bluuebunny/crossref_metadata_2025 huggingface dataset:
Forecasting range shifts of a dioecious plant species under climate change
Authors: Moutouama Jacob K. , Compagnoni Aldo , Miller Tom E.X.
Published: September 2024

Global warming has triggered an urgent need for predicting the reorganization of Earth’s biodiversity. Currently, the vast majority of models used to forecast population viability and range shifts in response to climate change ignore the complication of sex structure, and thus the potential for females and males to differ in their sensitivity to climate drivers. We developed demographic models of range limitation, parameterized from geographically distributed common garden experiments, with females and males of a dioecious grass species (Poa arachnifera) throughout and beyond its range in the south-central U.S. Female-dominant and two-sex model versions both predict that climate change will alter population viability and will induce a poleward niche shift beyond current northern limits. However, the magnitude of niche shift was underestimated by the female-dominant model, because females have broader temperature tolerance than males and become mate-limited under female-biased sex ratios. Our result illustrate how explicit accounting for both sexes could enhance population viability forecasts and conservation planning for dioecious species in response to climate change.
Biochemical Characterization and Inhibitor Discovery forPfSir2A – New Tricks for An Old Enzyme
Authors: Donu Dickson , Boyle Emily , Curry Alyson , Cen Yana
Published: September 2024

The Sir2 enzyme fromPlasmodium falciparum(PfSir2A) is essential for the antigenic variation of this parasite, and its inhibition is expected to have therapeutic effects for malaria. SelectivePfSir2A inhibitors are not available yet, partially due to the fact that this enzyme demonstrates extremely weakin vitrodeacetylase activity, making the characterization of its inhibitors rather challenging. In the current study, we report the biochemical characterization and inhibitor discovery for this enzyme.PfSir2A exhibits greater enzymatic activity in the presence of DNA for both the peptide and histone protein substrates, suggesting that nucleosomes may be the real substrates of this enzyme. Indeed, it demonstrates robust deacetylase activity against nucleosome substrates, stemming primarily from the tight binding interactions with the nucleosome. In addition to DNA/nucleosome, free fatty acids (FFAs) are also identified as endogenousPfSir2A regulators. Myristic acid, a biologically relevant FFA, shows differential regulation of the two distinct activities ofPfSir2A: activates deacetylation, but inhibits defatty-acylation. The structural basis of this differential regulation was further explored. Moreover, synthetic small molecule inhibitors ofPfSir2A were discovered through the screening of a library of human sirtuin regulators. The mechanism of inhibition of the lead compounds were investigated. Collectively, the mechanistic insights and inhibitors described in this study will facilitate the future development of small moleculePfSir2A inhibitors as antimalarial agents.
Maintenance of synaptic plasticity by negative-feedback of synaptic protein elimination: Dynamic modeling of KIBRA-PKMζ interactions in LTP and memory
Authors: Shouval Harel Z. , Flores-Obando Rafael E. , Sacktor Todd C.
Published: September 2024

Activity-dependent modifications of synaptic efficacies are a cellular substrate of learning and memory. Current theories propose that the long-term maintenance of synaptic efficacies and memory is accomplished via a positive-feedback loop at the level of production of a protein species or a protein state. Here we propose a qualitatively different theoretical framework based on negative-feedback at the level of protein elimination. This theory is motivated by recent experimental findings regarding the binding ofPKMζand KIBRA, two synaptic proteins involved in maintenance of memory, and on how this binding affects the proteins’ degradation. We demonstrate this theoretical framework with two different models, a simple abstract model to explore generic features of such a process, and an experimentally motivated phenomenological model. The results of these models are qualitatively consistent with existing data, and generate novel predictions that could be experimentally tested to further validate or reject the negative-feedback theory.
Tunable Elliptical Cylinders for Rotational Mechanical Studies of Single DNA Molecules
Authors: Hong Yifeng , Ye Fan , Gao Xiang , Inman James T. , Wang Michelle D.
Published: September 2024

The angular optical trap (AOT) is a powerful technique for measuring the DNA topology and rotational mechanics of fundamental biological processes. Realizing the full potential of the AOT requires rapid torsional control of these processes. However, existing AOT quartz cylinders are limited in their ability to meet the high rotation rate requirement while minimizing laser-induced photodamage. In this work, we present a novel trapping particle design to meet this challenge by creating small metamaterial elliptical cylinders with tunable trapping force and torque properties. The optical torque of these cylinders arises from their shape anisotropy, with their optical properties tuned via multilayered SiO2and Si3N4deposition. We demonstrate that these cylinders can be rotated at about 3 times the rate of quartz cylinders without slippage while enhancing the torque measurement resolution during DNA torsional elasticity studies. This approach opens new opportunities for previously inaccessible rotational studies of DNA processing.
DefiningTarget Population of Environmentsto Enviromics Studies Using R-based GIS Tools
Authors: Cruz Demila D. M. , Heinemann Alexandre B. , Marcatti Gustavo E. , Resende Rafael T.
Published: September 2024

We propose an R-based function that facilitates the definition of TPE (Target Population of Environments) as GIS polygons for enviromics studies in plant breeding. By adjusting parameters such as pixel size, buffers, and concavity, this function enhances envirotypic-based G×E interaction analysis and provides a flexible tool to optimize environmental and spatial assessments.
Second-Generation Cap Analogue Prodrugs for Targeting Aberrant Eukaryotic Translation Initiation Factor 4E (eIF4E) Activity in Drug-Resistant Melanoma
Authors: Cárdenas Emilio L. , O’Rourke Rachel L. , Menon Arya , Vega-Hernández Gabriela , Meagher Jennifer , Stuckey Jeanne , Garner Amanda L.
Published: September 2024

Melanoma is the deadliest form of skin cancer with a 5-year survival rate of less than 20%. While significant strides have been made in the field of kinase-targeted and immune-based therapies for melanoma, the development of resistance to these therapeutic agents has hindered the success of treatment. Drug-resistant melanoma is particularly reliant on enhanced cap-dependent translation to drive the production of oncoproteins that promote growth and survival. The m7GpppX cap-binding protein eukaryotic translation initiation factor 4E (eIF4E) is the rate-limiting factor of cap-dependent translation initiation, and its overexpression in melanoma tumors has been shown to drive resistance to BRAFV600Ekinase-targeted inhibitors. These findings point to eIF4E-targeted therapies as a promising strategy to overcome drug resistance in melanoma. Herein, we build upon our previous work of developing cell-permeable cap analogue inhibitors to design second-generation cap analogues that inhibit eIF4E-mediated cap-dependent translation in drug-resistant melanoma cells.
Temporal Information Encoding in Isolated Cortical Networks
Authors: Ferdous Zubayer Ibne , Berdichevsky Yevgeny
Published: September 2024

Time-dependent features are present in many sensory stimuli. In the sensory cortices, timing features of stimuli are represented by spatial as well as temporal code. A potential mechanism by which cortical neuronal networks perform temporal-to-spatial conversion is ‘reservoir computing’. The state of a recurrently-connected network (reservoir) represents not only the current stimulus, or input, but also prior inputs. In this experimental study, we determined whether the state of an isolated cortical network could be used to accurately determine the timing of occurrence of an input pattern – or, in other words, to convert temporal input features into spatial state of the network. We used an experimental system based on patterned optogenetic stimulation of dissociated primary rat cortical cultures, and read out activity via fluorescent calcium indicator. We delivered input sequences of patterns such that a pattern of interest occurred at different times. We developed a readout function for network state based on a support vector machine (SVM) with recursive feature elimination and custom error correcting output code. We found that the state of these experimental networks contained information about inputs for at least 900 msec. Timing of input pattern occurrence was determined with 100 msec precision. Accurate classification required many neurons, suggesting that timing information was encoded via population code. Trajectory of network state was largely determined by spatial features of the stimulus, with temporal features having a more subtle effect. Local reservoir computation may be a plausible mechanism for temporal/spatial code conversion that occurs in sensory cortices.

Significance Statement

Handling of temporal and spatial stimulus features is fundamental to the ability of sensory cortices to process information. Reservoir computation has been proposed as a mechanism for temporal-to-spatial conversion that occurs in the sensory cortices. Furthermore, reservoirs of biological, living neurons have been proposed as building blocks for machine learning applications such as speech recognition and other time-series processing. In this work, we demonstrated that living neuron reservoirs, composed of recurrently connected cortical neurons, can carry out temporal-spatial conversion with sufficient accuracy and at sufficiently long time scale to be a plausible model for information processing in sensory cortices, and to have potential computational applications.
Fis family members synergistically control the virulence ofLegionella pneumophila
Authors: Andréa Claire , Bresson Julie , Ginévra Christophe , Vianney Anne , Bailo Nathalie , Chapalain Annelise , Attaiech Laetitia , Picq Kevin , Ranquet Caroline , Nasser William , Doublet Patricia , Kay Elisabeth
Published: September 2024

Legionella pneumophilavirulence is controlled in a growth phase-dependent manner by a complex regulatory network involving several two-component systems, small regulatory RNAs and the translational CsrA regulator. Here, we address the additional role of Nucleoid-associated proteins (NAP) regulators in this network, by investigating the regulatory functions of the three Fis paralogs (Fis1, Fis2, Fis3), a unique feature among bacteria, in the infection cycle ofL. pneumophila. Specifically, we show that deletion offis1has a major impact onL. pneumophilavirulence, and that deletion offis2enhances the intensity of this phenotype. Consistently, RNA-seq analysis and reporter gene fusions demonstrate the predominant role of Fis1 in the regulation of many virulence-related genes, including those involved in the flagellum, pili biosynthesis, and Dot/Icm type 4 secretion machinery, as well as several genes encoding Dot/Icm effectors. Both Fis1 and Fis2 bind to AT-rich motifs upstream their target genes, but Fis1 with higher affinity than Fis2. Importantly, Fis1 and Fis2 would be capable of forming heterodimers that could bind with variable affinity to this AT-rich motif. It is also important to note that the three Fis proteins are not produced at the same time and in the same amounts. We therefore hypothesize that the duplication offisgenes inL. pneumophilais not simply a back-up system to compensate for potentially deleterious mutations in afisgene, but rather a means to fine-tune the expression of targeted genes, particularly virulence genes.

IMPORTANCE

Appropriate control of virulence gene expression is crucial to the success of bacterial infection. Nucleoid-associated protein regulators, including Fis proteins, have been shown to participate in the virulence of several human pathogens. The importance of our discovery lies in the fact thatL. pneumophilapossesses three non-homologous Fis proteins instead of just one. We demonstrate that Fis1 and Fis2 are not functional duplicates of each other. On the contrary, Fis1 and Fis2 are synthesized neither simultaneously nor in equal amounts during the bacterial growth phase, and they cooperate to regulate virulence gene expression by targeting similar AT-rich motifs, albeit with distinct affinity, and by being capable of forming heterodimers. Taken together, our data suggest that the high conservation offisgene duplication results from the need for fine-tuned control ofLegionellavirulence in response to its different environmental and human hosts, rather than from functional redundancy to circumvent deleteriousfismutations.
Testing for heavy metals in drinking water collected from Dog Aging Project participants
Authors: Sexton Courtney L. , O’Brien Janice , Lytle Justin , Rodgers Sam , Keyser Amber , Kauffman Mandy , Dunbar Matthew D. ,   Dog Aging Project Consortium, Edwards Marc , Krometis Leigh Anne , Ruple Audrey
Published: September 2024

Heavy metals are commonly found in groundwater and can affect the quality of drinking water. In this pilot study, we analyzed the quality of drinking water for dogs participating in the Dog Aging Project (DAP) who lived in homes not served by a municipal water supply. In order to capture both diverse and localized environmental factors that may affect drinking water, 200 owners of DAP dogs located in one of 10 selected states were invited to participate. We tested for the presence of 28 metals in dogs’ drinking water, including eight (8) heavy metals that have maximum contaminant levels (MCLs) designated by the Environmental Protection Agency (EPA) and five (5) heavy metals that have EPA health guidance levels. The eight metals with MCLs are known to cause chronic health issues in humans after long-term ingestion. Our aim in this pilot was to determine whether such elements could be detected by at-home sampling of dogs’ drinking water. We found detectable levels of all metals tested. There were 126 instances when an analyte (arsenic, lead, copper, sodium, strontium, nickel, or vanadium) was above the EPA MCL or health guidance level. We further identified potential association between the presence of titanium and chromium, and occurrence of a known health condition in dogs. This prompts further investigation with a larger, stratified sample analyzing dogs’ drinking water composition and long-term health and wellness outcomes in dogs living in diverse geographies. These results may impact veterinary care decisions and husbandry, and underscore the validity and importance of utilizing dogs as sentinels of human health outcomes in the context of drinking water contamination.
Simulation-based survey of TMEM16 family reveals that robust lipid scrambling requires an open groove
Authors: Stephens Christina Alexandra , van Hilten Niek , Zheng Lisa , Grabe Michael
Published: September 2024

Biological membranes are complex and dynamic structures with different populations of lipids in their inner and outer leaflets. The Ca2+-activated TMEM16 family of membrane proteins plays an important role in collapsing this asymmetric lipid distribution by spontaneously, and bidirectionally, scrambling phospholipids between the two leaflets, which can initiate signaling and alter the physical properties of the membrane. While evidence shows that lipid scrambling can occur via an open hydrophilic pathway ("groove") that spans the membrane, it remains unclear if all family members facilitate lipid movement in this manner. Here we present a comprehensive computational study of lipid scrambling by all TMEM16 members with experimentally solved structures. We performed coarse-grained molecular dynamics (MD) simulations of 27 structures from five different family members solved under activating and non-activating conditions, and we captured over 700 scrambling events in aggregate. This enabled us to directly compare scrambling rates, mechanisms, and protein-lipid interactions for fungal and mammalian TMEM16s, in both open (Ca2+-bound) and closed (Ca2+-free) conformations with statistical rigor. We show that all TMEM16 structures thin the membrane and that the majority of (>90%) scrambling occurs at the groove only when TM4 and TM6 have sufficiently separated. Surprisingly, we also observed 60 scrambling events that occurred outside the canonical groove, over 90% of which took place at the dimer-dimer interface in mammalian TMEM16s. This new site suggests an alternative mechanism for lipid scrambling in the absence of an open groove.
Rapid Emergence of Resistance to Broad-Spectrum Direct Antimicrobial Activity of Avibactam
Authors: Nägeli Michelle , Rodriguez Shade , Manson Abigail L. , Earl Ashlee M. , Brennan-Krohn Thea
Published: September 2024

Avibactam (AVI) is a diazabicyclooctane (DBO) β-lactamase inhibitor used clinically in combination with ceftazidime. At concentrations higher than those typically achievedin vivo, it also has broad-spectrum direct antibacterial activity againstEnterobacteralesstrains, including metallo-β-lactamase-producing isolates, mediated by inhibition of penicillin-binding protein 2 (PBP2). This activity is mechanistically similar to that of more potent novel DBOs (zidebactam, nacubactam) in late clinical development. We found that resistance to AVI emerged readily, with a mutation frequency of 2×10−6to 8×10−5. Whole genome sequencing of resistant isolates revealed a heterogeneous mutational target that permitted bacterial survival and replication despite PBP2 inhibition, in line with prior studies of PBP2-targeting drugs. While such mutations are believed to act by upregulating the bacterial stringent response, we found a similarly high mutation frequency in bacteria deficient in components of the stringent response, although we observed a different set of mutations in these strains. Although avibactam-resistant strains had increased lag time, suggesting a fitness cost that might render them less problematic in clinical infections, there was no statistically significant difference in growth rates between susceptible and resistant strains. The finding of rapid emergence of resistance to avibactam as the result of a large mutational target has important implications for novel DBOs with potent direct antibacterial activity, which are being developed with the goal of expanding cell wall-active treatment options for multidrug-resistant gram-negative infections but may be vulnerable to treatment-emergent resistance.
JAK Inhibitor Withdrawal Causes a Transient Proinflammatory Cascade: A Potential Mechanism for Major Adverse Cardiac Events
Authors: Gurevic Ilya , Meudec Loic , Mariette Xavier , Nocturne Gaetane , McCoy Sara S.
Published: September 2024

Objective

Our objective was to define the effect of JAK1/2 inhibitor (JAKinib) withdrawal on JAK/STAT biochemical response in the context of systemic rheumatic diseases.

Methods

We tested Type I (bind kinase active conformation) and Type II (bind kinase inactive conformation) JAKinibs in vitro using mesenchymal stromal cells and endothelial cells. We translated our findings in vivo studying NK cells from rheumatoid arthritis (RA) patients treated with Type I JAKinibs or methotrexate.

Results

Type I JAKinibs (ruxolitinib and baricitinib) increased phosphoJAK1 (pJAK1) and pJAK2 of IFNγ-stimulated MSCs and HUVECs in a time- and dose-dependent manner, with effect peaking after 24 hours. As expected, pSTAT1 was completely suppressed by JAKinibs. We found a marked and rapidincreaseof pSTATs upon discontinuation of Type I JAKinibs, that occurred to a lesser extent after Type II JAKinib withdrawal. Type I JAKinib withdrawal increased interferon and urokinase expression when compared to Type II JAKinib withdrawal. We found NK cells from RA patients taking Type I JAKinibs had a pro-inflammatory profile after JAKinib withdrawal compared to patients on methotrexate.

Conclusions

Type I JAKinibs paradoxically accumulate functionally defective pJAK. Upon withdrawal, the primed pJAKs are de-repressed and initiate a pSTAT signaling cascade, resulting in high interferon and urokinase. Type II JAKinibs do not cause pJAK accumulation, pSTAT cascade, and subsequent pro-inflammatory transcripts. The resultant cytokines and proteins produced from this cascade might be associated with adverse cardiac outcomes. Thus, JAKinib withdrawal is a possible mechanism contributing to the major adverse cardiac events described with JAKinib therapy.
Skeletons in the Forest: Using Entropy-Based Rogue Detection on Bayesian Phylogenetic Tree Distributions
Authors: Klawitter Jonathan , Bouckaert Remco R. , Drummond Alexei J.
Published: September 2024

In a phylogenetic analysis, rogue taxa and clades are those that, due to their uncertain placement, contribute disproportionally to the variance in a set of phylogenetics trees. They can obscure clear evolutionary relationships and complicate the interpretation of results. While existing rogue detection algorithms focus on improving the consensus tree for a set of trees, we introduce algorithms based on phylogenetic entropy to improve the analysis in a Bayesian framework. In particular, we introduce a tool that extracts a skeleton distribution of the posterior tree distribution that contains the core relationships by removing a minimal subset of rogues. Additionally, we enable detailed analyses of rogues at both the taxon and clade levels, including the visualisation of different rogue placements.
Environmental Enrichment Reducesadgrl3.1-Related Anxiety and Attention Deficits but Not Impulsivity
Authors: Fontana Barbara D. , Norton William H.J. , Parker Matthew O.
Published: September 2024

Environmental factors play a role in the development and severity of neuropsychiatric disorders. Externalizing disorders (EDs) are linked to genetic and environmental factors and frequently co-occur with internalizing disorders (ID), such as anxiety. Individuals experiencing both ED/ID are often among the most likely to seek healthcare services, as this co-occurrence is associated with more severe symptomatology and greater functional impairment. Here, we investigate the role of environmental enrichment (EE) on a gene associated with impulsivity and attention deficits in zebrafish,adgrl3.1. Zebrafish were reared in either standard or enriched environments (from 15 days-post fertilization), and attention, impulsivity, and anxiety-related phenotypes were assessed at adult stages (4 months-post fertilization) using the open field test and 5-choice serial reaction time task. EE mitigated anxiety-related behaviors inadgrl3.1knockouts, normalizing locomotor patterns and decreasing thigmotaxis. Although attention deficits were reduced inadgrl3.1-/-fish reared in EE, impulsive behaviors were not. Together, these findings suggest that while EE can alleviate some externalizing and internalizing phenotypes in zebrafish, impulsivity remains resistant to environmental modification. This study suggests that impulsivity is a stable trait inadgrl3.1-/-fish, but highlights the importance of EE in mitigating some externalizing and internalizing symptoms.

Summary statement

Environmental enrichment reduces attention deficits and anxiety-like behavior, but not impulsivity inadgr3.1knockout zebrafish, highlighting the interaction between genetic and environmental factors in shaping externalizing and internalizing phenotypes.
Discovery of electrophilic degraders that exploit SNAr chemistry
Authors: Zhuang Zhe , Byun Woong Sub , Kozicka Zuzanna , Dwyer Brendan G , Donovan Katherine A , Jiang Zixuan , Jones Hannah M , Abeja Dinah M , Nix Meredith N , Zhong Jianing , Slabicki Mikolaj , Fischer Eric S , Ebert Benjamin L , Gray Nathanael S
Published: September 2024

Targeted covalent inhibition (TCI) and targeted protein degradation (TPD) have proven effective in pharmacologically addressing formerly 'undruggable' targets. Integration of both methodologies has resulted in the development of electrophilic degraders where recruitment of a suitable E3 ubiquitin ligase is achieved through formation of a covalent bond with a cysteine nucleophile. Expanding the scope of electrophilic degraders requires the development of electrophiles with tempered reactivity that enable selective ligase recruitment and reduce cross-reactivity with other cellular nucleophiles. In this study, we report the use of chemical moieties that enable nucleophilic aromatic substitution (SNAr) reactions in the rational design of electrophilic protein degraders. Appending an SNAr covalent warhead to several preexisting small molecule inhibitors transformed them into degraders, obviating the need for a defined E3 ligase recruiter. The SNAr covalent warhead is versatile; it can recruit various E3 ligases, including DDB1 and CUL4 associated factor 11 (DCAF11), DDB1 and CUL4 associated factor 16 (DCAF16), and possibly others. The incorporation of an SNAr covalent warhead into the BRD4 inhibitor led to the discovery of degraders with low picomolar degradation potency. Furthermore, we demonstrate the broad applicability of this approach through rational functional switching from kinase inhibitors into potent degraders.
Metal Ion Sensing by Tetraloop-Like RNA Fragment: Role of Compact Intermediates with Non-Native Metal Ion-RNA Inner Shell Contacts
Authors: Habibullah Sk , Baidya Lipika , Kumar Sunil , Reddy Govardhan
Published: September 2024

Divalent metal ions influence the folding and function of RNA in the cells. The mechanism of how RNA structural elements in riboswitches sense specific metal ions is unclear. RNA interacts with ions through two distinct binding modes: direct interaction between the ion and RNA (inner-shell (IS) coordination) and indirect interaction between the ion and RNA mediated through water molecules (outer-shell (OS) coordination). To understand how RNA senses metal ions such as Mg2+and Ca2+, we studied the folding of a small RNA segment from the Mg2+sensing M-Box riboswitch using computer simulations. This RNA segment has the characteristics of a GNRA tetraloop motif and interestingly requires binding of a single Mg2+ion. The folding free energy surface of this simple tetraloop system is multidimensional, with a population of multiple intermediates where the tetraloop and cation interact through IS and OS coordination. The partially folded compact tetraloop intermediates form multiple non-native IS contacts with the metal ion. Thermal fluctuations should break these strong non-native IS contacts so that the tetraloop can fold to the native state, resulting in higher folding free energy barriers. Ca2+undergoes rapid OS to IS transitions and vice-versa due to its lower charge density than Mg2+. However, the ability of Ca2+to stabilize the native tetraloop state is weaker as it could not hold the loop-closing nucleotides together due to its weaker interactions with the nucleotides. These insights are critical to understanding the specific ion sensing mechanisms in riboswitches, and the predictions are amenable for verification by NMR experiments.
Single Versus Repeated Intravenous Oncolytic Virus Infusions – Implications for Rationalised Scheduling of Therapy in Hepatocellular Carcinoma
Authors: Scott Karen J. , West Emma , Brownlie Rebecca , Ismail Fay , Ralph Christy , Coffey Matt , Melcher Alan A. , Taylor Alison , Papa Salvatore , Samson Adel
Published: September 2024

Background

Oncolytic virus (OV) immunotherapy stands to widely improve patient outcomes in multiple solid malignancies. However, to date, the scheduling of OV therapy, with single versus multiple infusions on consecutive days, has not been correlated with immunological or clinical response. In hepatocellular carcinoma (HCC) patients, where the background liver is frequently chronically injured, repeated dosing may have deleterious implications, resulting in off-target immune-mediated damage, thereby tipping the balance between favourable clinical response and hepatotoxicity. As such, elucidation of the optimum dosing regime is necessary to ensure therapy, whilst limiting damage to the background liver.

Methods

Herein, we expand upon our previous experience in neoadjuvant OV therapy to compare the immunological response from single versus repeated doses of reovirus in cancer patients. The impact of OV immunotherapy on HCC outcomes was examinedin vivofollowing a high fat diet or induced liver fibrosis in the context of an abnormal background liver. Furthermore, we assess, in a syngeneic model of HCC, the potential immune-mediated toxicity of single versus multiple virus infusions in combination with PD-1 and PD-L1 blockade.

Results

Clinical trial data indicate that a single dose of reovirus is equivalent or superior to repeat doses in achieving: (a) induction of an inflammatory cytokine/chemokine response; (b) peripheral blood immune cell activation; and (c) migration of activated CD8+ CTLs. Repeated doses on consecutive days do not improve the amplitude or duration of the immune response following virus infusion. Furthermore, repeated viral dosing leads to an unwanted influx of activated T cells into background liver. An increase in PD-L1 expression on T cells resulting from a single virus dose was observed. Combination therapy of reovirus plus anti-PD-L1, but not anti-PD-1, limited tumour growth and extended survivalin vivo.

Conclusions

A single dose of oncolytic virus is equivalent or superior to multiple consecutive doses in inducing an anti-tumour immune response. Combination immune checkpoint blockade with anti-PD-L1 holds potential to maximise the beneficial effects of a single dose, whilst simultaneously avoiding undesirable toxicities in the background liver in the context of HCC.
Exploring the potential benefits and challenges of artificial intelligence for research funding organisations: a scoping review
Authors: Blatch-Jones Amanda Jane , Church Hazel , Crane Ksenia
Published: September 2024

Background

Artificial Intelligence (AI) is at the forefront of today’s technological revolution, enhancing efficiency in many organisations and sectors. However, in some research environments, its adoption is tempered by the risks AI poses to data protection, ethics, and research integrity. For research funding organisations (RFOs), although there is interest in the application of AI to boost productivity, there is also uncertainty around AI’s utility and its safe integration into organisational systems and processes. The scoping review explored:‘What does the evidence say about the current and emerging use of AI?’; ‘What are the potential benefits of AI for RFOs?’and‘What are the considerations and risks of AI for RFOs?’

Methods

A scoping review was undertaken with no study, language, or field limits. Due to the rapidly evolving AI field, searches were limited to the last three years (2022-2024). Four databases were searched for academic and grey literature in February 2024 (including 13 funding and professional research organisation websites). A classification framework captured the utility and potential, and considerations and risks of AI for RFOs.

Results

122 eligible articles revealed that current and emerging AI solutions could potentially benefit RFOs by enhancing data processes, administration, research insights, operational management, and strategic decision-making. These solutions ranged from AI algorithms to data management platforms, frameworks, guidelines, and business models. However, several considerations and risks need to be addressed before RFOs can successfully integrate AI (e.g., improving data quality, regulating ethical use, data science training).

Conclusion

While RFOs could potentially benefit from a breadth of AI-driven solutions to improve operations, decision-making and data management, there is a need to assess organisational ‘AI readiness’. Although technological advances could be the solution there is a need to address AI accountability, governance and ethics, address societal impact, and the risks to the research funding landscape.
Associations of Smoking Status and Leisure-time Physical Activity with Waist Circumference Change – Ten-year Follow-up among Twin Adults
Authors: Piirtola Maarit , Filippone Eeva-Liisa , Ranjit Anu , Kinnunen Taru , Kaprio Jaakko , Korhonen Tellervo
Published: September 2024

BACKGROUND

This follow-up study investigated the associations of smoking status and leisure-time physical activity (LTPA) with weight circumference (WC) change.

METHODS

In the FinnTwin16 cohort, 3,431 twins (47% men) reported smoking status, LTPA, and WC in early adulthood and 10 years later. Regression models were conducted to investigate associations of smoking status and of LTPA change (metabolic equivalent tasks [MET]-h/week) with WC change (cm) during the follow-up. Within-pair associations were analyzed using linear mixed fixed-effect regression among 800 same-sexed (409 identical) pairs.

RESULTS

During the 10-year follow-up, 40% (n=454) quit smoking. Among those who quit smoking, the mean WC increase was 7.4 cm (SD 8.2) and the mean LTPA decrease was -0.02 MET-h/week (SD 35.8). Compared to individuals continuing daily smoking, only quitters who smoked daily at baseline (β 1.87; 95% CI 0.68, 3.06) increased their WC. This association was not robust after shared familial influences were controlled for. Each additional MET-h/week lowered the risk for WC increase among individuals who smoked occasionally (β -0.054; -0,08, -0.003), quitters who smoked daily (β -0.05; -0.06, -0.02) and those who had never smoked (β -0.04; -0.05, -0.03). In the analyses among identical twin pairs, LTPA was associated with less WC increase among those who quit occasional smoking or had never smoked. For quitters from daily smoking, this association approached significance, but no association remained for those continuing smoking.

CONCLUSIONS

Smoking cessation seems to be associated with WC increase, but familial confounding is involved in this process. LTPA may inhibit post-cessation WC increase.

KEY MESSAGES

This will be published as a summary box after the abstract in the final published article.

What is already known on this topic

1. Individuals quitting smoking tend to gain weight, but less is known of post-cessation abdominal obesity and the role of leisure-time physical activity in this process.

What this study adds

2. Smoking cessation associates with moderate increase in waist circumference among those who quit daily smoking, but shared familial influences are involved in this process.

3. Increase in leisure-time physical activity may prevent post-cessation waist circumference increase.

How this study might affect research, practice, or policy

4. More research is needed to unravel genetic and epigenetic mechanisms underlying post-cessation waist circumference increase.

5. In practice, individuals who quit smoking should be encouraged to be physically active.
The post-pandemic hospital and mortality burden of COVID-19 compared with influenza: A national cohort study in Denmark, May 2022 to June 2024
Authors: Bager Peter , Bech Svalgaard Ingrid , Kristensen Lomholt Frederikke , Emborg Hanne-Dorthe , Engbo Christiansen Lasse , Soborg Bolette , Hviid Anders , Skafte Vestergaard Lasse
Published: September 2024

Background

In the post-pandemic period, COVID-19 continues to cause significant numbers of hospitalisations and deaths. We describe this burden and compare it to the burden of influenza in the first two post-pandemic years in Denmark.

Methods

A cohort study including residents in Denmark from May 16, 2022, to June 7, 2024. Data were obtained from national registries, including information on Polymerase chain reaction (PCR) test-positive COVID-19 and influenza admissions, mortality within 30 days of admission, sex, age, COVID-19 and influenza vaccination, comorbidity, and living in long-term care facility for elderly. Negative binomial regression was used to estimate adjusted incidence rate ratios (aIRRs) to compare rates of admissions between COVID-19 and influenza. To assess severity of COVID-19 among hospitalized patients, we used Cox proportional hazard models to estimate adjusted hazard ratios (aHR) of 30-day mortality between COVID-19 and influenza.

Results

Among 5,899,170 individuals, admissions with COVID-19 (n=24,687) were more frequent than admissions with influenza (n=8,682; aIRR 2.01, 95%CI 1.37-2.95), in particular during the first year (p=0.01), in the summer (p<0.001) and among people above 65 years of age (p<0.001). The number of deaths were also higher (COVID-19, n=2,393; influenza, n=522). Among patients, the risk of mortality of COVID-19 was higher than influenza in the 12-30 days following admission (0-11 days, aHR 1.08, 95%CI 0.94-1.25; 12-30 days, aHR 1.50, 95%CI 1.21-1.84), in particular among non-vaccinated for both COVID-19 and influenza (aHR 1.81, 95%CI 1.25-2.62), while it was similar to influenza among patients without comorbidities (aHR 1.07, 95%CI 0.63-1.80).

Conclusion

COVID-19 represented a greater disease burden than influenza, with more hospitalisations and deaths, and more severe disease primarily among non-vaccinated and comorbid patients. These results highlight the continued need for attention and public health efforts to mitigate the impact of SARS-CoV-2.
Cost-effectiveness of a 4 days-a-week triple therapy in persons living with HIV: an ancillary study of the ANRS 170 QUATUOR noninferiority trial
Authors: Hejblum Gilles , Daher Samih , Moulaire Paul , Amat Karine , Lambert-Niclot Sidonie , Allavena Clotilde , Katlama Christine , Lacombe Karine , Ponscarme Diane , Ghosn Jade , Gibowski Severine , Alvarez Jean-Claude , Capeau Jacqueline , Morand-Joubert Laurence , Costagliola Dominique , De Truchis Pierre , Landman Roland , Assoumou Lambert
Published: September 2024

Background

ANRS 170 QUATUOR study (NCT03256422) demonstrated the noninferiority of a triple antiretroviral therapy (ART) taken 4 days a week (4/7-days) compared to a triple therapy taken 7 days a week (7/7-days) for persons living with HIV and with suppressed viremia. We aimed at investigating corresponding cost-effectiveness issues.

Methods

All persons involved in the primary analysis of the QUATUOR noninferiority trial were considered (N=636, 318 per arm) in this cost-effectiveness study. Time horizon was the first 48 weeks of the trial. Effectiveness was considered as the noninferiority of the 4/7-days strategy, main criterion of the trial primary analysis. Direct health resource costs (year2022€) were considered and included costs for ART, laboratory tests, co-medications, hospitalizations, and medical consultations. Analyses were based on 10,000 simulations replicating the trial. Additional analyses explored the national impact of spreading the 4/7-days strategy all over France. Sensitivity analyses included considering treatment success as effectiveness, and various proportions of persons adopting the 4/7-days strategy.

Findings

The mean individual total costs amounted to € 5,049 [95% confidence interval: 4,798–5,345] and € 8,089 [7,706–8,527] in the 4/7-days and 7/7-days arm, respectively. Corresponding ART costs were € 3,678 [3,593–3,763] and € 6,450 [6,301–6,596], respectively (p<0.0001), and constituted the single cost element with a statistical difference between the two strategies. Considering noninferiority as the effectiveness criterion in a health economic perspective, the 4/7-day strategy provided average savings of € 3,013 [2829–3196] in ART costs per individual and per year. Adopting the 4/7-days regimen in 20% of the potential recipients in France was estimated to provide annual savings of € 61,752,467 [61,569,005; 61,925,136].

Interpretation

The 4/7-day strategy dominates the 7/7-day strategy since it spares substantial ART costs while maintaining treatment effectiveness. Study results support generalizing the adoption of 4/7-days triple ART regimens in France, when possible.
Pruritus and its Association with Cancer and Mortality in Dermatomyositis and Polymyositis: A Nationwide Cohort Study in Taiwan from 2005 to 2022
Authors: Huang Der-Jr , Shao Yu-Hsuan Joni , Shih Yi-Hsien , Lee Woan-Ruoh , Huang Ling-Ya , Kuo Yu-Min , Pham Quoc Thao Trang , Weng Hao-Jui
Published: September 2024

Background

Pruritus is the most common initial symptom reported by patients with dermatomyositis and polymyositis. However, there is limited data regarding the impact of pruritus on cancer and mortality in patients with dermatomyositis and polymyositis.

Objective

To investigate the associations of pruritus to cancer and mortality in patients with dermatomyositis and polymyositis.

Methods

This nationwide, population-based retrospective cohort study included adult dermatomyositis and polymyositis patients from Taiwan’s National Health Insurance Research Database between 2005 and 2022. Sex- and age-matched pruritic patients, identified by over six weeks of antipruritic medication use, and nonpruritic patients were analyzed. The primary outcome was cancer occurrence or all-cause mortality.

Results

Among 919 matched pairs of pruritic and non-pruritic patients, cancer was observed in 19.96% in the long-term pruritic group, 14.63% in the short-term pruritic group, and 10.34% in the nonpruritic group (p<0.0001). All-cause mortality was documented at 30.37% in the long-term pruritic group, 29.69% in the short-term pruritic group, and 37.76% in the nonpruritic group (p<0.0001). Pruritus was associated with an increased risk of cancer (hazard ratio 1.492, 95% confidence interval 1.093-2.036), and a lower risk of all-cause mortality (hazard ratio 0.489, 95% confidence interval 0.419-0.571).

Conclusion

This population-based study revealed pruritus appeared to be associated with increased cancer risk and decreased all-cause mortality. Thus, pruritus may serve as a pragmatic factor for risk stratification and tailored treatment strategies in dermatomyositis and polymyositis. Comprehensive cancer screening is recommended for patients with dermatomyositis or polymyositis, particularly those presenting with pruritus, whereas patients without pruritus may require vigilant management for potentially life-threatening complications and comorbidities.

Key points

Previous single-institutional studies and studies with small cohorts reported conflicting data regarding the impact of pruritus on cancer and mortality in patients with dermatomyositis and polymyositis

Pruritus in dermatomyositis and polymyositis appeared to be associated with increased cancer risk and decreased all-cause mortality.

Our findings suggest that pruritus may serve as a pragmatic factor for risk stratification and tailored treatment strategies in dermatomyositis and polymyositis.
Properties of rhythmogenic currents in spinal Shox2 interneurons across postnatal development
Authors: Singh Shayna , Yao Lihua , Shevtsova Natalia A. , Rybak Ilya A. , Dougherty Kimberly J.
Published: September 2024

Locomotor behaviors are performed by organisms throughout life, despite developmental changes in cellular properties, neural connectivity, and biomechanics. The basic rhythmic activity in the central nervous system that underlies locomotion is thought to be generated via a complex balance between network and intrinsic cellular properties. Within mature mammalian spinal locomotor circuitry, we have yet to determine which properties of spinal interneurons (INs) are critical to rhythmogenesis and how they change during development. Here, we combined whole cell patch clamp recordings, immunohistochemistry, and RNAscope targeting lumbar Shox2 INs in mice, which are known to be involved in locomotor rhythm generation. We focused on the properties of putatively rhythmogenic ionic currents and the expression of corresponding ion channels across postnatal time points in mice. We show that subsets of Shox2 INs display voltage-sensitive conductances, in addition to respective ion channels, which may contribute to or shape rhythmic bursting. Persistent inward currents, M-type potassium currents, slow afterhyperpolarization, and T-type calcium currents are enhanced with age. In contrast, the hyperpolarization-activated and A-type potassium currents were either found with low prevalence in subsets of neonatal, juvenile, and adult Shox2 INs or did not developmentally change. We show that Shox2 INs become more electrophysiologically diverse by juvenile and adult ages, when locomotor behavior is weight-bearing. These results suggest a developmental shift in the magnitude of rhythmogenic ionic currents and the expression of corresponding ion channels that may be important for mature, weight-bearing locomotor behavior.
Regulation of alternative polyadenylation isoforms ofTimp2is an effector event of RAS signaling in cell transformation
Authors: Ai Yuxi , Ding Qingbao , Wan Zezhong , Tyagi Sanjay , Indeglia Alexandra , Murphy Maureen , Tian Bin
Published: September 2024

Alternative polyadenylation (APA) generates mRNA isoforms with different lengths of the 3’ untranslated region (3’ UTR). The tissue inhibitor of metalloproteinase 2 (TIMP2) plays a key role in extracellular matrix remodeling under various developmental and disease conditions. Both human and mouse genes encoding TIMP2 contain two highly conserved 3’UTR APA sites, leading to mRNA isoforms that differ substantially in 3’UTR size. APA ofTimp2is one of the most significantly regulated events in multiple cell differentiation lineages. Here we show thatTimp2APA is highly regulated in transformation of NIH3T3 cells by the oncogene HRASG12V. Perturbations of isoform expression with long 3’UTR isoform-specific knockdown or genomic removal of the alternative UTR (aUTR) region indicate that the long 3’UTR isoform contributes to the secreted Timp2 protein much more than the short 3’UTR isoform. The short and long 3’UTR isoforms differ in subcellular localization to endoplasmic reticulum (ER). Strikingly,Timp2aUTR enhances secreted protein expression but no effect on intracellular proteins in reporter assays. Furthermore, downregulation ofTimp2long isoform mitigates gene expression changes elicited by HRASG12V. Together, our data indicate that regulation of Timp2 protein expression through APA isoform changes is an integral part of RAS-mediated cell transformation and 3’UTR isoforms ofTimp2can have distinct impacts on expression of secreted vs. intracellular proteins.
A binding site for the antibiotic GE81112 in the ribosomal mRNA channel
Authors: Schedlbauer Andreas , Han Xu , van Bakel Wouter , Kaminishi Tatsuya , Ochoa-Lizarralde Borja , Iturrioz Idoia , Çapuni Retina , Parry Ransford , Zegarra Ronny , Gil-Carton David , López-Alonso Jorge P. , Sanz Kristina Barragan , Brandi Letizia , Gualerzi Claudio O. , Fucini Paola , Connell Sean R.
Published: September 2024

The initiation phase is the rate-limiting step of protein synthesis (translation) and is finely regulated, making it an important drug target. In bacteria, initiation is guided by three initiation factors and involves positioning the start site on the messenger RNA within the P-site on the small ribosomal subunit (30S), where it is decoded by the initiator tRNA. This process can be efficiently inhibited by GE81112, a natural hydrophilic, noncyclic, nonribosomal tetrapeptide. It is found in nature in three structural variants (A, B and B1 with molecular masses of 643-658 Da). Previous biochemical and structural characterisation of GE81112 indicates that the primary mechanism of action of this antibiotic is to (1) prevent the initiator tRNA from binding correctly to the P-site and (2) block conformational rearrangements in initiation factor IF3, resulting in anunlocked30S preICstate. In this study, using cryoEM, we have determined the binding site of GE81112 in initiation complexes (3.2-3.7Å) and on empty ribosomes (2.09 Å). This binding site is within the mRNA channel (E-site) but remote from the binding site of the initiation factors and initiator tRNA. This suggests that it acts allosterically to prevent the initiator tRNA from being locked into place. The binding mode is consistent with previous biochemical studies and recent work identifying the key pharmacophores of GE81112.