also consuming considerably less RAM and GPU memory. Importantly, this significant increase in AlphaSC’s performance does not compromise its quality.1
Streamlining remote nanopore data access withslow5curl
Authors: Wong Bonson , Ferguson James M. , Gamaarachchi Hasindu , Deveson Ira W.
Published: November 2023

As adoption of nanopore sequencing technology continues to advance, the need to maintain large volumes of raw current signal data for reanalysis with updated algorithms is a growing challenge. Here we introduceslow5curl, a software package designed to streamline nanopore data sharing, accessibility and reanalysis.Slow5curlallows a user to fetch a specified read or group of reads from a raw nanopore dataset stored on a remote server, such as a public data repository, without downloading the entire file.Slow5curluses an index to quickly fetch specific reads from a large dataset in SLOW5/BLOW5 format and highly parallelised data access requests to maximise download speeds. Using all public nanopore data from the Human Pangenome Reference Consortium (>22 TB), we demonstrate howslow5curlcan be used to quickly fetch and reanalyse signal reads corresponding to a set of target genes from each individual in large cohort dataset (n= 91), minimising the time, egress costs, and local storage requirements for their reanalysis. We provideslow5curlas a free, open-source package that will reduce frictions in data sharing for the nanopore community:https://github.com/BonsonW/slow5curl
Apgr5suppressor screen uncovers a distinct mechanism safeguarding the cytochromeb6fcomplex from damage through PGR5
Authors: Penzler Jan-Ferdinand , Naranjo Belen , Walz Sabrina , Marino Giada , Kleine Tatjana , Leister Dario
Published: November 2023

PROTON GRADIENT REGULATION5 (PGR5) is thought to promote cyclic electron flow (CEF) and its deficiency causes increased photosensitivity of photosystem I (PSI), leading to lethality under fluctuating light (FL). By screening for suppressor mutations that rescue FL lethality ofpgr5plants, we identified a portfolio of mutations affecting 12 photosynthesis-related proteins. Six are required for proper PSII function, one (CcdA) promotes cytochrome (cyt)b6fassembly, and another (PAA1) provides plastocyanin with its copper cofactor. Two other mutations are associated with the chloroplast FBPase cFBP1. This, together with targeted knockout of other genes in thepgr5background, suggests three pathways to restore FL viability: (i) reduced electron flow to PSI due to defects in PSII, cytb6for plastocyanin but not PSI, (ii) increased electron flow from PSI due to inactivation of ACHT2, a regulator of cFBP1 activity, and (iii) hyperactivity of the NDH-dependent CEF due to inactivation of cFBP1. The remaining two suppressor mutations affected the cytb6fcomplex. PFSC1 controls cytb6faccumulation at early developmental stages. DEIP1/NTA1, previously suggested to be essential for cytb6fassembly, appears to protect cytb6ffrom deleterious effects of PGR5, since plants lacking both DEIP1/NTA1 and PGR5 are viable and accumulate cytb6f.
Multitrait engineering of Hassawi red rice for sustainable cultivation
Authors: Sedeek Khalid , Mohammed Nahed , Zhou Yong , Zuccolo Andrea , Sanikommu Krishnaveni , Kantharajappa Sunitha , Al-Bader Noor , Tashkandi Manal , Wing Rod A. , Mahfouz Magdy M.
Published: November 2023

Sustainable agriculture requires locally adapted varieties that produce nutritious food with limited agricultural inputs. Genome engineering represents a viable approach to develop cultivars that fulfill these criteria. For example, the red Hassawi rice, a native landrace of Saudi Arabia, tolerates local drought and high-salinity conditions and produces grain with diverse health-promoting phytochemicals. However, Hassawi has a long growth cycle, high cultivation costs, low productivity, and susceptibility to lodging. Here, to improve these undesirable traits via genome editing, we established efficient regeneration and Agrobacterium-mediated transformation protocols for Hassawi. In addition, we generated the first high-quality reference genome and targeted the key flowering repressor gene,Hd4, thus shortening the plant’s lifecycle and height. Using CRISPR/Cas9 multiplexing, we simultaneously disrupted negative regulators of flowering time (Hd2, Hd4, andHd5), grain size (GS3), grain number (GN1a), and plant height (Sd1). The resulting homozygous mutant lines flowered extremely early (∼56 days) and had shorter stems (approximately 107 cm), longer grains (by 5.1%), and more grains per plant (by 50.2%), thereby enhancing overall productivity. Furthermore, the awns of grains were 86.4% shorter compared to unedited plants. Moreover, the modified rice grain displayed improved nutritional attributes. As a result, the modified Hassawi rice combines several desirable traits that can incentivize large-scale cultivation and reduce malnutrition.
Prognostic significance of AI-identified markers for isoniazid resistance in Mycobacterium tuberculosis
Authors: Valafar Siavash , Valafar Aram
Published: November 2023

Antibiotic resistance in tuberculosis (TB), a disease that kills 1.5 million people annually, is a great concern. The emergence of drug resistance inM. tuberculosis, the obligate pathogen of TB seems to follow an order. In most cases resistance to isoniazid (INH) emerges first, followed by rifampicin, then either pyrazinamide or ethambutol, and finally followed by resistance to second-line drugs. Prevention of emergence of INH resistance can go a long way to prevent the emergence of resistance to other drugs. In this manuscript we present the prognostic value of specific mutations in the hope that resistance can be e predicted and hence avoided. Here we present evidence that resistance to INH follows a stepwise evolutionary trajectory in most cases. This information can therefore be used to predict and avoid INH resistance. In our approach, we used genomic and phenotypic data from over 16,000 samples collected by two large databases, the TB Portals and the CRyPTIC consortium. We used a deep learning neural network model to identify promising mutations using the TB Portal data. We then tested the prognostic value of the identified mutations using the CRyPTIC consortium data. In this manuscript, we estimate a prognostic accuracy of 73% for correctly predicting the emergence of three canonical INH resistance mutations (katG315, inhA-15, and inhA-8) by using two prognostic markers. Additional time course samples and analysis will undoubtedly uncover prognostic markers for other evolutionary trajectories that lead to resistance.
Smartphone keyboard dynamics predict affect in suicidal ideation
Authors: Knol Loran , Nagpal Anisha , Leaning Imogen E. , Idda Elena , Hussain Faraz , Ning Emma , Eisenlohr-Moul Tory A. , Beckmann Christian F. , Marquand Andre F. , Leow Alex
Published: November 2023

While digital phenotyping provides opportunities for unobtrusive, real-time mental health assessments, the integration of its modalities is not trivial due to high dimensionalities and discrepancies in sampling frequencies. We provide an integrated pipeline that solves these issues by transforming all modalities to the same time unit, applying temporal independent component analysis (ICA) to high-dimensional modalities, and fusing the modalities with linear mixed-effects models. We applied our approach to integrate high-quality, daily self-report data with BiAffect keyboard dynamics derived from a clinical suicidality sample of mental health outpatients. Applying the ICA to the self-report data (104 participants, 5712 days of data) revealed components related to well-being, anhedonia, and irritability and social dysfunction. Mixed-effects models (55 participants, 1794 days) showed that less phone movement while typing was associated with more anhedonia (β = -0.12, p = 0.00030). We consider this method to be widely applicable to dense, longitudinal digital phenotyping data.
The Social Sunshine of the Arctic Youth: Exploring friendship’s influence on Vitamin D levels
Authors: Nozal Cañadas Rafael A. , Nielsen Christopher Sivert , Furberg Anne-Sofie , Hanssen Anne Merethe , Bongo Lars Ailo
Published: November 2023

Background

Vitamin D status correlates with 25OHD levels which depends on nutritional intake and UVB exposure. These two factors are influenced by friends, as people tend to participate in the same activities or eat a similar diet to their peers.

Objectives

Investigate how social interactions in a general high school population above the Arctic Circle influence 25OHD levels in the population.

Methods

The Fit Futures 1 study was performed over 8 months and interview data on social contact among 1038 first-level students in 8 high schools in Northern Norway were collected. Serum levels of 25OHD were measured (n = 890). The participants filled in a questionnaire about nutritional consumption, solarium habits, ethnicity, and chronic diseases. The participant’s BMI was also measured.

Results

Once high schools’ social biases were accounted for, only UVB radiation levels explained the differences in 25OHD levels. For non-solarium users, logistic regression analysis showed a positive correlation between a person’s 25OHD levels and the 25OHD level of friends in the general population and within the same high school for most of the schools. We saw that women can influence other women into going to the solarium, while this influence was not present for men.

Conclusions

25OHD levels can be influenced by social networks. This study can help to add weight to current public health recommendations due to the positive spillover effect in the network.
Sex Differences in the Acute Effects of Oral THC: A Randomized, Placebo-Controlled, Crossover Human Laboratory Study
Authors: Aghaei Ardavan Mohammad , Spillane Lia Urban , Pittman Brian , Flynn L. Taylor , De Aquino Joao P. , Nia Anahita Bassir , Ranganathan Mohini
Published: November 2023

Rationale

Recent reports have shown increased cannabis use among women, leading to growing concerns about cannabis use disorder (CUD). Some evidence suggests a faster progression to addiction in women, known as the “telescoping effect.” While there is preclinical evidence suggesting biological sex influences cannabinoid effects, human research remains scant. We investigated sex differences in the response to oral tetrahydrocannabinol (THC) in humans.

Methods

56 healthy men and women with prior exposure to cannabis but no history of CUD participated in a randomized, placebo-controlled, human laboratory study where they received a single 10 mg dose of oral THC (dronabinol). Subjective psychoactive effects were assessed by the visual analog scale of “high”, psychotomimetic effects by the Clinician-Administered Dissociative Symptoms Scale and Psychotomimetic States Inventory, verbal learning and memory by Rey Auditory Verbal Learning Test (RAVLT), and physiological effects by heart rate. Outcomes were regularly measured on the test day, except for the RAVLT, which was assessed once. Peak differences from baseline were analyzed using a nonparametric method for repeated measures.

Results

Oral THC demonstrated significant dose-related effects in psychotomimetic and physiological domains, but not in RAVLT outcomes. A notable interaction between THC dose and sex emerged concerning the subjective “high” scores, with women reporting heightened sensations (p=0.05). No other significant effects of sex and THC dose interaction were observed.

Conclusion

Oral THC yields similar psychotomimetic and physiological effects across sexes, but women may experience a pronounced subjective psychoactive effect. Further research is needed to identify individual vulnerabilities and facilitate tailored interventions addressing CUD.
Effectiveness of Implementation Interventions in Musculoskeletal Healthcare: A Systematic Review
Authors: Hansen Peter Bech , Bahnsen Mikkel , Nørgaard Mikkel Sloth , Jepsen Jette Frost , Rathleff Michael Skovdal , Lyng Kristian Damgaard
Published: November 2023

Background

Implementing new knowledge into clinical practice is a challenge, but nonetheless crucial to improve our healthcare system related to the management of musculoskeletal pain. This systematic review aimed to assess the effectiveness of implementation interventions within musculoskeletal healthcare.

Methods

We searched Medline, Embase, Cochrane Central Register of Controlled Trials, and Scopus. Any type of randomised controlled trials investigating implementation strategies or interventions in relation to musculoskeletal pain conditions were included. Risk of bias were assessed using the Cochrane Risk of Bias 2 tool. Data analysis was done using frameworks from Powell et al. 2015, and Waltz et al. 2015 and outcomes were identified by Thompson et al. 2022 or self-made outcome domains were established.

Results

The literature search yielded 14,265 original studies, of which 38 studies from 31 trials, with 13,203 participating healthcare professionals and 30,320 participating patients were included in the final synthesis. Nineteen studies had a high risk of bias, sixteen had a moderate risk of bias, and three had a low risk of bias. Twenty distinct implementation interventions were identified. A significant heterogeneity in the utilised outcome measurements was observed, thereby rendering a meta-analysis infeasible; consequently, all outcomes were classified into six outcome domains for healthcare professionals, seven for patients and one for cost-effectiveness.

Conclusions

Our findings suggest that some implementation interventions may have a tendency towards a statistically significant positive effect in favour of the intervention group on the outcome domain “Adherence to the implemented interventions” for healthcare professionals in the included studies. The remaining outcome domains yielded varying results; therefore, these findings should be interpreted with caution. Future high-quality trials with clear reporting and rationale of implementation strategies and interventions utilising standardised nomenclature are needed to further advance our understanding of this area.

Trial registration

Open Science Framework, DOI:10.17605/OSF.IO/SRMP2
ChatGPT Provides Inconsistent Risk-Stratification of Patients With Atraumatic Chest Pain
Authors: Heston Thomas F. , Lewis Lawrence M.
Published: November 2023

BACKGROUND

ChatGPT is a large language model with promising healthcare applications. However, its ability to analyze complex clinical data and provide consistent results is poorly known. This study evaluated ChatGPT-4’s risk stratification of simulated patients with acute nontraumatic chest pain compared to validated tools.

METHODS

Three datasets of simulated case studies were created: one based on the TIMI score variables, another on HEART score variables, and a third comprising 44 randomized variables related to non-traumatic chest pain presentations. ChatGPT independently scored each dataset five times. Its risk scores were compared to calculated TIMI and HEART scores. A model trained on 44 clinical variables was evaluated for consistency.

RESULTS

ChatGPT showed a high correlation with TIMI and HEART scores (r = 0.898 and 0.928, respectively), but the distribution of individual risk assessments was broad. ChatGPT gave a different risk 45-48% of the time for a fixed TIMI or HEART score. On the 44 variable model, a majority of the five ChatGPT models agreed on a diagnosis category only 56% of the time, and risk scores were poorly correlated (r = 0.605). ChatGPT assigned higher risk scores to males and African Americans.

CONCLUSION

While ChatGPT correlates closely with established risk stratification tools regarding mean scores, its inconsistency when presented with identical patient data on separate occasions raises concerns about its reliability. The findings suggest that while large language models like ChatGPT hold promise for healthcare applications, further refinement and customization are necessary, particularly in the clinical risk assessment of atraumatic chest pain patients.
Metabolism-focused CRISPR screen unveils Mitochondrial Pyruvate Carrier 1 as a critical driver for PARP inhibitor resistance in lung cancer
Authors: Furusawa Takashi , Cavero Renzo , Liu Yue , Li Haojian , Xu Xia , Andresson Thorkell , Reinhold William , White Olivia , Boufraqech Myriem , Meyer Thomas J. , Hartmann Oliver , Diefenbacher Markus E. , Pommier Yves , Weyemi Urbain
Published: November 2023

Homologous recombination (HR) and poly ADP-ribosylation are partially redundant pathways for repair of DNA damage in normal and cancer cells. In cell lines that are deficient in HR, inhibition of poly (ADP-ribose) polymerase (PARP1/2) is a proven target with several PARP inhibitors (PARPi) currently in clinical use. Resistance to PARP inhibitors often develops, usually involving genetic alterations in DNA repair signaling cascades, but also metabolic rewiring particularly in HR-proficient cells. PARP1/2 utilize NAD+ (nicotinamide adenine dinucleotide), an essential substrate not only for PARPs but also for multiple pathways in cellular metabolism, TCA cycle and mitochondrial functions. Thus, NAD+ is central to many key cellular functions. Both activation of PARPs by DNA damage and their inhibition by drugs such as olaparib affect NAD+ consumption. We surmised that alterations in NAD+ metabolism by cancer drugs such as Olaparib might be involved in the development of resistance to drug therapy. To test this hypothesis, we conducted a metabolism-focused CRISPR knockout (KO) screen to identify genes which undergo alterations during treatment of tumor cells with PARP inhibitors. Of about 3000 genes in the screen, our data revealed that mitochondrial pyruvate carrier 1 (MPC1) is an essential factor in desensitizing NSCLC lung cancer lines to PARP inhibition. In contrast to NSCLC lung cancer cells, triple negative breast cancer cells do not exhibit such desensitization following MPC1 loss and reprogram the TCA cycle and oxidative phosphorylation pathways to overcome PARP inhibitor treatment. Our findings unveil a previously unknown synergistic response between MPC1 loss and PARP inhibition in lung cancer cells.
Preserving condensate structure and composition by lowering sequence complexity
Authors: Sood Amogh , Zhang Bin
Published: November 2023

Biological condensates play a vital role in organizing cellular chemistry. They selectively partition biomolecules, preventing unwanted cross-talk and buffering against chemical noise. Intrinsically disordered proteins (IDPs) serve as primary components of these condensates due to their flexibility and ability to engage in multivalent, nonspecific interactions, leading to spontaneous aggregation. Theoretical advancements are critical at connecting IDP sequences with condensate emergent properties to establish the so-called molecular grammar. We proposed an extension to the stickers and spacers model, incorporating non-specific pairwise interactions between spacers alongside specific interactions among stickers. Our investigation revealed that while spacer interactions contribute to phase separation and co-condensation, their non-specific nature leads to disorganized condensates. Specific sticker-sticker interactions drive the formation of condensates with well-defined structures and molecular composition. We discussed how evolutionary pressures might emerge to affect these interactions, leading to the prevalence of low complexity domains in IDP sequences. These domains suppress spurious interactions and facilitate the formation of biologically meaningful condensates.

Significance Statement

Biomolecular condensates serve as pivotal mechanisms in cellular organization, often characterized by an abundance of intrinsically disordered proteins (IDPs) that undergo frequent mutations in their sequences. Despite this, IDP sequences exhibit non-random patterns, yet the precise relationship between these sequences and the emergent properties of condensates remains unclear. To address this gap, we propose a molecular theory that delineates how various sequence features of IDPs contribute to the organization and composition of condensates. This theory not only sheds light on the evolution of IDPs but also elucidates the emergence of non-random sequence patterns as essential elements for the formation of functional condensates. Correspondingly, we posit that the prevalence of low-complexity regions within IDPs is a result of evolutionary selection.
Swi4-dependent SWI4 transcription couples cell size to cell cycle commitment
Authors: Goswami Pooja , Ghimire Abhishek , Coffin Carleton , Cheng Jing , Coulombe-Huntington Jasmin , Ghazal Ghada , Thattikota Yogitha , Tyers Mike , Tollis Sylvain , Royer Catherine
Published: November 2023

Growth-dependent accumulation of the limiting SBF transcription factor, composed of Swi4 and Swi6, occurs in G1 phase in budding yeast and is limiting for commitment to division, termed Start. Here we measure size-dependence of Swi4 protein copy number under different genetic contexts using the scanning number and brightness technique. Mutation of SBF binding sites in theSWI4promoter or disruption of SBF activation resulted in ∼33-50% decrease in Swi4 accumulation rate and concordantly increased cell size at Start. Ectopic inducible expression of Swi4 in G1 phase cells increased production of Swi4 from the endogenous promoter, upregulated transcription of the G1/S regulon, and accelerated Start. Despite the potential for Swi4 positive feedback, G1 phase Swi4 accumulation was linear unless the Whi5 transcriptional repressor was inactivated. A threshold model in which Swi4 titrates SBF binding sites in G1/S promoters predicted the effects of nutrients, ploidy, and G1/S regulatory mutations on cell size. These results exemplify how transcription factor auto-production can contribute to a cell state transition.
Unraveling the metabolomic architecture of autism in a large Danish population-based cohort
Authors: Ottosson Filip , Russo Francesco , Abrahamsson Anna , MacSween Nadia , Courraud Julie , Skogstrand Kristin , Melander Olle , Ericson Ulrika , Orho-Melander Marju , Cohen Arieh S. , Grove Jakob , Mortensen Preben Bo , Hougaard David M. , Ernst Madeleine
Published: November 2023

The prevalence of autism in Denmark has been increasing, reaching 1.65% among 10-year-old children and similar trends are seen elsewhere. Although there are several factors associated with autism, including genetic, environmental and prenatal factors, the molecular etiology of autism is largely unknown. Metabolomics has emerged as a tool to measure small molecules that reflect genetic, gut microbiome and dietary intake variations. Here, we apply untargeted metabolomics to over 1400 neonatal dried bloods spots, including neonates who later are diagnosed with autism and matching controls. Overall, we detect underlying molecular perturbations that precede autism related to metabolism of amino acids, acylcarnitines and peptides. In particular the cyclic dipeptide cyclo-leucine-proline and the carnitine-related 5-aminovaleric acid betaine (5-AVAB), were associated with an increased probability for autism. Analysis of genetic and dietary data in over 7000 adults revealed that 5-AVAB was associated with increased habitual dietary intake of dairy and with variantsSLC22A5, coding for a transmembrane carnitine transporter protein involved in controlling intracellular carnitine levels. We identify 5-AVAB as a novel and potentially modifiable early biomarker for autism that may influence carnitine homeostasis.
A healthful plant-based diet is associated with higher physical and mental well-being among older adults independent of circulating CRP
Authors: Schorr Kerstin , Beekman Marian , Agayn Venetka , de Vries Jeanne H.M. , De Groot Lisette C.P.G.M. , Slagboom P. Eline
Published: November 2023

Plant-based diets (PBD) have been found to be environmentally sustainable as well as beneficial for health. Observational research showed that higher plant-based diet quality improves well-being in adult women, however this is unclear for older adults. This association may be due to anti-inflammatory properties of PBD. Older adults, often suffering from chronic inflammation, may therefore profit from a more PBD. Therefore, we investigated the relation between PBD and well-being in older adults of both genders and tested whether the effects are influenced by circulating high-senstivity C-reactive protein (hsCRP) levels. We used the data of the population-based Lifelines Cohort Study (n=6,635, mean age=65.2 years) and a subsample in which hsCRP was measured (n=2,251, mean age=65.2 years). We applied a plant-based diet index measuring adherence to a healthful (hPDI) and an unhealthful (uPDI) plant-based diet based on food frequency questionnaires. The RAND-36 questionnaire was applied as measure of quality of life, from which we derived physical (PCS) and mental component scores (MCS). Older adults with the highest adherence to a healthful plant-based diet had respectively 14% and 12% greater odds for high physical well-being and mental well-being. Meanwhile, higher adherence to uPDI was associated with respectively 19% and 14% lower odds for high physical and mental well-being. We observed an additive but no mediating effect of hsCRP on the association between plant-based diets and well-being. We conclude that in older men and women, adherence to a healthful plant-based diet and circulating levels of inflammation are independently associated with physical and mental well-being.
Synthesis and redetermination of the crystal structure of NbF5
Authors: Möbs Martin , Kraus Florian
Published: November 2023

Single crystals of NbF5, niobium(V) fluoride, have been obtained by the reaction of niobium metal in a stream of dilute elemental fluorine at 473 K and subsequent sublimation. The as-obtained bulk phase compound was shown to be pure by powder X-ray diffraction at 293 K and by IR and Raman spectroscopy. A single-crystal X-ray analysis was conducted at 100 K. In comparison to the previously reported structure model [Edwards (1964). J. Chem. Soc. pp. 3714–3718], the lattice parameters and fractional atom coordinates were determined to much higher precision and individual, anisotropic displacement parameters were refined for all atoms.
Dimorphism of [Bi2O2(OH)](NO3) – the ordered Pna21 structure at 100 K
Authors: Weil Matthias , Missen Owen P. , Mills Stuart J.
Published: November 2023

The re-investigation of [Bi2O2(OH)](NO3), dioxidodibismuth(III) hydroxide nitrate, on the basis of single-crystal X-ray diffraction data revealed an apparent structural phase transition of a crystal structure determined previously (space group Cmc21 at 173 K) to a crystal structure with lower symmetry (space group Pna21 at 100 K). The Cmc21 → Pna21 group–subgroup relationship between the two crystal structures is klassengleiche with index 2. In contrast to the crystal structure in Cmc21 with orientational disorder of the nitrate anion, disorder does not occur in the Pna21 structure. Apart from the disorder of the nitrate anion, the general structural set-up in the two crystal structures is very similar: [Bi2O2]2+ layers extend parallel to (001) and alternate with layers of (OH)− anions above and (NO3)− anions below the cationic layer. Whereas the (OH)− anion shows strong bonds to the BiIII cations, the (NO3)− anion weakly binds to the BiIII cations of the cationic layer. A rather weak O—H...O hydrogen-bonding interaction between the (OH)− anion and the (NO3)− anion links adjacent sheets along [001].
Implications of legalisation of cannabis cultivation in Ghana: a critical review
Authors: Agboli Jacob Mensah
Published: November 2023

Purpose

Following the trend in the world over and on the African continent, the Parliament of Ghana passed a new law in 2020, the Narcotics Control Commission Act (Act 1019) that eased the legal restrictions on cannabis cultivation and use, subject to obtaining license from the relevant authority/authorities. This paper aims to examine the implications of Ghana’s decision to legalise the cultivation of cannabis for industrial purposes for the production of fibre and for medicinal purposes.

Design/methodology/approach

The author adopted the qualitative analysis critical review methodology in sourcing information from peer-reviewed articles, coupled with the author’s own professional knowledge, background and training, to critically analyse and review the reasons behind Ghana’s decision to legalise cannabis cultivation and the implications such a major policy change/shift.

Findings

It was found that, while the law mentions industrial and medicinal purposes for the legalisation of cannabis, the real reason, at least in the immediate term, is mainly economic. This agrees with those of other African countries that have legalised cannabis cultivation but appears to contrast with those of Europe and America.

Research limitations/implications

This research is limited to Ghana and the few African countries that have legalised cannabis cultivation so far. The main reason for the legalisation (economic benefits) may also change in the future when the economics of scale turn in the favour of the country. Therefore, Ghana’s case may not represent the case of all countries legalising cannabis cultivation.

Practical implications

The research implication of this paper is that it brings to the world the law on cannabis cultivation in Ghana. It provides a professional and scientific position paper on Ghana’s drug law regime regarding cannabis, thus, serving as a useful reference literature to the academic and research community on the topic. More importantly, it discusses the implications of such major policy change from an objective perspective, unravelling the real reason behind the State’s decision to legalise the cultivation of cannabis in Ghana.

Social implications

This paper will bring to the fore the other consequences of Ghana’s cannabis cultivation legalisation policy change, which little attention has been devoted to so far.

Originality/value

This paper, apart from reference to other published texts on the topic, which have been duly acknowledged, represents the sole work of the author. It has not been produced anywhere or by anyone else either in Ghana or elsewhere.