bluuebunny/crossref_metadata_2025 huggingface dataset:
Managing acute pain with inhaled methoxyflurane in non-cancer patients: a review of the latest evidence
Authors: Patel Partha , Al Aadah Carmen F. , Al Aadah Lelia F. , Wong Henry C.Y. , Lee Shing Fung , Alkhaifi Muna , Finkelstein Joel , Rivlin Leon
Published: September 2024

Purpose of the review

Penthrox® (inhaled methoxyflurane, IMF) is an inhaled analgesic used for the treatment of moderate-to-severe acute pain. It has various advantages including the capacity for being self-administered in the presence of healthcare providers (HCPs), rapid onset and offset, and having documented evidence for minimal adverse events post-use. In a variety of non-oncological settings such as pre-hospital transport and minor outpatient procedures, amongst others, IMF has significantly reduced acute pain. As IMF has the capacity to provide appreciable pain relief but is not as widely used as other acute analgesics (i.e., opioids), this review of past and current literature hopes to explore the impact of inhaled IMF on patient outcomes, procedures where it could be used, and to inform readers about this compound.

Recent findings

In general, patients who used IMF had decreased pain, improved psychosocial factors (i.e., reduced anxiety, improved satisfaction), and minimal adverse events thereby being concluded as safe for use.

Future use in remote medical interventions such as military contexts, in emergency room settings, and administration under the supervision of first responders such as non-paramedic and non-HCPs further broadens the scope of settings where IMF can meaningfully be implemented.
The serotonergic psychedelic DOI impairs deviance detection in the auditory cortex
Authors: Horrocks Max , Mohn Jennifer L , Jaramillo Santiago
Published: September 2024

Psychedelics are known to induce profound perceptual distortions, yet the neural mechanisms underlying these effects, particularly within the auditory system, remain poorly understood. In this study, we investigated the effects of the psychedelic compound 2,5-Dimethoxy-4-iodoamphetamine (DOI), a serotonin 2A receptor agonist, on the activity of neurons in the auditory cortex of awake mice. We examined whether DOI administration alters sound-frequency tuning, variability in neural responses, and deviance detection (a neural process reflecting the balance between top-down and bottom-up processing). Our results show that while DOI does not alter the frequency selectivity of auditory cortical neurons in a consistent manner, it increases trial-by-trial variability in responses and consistently diminishes the neural distinction between expected (standard) and unexpected (oddball) stimuli. This reduction in deviance detection was primarily driven by a decrease in the response to oddball sounds, suggesting that DOI dampens the auditory cortex's sensitivity to unexpected events. These findings provide insights into how psychedelics disrupt sensory processing and shed light on the neural mechanisms underlying the altered perception of auditory stimuli observed in the psychedelic state.
NucBalancer: Streamlining Barcode Sequence Selection for Optimal Sample Pooling for Sequencing
Authors: Gupta Saurabh , Sharma Ankur
Published: September 2024

Recent advancements in next-generation sequencing (NGS) technologies have brought to the forefront the necessity for versatile, cost-effective tools capable of adapting to a rapidly evolving landscape. The emergence of numerous new sequencing platforms, each with unique sample preparation and sequencing requirements, underscores the importance of efficient barcode balancing for successful pooling and accurate demultiplexing of samples. Recently launched new sequencing systems claim better affordability comparable to more established platforms further exemplifies these challenges, especially when libraries originally prepared for one platform need conversion to another. In response to this dynamic environment, we introduce NucBalancer, a Shiny app developed for the optimal selection of barcode sequences. While initially tailored to meet the nucleotide, composition challenges specific to G400 and T7 series sequencers, NucBalancer’s utility significantly broadens to accommodate the varied demands of these new sequencing technologies. Its application is particularly crucial in single-cell genomics, enabling the adaptation of libraries, such as those prepared for 10x technology, to various sequencers including G400 and T7 series sequencers. By facilitating the efficient balancing of nucleotide composition and the accommodation of differing sample concentrations, NucBalancer plays a pivotal role in reducing biases in nucleotide composition. This enhances the fidelity and reliability of NGS data across multiple platforms. As the NGS field continues to expand with the introduction of new sequencing technologies, the adaptability and wide-ranging applicability of NucBalancer render it an invaluable asset in genomic research. This tool addresses the current sequencing challenges ensuring that researchers can effectively balance barcodes for sample pooling regardless of the sequencing platform used.

Availability and implementation

NucBalancer is implemented in R and is available athttps://github.com/ersgupta/NucBalancer. Additionally, a shiny interface is made available athttps://ersgupta.shinyapps.io/NucBalancer/.
Coagulation factor XII contributes to renin activation, heart failure progression, and mortality
Authors: Gladysheva Inna P. , Sullivan Ryan D. , Saleem Sofiyan , Castellino Francis J. , Ploplis Victoria A. , Reed Guy L.
Published: September 2024

Symptomatic heart failure (sHF) with cardiac dysfunction, edema, and mortality are driven by overactivation of the renin-angiotensin-aldosterone system (RAAS). Renin is widely recognized as a key initiator of RAAS function, yet the mechanisms that activate renin remain a mystery. We discovered that activated coagulation factor XII generates active renin in the circulation and is directly linked to pathological activation of the systemic RAAS, development of sHF, and increased mortality. These findings suggest a new paradigm for therapeutically modulating the RAAS in sHF and other pathological conditions.
High-efficiency discovery and structure-activity-relationship analysis of non-substrate-based covalent inhibitors of S-adenosylmethionine decarboxylase
Authors: Ai Yuanbao , Xu Siyu , Zhang Yan , Liu Zhaoxiang , Liu Sen
Published: September 2024

Targeted covalent inhibitors (TCIs) form covalent bonds with targets following initial non-covalent binding. The advantages of TCIs have driven a resurgence in rational TCI design over the past decade, resulting in the approval of several blockbuster covalent drugs. To support TCI discovery, various computational methods have been developed. However, accurately predicting TCI reactivity remains challenging due to interference between non-covalent scaffolds and reactive warheads, leading to inefficiencies in computational screening and high experimental costs. In this study, we enhanced the SCARdock protocol, a validated computational screening tool developed by our lab, by incorporating quantum chemistry-based warhead reactivity calculations. By integrating these calculations with non-covalent docking scores, docking ranks, and bonding-atom distances, non-covalent and covalent inhibitors of S-adenosylmethionine decarboxylase (AdoMetDC) were correctly classified. Using the optimized SCARdock, we successfully identified twelve new AdoMetDC covalent inhibitors from 17 compounds, achieving a 70.6% hit rate. From these novel inhibitors, we analyzed the contributions of non-covalent interactions and covalent bonding, enabling a structure-activity relationship (SAR) analysis for AdoMetDC covalent inhibitors, which was previously unexplored with substrate-based inhibitors. Overall, this work presents an efficient computational protocol for TCI discovery and offers new insights into AdoMetDC inhibitor design. We anticipate that this approach will stimulate TCI development by improving computational screening efficiency and reducing experimental costs.
Temporal dynamics of viral fitness and the adaptive immune response in HCV infection
Authors: Walker Melanie R. , Leung Preston , Keoshkerian Elizabeth , Pirozyan Mehdi R. , Lloyd Andrew R. , Luciani Fabio , Bull Rowena A.
Published: September 2024

Numerous studies have shown that viral variants that elude the host immune response may incur a fitness expense, diminishing the survival of the viral strain within the host, and the capacity of the variant to survive future transmission events. However, this generic definition can be further divided into two categories where intrinsic fitness describes the viral fitness without the influence of any immune pressure and effective fitness considers both intrinsic fitness with the influence of host immune pressure. Furthermore, co-occurring mutations outside the epitope regions targeted by the immune response may increase or decrease the likelihood of survival of the variant (known as epistasis). Analysis of viral fitness and epistasis over the non-structural protein regions is lacking for hepatitis C virus (HCV). Here, using a rare cohort of subjects very recently infected with HCV, we build upon our prior investigations by integrating mathematical modelling and experimental data to examine the interplay between the evolving transmitted/founder (T/F) viruses, the adaptive immune response, viral fitness, and co-occurring mutations. We show that viral fitness decreases during the first 90 days post-infection (DPI) associated with the magnitude of CD8+ T-cell responses and the initial level of diversification. Thereafter, viral fitness rebounds in a complex pattern of evolution characterized by multiple sets of co-occurring mutations. Finally, we show that an early and strong CD8+ T-cell response in the absence of neutralizing antibodies (nAbs) imposes a strong selective force on the T/F virus population, enabling the virus to escape and establish chronic infection. Understanding these dynamics is highly relevant for HCV vaccine design and supports a vaccine strategy that induces broad immunity targeting both T and B cell responses.
Single cone photoreceptors experience global image statistics through gaze shifts
Authors: Morimoto Takuma , Wang Luna , Amano Kinjiro , Foster David H. , Nascimento Sérgio M. C.
Published: September 2024

Our visual experience does not merely reflect a static view of the world but is a dynamic consequence of our actions, most notably our continuously shifting gaze. These shifts determine the spectral diet of any individual cone photoreceptor. The aim of this study was to characterize that diet and its relationship to scene adaptation. Gaze shifts were recorded from observers freely viewing scenes outdoors for five minutes. Hyperspectral images of the scenes were also recorded from the observer’s eye position. As a control, gaze shifts were also recorded from observers viewing the images on a computer-controlled display in the laboratory. From the hyperspectral data, spatially local histograms of estimated excitations in long-, medium-, and short-wavelength-sensitive cones were accumulated over time at different retinal locations. A global illuminant change was then introduced to test how well local retinal adaptation discounted its effects. The results suggest that over short periods individual cones tend to experience the statistics of full scenes, with local adaptation compensating for illumination changes almost as well as global adaptation. This compensation may help to maintain our stable local perception of scene colour despite changes in scene illumination.
Nicotine interacts with DNA lesions induced by alpha radiation which may contribute to erroneous repair in human lung epithelial cells
Authors: Boroumand Nadia , Baghdissar Carol , Elihn Karine , Lundholm Lovisa
Published: September 2024

Purpose

Epidemiological studies show that radon and cigarette smoke interact in inducing lung cancer, but the contribution of nicotine in response to alpha radiation emitted by radon is not well understood.

Materials and methods

Bronchial epithelial BEAS-2B cells were either pre-treated with 2 μM nicotine during 16 h, exposed to radiation, or the combination. DNA damage, cellular and chromosomal alterations, oxidative stress as well as inflammatory responses were assessed to investigate the role of nicotine in modulating responses.

Results

Less γH2AX foci were detected at 1 h after alpha radiation exposure (1–2 Gy) in the combination group versus alpha radiation alone, whereas nicotine alone had no effect. Comet assay showed less DNA breaks already just after combined exposure, supported by reduced p-ATM, p-DNA-PK, p-p53 and RAD51 at 1 h, compared to alpha radiation alone. Yet the frequency of translocations was higher in the combination group at 27 h after irradiation. Although nicotine did not alter G2 arrest at 24 h, it assisted in cell cycle progression at 48 h post radiation. A slightly faster recovery was indicated in the combination group based on cell viability kinetics and viable cell counts, and significantly using colony formation assay. Pan-histone acetyl transferase inhibition using PU139 blocked the reduction in p-p53 and γH2AX activation, suggesting a role for nicotine-induced histone acetylation in enabling rapid DNA repair. Nicotine had a modest effect on reactive oxygen species induction, but tended to increase alpha particle-induced pro-inflammatory IL-6 and IL-1β (4 Gy). Interestingly, nicotine did not alter gamma radiation-induced γH2AX foci.

Conclusions

This study provides evidence that nicotine modulates alpha-radiation response by causing a faster but more error-prone repair, as well as rapid recovery, which may allow expansion of cells with genomic instabilities. These results hold implications for estimating radiation risk among nicotine users.
Aging-associated vacuolation of multi-ciliated cells in the distal mouse oviduct reflects unique cell identity and luminal microenvironment
Authors: Harwalkar Keerthana , Yamanaka Nobuko , Pacis Alain S , Zhao Selina , Teng Katie , Pitman Warwick , Taskar Mitaali , Lynn Vera , Thornton Alex Frances , Ford Matthew J , Yamanaka Yojiro
Published: September 2024

The female reproductive organs present with the earliest aging characteristics, such as a decline in fertility and estrous cyclicity. While age-related changes in the ovary are well-documented, it is unclear if any age-associated changes occur in the other female reproductive organs, such as the oviduct/fallopian tube. The recent recognition of the distal end of the fallopian tube as the tissue of origin of high-grade serous tubal ovarian carcinomas (HGSCs), and that its patient demographic is strongly biased to postmenopausal women, motivated us to investigate age-associated changes in this organ.

At the distal end of aged oviducts in mice, we found vacuolated multi-ciliated cells (MCCs) with a severely apically displaced and deformed nucleus. This phenotype was unique to the distal oviduct epithelium –infundibulum (INF) and ampulla (AMP). Ovariectomy did not affect the timeline of MCC vacuolation, suggesting little involvement of ovulation and hormonal regulation. MCC vacuolation was induced in hypoxia or hydroxyurea treatments inin vitroorganotypic culture of all oviduct regions, not limited to the INF/AMP epithelium. This suggests high oxygen demand in MCCs, compared to other cell types, and a uniquely stressed INF/AMP epithelial microenvironmentin vivo. We found that the blood circulation of INF/AMP depended on the ovarian artery, different from the rest of the oviduct epithelium and its circulation declined along with ovarian activities. We conclude that a decline in local blood circulation and distinct cellular identity of the INF/AMP epithelium caused age-associated MCC vacuolation, reflecting its mild, chronically stressed microenvironment.
Adjuvant-dependent impacts on vaccine-induced humoral responses and protection in preclinical models of nasal and genital colonization by pathogenic Neisseria
Authors: Islam Epshita A. , Fegan Jamie E. , Zeppa Joseph J. , Ahn Sang K. , Ng Dixon , Currie Elissa G. , Lam Jessica , Moraes Trevor F. , Gray-Owen Scott D.
Published: September 2024

Neisseria gonorrhoeae, which causes the sexually transmitted infection gonorrhea and N. meningitidis, a leading cause of bacterial meningitis and septicemia, are closely related human-restricted pathogens that inhabit distinct primary mucosal niches. While successful vaccines against invasive meningococcal disease have been available for decades, the rapid rise in antibiotic resistance has led to an urgent need to develop an effective gonococcal vaccine. Several surface antigens are shared among these two pathogens, making cross-species protection an exciting prospect. However, the type of vaccine-mediated immune response required to achieve protection against respiratory versus genital infection remains ill defined. In this study, we utilize well established mouse models of female lower genital tract colonization by N. gonorrhoeae and upper respiratory tract colonization by N. meningitidis to examine the performance of transferrin binding protein B (TbpB) vaccines formulated with immunologically distinct vaccine adjuvants. We demonstrate that vaccine-mediated protection is influenced by the choice of adjuvant, with Th1/2-balanced adjuvants performing optimally against N. gonorrhoeae, and both Th1/2-balanced and Th2-skewing adjuvants leading to a significant reduction in N. meningitidis burden. We further establish a lack of correlation between protection status and the humoral response or bactericidal titre. Combined, this work provides supports the feasibility for a single vaccine formulation to achieve pan-neisserial coverage.
BEGAN: Boltzmann-Reweighted Data Augmentation for Enhanced GAN-Based Molecule Design in Insect Pheromone Receptors
Authors: Dai Jialei , Zhang Yutong , Shi Chen , Liu Yang , Xiu Peng , Wang Yong
Published: September 2024

Identifying molecules that bind strongly to target proteins in rational drug design is crucial. Machine learning techniques, such as generative adversarial networks (GAN), are now essential tools for generating such molecules. In this study, we present an enhanced method for molecule generation using objective-reinforced GANs. Specifically, we introduce BEGAN (Boltzmann-Enhanced GAN), a novel approach that adjusts molecule occurrence frequencies during training based on the Boltzmann distribution exp(−∆U/τ), where ∆U represents the estimated binding free energy derived from docking algorithms and τ is a temperature-related scaling hyperparameter. This Boltzmann reweighting process shifts the generation process towards molecules with higher binding affinities, allowing the GAN to explore molecular spaces with superior binding properties. The reweighting process can also be refined through multiple iterations without altering the overall distribution shape. To validate our approach, we apply it to the design of sex pheromone analogs targeting Spodoptera frugiperda pheromone receptor SfruOR16, illustrating that the Boltzmann reweighting significantly increases the likelihood of generating promising sex pheromone analogs with improved binding affinities to SfruOR16, further supported by atomistic molecular dynamics simulations. Furthermore, we conduct a comprehensive investigation into parameter dependencies and propose a reasonable range for the hyperparameter τ. Our method offers a promising approach for optimizing molecular generation for enhanced protein binding, potentially increasing the efficiency of drug discovery pipelines.
Sex differences in contextual fear expression are associated with altered medial prefrontal cortex activity
Authors: Vazquez Katherine , Parsons Ryan G.
Published: September 2024

Understanding the neural basis of fear expression in rodents has implications for understanding pathological fear responses that characterize posttraumatic stress disorder. Even though posttraumatic stress disorder is more common in females, little is known about the neural circuit interactions supporting fear expression in female rodents. In this study, we were interested in determining whether neural activity associated with the expression of contextual fear differed between males and females within the projections from the medial prefrontal cortex to the ventrolateral periaqueductal gray, and in the medial prefrontal cortex in neurons that do not project to the periaqueductal gray. We infused a viral retrograde tracer into the ventrolateral periaqueductal gray in male and female rats and trained them in a contextual fear conditioning task. The following day rats were re-exposed to the conditioning context and were sacrificed shortly thereafter. Neural activity was measured using EGR1 immunofluorescence. The behavioral results showed that males exhibited higher levels of freezing during the context test than females. Male rats that underwent training and testing showed an increase in the proportion of viral infected cells that express EGR1 in the PL compared to rats that had only received context exposure. Trained female rats were not different than controls, however a direct comparison between sexes was not different. In cells not labeled by the tracer, males showed higher levels of fear-induced EGR1 expression in the prelimbic cortex than females. Conversely, females showed higher levels of EGR1 expression in the infralimbic cortex following testing as compared to males. These results suggest that sex differences in the expression of contextual fear may involve differences in the relative activity levels of the prelimbic and infralimbic cortex.
METTL3 Modulates Radiation-Induced Cardiac Fibrosis via the Akt/mTOR Pathway
Authors: Gu Xiao-song
Published: September 2024

BACKGROUND: Radiation therapy for cancer treatment frequently leads to radiation-induced heart disease (RIHD), characterized as cardiac fibrosis and heart failure. The enzyme METTL3, a key player in RNA methylation, is known to influence various cellular processes, while its specific role and mechanism in RIHD are not well understood. OBJECTIVES: The purpose of this study was to explore the potential mechanism of METTL3 in regulating cardiac fibrosis induced by radiation. METHODS: We constructed an X-ray-modulated RIHD mice models to investigate the role of METTL3 in cardiac fibroblasts. In parallel, METTL3 overexpression and silence were conducted on fibroblasts and mice heart to evaluate pro-fibrotic protein expression, cardiac fibrosis, and heart function. RESULTS: Elevated METTL3 expression was observed in both irradiated cardiac tissues and fibroblasts. Moreover, overexpression of METTL3 in cardiac fibroblasts was associated with increased expression of pro-fibrotic proteins and exacerbated fibrosis, whereas METTL3 silencing attenuated these adverse effects. Likewise, METTL3 knockdown ameliorated cardiac dysfunction and reduced fibrosis. Taken together, METTL3 could induce cardiac fibrosis via activating the Akt/mTOR signaling pathway to promote fibroblast proliferation and myofibroblast differentiation. CONCLUSIONS: METTL3 is a critical of RICD through modulating the Akt/mTOR pathway, hence targeting METTL3 presents a promising therapeutic strategy to mitigate the adverse cardiac effects of radiation therapy in cancer patients.
Stronger premicrosaccadic sensitivity enhancement for dark contrasts in the primate superior colliculus
Authors: Wu Wenbin , Hafed Ziad M.
Published: September 2024

Microsaccades are associated with enhanced visual perception and neural sensitivity right before their onset, and this has implications for interpreting experiments involving the covert allocation of peripheral spatial attention. However, the detailed properties of premicrosaccadic enhancement are not fully known. Here we investigated how such enhancement in the superior colliculus depends on luminance polarity. Rhesus macaque monkeys fixated a small spot while we presented either dark or bright image patches of different contrasts within the recorded neurons’ response fields. Besides replicating premicrosaccadic enhancement of visual sensitivity, we observed stronger enhancement for dark contrasts. This was especially true at moderate contrast levels (such as 10-20%), and it occurred independent of an individual neuron’s preference for either darks or brights. On the other hand, postmicrosaccadic visual sensitivity suppression was similar for either luminance polarity. Our results reveal an intriguing asymmetry in the properties of perimicrosaccadic modulations of superior colliculus visual neural sensitivity.
Effects of fasting on heat-stressed broiler chickens: part I- growth performance, meat quality, gut histomorphological and microbial responses
Authors: Ahmed Tanvir , Hashem Md. Abul , Afrin Afifa , Lahiry Ankon , Rahman Shahina , Bungo Takashi , Das Shubash Chandra
Published: September 2024

The current study aimed to optimize the fasting duration in order to mitigate the detrimental effects of heat stress on broilers raised in hot and humid climatic environments. A total of 500 broiler DOCs were assigned to five distinct treatment groups: Tₒ= Non-fasted controlled temperature (24-26℃) (NF-CT), T1= Non-fasted heat stressed (30-38℃) (NF-HS), T2= 6 hours fasted heat stressed (6-h FHS), T3= 8 hours fasted heat stressed (8-h FHS), and T4= 10 hours fasted heat stressed (10-h FHS). Each treatment was replicated five times, with 20 birds in each replicate group. As expected, the birds in NF-CT group showed significantly better performances for all the growth parameters, although birds who fasted for 8-h under heat stress exerted better growth and FCR in comparison to the other HS groups. Fasting of birds under heat stress significantly showed the lowest mortality. Like the NF-CT group, birds in 8-h FHS achieved significantly higher dressing percentage, breast meat, liver yields, and the lowest abdominal fat. Fasting for 8- and 10-h significantly increased breast meat pH and water holding capacity and thus reduced cooking loss. Fasting also improved the breast meat color quality by increasing redness (a*) and reducing the hue angle values comparable with the NF-CT group. A significantly upward trend in villi height (VH), width (VW) and crypt depth (CD) of gut segments was also observed in the birds of the 8-h FHS group. Total bacterial and coliform counts in cecum contents were reduced significantly with the increase in the fasting period. Benefit-cost analysis showed better profitability in the 8-h FHS group than other HS groups. Taken altogether, it can be concluded that broiler chicken exposed to 8-h fasting period is an effective approach to mitigate heat stress under hot and humid climatic conditions.
Trace Elements in Fish: Assessment of bioaccumulation and associated health risks.
Authors: Naz Saima , Ullah Qudrat , Fouad Dalia , Qadeer Abdul , Lateef Maria , Hassan Muhammad Waqar , Chatha Ahmad Manan Mustafa
Published: September 2024

Industrial and agricultural water run-off are polluting the aquatic ecosystem by depositing different toxic trace elements (TTEs) in riverine system. It has become a global concern impacting not only the well-being of aquatic organisms but human health as well. Current study evaluated the impact of four TTEs (Cadmium (Cd), copper (Cu), lead (Pb), and nickel (Ni)) in three organs (liver, gills, and muscles) of five fish species viz, Rita rita, Sperata sarwari, Wallago attu, Mastacembelus armatus, and Cirrhinus mrigala collected from right and left banks of Punjnad headworks during winter, spring and summer. We investigated accumulation (mg/kg) of these TTEs in fish in addition to the human health risk assessment by estimating exposure hazards, hazardous index (THQ and TTHQ) and metal pollution index (MPI). The obtained results showed that W. attu accumulated significantly more TTEs (p < 0.00) as compared to other fish. Among seasons, summer had significantly more (p < 0.00) accumulation of TTEs than other seasons. Lead (Pb) accumulation was highest across TTEs in fish liver as compared to gills and muscles. Right bank showed higher accumulation (p < 0.00) of all TTEs in all fish species in contrast to the left bank. The human health risk assessment showed that Cd and Pb had higher exposure levels than Cu and Ni. Furthermore, the THQ was in the order of Cd > Pb > Ni > Cu. All fish species had THQ 1 for Cd and Pb and TTHQ > 1 for all fish. MPI index showed moderate to high level of TTE contamination if all fish species. The study concluded that right bank has higher metal accumulation than left bank. However, fish consumption from both of the study site was not safe for human consumption.
Preventing surgery induced immune suppression and metastases by inhibiting PI3K-gamma signalling in Myeloid-Derived Suppressor Cells
Authors: Angka Leonard , Tennakoon Gayashan , Cook David P. , Martel Andre B. , Market Marisa , de Souza Christiano Tanese , Cummins Emma , Samudio Ismael , Kekre Natasha , Ardolino Michele , Vanderhyden Barbara , Kennedy Michael A. , Auer Rebecca C.
Published: September 2024

Myeloid derived suppressor cells (MDSCs) have a dominating presence in the postoperative period and mediate the suppression of Natural Killer (NK) cells and promotion of cancer metastases after surgery. However, their functional characteristics and effect on cellular immunity after surgery have not been comprehensively investigated. Here, we characterize the expansion of surgery-induced (sx) MDSCs via multi-colour flow cytometry, single-cell RNA sequencing, and functionalex vivoNK cell suppression assays. We then screened a small molecule library using our sx-MDSC:NK cell suppression assay to identify compounds that could inhibit sx-MDSCs. These studies provide evidence that PI3K-γ signalling is upregulated in sx-MDSCs and blockade with PI3K-γ specific inhibitors attenuates NK cell suppression in humans and mice and reduces postoperative metastases in murine models. Upregulated PI3K-γ in sx-MDSCs is a potential pathway amenable to therapeutic targeting in the postoperative period.

One Sentence Summary

The suppressive mechanisms of surgery-induced myeloid derived suppressor cells use PI3K signalling and are amenable to PI3K-gamma specific inhibitors.
Landscape-wide metabarcoding of the invasive bumblebee(Bombus terrestris)shows interactions among the gut microbiome and pollenbiome
Authors: Haque Sabrina , Gamage Hasinika KAH , Kardum Hjort Cecilia , Ponton Fleur , Encinas-Viso Francisco , Paulsen Ian T , Dudaniec Rachael Y
Published: September 2024

Many species of social insects introduced to regions beyond their native ranges have become highly invasive. The introduction of the eusocial European buff-tailed bumblebee,Bombus terrestris, to the island of Tasmania (Australia) ∼30 years ago is of concern due to its ecological impacts and its potential to spill over pathogens to native bees or commercially important honeybees. The health ofB. terrestrisis intricately connected with its gut microbiome and diet; however, environmental variables may also interact, particularly during invasion into novel environments. Using landscape-wide sampling and a metabarcoding approach to characterize the gut bacteria (16S rRNA) and diet composition from foraged pollen (ITS2: floristic diversity of pollen baskets), this study investigates how the gut microbiota ofB. terrestrisworkers is affected by nutritional diversity (‘pollenbiome’) and environmental variation across diverse landscapes of its invasive range in Tasmania. Gut bacterial community composition and diversity were significantly predicted by site annual precipitation and percentage of pasture. Further, a positive interaction between site annual precipitation and site annual temperature significantly predicted gut bacterial diversity. The interaction effect of pollen diversity and average summer wind velocity was also significantly and positively related to gut bacterial diversity. Following comparison of Akaike information criterion (AIC) and sum of weights, the percentage of pasture was identified as the most strongly weighted variable, which, along with pollen diversity, had a negative impact on gut bacterial diversity. These insights help to uncover how environmental interactions affect the gut microbiome ofB. terrestrisin an invaded landscape with novel nutritional resources. This knowledge contributes to understanding the factors that predict the spread and persistence of invasive bumblebees.
Meningococcal vaccine Bexsero elicits a robust cellular immune response that targets but is not consistently protective against Neisseria gonorrhoeae during murine vaginal infection
Authors: Zeppa Joseph J. , Fegan Jamie E. , Maiello Pauline , Islam Epshita A. , Lee Isaac S. , Pham Christine , Caruso Laura-Lee , Gray-Owen Scott D.
Published: September 2024

Retrospective epidemiological studies suggest that the licensed serogroup B meningococcal vaccine 4CMenB (Bexsero) provides some protection against the closely related pathogen Neisseria gonorrhoeae in humans. This result has been replicated in murine models of gonococcal colonization, with a gonococci-reactive humoral response and more rapid clearance of vaginal infection. However, immunization with Bexsero consistently elicits a robust humoral response but does not protect all individuals, so the correlates of protection remain undefined. Herein, we exploit the fact that Bexsero promotes clearance in only a subset of immunized mice to perform a broad analysis of the adaptive response in animals that are or are not protected. We observe that Bexsero vaccination induces high levels of anti-neisserial antibodies in both serum and the vaginal lumen, and a robust cellular response highlighted by an increase in both conventional naive and memory populations as well as unconventional lymphocyte subsets. Multiplex and flow cytometry results show that Bexsero vaccination generates a robust, multi-faceted cytokine response that spans numerous T cell subsets (TH1, TH2, Treg and TH17 responses) and that non-T non-B lymphocytes play an important role in this response, as indicated by an unbiased principal component analysis. Together, this work provides the first comprehensive analysis of the robust humoral and complex cellular response to Bexsero so as to reveal the effector mechanisms that may contribute to immunity against vaginal gonococcal infection.
The origins and functional significance of bivalve genome diversity
Authors: Liu Shikai , Shi Chenyu , Chen Chenguang , Tan Ying , Tian Yuan , Macqueen Daniel , Li Qi
Published: September 2024

Bivalves are famed for exhibiting vast genetic diversity of poorly understood origins and functional significance. Within bivalves, oysters are an ancient group showing remarkable genetic and phenotypic variability alongside extensive adaptability, serving as an ideal system to understand the origins and functional significance of genomic diversity. Here, we reveal the divergent genomic landscape of Crassostrea oysters, characterized by a history of genome size reduction associated with transposable elements (TEs). By constructing a haplotype-resolved genome for Kumamoto oyster C. sikamea, we demonstrate the widespread presence of haplotype divergent sequences (HDS); genomic regions present in just one haplotype. Combined with population resequencing, we define the role of genomic divergence driven by TEs in shaping oyster genetic diversity. Comparisons of haplotype-resolved genomes across four bivalve orders reveal that while extensive HDS is common, its origins may differ markedly. We show that HDS are a hotspot of genetic innovation, harboring rapidly evolving genes of various evolutionary ages, while also strongly influencing gene expression phenotypes. A widespread lack of allele-specific expression shared among oyster individuals indicates that haplotype polymorphism provides a key source of expression variation, promoting phenotypic plasticity and adaptation. These findings advance understanding on the origins of genomic diversity and its role in adaptive evolution.
Mind the polar sun: Solar radiations trigger frequent heat stress in breeding king penguins, despite relatively cool air temperatures.
Authors: Noiret Aude , Lewden Agnes , Lemonnier Camille , Bocquet Celine , Montblanc Marine , Bertile Fabrice , Hoareau Marine , Marcon Elsa , Robin Jean-Patrice , Viblanc Vincent A , Stier Antoine
Published: September 2024

Polar and sub-polar animals evolved to thrive in cold climates and may thus be particularly vulnerable to the rising temperatures associated with climate change. Polar and sub-polar penguins may be especially vulnerable due to their dual habitat, alternating between foraging in cold waters and breeding/moulting on an increasingly warm land. Here, we characterized heat stress occurrence in breeding king penguins through behavioural observations and subcutaneous body temperature measurements. We show that heat stress is frequent (> 20% of observations at mid-day) in king penguins breeding in the sub-Antarctic region, and that thermoregulatory mechanisms appear insufficient to maintain stable sub-cutaneous temperature. Air temperature alone was a poor predictor of heat stress occurrence, while the combination of high solar radiations, low wind speed and high temperatures was its best predictor. Importantly, reproductive failure occurred on days warmer than average, suggesting potential significant sublethal effects of heat stress being likely to affect population dynamics.
Novae: a graph-based foundation model for spatial transcriptomics data
Authors: Blampey Quentin , Benkirane Hakim , Bercovici Nadège , André Fabrice , Cournède Paul-Henry
Published: September 2024

Spatial transcriptomics is advancing molecular biology by providing high-resolution insights into gene expression within the spatial context of tissues. This context is essential for identifying spatial domains, enabling the understanding of micro-environment organizations and their implications for tissue function and disease progression. To improve current model limitations on multiple slides, we have designed Novae (https://github.com/MICS-Lab/novae), a graph-based foundation model that extracts representations of cells within their spatial contexts. Our model was trained on a large dataset of nearly 30 million cells across 18 tissues, allowing Novae to perform zero-shot domain inference across multiple gene panels, tissues, and technologies. Unlike other models, it also natively corrects batch effects and constructs a nested hierarchy of spatial domains. Furthermore, Novae supports various downstream tasks, including spatially variable gene or pathway analysis and spatial domain trajectory analysis. Overall, Novae provides a robust and versatile tool for advancing spatial transcriptomics and its applications in biomedical research.
Programmed cell death and stomatal density regulate anther opening in response to ambient humidity
Authors: Kampova Anna , Nowack Moritz K , Fendrych Matyas , Vosolsobe Stanislav
Published: September 2024

Anther dehiscence is the process that facilitates pollen release from mature anthers in flowering plants. Despite its crucial importance to reproduction, the underlying molecular regulations and the integration of environmental information remain poorly understood. Using controlled humidity treatments of Arabidopsis thaliana flowers, we show here that high humidity prevents anthers from opening. Lower and higher stomatal densities correlate with slower and faster dehiscence dynamics, respectively, suggesting that controlled transpiration regulates anther opening. Furthermore, analyses of subcellular markers revealed that specific anther tissues undergo a spatially controlled programmed cell death (PCD) process as anthers open. Notably, genetic inhibition of PCD networks delays, whereas precocious PCD induction promotes, anther dehiscence. Our data shed new light on the interplay between ambient humidity, controlled transpiration, and PCD processes in regulating timely pollen release in the model plant Arabidopsis.
Additive, substitutable, and antagonistic prey responses to feral and native predator combinations
Authors: St. Juliana Justin R , Bleicher Sonny Shlomo , Mukherjee Shomen , Sundararaj Vijayan , Brown Joel S , Kotelr Burt P
Published: September 2024

Question: Do combinations of human commensal mesocarnivores with native predators alter wild prey behavior in additive or substitutable responses? Hypothesis: Feral mesocarnivores will have a greater impact on prey energy acquisition than native predators. Organisms: Allenbys gerbils (Gerbillus andersoni allebyi) and Greater Egyptian Gerbils (Gerbillus pyramidum) as prey and feral dogs (Canis lupus familliaris), feral cats (Felis catus), barn owls (Tyto alba) horned vipers (Cerastes gasperetti) as predators. Field Site: A 17x34 meter semi natural arena mimicking sand dune environments in Sde Boker, Israel. Methods: Gerbil perceived risk was measured using optimal patch-use, predator exposures were conducted with guided (leashed) predators on an hourly basis throughout the night. Viper musk was used in lieu of live vipers. On nights with combined predators, two predators were exposed, rotating between the predators every hour. Conclusions: Human-commensal predators induced a stronger foraging aversion from the gerbils than the owl. When combining predators, the gerbils significantly decrease their foraging only when a predator perceived to be of greater risk is introduced. This was exemplified by a significantly higher GUD for dog and cat combination over dog alone, but insignificant increase, compared to the cat alone. The impact of human commensals, especially feral cats, appears to outweigh the ecological impacts of native predators.
Virally encoded single-chain antibody fragments targeting alpha-synuclein protect against motor impairments and neuropathology in a mouse model of synucleinopathy
Authors: Castonguay Anne-Marie , Morin Beatrice , Parent Martin , Durcan Thomas M , Luo Wen , Shlaifer Irina , Julien Jean-Pierre , Gravel Claude , Levesque Martin
Published: September 2024

Parkinson's disease (PD) is a neurodegenerative disorder mainly characterized by the loss of dopaminergic neurons from the substantia nigra. Affected neurons exhibit intracellular aggregates primarily composed of misfolded and phosphorylated alpha-synuclein (aSyn). In pathological conditions, this presynaptic protein has been shown to be transmitted from cell to cell in a prion-like manner, which contributes to the progression of the disease. Single-chain variable fragments (scFvs) are small polypeptides derived from the binding domains of antibodies that are less immunogenic and have better tissue penetration compared to full antibodies. In this work, we aimed to demonstrate the potential of extracellular scFvs to slow down the propagation of pathological aSyn in an in vivo model of synucleinopathy. We generated scFvs that target aSyn, and tested two of them in a PD mouse model consisting of transgenic M83 mice injected with human aSyn pre-formed fibrils (PFFs). The sequence encoding each anti-aSyn scFv was cloned in a self-complementary AAV2 viral vector, and purified particles were administered intravenously. CNS expression of either scFv protected against the development of paralysis and limb weakness, in addition to significantly reducing pathologic aggregates of phosphorylated aSyn in the brain. Moreover, in vitro results in human iPSCs-derived dopaminergic neurons suggest that the scFvs can mitigate aSyn spreading by preventing its internalization. Overall, our findings demonstrate that single-chain antibody fragments exhibit strong therapeutic potential in a preclinical mouse model. Thus, our minimally invasive, gene-mediated immunotherapy approach has the potential to serve as an effective treatment for halting the progression of Lewy body diseases.
DNA Damage Response Deficiency Enhances Neuroblastoma Progression and Sensitivity to Combination PARP and ATR Inhibition
Authors: Hayes Madeline N. , Cohen-Gogo Sarah , Kee Lynn , Weiss Alex , Layeghifard Mehdi , Ladumor Yagnesh , Valencia-Sama Ivette , Rajaselvam Anisha , Kaplan David R. , Villani Anita , Shlien Adam , Morgenstern Daniel A. , Irwin Meredith S.
Published: September 2024

Next generation sequencing of neuroblastoma (NB) tumors have revealed frequent somatic and germline genetic alterations in genes encoding proteins involved in DNA damage response (DDR) pathways. Despite being well-studied in many adult cancers, roles for DDR disruption in pediatric solid tumors remains poorly understood. To address this, patient-relevant loss-of-function mutations in DDR pathway components including Brca2, Atm, and Palb2 were incorporated into an established zebrafish MYCN transgenic model (Tg(dbh:EGFP-MYCN)). These mutations were found to enhance NB formation and metastasisin vivo, and result in upregulation of proliferation, cell cycle checkpoint and DNA damage repair transcriptional signatures, revealing potential molecular vulnerabilities in DDR-deficient NB. Zebrafish DDR-deficient NB and human NB cells with DDR protein knock-down were sensitive to the poly(ADP-ribose)-polymerase (PARP) inhibitor olaparib, and this effect was further enhanced by inhibition of the ataxia telangiectasia and rad3 related (ATR) kinase. Altogether, our data supports a functional role for DDR-deficiency in NBin vivoand therapeutic potential for combination PARP + ATR inhibition in NB patients with alterations in DDR genes.

Significance

This work provides the firstin vivoevidence supporting a functional role for DDR-deficiency in NB by demonstrating that alterations in certain DDR pathway genes promote NB formation and metastasis. NGS and pre-clinical drug testing also provides rationale for PARP + ATR inhibitor therapy combinations for patients with NB and pathogenic DDR pathway alterations.
Barcode activity in a recurrent network model of the hippocampus enables efficient memory binding
Authors: Fang Ching , Lindsey Jack , Abbott L.F. , Aronov Dmitriy , Chettih Selmaan
Published: September 2024

Forming an episodic memory requires binding together disparate elements that co-occur in a single experience. One model of this process is that neurons representing different components of a memory bind to an “index” — a subset of neurons unique to that memory. Evidence for this model has recently been found in chickadees, which use hippocampal memory to store and recall locations of cached food. Chickadee hippocampus produces sparse, high-dimensional patterns (“barcodes”) that uniquely specify each caching event. Unexpectedly, the same neurons that participate in barcodes also exhibit conventional place tuning. It is unknown how barcode activity is generated, and what role it plays in memory formation and retrieval. It is also unclear how a memory index (e.g. barcodes) could function in the same neural population that represents memory content (e.g. place). Here, we design a biologically plausible model that generates barcodes and uses them to bind experiential content. Our model generates barcodes from place inputs through the chaotic dynamics of a recurrent neural network and uses Hebbian plasticity to store barcodes as attractor states. The model matches experimental observations that memory indices (barcodes) and content signals (place tuning) are randomly intermixed in the activity of single neurons. We demonstrate that barcodes reduce memory interference between correlated experiences. We also show that place tuning plays a complementary role to barcodes, enabling flexible, contextually-appropriate memory retrieval. Finally, our model is compatible with previous models of the hippocampus as generating a predictive map. Distinct predictive and indexing functions of the network are achieved via an adjustment of global recurrent gain. Our results suggest how the hippocampus may use barcodes to resolve fundamental tensions between memory specificity (pattern separation) and flexible recall (pattern completion) in general memory systems.