bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations between social determinants of health and comorbidity and multimorbidity in people of black ethnicities with HIV
Authors: Dominguez-Dominguez Lourdes , Campbell Lucy , Barbini Birgit , Fox Julie , Nikiphorou Elena , Goff Louise , Lempp Heidi , Tariq Shema , Hamzah Lisa , Post Frank A.
Published: January 2024

Objective:

Social determinants of health (SDH) are important determinants of long-term conditions and multimorbidity in the general population. The intersecting relationship between SDH and multimorbidity in people with HIV remains poorly studied.

Design:

A cross-sectional study investigating the relationships between eight socio-economic parameters and prevalent comorbidities of clinical significance and multimorbidity in adults of African ancestry with HIV aged 18–65 years in South London, UK.

Methods:

Multivariable logistic regression analysis was used to evaluate associations between SDH and comorbidities and multimorbidity.

Results:

Between September 2020 and January 2022, 398 participants (median age 52 years, 55% women) were enrolled; 85% reported at least one SDH and 72% had at least one comorbidity. There were no associations between SDH and diabetes mellitus or kidney disease, few associations between SDH (job and food insecurity) and cardiovascular or lung disease, and multiple associations between SDH (financial, food, housing and job insecurity, low educational level, social isolation, and discrimination) and poor mental health or chronic pain. Associations between SDH and multimorbidity mirrored those for constituent comorbidities.

Conclusion:

We demonstrate strong associations between SDH and poor mental health, chronic pain and multimorbidity in people of black ethnicities living with HIV in the UK. These findings highlight the likely impact of enduring socioeconomic hardship in these communities and underlines the importance of holistic health and social care for people with HIV to address these adverse psychosocial conditions.
Comparison of Short-term and Three-year Oncological Outcomes Between Robotic and Laparoscopic Gastrectomy for Gastric Cancer
Authors: Lu Jun , Li Tai-Yuan , Zhang Li , Wang Zu-Kai , She Jun-Jun , Jia Bao-Qing , Qin Xin-Gan , Ren Shuang-Yi , Yao Hong-Liang , Huang Ze-Ning , Liu Dong-Ning , Liang Han , Shi Fei-Yu , Li Peng , Li Bo-Pei , Zhang Xin-Sheng , Liu Kui-Jie , Zheng Chao-Hui , Huang Chang-Ming ,   on behalf of the Chinese Multi-center Research Group of Robotic Gastric Surgery
Published: January 2024

Objective:

To compare the short- and long-term outcomes between robotic gastrectomy (RG) and laparoscopic gastrectomy (LG) for gastric cancer.

Summary Background Data:

The clinical outcomes of RG over LG have not yet been effectively demonstrated.

Methods:

This retrospective cohort study included 3,599 patients with gastric cancer who underwent radical gastrectomy at eight high-volume hospitals in China from August 2016 to June 2019. Propensity score matching (PSM) was performed between patients who received RG and LG. The primary endpoint was 3-year disease-free survival (DFS).

Results:

After 1:1 PSM, 1034 pairs of patients were enrolled in a balanced cohort for further analysis. The 3-year DFS in the RG and LG was 83.7% and 83.1% (P=0.745), respectively, and the 3-year overall survival (OS) was 85.2% and 84.4%, respectively (P=0.647). During three years of follow-up, 154 patients in the RG and LG groups relapsed (cumulative incidence of recurrence: 15.0% vs. 15.0%, P=0.988). There was no significant difference in the recurrence sites between the two groups (all P>0.05). Sensitivity analysis showed that RG had comparable 3-year DFS (77.4% vs. 76.7%, P=0.745) and OS (79.7% vs. 78.4%, P=0.577) to LG in patients with advanced (pathological T2-4a) disease, and the recurrence pattern within three years was also similar between the two groups (all P>0.05). RG had less intraoperative blood loss, lower conversion rate, and shorter hospital stays than LG (all P>0.05).

Conclusions:

For resectable gastric cancer, including advanced cases, RG is a safe approach with comparable 3-year oncological outcomes to LG when performed by experienced surgeons.
Perceived Barriers to Using Neurostimulation
Authors: Cortright Marissa K. , Bluhm Robyn , Achtyes Eric D. , McCright Aaron M. , Cabrera Laura Y.
Published: January 2024

Objectives

Neurostimulation interventions often face heightened barriers limiting patient access. The objective of this study is to examine different stakeholders' perceived barriers to using different neurostimulation interventions for depression.

Methods

We administered national surveys with an embedded experiment to 4 nationwide samples of psychiatrists (n = 505), people diagnosed with depression (n = 1050), caregivers of people with depression (n = 1026), and members of the general public (n = 1022). We randomly assigned respondents to 1 of 8 conditions using a full factorial experimental design: 4 neurostimulation modalities (electroconvulsive therapy [ECT], repetitive transcranial magnetic stimulation [rTMS], deep brain stimulation [DBS], or adaptive brain implants [ABIs]) by 2 depression severity levels (moderate or severe). We asked participants to rank from a list what they perceived as the top 3 barriers to using their assigned intervention. We analyzed the data with analysis of variance and logistic regression.

Results

Nonclinicians most frequently reported “limited evidence of the treatment's effectiveness” and “lack of understanding of intervention” as their top 2 most important practical barriers to using ECT and TMS, respectively. Compared with nonclinicians, psychiatrists were more likely to identify “stigma about treatment” for ECT and “lack of insurance coverage” for TMS as the most important barriers.

Conclusions

Overall, psychiatrists' perceptions of the most important barriers to using neurostimulation interventions were significantly different than those of nonclinicians. Perceived barriers were significantly different for implantable DBS and ABI) versus nonimplantable (rTMS and ECT) neurostimulation interventions. Better understanding of how these barriers vary by neurostimulation and stakeholder group could help us address structural and attitudinal barriers to effective use of these interventions.
Use of ECT for Children With and Without Catatonia
Authors: Smith Joshua R. , Baldwin Isaac , Termini Katherine Audrey , McGonigle Trey , Vandekar Simon , Luccarelli James
Published: January 2024

Objectives

The objective study was to investigate the safety and efficacy of electroconvulsive therapy (ECT) in a retrospective cohort of pediatric patients.

Methods

A single-site retrospective analysis was conducted of patients aged younger than 18 years who received ECT in a private university hospital from January 28, 2012 to April 8, 2023. Treatment efficacy and adverse events were determined retrospectively through review of the medical record.

Results

A total of 36 pediatric patients met the inclusion criteria. Catatonia was the most common presenting indication for ECT, followed by psychosis and suicidal ideation. For all patients, Clinical Global Impressions–Improvement scale scores indicated that it was very likely for a subject to experience at least “much improvement” with the estimated probability of receiving a Clinical Global Impressions–Improvement scale score better than 3 of 0.852 (t.s. = 16.3; P < 0.001; 95% confidence interval, 0.711–0.931). All patients with catatonia demonstrated a positive clinical response and experienced a statistically significant reduction in total Bush-Francis Catatonia Rating Scale scores observed (t = 11.9; df = 20; SD = 6.3; P < 0.001; 95% confidence interval, 12.6–17.9). No significant adverse events were reported for any patient in the cohort. However, 14 (38.9%) patients experienced prolonged seizures, all of which were terminated with propofol (mean, 49.7 mg).

Conclusions

This study provides further data supporting the safe and effective use of pediatric ECT in the treatment of various psychiatric conditions. However, more research is needed to determine the risk factors associated with prolonged seizures and the optimal seizure parameters in young people.
IqgC is a potent regulator of macropinocytosis in the presence of NF1 and its loading to macropinosomes is dependent on RasG
Authors: Putar Darija , Čizmar Anja , Chao Xiaoting , Šimić Marija , Šoštar Marko , Ćutić Tamara , Mijanović Lucija , Smolko Ana , Tu Hui , Cosson Pierre , Weber Igor , Cai Huaqing , Filić Vedrana
Published: January 2024

RasG is a major regulator of macropinocytosis in
Dictyostelium discoideum
. Its activity is under the control of an IQGAP-related protein, IqgC, which acts as a RasG-specific GAP (GTPase activating protein). IqgC colocalizes with the active Ras at the macropinosome membrane during its formation and for some time after the cup closure. However, the loss of IqgC induces only a minor enhancement of fluid uptake in axenic cells that already lack another RasGAP, NF1. Here, we show that IqgC plays an important role in the regulation of macropinocytosis in the presence of NF1 by restricting the size of macropinosomes. We further provide evidence that interaction with RasG is indispensable for the recruitment of IqgC to forming macropinocytic cups. We also demonstrate that IqgC interacts with another small GTPase from the Ras superfamily, Rab5A, but is not a GAP for Rab5A. Since mammalian Rab5 plays a key role in early endosome maturation, we hypothesized that IqgC could be involved in macropinosome maturation via its interaction with Rab5A. Although an excessive amount of Rab5A reduces the RasGAP activity of IqgC
in vitro
and correlates with IqgC dissociation from endosomes
in vivo
, the physiological significance of the Rab5A–IqgC interaction remains elusive.
Modelling of longitudinally cut carrot curling induced by the vascular cylinder-cortex interference pressure
Authors: Vo-Bui Nguyen A. , Rogers Benedict A. , Pegg Elise C.
Published: January 2024

Cut carrot pieces are popular convenience foods, which enable the use of misshapen or physiologically imperfect produce. Cut carrots curl due to residual stress, which limits their shelf life and causes unnecessary food waste. The aim of this study is to identify the geometrical and environmental factors which have the most influence on their longevity. An analytical equation was developed using compound cylinder solutions, and this was used to define carrot-specific finite element (FE) models. Over 100 longitudinally cut Lancashire Nantes carrot halves were characterized, each was modelled analytically and verified using FE models. This model was evaluated by comparing predicted curvatures to ones experimentally measured over a week. The average radius of curvature decreased from 1.61 to 1.1 m a week after. A 1.32× reduction in the elastic modulus after 7 days was observed. The moisture content reduction relates to 22% weight loss, correlating to the decreasing radius of curvature. Subsequently, carrots are recommended to be stored in humidity-controlled environments. The experimental results from this study match the predictions made using mechanical principles. The research provides a methodology to predict the deformation of cut root vegetables, and the procedure is likely to be applicable to other plant structures.
Surface impedance and topologically protected interface modes in one-dimensional phononic crystals
Authors: Coutant A. , Lombard B.
Published: January 2024

When semi-infinite phononic crystals (PCs) are in contact, localized modes may exist at their boundary. The central question is generally to predict their existence and to determine their stability. With the rapid expansion of the field of topological insulators, powerful tools have been developed to address these questions. In particular, when applied to one-dimensional systems with mirror symmetry, the bulk-boundary correspondence claims that the existence of interface modes is given by a topological invariant computed from the bulk properties of the PC, which ensures strong stability properties. This one-dimensional bulk-boundary correspondence has been proven in various works. Recent attempts have exploited the notion of surface impedance, relying on analytical calculations of the transfer matrix. In the present work, the monotonic evolution of surface impedance with frequency is proven for all one-dimensional PCs with mirror symmetry. This result allows us to establish a stronger version of the bulk-boundary correspondence that guarantees not only the existence but also the uniqueness of a topologically protected interface state. This correspondence is extended to a larger class of one-dimensional models that include imperfect interfaces, array of resonators, or dispersive media. Numerical simulations are proposed to illustrate the theoretical findings.
Scattering kernel of an array of floating ice floes: application to water wave transport in the marginal ice zone
Authors: Montiel F. , Meylan M. H. , Hawkins S. C.
Published: January 2024

A radiative transfer model of water wave scattering in the marginal ice zone is considered. In this context, wave energy redistribution across the directional components of the spectrum as a result of scattering by the constituent ice floes is typically modelled via a scattering kernel describing the far-field directionality of the scattered wave field produced by a single floe in isolation. Recognizing the potential importance of the floe size distribution (FSD) on wave scattering, we propose an enhanced scattering kernel constructed from the far-field scattering pattern of a circular array of floes. This is achieved by solving the self-consistent multiple scattering of a time-harmonic plane wave by a large array of floating circular floes with radii sampled from a prescribed FSD. A fast multipole method is implemented to accelerate the numerical estimation of the solution. Simulations are then conducted to characterize the properties of the scattering kernel for a range of configurations. It is found that the scattering kernel obtained for a wide array has a large, narrow transmission peak in the forward direction, while it uniformizes low-amplitude scattered waves in other directions. An idealized application to radiative transfer theory is also considered.
Oxygen extraction efficiency of the tidally-ventilated rectal gills of dragonfly nymphs
Authors: Lee Daniel J. , Matthews Philip G. D.
Published: January 2024

Dragonfly nymphs breathe water using tidal ventilation, a highly unusual strategy in water-breathing animals owing to the high viscosity, density and low oxygen (O
2
) concentration of water. This study examines how well these insects extract O
2
from the surrounding water during progressive hypoxia. Nymphs were attached to a custom-designed respiro-spirometer to simultaneously measure tidal volume, ventilation frequency and metabolic rate. Oxygen extraction efficiencies (OEE) were calculated across four partial pressure of oxygen (pO
2
) treatments, from normoxia to severe hypoxia. While there was no significant change in tidal volume, ventilation frequency increased significantly from 9.4 ± 1.2 breaths per minute (BPM) at 21.3 kPa to 35.6 ± 2.9 BPM at 5.3 kPa. Metabolic rate increased significantly from 1.4 ± 0.3 µl O
2
min
−1
at 21.3 kPa to 2.1 ± 0.4 µl O
2
min
−1
at 16.0 kPa, but then returned to normoxic levels as O
2
levels declined further. OEE of nymphs was 40.1 ± 6.1% at 21.3 kPa, and did not change significantly during hypoxia. Comparison to literature shows that nymphs maintain their OEE during hypoxia unlike other aquatic tidal-breathers and some unidirectional breathers. This result, and numerical models simulating experimental conditions, indicate that nymphs maintain these extraction efficiencies by increasing gill conductance and/or lowering internal pO
2
to maintain a sufficient diffusion gradient across their respiratory surface.
A reformulation of Fisher's runaway identifies the heritability of mate choices as a key parameter and highlights limitations of the hypothesis
Authors: Fry James D.
Published: January 2024

Fisher proposed that female preference for mates with extreme traits could evolve as an essentially arbitrary outcome of a self-reinforcing process. Although Fisher's runaway has been shown to be a theoretical possibility, it is not clear whether it occurs in real populations, in part because existing models express the necessary conditions in terms of parameters that would be nearly impossible to estimate in the wild. Here, I reformulate models of the runaway in terms of two estimable parameters, the heritability and phenotypic variance of realized mate choices. Higher values of both quantities make the runaway more likely. In the most realistic model considered, in which mate choices are based on a mixture of absolute and relative criteria, a runaway cannot occur unless mate choice increases the variance of the male trait, which seems incompatible with the strong directional mating preferences typically observed in polygynous species. Even in the most favourable case for the runaway, purely relative preference without direct selection on preference, a substantial heritability of realized mate choices would be required if there is moderately strong stabilizing selection on the male trait. These results cast some doubt on whether the runaway is a plausible outcome in natural populations.
Mosquito thermal tolerance is remarkably constrained across a large climatic range
Authors: Couper Lisa I. , Farner Johannah E. , Lyberger Kelsey P. , Lee Alexandra S. , Mordecai Erin A.
Published: January 2024

How mosquitoes may respond to rapid climate warming remains unknown for most species, but will have major consequences for their future distributions, with cascading impacts on human well-being, biodiversity and ecosystem function. We investigated the adaptive potential of a wide-ranging mosquito species,
Aedes sierrensis
, across a large climatic gradient by conducting a common garden experiment measuring the thermal limits of mosquito life-history traits. Although field-collected populations originated from vastly different thermal environments that spanned over 1200 km, we found limited variation in upper thermal tolerance between populations. In particular, the upper thermal limits of all life-history traits varied by less than 3°C across the species range and, for most traits, did not differ significantly between populations. For one life-history trait—pupal development rate—we did detect significant variation in upper thermal limits between populations, and this variation was strongly correlated with source temperatures, providing evidence of local thermal adaptation for pupal development. However, we found that maximum environmental temperatures across most of the species' range already regularly exceed the highest upper thermal limits estimated under constant temperatures.

This result suggests that strategies for coping with and/or avoiding thermal extremes are likely key components of current and future mosquito thermal tolerance.
Spatial variation in avian bill size is associated with temperature extremes in a major radiation of Australian passerines
Authors: Subasinghe Kalya , Symonds Matthew R. E. , Prober Suzanne M. , Bonnet Timothée , Williams Kristen J. , Ware Chris , Gardner Janet L.
Published: January 2024

Morphology is integral to body temperature regulation. Recent advances in understanding of thermal physiology suggest a role of the avian bill in thermoregulation. To explore the adaptive significance of bill size for thermoregulation we characterized relationships between bill size and climate extremes. Most previous studies focused on climate means, ignoring frequencies of extremes, and do not reflect thermoregulatory costs experienced over shorter time scales. Using 79 species (9847 museum specimens), we explore how bill size variation is associated with temperature extremes in a large and diverse radiation of Australasian birds, Meliphagides, testing a series of predictions. Overall, across the continent, bill size variation was associated with both climate extremes and means and was most strongly associated with winter temperatures; associations at the level of climate zones differed from continent-wide associations and were complex, yet consistent with physiology and a thermoregulatory role for avian bills. Responses to high summer temperatures were nonlinear suggesting they may be difficult to detect in large-scale continental analyses using previous methodologies. We provide strong evidence that climate extremes have contributed to the evolution of bill morphology in relation to thermoregulation and show the importance of including extremes to understand fine-scale trait variation across space.
A restatement of the natural science evidence base concerning grassland management, grazing livestock and soil carbon storage
Authors: Jordon Matthew W. , Buffet Jean-Charles , Dungait Jennifer A. J. , Galdos Marcelo V. , Garnett Tara , Lee Michael R. F. , Lynch John , Röös Elin , Searchinger Timothy D. , Smith Pete , Godfray H. Charles J.
Published: January 2024

Approximately a third of all annual greenhouse gas emissions globally are directly or indirectly associated with the food system, and over a half of these are linked to livestock production. In temperate oceanic regions, such as the UK, most meat and dairy is produced in extensive systems based on pasture. There is much interest in the extent to which such grassland may be able to sequester and store more carbon to partially or completely mitigate other greenhouse gas emissions in the system. However, answering this question is difficult due to context-specificity and a complex and sometimes inconsistent evidence base. This paper describes a project that set out to summarize the natural science evidence base relevant to grassland management, grazing livestock and soil carbon storage potential in as policy-neutral terms as possible. It is based on expert appraisal of a systematically assembled evidence base, followed by a wide stakeholders engagement. A series of evidence statements (in the appendix of this paper) are listed and categorized according to the nature of the underlying information, and an annotated bibliography is provided in the electronic supplementary material.
Halomonas citrativorans sp. nov., Halomonas casei sp. nov. and Halomonas colorata sp. nov., isolated from French cheese rinds
Authors: Kothe Caroline Isabel , Monnet Christophe , Irlinger Françoise , Virsolvy Mathieu , Frühling Anja , Neumann-Schaal Meina , Wolf Jacqueline , Renault Pierre
Published: January 2024

Eight Gram-stain-negative bacterial strains were isolated from cheese rinds sampled in France. On the basis of 16S rRNA gene sequence analysis, all isolates were assigned to the genus

Halomona

s. Phylogenetic investigations, including 16S rRNA gene studies, multilocus sequence analysis, reconstruction of a pan-genome phylogenetic tree with the concatenated core-genome content and average nucleotide identity (ANI) calculations, revealed that they constituted three novel and well-supported clusters. The closest relative species, determined using the whole-genome sequences of the strains, were

Halomonas zhanjiangensis

for two groups of cheese strains, sharing 82.4 and 93.1 % ANI, and another cluster sharing 92.2 % ANI with the

Halomonas profundi

type strain. The strains isolated herein differed from the previously described species by ANI values <95 % and several biochemical, enzymatic and colony characteristics. The results of phenotypic, phylogenetic and chemotaxonomic analyses indicated that the isolates belonged to three novel

Halomonas

species, for which the names Halomonas citrativorans sp. nov., Halomonas casei sp. nov. and Halomonas colorata sp. nov. are proposed, with isolates FME63T (=DSM 113315T=CIRM-BIA2430T=CIP 111880T=LMG 32013T), FME64T (=DSM 113316T=CIRM-BIA2431T=CIP 111877T=LMG 32015T) and FME66T (=DSM 113318T=CIRM-BIA2433T=CIP 111876T=LMG 32014T) as type strains, respectively.
Lignin isolated by microwave-assisted acid-catalyzed solvolysis induced cell death on mammalian tumor cells by modulating apoptotic pathways
Authors: Kashimoto Rio , Ohgitani Eriko , Makimura Yutaka , Miyazaki Tatsuya , Kimura Chihiro , Shin-Ya Masaharu , Nishimura Hiroshi , Pezzotti Giuseppe , Watanabe Takashi , Mazda Osam
Published: January 2024

Lignin, the most abundant renewable aromatic polymer, has been shown to suppress the growth of mammalian tumor cells. Despite being a textbook example, there is little information on the biological activity of lignin in relation to its molecular structure or the molecular mechanisms by which lignin suppresses tumor cells in mammalian species. Here, we prepared Microwave-assisted Acid-catalyzed Solvolysis Lignin (MASL) and assessed its effects on human and mouse tumor cells. Our data showed MASL significantly reduced viability of tumor cells by modulating apoptotic pathways. MASL treatment upregulated TNF-α, Fas, and FasL expression levels, while suppressing anti-apoptotic NF-κB and mTOR pathways in tumor cells. In-vivo experiments were also performed using tumor-bearing mice to confirm the anti-tumor effects of MASL. An administration of MASL significantly suppressed tumor growth in mice in association with elevation of caspase 3 expression. These findings strongly suggest the potential usefulness of low molecular weight lignin as an effective therapeutic against malignancies.
Cause and chondroprotective effects of prostaglandin E2 secretion during mesenchymal stromal cell chondrogenesis
Authors: Schmidt S. , Klampfleuthner F.A.M. , Renkawitz T. , Diederichs S.
Published: January 2024

Mesenchymal stromal cells (MSCs) that are promising for cartilage tissue engineering secrete high amounts of prostaglandin E2 (PGE2), an immunoactive mediator involved in endochondral bone development. This study aimed to identify drivers of PGE2 and its role in the inadvertent MSC misdifferentiation into hypertrophic chondrocytes. PGE2 release which rose in the first three weeks of MSC chondrogenesis was jointly stimulated by endogenous BMP, WNT, and hedgehog activity that supported the exogenous stimulation by TGF-β1 and insulin, and overcame the PGE2 inhibition by dexamethasone. Experiments with PGE2 treatment or the inhibitor celecoxib or specific receptor antagonists demonstrated that although driven by prohypertrophic signals, PGE2 exerted broad autocrine antihypertrophic effects. This chondroprotective effect makes PGE2 not only a promising option for future combinatorial approaches to direct MSC tissue engineering approaches into chondral instead of endochondral development, but could potentially have implications for the use of COX-2-selective inhibitors in osteoarthritis pain management.
Collagen mineralization decreases NK cell-mediated cytotoxicity of breast cancer cells via increased glycocalyx thickness
Authors: Park Sangwoo , Choi Siyoung , Shimpi Adrian A. , Estroff Lara A. , Fischbach Claudia , Paszek Matthew J.
Published: January 2024

Skeletal metastasis is common in patients with advanced breast cancer, and often caused by immune evasion of disseminated tumor cells (DTCs). In the skeleton, tumor cells not only disseminate to the bone marrow, but also to osteogenic niches in which they interact with newly mineralizing bone extracellular matrix (ECM). However, it remains unclear how mineralization of collagen type I, the primary component of bone ECM, regulates tumor-immune cell interactions. Here, we have utilized a combination of synthetic bone matrix models with controlled mineral content, nanoscale optical imaging, and flow cytometry to evaluate how collagen type I mineralization affects the biochemical and biophysical properties of the tumor cell glycocalyx, a dense layer of glycosylated proteins and lipids decorating their cell surface. Our results suggest that collagen mineralization upregulates mucin-type O-glycosylation and sialylation by tumor cells, which increased their glycocalyx thickness while enhancing resistance to attack by Natural Killer (NK) cells. These changes were functionally linked as treatment with a sialylation inhibitor decreased mineralization-dependent glycocalyx thickness and made tumor cells more susceptible to NK cell attack. Together, our results suggest that interference with glycocalyx sialylation may represent a therapeutic strategy to enhance cancer immunotherapies targeting bone-metastatic breast cancer.
A general model for two-locus assortative mating analysis and prediction
Authors: Smith Reginald D.
Published: January 2024

The analytical framework to investigate the effect of assortative mating for phenotypes that are determined by two loci is over a hundred years old and well established by Jennings, Wentworth, Remick, Robbins, and Wright. However, some known aspects of assortative mating have not received a concise analytical analysis or clear expression. Chief among these are linkage disequilibrium and identity disequilibrium but also the change in heterozygosity outside of the simple case ofPA=PB= 1/2. In order to understand the effects of assortative mating in more detail, a general model is proposed that uses recursive difference equations rather than simulation to solve most assortative mating problems. Using this, we will expand the cases for which an exact or approximate expression for population genetic variables can be determined. In particular, the first closed form expressions for linkage disequilibrium and identity disequilibrium for two-locus assortative mating are given. We also show that assortative mating does not generate linkage disequilibrium when the loci are completely linked. Finally, this model will be used to investigate two possible cases of two-locus assortative mating in human populations regarding variants for non-syndromic deafness and the variants that largely determine blue eye color.
Stronger evidence for relaxed selection than adaptive evolution in high-elevation animal mtDNA
Authors: Iverson Erik N. K. , Criswell Abby , Havird Justin C.
Published: January 2024

Mitochondrial (mt) genes are the subject of many adaptive hypotheses due to the key role of mitochondria in energy production and metabolism. One widespread adaptive hypothesis is that selection imposed by life at high elevation leads to the rapid fixation of beneficial alleles in mtDNA, reflected in the increased rates of mtDNA evolution documented in many high-elevation species. However, the assumption that fast mtDNA evolution is caused by positive, rather than relaxed purifying selection has rarely been tested. Here, we calculated thedN/dSratio, a metric of nonsynonymous substitution bias, and explicitly tested for relaxed selection in the mtDNA of over 700 species of terrestrial vertebrates, freshwater fishes, and arthropods, with information on elevation and latitudinal range limits, range sizes, and body sizes. We confirmed that mitochondrial genomes of high-elevation taxa have slightly higherdN/dSratios compared to low-elevation relatives. High-elevation species tend to have smaller ranges, which predict higherdN/dSratios and more relaxed selection across species and clades, while absolute elevation and latitude do not predict higherdN/dS. We also find a positive relationship between body mass anddN/dS, supporting a role for small effective population size leading to relaxed selection. We conclude that higher mtdN/dSamong high-elevation species is more likely to reflect relaxed selection due to smaller ranges and reduced effective population size than adaptation to the environment. Our results highlight the importance of rigorously testing adaptive stories against non-adaptive alternative hypotheses, especially in mt genomes.
Postmortem MRI of Tissue Frozen at Autopsy
Authors: Nair Govind , Sun Roy , Merkle Hellmut , Hoskin Kyra , Bree Kendyl , Dodd Stephen , Koretsky Alan
Published: January 2024

Introduction

Postmortem MRI provides insight into location of pathology within tissue blocks, enabling efficient targeting of histopathological studies. While postmortem imaging of fixed tissue is gaining popularity, imaging tissue frozen at the time of extraction is significantly more challenging.

Methods

Tissue integrity was examined using RNA integrity number (RIN), in mouse brains placed between -20 °C and 20 °C for up to 24 hours, to determine the highest temperature that could potentially be used for imaging without tissue degeneration. Human tissue frozen at the time of autopsy was sealed in a tissue chamber filled with 2-methylbutane to prevent contamination of the MRI components. The tissue was cooled to a range of temperatures in a 9.4T MRI using a recirculating aqueous ethylene glycol solution. MRI was performed using a magnetization-prepared rapid gradient echo (MPRAGE) sequence with inversion time of 1400 ms to null the signal from 2-methylbutane bath, isotropic resolution between 0.3-0.4 mm, and scan time of about 4 hours was used to study the anatomical details of the tissue block.

Results and Discussion

A temperature of -7 °C was chosen for imaging as it was below the highest temperature that did not show significant RIN deterioration for over 12 hours, at the same time gave robust imaging signal and contrast between brain tissue types. Imaging performed on various human tissue blocks revealed good gray-white matter contrast and revealing subpial, subcortical, and deep white matter lesions typical of multiple sclerosis enabling further spatially targeted studies.

Conclusion

Here, we describe a new method to image cold tissue, while maintaining tissue integrity and biosafety during scanning. In addition to improving efficiency of downstream processes, imaging tissue at sub-zero temperatures may also improve our understanding of compartment specificity of MRI signal.
The unseen invaders: tracking phylogeographic dynamics and genetic diversity of crypticPomacea canaliculata and P. maculata(Golden Apple Snails) across Taiwan
Authors: Banerjee Pritam , Dey Gobinda , Maity Jyoti Prakash , Stewart Kathryn A. , Sharma Raju Kumar , Chan Michael W.Y. , Lee Kuan Hsien , Chen Chien-Yen
Published: January 2024

The cryptic invasion of golden apple snails (Pomacea canaliculata and P. maculata) in Taiwan has caused significant ecological and economical damage over last few decades, however, their management remains difficult due to inadequate taxonomic identification, complex phylogeny and limited population genetic information. We aim to understand the current distribution, putative population of origin, genetic diversity and potential path of cryptic invasion ofPomacea canaliculata and P. maculataacross Taiwan to aid in improved mitigation approaches. The present investigation conducted a nationwide survey with 254 samples collected from 41 locations from 14 counties or cities across Taiwan. We identifiedP. canaliculataandP. maculatabased on mitochondrial COI and compared their genetic diversity across Taiwan, as well as other introduced and native countries (based on publicly available COI data) to understand the possible paths of invasion in Taiwan. Based on mitochondrial COI barcoding, sympatric and heterogeneous distributions of invasiveP. canaliculataandP. maculatawere noted. Our haplotype analysis and mismatch distribution suggested multiple introductions ofP. canaliculatain Taiwan was likely originated directly from Argentina, whereasP. maculatawas probably introduced from a single, or a few, introduction event(s) from Argentina and Brazil. Our population genetic data further demonstrated a higher haplotype and genetic diversity forP. canaliculataandP. maculatain Taiwan compared to other introduced regions. Based on our current understanding, the establishment ofP. canaliculataandP. maculatais alarming and widespread beyond geopolitical borders, requiring a concerted and expedited national and international invasive species mitigation program.
Diurnal rhythmicity in metabolism and salivary effector expression shapes host colonization by aphids
Authors: Han Jinlong , Kunk Daniel , Cui Meihua , Goldstein Yoshiahu , Tzin Vered , Nalam Vamsi J.
Published: January 2024

Diurnal rhythms influence insect behavior, physiology, and metabolism, optimizing their performance by adapting to daily changes in the environment. While their impact on agricultural pests has been briefly explored, our understanding of how these rhythms drive adaptative responses in pest biology and influence host colonization remains elusive. Here, we show that a notorious global aphid pest,Rhopalosiphum padi, exhibits distinct diurnal patterns in feeding behavior, with elevated honeydew excretion at night and extended phloem salivation during early nighttime. Temporal aphid transcriptome profiling reveals four diurnally rhythmic clusters, two of which peak at night, exhibiting enrichment in carbohydrate and amino acid metabolism. Beyond the established role in manipulating host responses and allowing sustained feeding, our study reveals the first evidence in any insect species for cyclical fluctuations in salivary effector expression. Silencing key effector genes, peaking in expression during the increased nighttime salivation, results in a more pronounced reduction in aphid feeding activity on host plants during the night compared to the day, a phenomenon not observed on artificial diets. A better understanding of aphid diurnal rhythms and their roles on host colonization provides a promising avenue to refine and optimize pest management, granting a strategic advantage for minimizing crop damage.
Pulmonary primary oxysterol and bile acid synthesis as a predictor of outcomes in pulmonary arterial hypertension
Authors: Alotaibi Mona , Harvey Lloyd D. , Nichols William C. , Pauciulo Michael W. , Hemnes Anna , Long Tao , Watrous Jeramie D. , Begzati Arjana , Tuomilehto Jaakko , Havulinna Aki S. , Niiranen Teemu J. , Jousilahti Pekka , Salomaa Veikko , Bertero Thomas , Kim Nick H. , Desai Ankit A. , Malhotra Atul , Yuan Jason X.-J. , Cheng Susan , Chan Stephen Y. , Jain Mohit
Published: January 2024

Pulmonary arterial hypertension (PAH) is a rare and fatal vascular disease with heterogeneous clinical manifestations. To date, molecular determinants underlying the development of PAH and related outcomes remain poorly understood. Herein, we identify pulmonary primary oxysterol and bile acid synthesis (PPOBAS) as a previously unrecognized pathway central to PAH pathophysiology. Mass spectrometry analysis of 2,756 individuals across five independent studies revealed 51 distinct circulating metabolites that predicted PAH-related mortality and were enriched within the PPOBAS pathway. Across independent single-center PAH studies, PPOBAS pathway metabolites were also associated with multiple cardiopulmonary measures of PAH-specific pathophysiology. Furthermore, PPOBAS metabolites were found to be increased in human and rodent PAH lung tissue and specifically produced by pulmonary endothelial cells, consistent with pulmonary origin. Finally, a poly-metabolite risk score comprising 13 PPOBAS molecules was found to not only predict PAH-related mortality but also outperform current clinical risk scores. This work identifies PPOBAS as specifically altered within PAH and establishes needed prognostic biomarkers for guiding therapy in PAH.

One-Sentence Summary

This work identifies pulmonary primary oxysterol and bile acid synthesis as altered in pulmonary arterial hypertension, thus establishing a new prognostic test for this disease.
Bioreversible anionic cloaking enables intracellular protein delivery with ionizable lipid nanoparticles
Authors: Alamgir Azmain , Ghosal Souvik , DeLisa Matthew P. , Alabi Christopher A.
Published: January 2024

Protein-based therapeutics comprise a rapidly growing subset of pharmaceuticals, but enabling their delivery into cells for intracellular applications has been a longstanding challenge. To overcome the delivery barrier, we explored a reversible, bioconjugation-based approach to modify the surface charge of protein cargos with an anionic “cloak” to facilitate electrostatic complexation and delivery with lipid nanoparticle (LNP) formulations. We demonstrate that the conjugation of lysine-reactive sulfonated compounds can allow for the delivery of various protein cargos using FDA-approved LNP formulations of the ionizable cationic lipid DLin-MC3-DMA (MC3). We apply this strategy to functionally deliver RNase A for cancer cell killing as well as a full-length antibody to inhibit oncogenic β-catenin signaling. Further, we show that LNPs encapsulating cloaked fluorescent proteins distribute to major organs in mice following systemic administration. Overall, our results point towards a generalizable platform that can be employed for intracellular delivery of a wide range of protein cargos.
Tirzepatide attenuates mammary tumor progression in diet-induced obese mice
Authors: Glenny Elaine M. , Ho Alyssa N. , Kiesel Violet A. , Chen Fangxin , Gates Claire E. , Paules Evan M. , Xu Ruihan , Holt C. Alex , Coleman Michael F. , Hursting Stephen D.
Published: January 2024

We report for the first time an anticancer benefit of tirzepatide—a dual glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptor agonist—in a model of obesity and breast cancer in female mice. Long-term tirzepatide treatment induced weight loss, mitigated obesity-driven changes in circulating metabolic hormone levels, and suppressed orthotopic E0771 mammary tumor growth. Relative to tirzepatide, chronic calorie restriction, an established anticancer intervention in preclinical models, promoted even greater weight loss, systemic hormonal regulation, and tumor suppression. We conclude that tirzepatide represents a promising pharmacologic approach for mitigating the procancer effects of obesity. Moreover, strategies promoting greater weight loss than achieved with tirzepatide alone may augment the anticancer benefits of tirzepatide.
A CANCER PERSISTENT DNA REPAIR CIRCUIT DRIVEN BY MDM2, MDM4 (MDMX), AND MUTANT P53 FOR RECRUITMENT OF MDC1 AND 53BP1 TO CHROMATIN
Authors: Ellison Viola , Polotskaia Alla , Xiao Gu , Leybengrub Pamella , Qiu Weigang , Lee Rusia , Hendrickson Ronald , Hu Wenwei , Bargonetti Jill
Published: January 2024

The influence of the metastasis promoting proteins mutant p53 (mtp53) and MDM2 onCancerPersistentRepair(CPR) to promote cancer cell survival is understudied. Interactions between the DNA repair choice protein 53BP1 and wild type tumor suppressor protein p53 (wtp53) regulates cell cycle control. Cancer cells often express elevated levels of transcriptionally inactive missense mutant p53 (mtp53) that interacts with MDM2 and MDM4/MDMX (herein called MDMX). The ability of mtp53 to maintain a 53BP1 interaction while in the context of interactions with MDM2 and MDMX has not been described. We asked if MDM2 regulates chromatin-based phosphorylation events in the context of mtp53 by comparing the chromatin of T47D breast cancer cells with and without MDM2 in a phospho-peptide stable isotope labeling in cell culture (SILAC) screen. We found reduced phospho-53BP1 chromatin association, which we confirmed by chromatin fractionation and immunofluorescence in multiple breast cancer cell lines. We used the Proximity Ligation Assay (PLA) in breast cancer cell lines and detected 53BP1 in close proximity to mtp53, MDM2, and the DNA repair protein MDC1. Through disruption of the mtp53-MDM2 interaction, by either Nutlin 3a or a mtp53 R273H C-terminal deletion, we uncovered that mtp53 was required for MDM2-53BP1 interaction foci. Our data suggests that mtp53 works with MDM2 and 53BP1 to promote CPR and cell survival.
Nutrient addition on grazing lawns and selection by free-roaming mammalian herbivores in a nutrient poor savanna
Authors: Schroder Bradley , Van Langevelde Frank , Schroder Nicola-Anne Hawkins , Prins Herbert H. T.
Published: January 2024

Grazing lawns are important food sources in nutrient poor savannas for free-roaming mammalian herbivores. It has been hypothesized that increased grazing pressure by mammalian herbivores can create and maintain patches of lawn grass. We tested whether the application of specific nutrients, nitrogen (N), phosphorus (P) or in combination with calcitic and dolomitic lime (Ca), in a nutrient poor African savanna, would make the grass sward more nutrient rich, which would attract mammalian herbivores to graze more frequently. We investigated the grazing patterns of six species of mammalian herbivores, namely, blue wildebeest (Connochaetes taurinus), Burchell’s zebra (Equus quagga burchellii), common eland (Taurotragus oryx), impala (Aepyceros melampus), square-lipped rhinoceros (Ceratotherium simum) and warthog (Phacochoerus africanus). We show that the addition of N attracts and increases the grazing pressure for three of the herbivore species, namely, blue wildebeest, Burchell’s zebra and impala. Our findings suggest that these often abundantly present mammalian herbivores with intermediate body mass, attracted to grazing lawns by the addition of N, can maintain grazing lawns.

Conservation implications

Artificial fertilization with nitrogen attracts large free-roaming herbivore species to localized grazing lawns, stimulating the creation and expansion of high nutrient quality lawn grasses in nutrient poor savannas. This results in a nutrient high food source which would normally not be available in nutrient poor savannas.
β-Cells as a Cell Factory for On-Demand Recombinant Protein Dosing: Harnessing the Neuroendocrine Cell Secretory Pathway for Controlled Release
Authors: Thomson Ella A. , Xu Haixia , Lee Sooyeon , Lal Rayhan A. , Annes Justin P. , Poon Ada S. Y.
Published: January 2024

This study explores the potential of utilizingβ-cells, exemplified with R7T1β-cell pseudoislets, as a transplantable cell factory for on-demand recombinant protein therapeutic delivery. While mammalian cell lines are widely used forin vitroprotein production, the commonly utilized constitutive secretion pathway poses challenges toin vivocell therapy, especially for delivering proteins requiring precise exposure kinetics. The proposed approach capitalizes on unique aspects ofβ-cells, including substantial vesicular protein storage capacity and electrochemically-regulated protein release, to facilitate timely and titratablein vivotherapeutic delivery. Examining a variety of strategies to acheiveβ-cell glucagon or glucagon-like peptide 1 (GLP-1) storage and secretion, we devised a flexibleβ-cell-based expression platform for efficient cellular peptide production and on-demand release. This platform utilizes the preproinsulin coding sequence as a template, wherein therapeutic peptides of interest (glucagon or GLP-1) are substituted for C-peptide while the A- and B-peptide insulin chains are mutated to prevent bio-active insulin production. This approach overcomes the challenge of efficient bio-active peptide expression by leveraging the endogenousβ-cell peptide expression, translation, processing, storage and secretion machinery. Furthermore,β-cells provide a mechanism for scalable electyrochemnically-triggered peptide delivery. This transformative strategy, which may be extended to other proteins and peptide expression cassettes, holds significant promise for targeted and temporally controlledin vivoproduction and release of recombinant protein therapeutics. The study suggests potential applications in addressing challenges in metabolic disorders, blood disorders, and oncology. Future refinements may focus on optimizing vector design, peptide production, andin vivoadaptation.