bluuebunny/crossref_metadata_2025 huggingface dataset:
Early palliative care and its impact on end of life care
Authors: Monnery Dan , Droney Joanne
Published: October 2024

Purpose of review

The impacts of early palliative care for patients with advanced cancer are well described. This has led to endorsement of early palliative care, alongside cancer treatment, by leading cancer organisations. The aim of this review is to consider how best to adopt and integrate the learning from studies of early palliative care into an effective, sustainable service that is offered as part of routine cancer care.

Recent findings

‘Timely’, ‘targeted’ and ‘precision’ approaches have been proposed to ensure that limited palliative care resources are available to those who are most likely to benefit. Triage and referral based on individual patients’ needs has been shown to be both efficient and effective. Standardised referral criteria and the use of tools to assess complexity may support equitable service development. A specialist multidisciplinary approach is a common factor underpinning successful integration between palliative care and oncology but does not negate the importance patient-centred considerations such as advance care planning, which can be facilitated by non-specialist teams.

The challenge is no longer whether early palliative care should be provided, but how. Evidence-based strategies about how best to implement early palliative care are needed to inform appropriate resourcing, funding, and delivery.
Small-angle X-ray scattering analysis of poly(amic acid) dispersed in a liquid matrix to understand the size control of polyimide nanoparticles
Authors: Kuretani Satoshi , Hori Kazushige , Hirai Tomoyasu , Ohta Noboru , Hatakeyama-Sato Kan , Hayakawa Teruaki , Nabae Yuta
Published: October 2024

Poly(amic ‍acid) ‍nanoparticles ‍prepared ‍by ‍‍precipitation ‍polymerization with a dispersant were evaluated by small-angle X-ray scattering (SAXS) and field-emission scanning electron microscopy (FE-SEM). The particle size evaluation of poly(amic acid) nanoparticles in the liquid phase by SAXS was performed to gain insight into the size control of poly(amic acid) nanoparticles, and showed good agreement with visual observation by FE-SEM, explaining the effect of the dispersant in obtaining polyimide nanoparticles with small particle size. This indicates that the particle size is maintained without change during the solvent evaporation process. The polyamide nanoparticles controlled by the dispersant effect maintained their size after imidization, and polyimide nanoparticles with a minimum radius of about 60 nm were prepared.
Coyotes can do ‘puppy dog eyes’ too: comparing interspecific variation in
Canis
facial expression muscles
Authors: Cunningham Patrick , Shankar Mahita , vonHoldt Bridgett , Brzeski Kristin E. , Kienle Sarah S.
Published: October 2024

Facial expressions are critical for non-verbal communication. The
Canis
genus epitomizes the interplay between behaviour and morphology in the evolution of non-verbal communication. Recent work suggests that the levator anguli oculi medialis (LAOM) muscle is unique to dogs (
Canis familiaris
) within the
Canis
genus and evolved due to domestication. The LAOM raises the inner eyebrows, resulting in the ‘puppy dog eyes’ expression. Here, we test whether the LAOM is a derived trait in dogs by (i) examining the facial expression muscles of a closely related and ancestral wild
Canis
species, the coyote (
C. latrans
) and (ii) comparing our results with other
Canis
and canid taxa. We discover that coyotes have a well-developed LAOM like dogs, which differs from the modified/absent LAOM in grey wolves. Our findings challenge the hypothesis that the LAOM developed due to domestication. We suggest that the LAOM is a basal trait that was lost in grey wolves. Additionally, we find inter- and intraspecific variations in the size of the muscles of the outer ear, forehead, lips and rostrum, indicating potential adaptations related to sensory perception, communication and individual-level functional variations within canids. Together, this research expands our knowledge of facial expressions, their evolution and their role in communication.
Fertility loss and recovery dynamics after repeated heat stress across life stages in male
Drosophila melanogaster
: patterns and processes
Authors: Meena Abhishek , De Nardo Alessio N. , Maggu Komal , Sbilordo Sonja H. , Roy Jeannine , Snook Rhonda R. , Lüpold Stefan
Published: October 2024

Frequent and extreme temperatures associated with climate change pose a major threat to biodiversity, particularly for organisms whose metabolism is strictly linked to ambient temperatures. Many studies have explored thermal effects on survival, but heat-induced fertility loss is emerging as a greater threat to population persistence. However, while evidence is accumulating that both juvenile and adult stages heat exposure can impair fertility in their own ways, much less is known about the immediate and longer-term fitness consequences of repeated heat stress across life stages. To address this knowledge gap, we used male
Drosophila melanogaster
to investigate (i) the cumulative fitness effects of repeated heat stress across life stages, (ii) the potential of recovery from these heat exposures, and (iii) the underlying mechanisms. We found individual and combined effects of chronic juvenile and acute adult heat stress on male fitness traits. These effects tended to exacerbate over several days after brief heat exposure, indicating a substantial fertility loss for these short-lived organisms. Our findings highlight the cumulative and persistent effects of heat stress on fitness. Such combined effects could accelerate population declines, particularly in more vulnerable species, emphasizing the importance of considering reproduction and its recovery for more accurate models of species persistence.
Analytical and numerical study of anti-plane elastic wave scattering in a structured quadrant subjected to a boundary point load
Authors: Nieves M. , Kisil A. , Mishuris G. S.
Published: October 2024

We verify the recently developed method by Kisil (Kisil 2024
SIAM J. Appl. Math.
84
, 464–476 (doi:
10.1137/23M1562445
)) through its application in the study of the anti-plane dynamic response of an elastic square-cell lattice quadrant having a free lateral boundary that is subjected to a sinusoidal point load. The vertical boundary of the quadrant is assumed to be either fixed or free. The approach adopted utilizes the discrete Fourier transform in both principal lattice directions to reduce the governing equations to a functional equation linking both the bulk and boundary response of the system. For both problems, this functional equation is shown to reduce to scalar Wiener–Hopf equation whose solution can be exploited to determine the full response of the lattice system. The analytical solutions based on the Wiener–Hopf method are also implemented in numerical investigations that demonstrate the lattice response to various positions and frequencies of the load. In particular, this study includes dynamic regimes induced by the load that possess strong anisotropy and shows how the associated waveforms interact with the boundaries of the quadrant.
Linking intercontinental biogeographic events to decipher how European vineyards escaped Pierce’s disease
Authors: Moralejo Eduardo , Giménez-Romero Àlex , Matías Manuel A.
Published: October 2024

Global change is believed to be a major driver of the emergence of invasive pathogens. Yet, there are few documented examples that illustrate the processes that hinder or trigger their geographic spread. Here, we present phylogenetic, epidemiological and historical evidence to explain how European vineyards escaped
Xylella fastidiosa
(Xf), the vector-borne bacterium responsible for Pierce’s disease (PD). Using Bayesian temporal reconstruction, we show that the export of American grapevines to France as rootstocks to combat phylloxera (~1872–1895) preceded the spread of the Xf grapevine lineage in the USA. We found that the time of the most recent common ancestor in California dates to around 1875, which agrees with the emergence of the first PD outbreak and the expansion into the southeastern US around 1895. We also show that between 1870 and 1990, climatic conditions in continental Europe were mostly below the threshold for the development of PD epidemics. However, our model indicates an inadvertent expansion of risk in southern Europe since the 1990s, which is accelerating with global warming. Our temporal approach identifies the biogeographical conditions that have so far prevented PD in southern European wine-producing areas and predicts that disease risk will increase substantially with increasing temperatures.
Warmer is better for evolutionary rescue, driving a warm-to-cold bias in habitat colonization dynamics
Authors: Zhou Dong-Hao , Zhang Quan-Guo
Published: October 2024

Evolutionary rescue occurs when populations survive lethal environmental stresses through the rising and fixation of tolerant genotypes. Temperature has long been believed to determine the evolutionary speed of populations and species. Here, we suggest that warmer temperatures can facilitate evolutionary rescue. Moreover, with dispersal among habitats, the advantage in evolutionary rescue for warmer populations may cause a bias in habitat colonization dynamics towards the warm-to-cold direction. We experimentally tested these hypotheses with a model microbial system. Our first experiment showed that bacterial populations at warmer temperatures had a greater chance to evolve resistance and escape the fate of extinction under an antibiotic treatment. In the second experiment, metapopulations that consisted of warm and cold habitats were exposed to the antibiotic stress; local populations that went extinct might be recolonized, and such recolonization events were biased to the warm-to-cold direction. We also examined possible mechanisms underlying the temperature effect on the rapid evolution of resistance in our study system. Our results may help to understand the mechanisms of maintenance of biodiversity and patterns of gene flow among climatic regions, particularly in pest species subject to chemical control treatments.
Patterns of girdle shape and their correlates in Australian limb-reduced skinks
Authors: Camaiti Marco , Hutchinson Mark N. , Hipsley Christy A. , Aguilar Rocio , Black Jay , Chapple David G. , Evans Alistair R.
Published: October 2024

The evolution of limb reduction in squamates is a classic example of convergence, but the skeletal morphological patterns associated with it are underexplored. To provide insights on the biomechanical and developmental consequences of transitions to limb reduction, we use geometric morphometrics to examine the morphology of pectoral and pelvic girdles in 90 species of limb-reduced skinks and their fully limbed relatives. Clavicle shapes converge towards an acute anterior bend when forelimbs are lost but hindlimbs are retained—a morphology typical of sand-swimmers. This may either indicate functional adaptations to locomotion in fine substrates, or a developmental consequence of complete limb loss. The shape of limb-bearing elements of both girdles (coracoid and pelvis) instead closely mirrors limb reduction, becoming more simplified as undulation replaces limbed locomotion. Integration between girdles decreases in taxa lacking elements of the forelimbs but not hindlimbs, indicating differential selection on each girdle in response to distinct locomotory strategies. However, this pattern becomes less clear when considering phylogenetic history, perhaps because it is limited to one specific clade (
Lerista
). We show how the functional demands of locomotion can induce changes at different levels of organismal organization, including both external and internal structures.
Social behaviour mediates the microbiome response to antibiotic treatment in a wild mammal
Authors: Brown Bianca R. P. , Williams Allison E. , Sabey Kate A. , Onserio Aaron , Ewoi John , Song Se Jin , Knight Rob , Ezenwa Vanessa O.
Published: October 2024

High levels of social connectivity among group-living animals have been hypothesized to benefit individuals by creating opportunities to rapidly reseed the microbiome and maintain stability against disruption. We tested this hypothesis by perturbing the microbiome of a wild population of Grant’s gazelles with an antibiotic and asking whether microbiome recovery differs between individuals with high versus low levels of social connectivity. We found that after treatment, individuals with high social connectivity experienced a faster increase in microbiome richness than less socially connected individuals. Unexpectedly, the rapid increase in microbiome richness of highly connected individuals that received treatment led to their microbiomes becoming more distinct relative to the background population. Our results suggest that the microbiome of individuals with high social connectivity can be rapidly recolonized after a perturbation event, but this leads to a microbiome that is more distinct from, rather than more similar to the unperturbed state. This work provides new insight into the role of social interactions in shaping the microbiome.
Yamadazyma thunbergiae sp. nov., a novel yeast species associated with Bengal clock vines and soil in Okinawa, Japan
Authors: Seike Taisuke , Takekata Hiroki , Sakata Natsue , Furusawa Chikara , Matsuda Fumio
Published: October 2024

Two strains, designated JCM 36746T and JCM 36749, were isolated from Bengal clock vine (Thunbergia grandiflora) and soil, respectively, in Okinawa, Japan. Analysis of the internal transcribed spacer (ITS) regions and D1/D2 domains of the large subunit rRNA gene sequences revealed identical sequences in both strains, indicating that they belong to the same species. Sequence analysis and physiological characterization identified these strains as representing a novel yeast species in the genus Yamadazyma. The sequence similarities of the concatenated ITS regions and D1/D2 domains indicated that JCM 36746T and JCM 36749 formed a well-supported distinct from closely related species belonging to the Yamadazyma clade, including Candida dendronema, C. diddensiae, C. germanica, C. kanchanaburiensis, C. naeodendra, C. vaughaniae, Y. akitaensis, Y. koratensis, Y. nakazawae, Y. philogaea, Y. phyllophila, Y. siamensis, Y. ubonensis, and three undescribed species, comprising Candida aff. naeodendra/diddensiae Y151, Candida sp. GE19S08, and Yamadazyma sp. strain NYNU 22830. The sequences of the D1/D2 domains and ITS regions differed in nucleotide substitutions by 1.51% and 2.57% or greater, respectively, from those of the previously described and undescribed related species. In addition, the physiological characteristics of the novel species were distinct from those of the closely related described species. On the basis of these findings, we propose the name Yamadazyma thunbergiae sp. nov. to classify this species within the genus Yamadazyma. The holotype used is JCM 36746T (ex-type strains CBS 18614 and NBRC 116657). The MycoBank accession number is MB 853823.
On Long-Term Species Coexistence in Five-Species Evolutionary Spatial Cyclic Games with Ablated and Non-Ablated Dominance Networks
Authors: Cliff Dave
Published: October 2024

I present a replication and, to some extent, a refutation of key results published by Zhong, Zhang, Li, Dai, & Yang in their 2022 paper “Species coexistence in spatial cyclic game of five species” (Chaos, Solitons and Fractals, 156: 111806), where ecosystem species coexistence was explored via simulation studies of the evolutionary spatial cyclic game (Escg) Rock-Paper-Scissors-Lizard-Spock (Rpsls) with certain predator-prey relationships removed from the game’s “interaction structure”, i.e. with specific arcs ab-lated in the Escg’s dominance network, and with the Escgrun for 105Monte Carlo Steps (mcs) to identify its asymptotic behaviors. I replicate the results presented by Zhong et al. for interaction structures with one, two, three, and four arcs ablated from the dominance network. I then empiri-cally demonstrate that the dynamics of the RpslsEscghave sufficiently long time constants that the true asymptotic outcomes can often only be identified after running the ablated Escgfor 107mcsor longer, and that the true long-term outcomes can be markedly less diverse than those reported by Zhong et al. as asymptotic. Finally I demonstrate that, when run for sufficiently manymcs, the original unablated Rpslssystem exhibits essentially the same asymptotic outcomes as the ablated Rpslssystems, and in this sense the only causal effect of the ablations is to alter the time required for the system to converge to the long-term asymptotic states that the unablated system eventually settles to anyhow.

Graphical Abstract

Highlights

I replicate key results from Zhong et al. (2022) where biodiversity was explored via the game Rock-Paper-Scissors-Lizard-Spock (Rpsls).

Zhong et al. reported results from Rpslsgames where specific predatorprey interactions were ablated from the game’s dominance network.

My replication reveals problems in Zhong et al.’s design of experiments.

Zhong et al. did not run their simulations for sufficiently long to reveal the true asymptotic behavior of the ablated Rpslssystems.

Zhong et al. did not present control outcomes from the unablated Rp-slssystem, so there is no baseline data for comparison to the treatment outcomes.

I present results from simulations that are run for 100 to 1000 times longer than the experiments reported by Zhong et al., thereby revealing the true asymptotic behaviors of the system.

The asymptotic outcomes are remarkably uniform – practically indistinguishable – in the cases where one, two, or three arcs are ablated from the Rpslsdominance network.

My asymptotic results for the baseline original unablated system are also very similar to those for the one-two- and three-ablation systems.

My results question whether the ablations have any effect other than speeding the system’s convergence to its eventual asymptotic state.

Results from Zhong et al.’s four-ablation system do not fit so well with the lower-ablation-count systems: potential reasons for this, and avenues for further research on it, are discussed.
Lack of circadian entrainment and limited nocturnal plasticity in response to a cyclic aversive stimulus in a diurnal rodent, the antelope ground squirrel (Ammospermophilus leucurus)
Authors: Zhang Victor Y. , Kenagy G.J. , de la Iglesia Horacio O.
Published: October 2024

Recent studies have shown that cyclic aversive stimuli, such as random footshocks, act as a nonphotic zeitgeber to entrain circadian behaviors in nocturnal rodents, a pattern termed “fear entrainment”. However, it remains unknown whether diurnal species exhibit similar plasticity in behavioral timing. This study aimed to determine if antelope ground squirrels (Ammospermophilus leucurus;AGS), a naturally diurnal rodent, can also shift their activity patterns to cyclic aversive stimuli. We conducted two experiments with 20 AGS housed in custom cages featuring a safe nesting area and a separate foraging area (for feeding and drinking), rendered aversive by presentation of unsignaled, time-specific footshocks. In the first experiment, animals were subjected to a 12:12 light-dark (LD) cycle. One group experienced aversion during the light phase, while the control group received the same treatment during the dark phase. In the second experiment, a 16:8 LD cycle was used, and animals were divided into three groups with the foraging area rendered aversive either during the first or second half of the light phase or during the dark phase. Following each of these treatments, animals were released into constant darkness (DD) to assess the phase and period of free-running rhythms. Contrary to previous findings in nocturnal rodents, AGS did not exhibit consistent shifts in activity to avoid footshocks. Most animals maintained their normal diurnal activity, with only minor and inconsistent phase shifts. In experiment two, animals exposed to footshocks during half of the light phase also failed to reliably shift activity to the opposite “safe” portion of the light phase. Together, these findings show AGS lack the ability to entrain to cyclic aversive stimuli or become nocturnal; this result suggests a lack of substantial plasticity in activity timing. These results highlight the importance of considering species-specific differences in nonphotic circadian entrainment and temporal niche plasticity.
Competitive Adsorption of a Monoclonal Antibody and Amphiphilic Polymers to the Air-Water Interface
Authors: Hingst Elise J. , Blech Michaela , Hinderberger Dariush , Garidel Patrick , Schwieger Christian
Published: October 2024

Understanding structure and self-organization of monoclonal antibodies (mAbs) at the air-water interface is important for the stability and effectiveness of protein drug formulations used in pharmaceutical industry. This paper investigates the competitive adsorption of a mAb and the amphiphilic surfactants poloxamer 188 (P188) and polysorbate 20 (PS20), both of which are commonly used to prevent mAb surface adsorption. Firstly, it is studied whether these surfactants prevent mAb adsorption, and secondly, whether it is possible to desorb mAb molecules from the air-water interface by surfactant addition. For surface pressure and surface tension data, Langmuir film balance measurements and drop shape tensiometry were used. Infrared Reflection-Absorption Spectroscopy (IRRAS) provided information on the surface composition, including the amount of adsorbed molecules. P188 exists in different self-assembled phases depending on its surface concentration. Our experiments show that the phase state of P188 has a significant impact on mAb adsorption. The presence of P188 in the brush phase (≥ 0.3 mg/L) consistently inhibits mAb adsorption. On the contrary, addition of P188 after mAb film formation could not cause desorption of mAb. However, addition of PS20 leads to desorption of freshly formed interfacial mAb layers of up to two hours age. Interestingly, an aged mAb layer of 17 hours could not be desorbed by PS20. This suggests a time dependent reorganization of mAb at the air-water interface, which increases its resistance to desorption. These findings are discussed with respect to possible inter-molecular interactions within the interfacial film.
RapA opens the RNA polymerase clamp to disrupt post-termination complexes and prevent cytotoxic R-loop formation
Authors: Brewer Joshua J. , Inlow Koe , Mooney Rachel A. , Bosch Barbara , Olinares Paul Dominic B. , Marcelino Leandro Pimentel , Chait Brian T. , Landick Robert , Gelles Jeff , Campbell Elizabeth A. , Darst Seth A.
Published: October 2024

Following transcript release during intrinsic termination,Escherichia coliRNA polymerase (RNAP) often remains associated with DNA in a post-termination complex (PTC). RNAPs in PTCs are removed from the DNA by the Swi2/Snf2 ATPase RapA. Here, we determined PTC structures on negatively-supercoiled DNA as well as of RapA engaged to dislodge the PTC. We found that core RNAP in the PTC can unwind DNA and initiate RNA synthesis but is prone to producing R-loops. We show that RapA helps control cytotoxic R-loop formationin vivo, likely by disrupting PTCs. Nucleotide binding to RapA triggers a conformational change that opens the RNAP clamp, allowing DNA in the RNAP cleft to reanneal and dissociate. We suggest that analagous ATPases acting on PTCs to suppress transcriptional noise and R-loop formation may be widespread. These results hold significance for the bacterial transcription cycle and highlight a role for RapA in maintaining genome stability.
Suppression of cyclooxygenase-2 predisposes to heart failure with preserved ejection fraction
Authors: Ricciotti Emanuela , Haines Philip G. , Beerens Manu , Kartoun Uri , Castro Cecilia , Tang Soon Yew , Ghosh Soumita , Das Ujjalkumar S. , Lahens Nicholas F. , Wang Tao , Griffin Jules L. , Shaw Stanley Y. , MacRae Calum A. , FitzGerald Garret A.
Published: October 2024

Heart failure (HF) is one of the most strongly associated adverse cardiovascular events linked to the use of cyclooxygenase (COX)-2 selective and non-selective nonsteroidal anti-inflammatory drug (NSAID). Nevertheless, it remains uncertain whether NSAID exposure is more likely to lead to heart failure with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF).

In adult mice, postnatal genetic deletion or pharmacological inhibition of COX-2 did not affect cardiac function. In contrast, aged female inducible COX-2 (iCOX-2) knockout (KO) mice displayed diastolic dysfunction, cardiac hypertrophy, pulmonary congestion, and elevated levels of plasma N-terminal pro B-type natriuretic peptide (BNP) when compared to age- and sex- matched controls, while their ejection fraction (EF) remained preserved (≥ 50%). No such phenotype was observed in aged male iCox-2 KO mice. Aged female iCox-2 KO mice showed a shift from prostanoid to leukotriene biosynthesis, along with changes in the expression of mitochondrial genes and calcium-handling proteins in the myocardium. The ratio of phospholamban to SERCA2a was increased, indicating an inhibitory effect on SERCA2a activity, which may contribute to impaired myocardial relaxation. In larval zebrafish, COX-2 inhibition by celecoxib caused a modest yet significant reduction in heart rate and diastolic function, while EF was preserved. Additionally, celecoxib increased BNP expression and ventricular calcium transient amplitude. Diabetic patients in the Harvard-Partners electronic medical record exposed to NSAIDs selective for COX-2 inhibition were more strongly associated with an increased risk of HFpEF compared to HFrEF.

Collectively, these findings indicate that COX-2 deletion or inhibition does not impair systolic cardiac function but instead leads to an HFpEF phenotype in mice, zebrafish, and humans. An imbalance in calcium handling may mediate the impairment of myocardial relaxation following COX-2 suppression.

Genetic deletion or pharmacological inhibition of COX-2 results in heart failure with preserved ejection fraction across zebrafish, mice, and humans.
Kinetochore-centrosome feedback linking CENP-E and Aurora kinases controls chromosome congression
Authors: Vukušić Kruno , Tolić Iva M.
Published: October 2024

Chromosome congression is crucial for accurate cell division, with key roles played by kinetochore components such as CENP-E/kinesin-7 and Aurora B kinase. However, Aurora kinases can both inhibit and promote congression, suggesting the presence of a larger, yet poorly understood, signaling network. Our study demonstrates that centrosomes primarily inhibit congression initiation when CENP-E is inactive or absent by regulating the activity of kinetochore components. Depleting centrioles via Plk4 inhibition allows chromosomes near acentriolar poles to initiate congression independently of CENP-E. In contrast, at centriolar poles high Aurora A activity enhances Aurora B activity, increasing phosphorylation of microtubule-binding proteins at kinetochores and preventing stable microtubule attachments in the absence of CENP-E. Conversely, inhibiting Aurora A reduces Aurora B activity, enabling congression initiation even without CENP-E. These findings suggest a feedback network involving Aurora kinases and CENP-E that regulates timing of chromosome movement by modulating kinetochore-microtubule interactions, with centrosomes and the Aurora A activity gradient providing critical spatial cues for the network’s function.
A minimalist model lipid system mimicking the biophysical properties ofEscherichia coli’smembrane
Authors: Tormena Nicolo , Pilizota Teuta , Voitchovsky Kislon
Published: October 2024

Biological membrane are highly complex systems that are of fundamental importance to the development and survival of organisms. Native membranes typically comprise different types of lipids, biomolecules and proteins assembled around a lipid bilayer structure. This complexity can render investigations challenging, with many studies relying on model membranes such as artificial vesicles and supported lipid bilayers (SLBs). The purpose of a model system is to capture the desired dominant features of the native context while remaining uniquely defined and simpler. Here, we search for a minimal lipid-only model system of theEscherichia coliinner membrane. We aim to retain the main lipidomic components in their native ratio while mimicking the membrane thermal and mechanical properties. We design a collection of candidate model systems reflecting the main aspects of the known native lipidomic composition and narrow down our selection based on the systems’ phase transition temperature. We further test our candidate model systems by independently measuring their elastic properties. We identify 3 ternary model systems able to form stable bilayers that closely mimicE. coli’s inner membrane lipid composition and mechanical properties. These model systems are made of commercially available synthetic 16:0-18:1 phosphatidylethanolamine (POPE), 16:0-18:1 phosphatidylglycerol (POPG), and 16:0-18:1 Cardiolipin (CL). We anticipate our results to be of interest for future studies making use ofE. colimodels, for example investigating membrane proteins’ function or macromolecule-membrane interactions.

Significance Statement

Escherichia Colimembranes serve as model systems for numerous fundamental and technological applications in the field of membrane biophysics. Being a Gram-negative bacterium,E. Coliis characterized by a thin cell wall that separates two phospholipid membranes: the inner and outer membranes. These membranes are complex, comprising many different lipids, proteins and other biomolecules. Here we develop a minimalist system to mimic the biophysical properties and lipidic composition of E. Coli’s inner membrane. Using only commercially available lipids, we develop a model membrane that can be used for studies where simplicity is needed to aid interpretation of the results, for example to investigate protein-induced mechano-transduction across E. Coli membranes.
Lgl resets Par complex membrane loading at mitotic exit to enable asymmetric neural stem cell division
Authors: LaFoya Bryce , Welch Sarah E. , Prehoda Kenneth E.
Published: October 2024

The Par complex regulates cell polarity in diverse animal cells1–4, but how its localization is restricted to a specific membrane domain remains unclear. We investigated how the tumor suppressor Lethal giant larvae (Lgl) polarizes the Par complex inDrosophilaneural stem cells (NSCs or neuroblasts). In contrast to epithelial cells, where Lgl and the Par complex occupy mutually exclusive membrane domains, Lgl is cytoplasmic when the Par complex is apically polarized in NSCs5. Importantly, we found that Lgl’s key function is not in directly regulating metaphase Par polarity, but rather in removing the Par complex from the membrane at the end of mitosis, creating a "polarity reset" for the next cell cycle. Without this Lgl-mediated reset, we found that residual Par complex remains on the basal membrane during subsequent divisions, disrupting fate determinant polarization and proper asymmetric cell division. These findings reveal a novel mechanism of polarity regulation by Lgl and highlight the importance of the pre-polarized state in Par-mediated polarity.
Efficient Derivation of Immortalized, Isogenic Cell Lines from Genetically Defined Murine Hepatoblastomas
Authors: Wang Huabo , Lu Jie , Chen Keyao , Ma Bingwei , Henchy Colin , Knapp Jessica , Ranganathan Sarangarajan , Prochownik Edward V.
Published: October 2024

Background & Aims

Molecularly, hepatoblastoma (HB), the most common childhood liver cancer, is the simplest of all human neoplasms, with the vast majority deregulating the Wnt/β-catenin, Hippo and/or NFE2/NRF2 signaling pathways. Murine HBs can be generated by over-expressing any pairwise or triple combination of mutant forms of these pathways’ terminal effectors, namely β-catenin (B), YAP (Y) and NFE2L2/NRF (N). Each molecular subtypes displays distinct features resembling those of human HBs. However, research has been hampered by a paucity of established cell lines of any species.

Methods

We show here that immortalized cell lines can be routinely established from murine HBs that over-express B+Y and B+Y+N. This is facilitated by the concurrentin vivo,Crispr-mediated inactivation of theCdkn2atumor suppressor locus.

Results

Eight BY and 3 BYN cell lines have been generated and characterized and are available to the HB research community. Ten of these lines can be regrown as subcutaneous and metastatic lung tumors in the immuno-competent mice from which they originated while retaining their original histologic features. During maintenance as spheroidsin vitro, or duringin vivopropagation, tumor cells express endothelial cell markers, particularly in regions that are hypoxic and/or in proximity to incipient blood vessels.

Conclusions

The ability to generate isogenic HB cell lines with defined oncogenic drivers should facilitate studies that are best performedin vitro. The approach may also be useful for deriving HB cell lines associated with less common molecular drivers and from human tumors.

Synopsis

The derivation of multiple immortalized murine hepatoblastoma cell lines driven by defined oncogenes is described. These lines are isogenic, retain their tumorigenicity in immuno-competent mice, readily form spheroids and express endothelial markers in response to hypoxia. They will allow studies that have heretofore been difficult or impossible to performin vivo.
Thrifty superorganism phenotypes emerge as a plastic response to extreme environments in the Hercules ant
Authors: Plante Érik , Abouheif Ehab , Lessard Jean-Philippe
Published: October 2024

High-altitude human populations are a classic example of adaptation to extremely stressful environments through thrifty phenotypes, where individuals adapt plastically by reducing specific organ size, like limbs, while maintaining overall size. However, it remains unknown, whether other organisms exhibit thrifty phenotypes, and which external factors may shape them. Here, we address these questions in ant colonies, considered superorganisms. Thethrifty phenotype hypothesisapplied to eusocial organisms predicts that colonies experiencing food shortage should reduce investment in costly individuals. In polymorphic colonies, the largest workers known as “majors” are costly to produce and should therefore be less abundant in colonies experiencing food shortage. Alternatively, thestarvation resistance hypothesisposits that colonies in stressful environments should maintain larger colonies, which provide a nutritional buffer in times of food shortage. We show that the proportion of majors in colonies of the Hercules ant,Camponotus herculeanus, decreases plastically with increasing latitude across the temperate and boreal forest biomes of eastern Canada, independently of their average body size, or colony size, resulting in a thrifty superorganism phenotype. Furthermore, we find that the low number of days, annually, when workers can nurse the brood, best predicts these phenotypes. Our study reinforces claims that eusocial organisms may adapt plastically to fluctuating environments, and that extreme environments favour thrifty phenotypes in both humans and ants.
Disrupted functional brain network associated with presence of hallucinations in Parkinson’s Disease
Authors: Montagnese Marcella , Mehta Mitul A , ffytche Dominic , Firbank Michael , Lawson Rachael A , Taylor John-Paul , Bullmore Edward T , Morgan Sarah E
Published: October 2024

Background

Hallucinations negatively impact quality of life in Parkinson’s disease, yet their neural mechanisms remain poorly understood, particularly in early disease stages. This study aimed to identify functional connectivity differences associated with visual hallucinations in early Parkinson’s Disease and to validate these findings across independent datasets.

Methods

Resting state fMRI data from two prior independent studies was used (total N=185; N=84 hallucinators and N=101 non-hallucinators). Group differences in functional connectivity were assessed within predefined cytoarchitectonic cortical classes and functional networks, followed by whole-brain analysis using Network-Based Statistics (NBS). Associations with clinical measures, including hallucination severity, motor symptoms, cognition, and attention, were also evaluated.

Results

NBS identified a subnetwork of reduced functional connectivity in hallucinators, connecting regions involved in the default mode, somatomotor and attentional networks. This subnetwork was replicated in a matched sample from our independent cohort (N=50; p<0.01). Functional connectivity within the identified network was significantly associated with hallucination severity (R² = 0.35, p = 0.01), and with baseline and future motor symptoms, cognition, and attention in hallucinators.

Conclusions

The identified functional subnetwork shows promise as a potential biomarker and therapeutic target for Parkinson’s disease psychosis, warranting further investigation and validation in future studies.
Pretrained Patient Trajectories for Adverse Drug Event Prediction Using Common Data Model-based Electronic Health Records
Authors: Kim Junmo , Kim Joo Seong , Lee Ji-Hyang , Kim Min-Gyu , Kim Taehyun , Cho Chaeeun , Park Rae Woong , Kim Kwangsoo
Published: October 2024

Background

Pretraining electronic health record (EHR) data using language models by treating patient trajectories as natural language sentences has enhanced performance across various medical tasks. However, EHR pretraining models have never been utilized in adverse drug event (ADE) prediction. We constructed and externally validated the EHR pretraining model for several ADE prediction tasks and qualitatively analyzed the important features of each ADE cohort.

Methods

A retrospective study was conducted on observational medical outcomes partnership (OMOP)-common data model (CDM) based EHR data from two separate tertiary hospitals. The data included patient information in various domains such as diagnosis, prescription, measurement, and procedure. For pretraining, codes were randomly masked, and the model was trained to infer the masked tokens utilizing preceding and following history. In this process, we adopted domain embedding (DE) to provide information about the domain of the masked token, preventing the model from finding codes from irrelevant domains. For qualitative analysis, we identified important features using the attention matrix from each finetuned model.

Results

510,879 and 419,505 adult inpatients from two separate tertiary hospitals were included in internal and external datasets. EHR pretraining model with DE outperformed all the other baselines in all cohorts. For feature importance analysis, we demonstrated that the results were consistent with priorly reported background clinical knowledge. In addition to cohort-level interpretation, patient-level interpretation was also available.

Conclusions

EHR pretraining model with DE is a proper model for various ADE prediction tasks. The results of the qualitative analysis were consistent with background clinical knowledge.
Altered association of plasmatic oxytocin with affective stress response in alcohol use disorder
Authors: Mayer Annalina V. , Schwarze Yana , Stierand Janine , Voges Johanna , Schröder Alexander , Gablentz Janina von der , Junghanns Klaus , Voß Oliver , Krach Sören , Paulus Frieder M. , Rademacher Lena
Published: October 2024

Oxytocin has been proposed to play a role in the development and maintenance of alcohol use disorder (AUD) through its interactions with stress pathways. Empirical evidence that indicates altered associations between endogenous oxytocin and stress reactivity in AUD is currently lacking. In this study, we investigated baseline plasmatic oxytocin concentrations of early-abstinent patients with AUD (N= 40) and matched healthy control participants (N= 37), who completed the Trier Social Stress Test (TSST) as well as a control task on two separate visits. We measured salivary cortisol and pulse rate as indicators of a physiological stress response, and anxiety ratings as an indicator of an affective stress response at multiple time points. Baseline oxytocin levels did not significantly differ between the groups. However, our results suggest an altered association of oxytocin and affective stress responses in participants with AUD: while participants with AUD showed a positive relationship between plasmatic oxytocin levels and stress-induced anxiety increase, the opposite relationship was found in control participants. We did not find evidence for an association of oxytocin with physiological stress responses. Assuming that affective stress responses mediate addiction-related behaviors like craving and relapse, our findings suggest that administering exogenous oxytocin might not be beneficial in treating AUD, at least during the early stages of abstinence.
Beta-blockers Increase Cardiovascular Mortality in Hemodialysis Patients with Orthostatic Hypotension
Authors: Schiavone M. , Castellaro C , Pereira Redondo JC. , Diaz C. , Laham G.
Published: October 2024

Background

Orthostatic hypotension (OH) is prevalent among dialysis patients and is a known cardiovascular (CV) risk factor. Beta-blockers (BBs) are commonly prescribed to mitigate CV mortality in this population, despite potential risks associated with OH. This study examines the impact of BBs on CV mortality among dialysis patients with OH.

Methods

We conducted a prospective analysis of 134 dialysis patients from the PRECADIA program at the Centro de Educación Médica e Investigaciones Clínicas (CEMIC), focusing on hemodynamic assessments including blood pressure changes from supine to standing positions, and evaluating CV mortality over a 3-year follow-up. OH was defined by a decrease of ≥10 mmHg in diastolic blood pressure or ≥20 mmHg in systolic blood pressure upon standing. Cox regression analyses were utilized to identify independent predictors of CV mortality.

Results

Of the patients, 23.1% were identified with OH. No significant differences in demographic or baseline clinical characteristics were observed between patients with and without OH, except for a higher diabetes prevalence in the OH group. OH patients treated with BBs demonstrated significantly higher CV mortality (29.6%) compared to those not receiving BBs. Independent predictors of CV mortality included age, time on dialysis, and BB use, with BBs significantly associated with increased CV mortality risk.

Conclusions

Dialysis patients with OH exhibit a high CV mortality rate, significantly influenced by BB usage. While BBs are recommended for managing CV risks in dialysis patients, their association with increased CV mortality in patients with OH necessitates careful consideration and management strategies.
Unsaturation and Approximate Isotopic Homogeneity in Leaf Air Spaces
Authors: Collaviti Spencer E. , Stuart-Williams Hilary , Farquhar Graham D. , Cernusak Lucas A. , Márquez Diego A.
Published: October 2024

- We consider two assumptions of leaf isotope gas exchange measurements: that leaf air spaces are saturated with water vapour, and that this vapour is of a homogeneous isotopic composition. In particular, we consider whether these assumptions can concurrently hold and, if not, which assumption is preferable to retain. - We present two methods using independent measurements of both leaf surfaces to consider these assumptions. The first method determines the isotopic inhomogeneity between the abaxial and adaxial evaporative sites when saturation is assumed. The second method determines the unsaturation in the abaxial and adaxial substomatal cavities when isotopic homogeneity is assumed. The methods are applied on Gossypium hirsutum (cotton) under benign atmospheric demand conditions (1.0 kPa air saturation deficit). - We find evidence that assuming saturation contradicts isotopic homogeneity and vice-versa. We compare each assumption to pre-existing data and find that it is reasonable to assume isotopic homogeneity, but not leaf vapour saturation. Thus, we find that leaves experience unsaturation even under benign atmospheric demand conditions and have a spatial variation in their unsaturation, with lower humidities associated with the surface of least stomatal resistance. - We conclude that leaves cannot be considered to be both saturated and of a homogeneous vapour isotopic composition. They are best approximated as isotopically homogeneous.
Typhi Mykrobe: fast and accurate lineage identification and antimicrobial resistance genotyping directly from sequence reads for the typhoid fever agentSalmonellaTyphi
Authors: Ingle Danielle J. , Hawkey Jane , Hunt Martin , Iqbal Zamin , Keane Jacqueline A. , Afolayan Ayorinde O. , Ahmed Niyaz , Andleeb Saadia , Ashton Philip M. , Bogoch Isaac I. , Carey Megan E. , Chattaway Marie Anne , Crump John A. , Guevara Paula Diaz , Howden Benjamin P. , Izumiya Hidemasa , Jacob Jobin John , Judd Louise M. , Kapil Arti , Keddy Karen H. , Kim Justin Y. , Levine Myron M. , Morita Masatomo , Nair Satheesh , Octavia Sophie , Okeke Iruka N. , Osadebamwen Precious E. , Rahman Sadia Isfat Ara , Rokney Assaf , Rasko David A. , Shamanna Varun , Sikorski Michael J. , Smith Anthony M. , Sunmonu Gabriel T. , Tagg Kaitlin A. , Wick Ryan R. , Dyson Zoe A. , Holt Kathryn E. ,   Global Typhoid Genomics Consortium
Published: October 2024

Background

Typhoid fever results from systemic infection withSalmonella entericaserovar Typhi (Typhi) and causes 10 million illnesses annually. Disease control relies on prevention (water, sanitation, and hygiene interventions or vaccination) and effective antimicrobial treatment. Antimicrobial resistant (AMR) Typhi lineages have emerged and become established in many parts of the world. Knowledge of local pathogen populations informed by genomic surveillance, including of lineages (defined by the GenoTyphi scheme) and AMR determinants, is increasingly used to inform local treatment guidelines and to inform vaccination strategy. Current tools for genotyping Typhi require multiple read alignment or assembly steps and have not been validated for analysis of data generated with Oxford Nanopore Technologies (ONT) long-read sequencing devices. Here, we introduce Typhi Mykrobe, a command line software tool for rapid genotyping of Typhi lineages, AMR determinants, and plasmid replicons direct from sequencing reads.