bluuebunny/crossref_metadata_2025 huggingface dataset:
Open Abdominal Management for Damage Control in Liver Transplantation: A Single-center Experience
Authors: Hara Takanobu , Soyama Akihiko , Matsushima Hajime , Imamura Hajime , Yamashita Mampei , Ishizaki Hironori , Yano Rintaro , Matsumoto Sojiro , Ichinomiya Taiga , Higashijima Ushio , Sekino Motohiro , Fukumoto Masayuki , Migita Kazushige , Kawaguchi Yuta , Adachi Tomohiko , Hara Tetsuya , Eguchi Susumu
Published: August 2024

Background.

Patients undergoing liver transplantation are in a state of coagulopathy before surgery because of liver failure. Intraoperative hemorrhage, massive transfusions, and post–reperfusion syndrome further contribute to coagulopathy, acidosis, and hypothermia. In such situations, temporary cessation of surgery with open abdominal management and resuscitation in the intensive care unit (ICU), which is commonly used as a damage control strategy in trauma care, may be effective. We assessed the outcomes of open abdominal management in liver transplantation and the corresponding complication rates.

Methods.

We retrospectively reviewed the outcomes of patients undergoing open abdominal management among 250 consecutive liver transplantation cases performed at our institution from 2009 to 2022.

Results.

Open abdominal management was indicated in 16 patients. The open abdomen management group had higher Model for End-stage Liver Disease scores (24 versus 16, P < 0.01), a higher incidence of previous upper abdominal surgery (50% versus 18%, P < 0.01), more pretransplant ICU treatment (31% versus 10%, P = 0.03), and more renal replacement therapy (38% versus 12%, P = 0.01). At the time of the damage control decision, coagulopathy (81%), acidosis (38%), hypothermia (31%), and a high-dose noradrenaline requirement (75%) were observed. The abdominal wall was closed in the second operation in 75% of patients, in the third operation in 19%, and in the fourth operation in 6%. Postoperatively, the frequency of early allograft dysfunction was predominantly higher in the open abdominal management group (69%), whereas the frequency of vascular complications and intra-abdominal infection was the same as in other patients.

Conclusions.

Open abdominal management can be a crucial option in cases of complex liver transplant complicated by conditions such as hypothermia, acidosis, coagulopathy, and hemodynamic instability. Damage control management minimizes deterioration of the patient’s condition during surgery, allowing completion of the planned procedure after stabilizing the patient’s overall condition in the ICU.
The diversity of clinical Mycobacterium abscessus isolates in morphology, glycopeptidolipids and infection rates in a macrophage model
Authors: Pichler Virginia , Dalkilic Lara , Shoaib Ghazaleh , Shapira Tirosh , Rankine-Wilson Leah , Boudehen Yves-Marie , Chao Joseph D. , Sexton Danielle , Prieto Miguel , Quon Bradley S. , Tocheva Elitza I. , Kremer Laurent , Hsiao William , Av-Gay Yossef
Published: August 2024

Introduction.
Mycobacterium abscessus (MABS) is a pathogenic bacterium that can cause severe lung infections, particularly in individuals with cystic fibrosis. MABS colonies can exhibit either a smooth (S) or rough (R) morphotype, influenced by the presence or absence of glycopeptidolipids (GPLs) on their surface, respectively. Despite the clinical significance of these morphotypes, the relationship between GPL levels, morphotype and the pathogenesis of MABS infections remains poorly understood.

Gap statement. The mechanisms and implications of GPL production and morphotypes in clinical MABS infections are unclear. There is a gap in understanding their correlation with infectivity and pathogenicity, particularly in patients with underlying lung disease.

Aim. This study aimed to investigate the correlation between MABS morphology, GPL and infectivity by analysing strains from cystic fibrosis patients’ sputum samples.

Methodology. MABS was isolated from patient sputum samples and categorized by morphotype, GPL profile and replication rate in macrophages. A high-content ex vivo infection model using THP-1 cells assessed the infectivity of both clinical and laboratory strains.

Results. Our findings revealed that around 50 % of isolates displayed mixed morphologies. GPL analysis confirmed a consistent relationship between GPL content and morphotype that was only found in smooth isolates. Across morphotype groups, no differences were observed in vitro, yet clinical R strains were observed to replicate at higher levels in the THP-1 infection model. Moreover, the proportion of infected macrophages was notably higher among clinical R strains compared to their S counterparts at 72 h post-infection. Clinical variants also infected THP-1 cells at significantly higher rates compared to laboratory strains, highlighting the limited translatability of lab strain infection data to clinical contexts.

Conclusion. Our study confirmed the general correlation between morphotype and GPL levels in smooth strains yet unveiled more variability within morphotype groups than previously recognized, particularly during intracellular infection. As the R morphotype is the highest clinical concern, these findings contribute to the expanding knowledge base surrounding MABS infections, offering insights that can steer diagnostic methodologies and treatment approaches.
An instantaneous voice synthesis neuroprosthesis
Authors: Wairagkar Maitreyee , Card Nicholas S. , Singer-Clark Tyler , Hou Xianda , Iacobacci Carrina , Hochberg Leigh R. , Brandman David M. , Stavisky Sergey D.
Published: August 2024

Brain computer interfaces (BCIs) have the potential to restore communication to people who have lost the ability to speak due to neurological disease or injury. BCIs have been used to translate the neural correlates of attempted speech into text1–3. However, text communication fails to capture the nuances of human speech such as prosody, intonation and immediately hearing one’s own voice. Here, we demonstrate a “brain-to-voice” neuroprosthesis that instantaneously synthesizes voice with closed-loop audio feedback by decoding neural activity from 256 microelectrodes implanted into the ventral precentral gyrus of a man with amyotrophic lateral sclerosis and severe dysarthria. We overcame the challenge of lacking ground-truth speech for training the neural decoder and were able to accurately synthesize his voice. Along with phonemic content, we were also able to decode paralinguistic features from intracortical activity, enabling the participant to modulate his BCI-synthesized voice in real-time to change intonation, emphasize words, and sing short melodies. These results demonstrate the feasibility of enabling people with paralysis to speak intelligibly and expressively through a BCI.
Extracellular Vesicles heterogeneity through the lens of multiomics
Authors: Silva Taylon F , Hutchins Elizabeth , Zhao Wenyan , Ciani Yari , Kim Minhyung , Mariscal Javier , Qiu Zhuyu , Kittel Agnes , Zhou Bo , Wang Yang , Hall Megan , Galasso Francesca , Reiman Rebecca , Freeman Michael R , Parker Sarah , Van Eyk Jennifer , Yang Wei , Posadas Edwin , Guarnerio Jlnenia , Nolan John , Thery Clotilde , Zijlstra Andries , Stott Shannon , You Sungyong , Demichelis Francesca , Boutros Paul , Van Keuren-Jensen Kendall , Di Vizio Dolores
Published: August 2024

Extracellular vesicles (EVs) are heterogenous in size, biogenesis, cargo and function. Beside small EVs, aggressive tumor cells release a population of particularly large EVs, namely large oncosomes (LO). This study provides the first resource of label-free quantitative proteomics of LO and small EVs obtained from distinct cancer cell types (prostate, breast, and glioma). This dataset was integrated with a SWATH Proteomic assay on LO, rigorously isolated from the plasma of patients with metastatic prostate cancer (PC). Proteins enriched in LO, which were identified also at the RNA level, and found in plasma LO significantly correlated with PC progression. Single EV RNA-Seq of the PC cell-derived LO confirmed some of the main findings from the bulk RNA-Seq, providing first evidence that single cell technologies can be successfully applied to EVs. This multiomics resource of cancer EVs can be leveraged for developing a multi-analyte approach for liquid biopsy.
Disentangling the drivers of heterogeneity in SARS-CoV-2 transmission from data on viral load and daily contact rates
Authors: Quilty Billy J , Chapman Lloyd AC , Munday James D , Wong Kerry LM , Gimma Amy , Pickering Suzanne , Neil Stuart JD , Galão Rui Pedro , Edmunds W John , Jarvis Christopher I , Kucharski Adam J
Published: August 2024

SARS-CoV-2 spreads predominantly through superspreading, with a minority of individuals responsible for the majority of transmission, though the drivers of this heterogeneity are unclear. Here, we assess the contribution of variation in viral load and daily contact rates to this heterogeneity by combining viral load and contact survey data in a mathematical model to estimate the secondary infection distribution. Using data from the BBC Pandemic and CoMix contact surveys, we estimate the basic reproduction number (R0= 2.2, 95% CI 2.1-2.2) from first principles and the secondary infection distribution throughout the pandemic in the UK in 2020, and the effectiveness of frequent and pre-event rapid testing for reducing superspreading events. We find that individual heterogeneity in contacts – rather than individual heterogeneity in shedding – drives observed heterogeneity in the secondary infection distribution. Our results suggest that regular testing every 3 days, or pre-event testing with a minimum event size of 10, could reduce the mean reproduction number below 1 with moderate to high levels of uptake (60-80%) for pre-pandemic contact levels. This work demonstrates the potential for using viral load and contact data to predict heterogeneity in transmission and the effectiveness of rapid testing strategies for curbing transmission in future pandemics.
Exploring ancestry inference of the Middle East
Authors: Herrick Noah , Ghemrawi Mirna , Singh Sylvia , Mahfouz Rami , Walsh Susan
Published: August 2024

The capability to infer biogeographic ancestry with curated panels of ancestry informative markers (AIMs) is a critical component to DNA intelligence. There are many AIM panels that resolve population differentiation at a continental level. Of late, several studies have directed marker discovery to the Middle East because of the difficulties for AIM panels to resolve this region amongst populations in Eurasia. The AIM discovery process has remained largely unchanged, except for the most recent additions of whole-genome sequence (WGS) data repositories which now include Middle Eastern individuals. Here, the latest WGS data from 1000 Genomes Project and Human Genome Diversity Project was paired with novel Middle Eastern population data from Lebanon for AIMs discovery. An unbiased genetic clustering approach was employed for selecting population clusters for allelic frequency comparisons. Two candidate AIMs were reported, compared, and evaluated together with the autosomal AIMs from the VISAGE Enhanced Tool. These comparisons involved a validation dataset from Middle Eastern WGS data published by the Wellcome Sanger Institute and resulted in slight gains of Middle Eastern ancestry proportions for several Middle Eastern samples with varying levels of co-ancestries. The validation samples also underwent an unsupervised worldwide ADMIXTURE analysis alongside previously mentioned WGS datasets using nearly two million markers (r2 < 0.1) to establish a ‘ground truth’ population membership. Lastly, a novel application of the deep learning dimensional reduction algorithm ‘popVAE’ is provided as an open-source web tool to illustrate the AIM panels variance among these population clusters within two dimensions for easy global ancestry visualization in addition to providing a closest population membership metric.
Investigating Polyreactivity of CD4+ T Cells to the Intestinal Microbiota
Authors: Saadawi Ahmed , Mair Florian , Rosenwald Esther , Hoces Daniel , Slack Emma , Kopf Manfred
Published: August 2024

The symbiotic relationship between host and microbiota plays a pivotal role in training and development of the host’s innate and adaptive immune systems. Antigen-specific recognition of microbiota by T cells enforces tolerance at homeostasis. Conversely, dysbiosis—characterized by alterations in microbiota diversity and abundance—leads to imbalanced T cell responses and triggering of inflammatory and autoimmune diseases. Despite their significance, the identities of immunogenic microbial antigens are still largely enigmatic. Here, we leveraged an in-house developed antigen screening platform, the MCR system1, to delineate CD4+ T cell reactivity againstAkkermansia muciniphila(AKK) andBacteroides thetaiotaomicron(BT), —two prominent members of the gut microbiota. T-cell hybridomas reactive to AKK and BT bacteria showed polyreactivity to select microbiota-derived peptides in MCR co-cultures. We discovered 13 novel antigenic epitopes from AKK and 14 from BT. Steady-state T cells recognized these epitopes in an MHC-restricted fashion. Ex vivo stimulation of peptide-specific T cells revealed induction of type 1 and type 17 immune responses, albeit with non-overlapping specificities, contrary to MCR system results. Our findings further demonstrated that most identified epitopes are broadly conserved within the given phylum and originate from both membrane and intracellular proteins. Our work showcases the potential of the MCR system for identifying immunogenic microbial epitopes, providing a valuable resource. Additionally, it indicates the existence of mucosal T cells with a tropism toward broadly conserved bacterial epitopes. Overall, our study forms the basis for decoding antigen specificity in immune system-bacterial interactions, with applications in understanding both microbiome and pathogenic bacterial immunity.
Personalized whole-brain activity patterns predict human corticospinal tract activation in real-time
Authors: Khatri Uttara U , Pulliam Kristen , Manesiya Muskan , Cortez Melanie Vieyra , Millán José del R. , Hussain Sara J
Published: August 2024

BACKGROUND

Transcranial magnetic stimulation (TMS) interventions could feasibly treat stroke-related motor impairments, but their effects are highly variable. Brain state-dependent TMS approaches are a promising solution to this problem, but inter-individual variation in lesion location and oscillatory dynamics can make translating them to the poststroke brain challenging. Personalized brain state-dependent approaches specifically designed to address these challenges are therefore needed.

METHODS

As a first step towards this goal, we tested a novel machine learning-based EEG-TMS system that identifies personalized brain activity patterns reflecting strong and weak corticospinal tract (CST) output (strong and weak CST states) in healthy adults in real-time. Participants completed a single-session study that included the acquisition of a TMS-EEG-EMG training dataset, personalized classifier training, and real-time EEG-informed single pulse TMS during classifier-predicted personalized CST states.

RESULTS

MEP amplitudes elicited in real-time during personalized strong CST states were significantly larger than those elicited during personalized weak and random CST states. MEP amplitudes elicited in real-time during personalized strong CST states were also significantly less variable than those elicited during personalized weak CST states. Personalized CST states lasted for ∼1-2 seconds at a time and ∼1 second elapsed between consecutive similar states. Individual participants exhibited unique differences in spectro-spatial EEG patterns between personalized strong and weak CST states.

CONCLUSION

Our results show for the first time that personalized whole-brain EEG activity patterns predict CST activation in real-time in healthy humans. These findings represent a pivotal step towards using personalized brain state-dependent TMS interventions to promote poststroke CST function.
Bio-macromolecular assembly machine for human limb lengthening
Authors: Xie Chang , Li Wenyue , Yao Xudong , Wu Boxuan , Fang Jinghua , Mao Renwei , Yan Yiyang , Meng Hongxu , Wu Yan , Zhang Xianzhu , Duan Wangping , Dai Xuesong , Wang Xiaozhao , Hongwei Ouyang
Published: August 2024

Growth plate (GP) is the critical cartilaginous structure for longitudinal bone growth. Herein, employing high-resolution analytical techniques, we explore the intricate mechanisms that govern the polarized mineralization patterns within GP. The GP-epiphysis interface displays a sharp transition in tissue modulus, acting as a "protective shell" for the underlying GP, whereas the GP-metaphysis interface exhibits a gradual modulus increase, enabling efficient load redistribution to metaphysis. The unique mechanical environments at these two interfaces contribute to polarized CaP mineralization patterns, which are regulated by a complex protein-based molecular machinery. The mineralization inhibitors SPP1 and AHSG enriched at the GP-epiphysis interface could act as a line of defence against mineralization. When these two proteins coexisted with the mineralization-promoting ENPP1 and ALPL at the GP-metaphysis interface, a sequential event of precise nucleation and programmable assembly of CaP minerals occur, forming "mineralization waves" to guide bone elongation. By replicating such specific macromolecular environment at GP-metaphysis interface, a hypertable amorphous calcium phosphate (ACP) phase is well-retained in vitro, demonstrating the possibility for precise and gentle control of ACP-hydroxyapatite (HAp) transformation under physiological conditions. Our study defines a novel concept of "mineralization waves" that govern the velocity and amplitude of GP-guided mineralization process.
Headwinds to Understanding Stress Response Physiology: A Systematic Review Reveals Mismatch between Real and Simulated Marine Heatwaves
Authors: Martell Harmony A. , Donner Simon D.
Published: August 2024

Laboratory experiments have long been used to guide predictions of organismal stress in response to our rapidly changing climate. However, the ability to simulate real world conditions in the laboratory can be a major barrier to prediction accuracy, creating obstacles to efforts informing ecosystem conservation and management. Capitalizing on an extensive experimental literature of coral bleaching physiology, we performed a systematic review of the literature and assembled a database to identify the methods being used to measure coral bleaching in heating experiments and assess how closely heating experiments resembled marine heatwaves (MHWs) on coral reefs. Observations of the maximum photochemical yield of Photosystem II (FV/FM), though not a direct measure of bleaching, vastly outnumbered Symbiodiniaceae density and chlorophyll (μg cm-2, pg cell-1) observations in the available literature, indicating the widespread misuse ofFV/FMas a proxy for coral bleaching. Laboratory studies in our database used significantly higher maximum temperatures, degree heating times (∼ 1.7 ×) and heating rates (∼ 7.3 ×), and significantly shorter durations (∼ 1.5 ×), than MHWs on coral reefs. We then asked whether exposure differences between lab and reef altered the relationship between coral bleaching and heating metrics using the example of hormesis, the biphasic dose response wherein low to moderate doses elicit some benefit, while high doses are deleterious. We fit curves on the data both with and without ecologically relevant heating metrics and found hormetic curves in some response variables were altered with the exclusion of exposures that fell outside of the bounds of MHWs on coral reefs. Differences between lab exposures and real-world MHWs were large enough to alter the relationships, indicating a high likelihood of prediction error. We recommend laboratory-based studies of coral bleaching use ecologically relevant exposures to improve our predictions of the coral physiological response to our rapidly warming oceans.
More similarity than difference: comparison of within- and between-sex variance in early adolescent brain structure
Authors: Torgerson Carinna , Bottenhorn Katherine L , Ahmadi Hedyeh , Choupan Jeiran , Herting Megan M
Published: August 2024

Adolescent neuroimaging studies of sex differences in the human brain predominantly examine mean differences between males and females. This focus on between-groups differences without probing relative distributions and similarities may contribute to both conflation and overestimation of sex differences and sexual dimorphism in the developing human brain. We aimed to characterize the variance in brain macro- and micro-structure in early adolescence as it pertains to sex at birth using a large sample of 9-11 year-olds from the Adolescent Brain Cognitive Development (ABCD) Study (N=7,723). Specifically, for global and regional estimates of gray and white matter volume, cortical thickness, and white matter microstructure (i.e., fractional anisotropy and mean diffusivity), we examined: within- and between-sex variance, overlap between male and female distributions, inhomogeneity of variance via the Fligner-Killeen test, and an analysis of similarities (ANOSIM). For completeness, we examined these sex differences using both uncorrected (raw) brain estimates and residualized brain estimates after using mixed-effects modeling to account for age, pubertal development, socioeconomic status, race, ethnicity, MRI scanner manufacturer, and total brain volume, where applicable. The overlap between male and female distributions was universally greater than the difference (overlap coefficient range: 0.585 - 0.985) and the ratio of within-sex and between-sex differences was similar (ANOSIM R range: -0.001 - 0.117). All cortical and subcortical volumes showed significant inhomogeneity of variance, whereas a minority of brain regions showed significant sex differences in variance for cortical thickness, white matter volume, fractional anisotropy, and mean diffusivity. Inhomogeneity of variance was reduced after accounting for other sources of variance. Overlap coefficients were larger and ANOSIM R values were smaller for residualized outcomes, indicating greater within- and smaller between-sex differences once accounting for other covariates. Reported sex differences in early adolescent human brain structure may be driven by disparities in variance, rather than binary, sex-based phenotypes. Contrary to the popular view of the brain as sexually dimorphic, we found more similarity than difference between sexes in all global and regional measurements of brain structure examined. This study builds upon previous findings illustrating the importance of considering variance when examining sex differences in brain structure.
Robustness and variability inCaenorhabditis elegansdauer gene expression
Authors: Corchado Johnny Cruz , Godthi Abhishiktha , Selvarasu Kavinila , Prahlad Veena
Published: August 2024

Both plasticity and robustness are pervasive features of developmental programs. The dauer inCaenorhabditis elegansis an arrested, hypometabolic alternative to the third larval stage of the nematode. Dauers undergo dramatic tissue remodeling and extensive physiological, metabolic, behavioral, and gene expression changes compared to conspecifics that continue development and can be induced by several adverse environments or genetic mutations that act as independent and parallel inputs into the larval developmental program. Therefore, dauer induction is an example of phenotypic plasticity. However, whether gene expression in dauer larvae induced to arrest development by different genetic or environmental triggers is invariant or varies depending on their route into dauer has not been examined. By using RNA-sequencing to characterize gene expression in different types of dauer larvae and computing the variance and concordance within Gene Ontologies (GO) and gene expression networks, we find that the expression patterns within most pathways are strongly correlated between dauer larvae, suggestive of transcriptional robustness. However, gene expression within specific defense pathways, pathways regulating some morphological traits, and several metabolic pathways differ between the dauer larvae. We speculate that the transcriptional robustness of core dauer pathways allows for the buffering of variation in the expression of genes involved in adaptation, allowing the dauers induced by different stimuli to survive in and exploit different niches.
Outside-in engineering of cadherin endocytosis using a conformation strengthening antibody.
Authors: Xie Bin , Xu Shipeng , Sivasankar Sanjeevi
Published: August 2024

P-cadherin, a crucial cell-cell adhesion protein which is overexpressed in numerous malignant cancers, is a popular target for drug delivery antibodies. However, molecular guidelines for engineering antibodies that can be internalized upon binding to P-cadherin are unknown. Here, we use a combination of biophysical, biochemical, and cell biological methods to demonstrate that trapping the cadherin extracellular region in an X-dimer adhesive conformation, triggers cadherin endocytosis via a novel outside-in signaling mechanism. We show that the monoclonal antibody CQY684 traps P-cadherin in an X-dimer conformation and strengthens this adhesive structure. Formation of stable X-dimers results in the dissociation of p120-catenin, a suppressor of cadherin endocytosis, from the X-dimer cytoplasmic region. This increases the turnover of P-cadherin and targets the cadherin-antibody complex to the lysosome. Our results establish a previously unknown outside-in signaling mechanism that provides fundamental insights into how cells regulate adhesion and that can be exploited by anti-cadherin antibodies for intracellular drug delivery.
Low-cost animal tracking using Bluetooth low energy beacons on a crowd-sourced network
Authors: Farine Damien R , Penndorf Julia , Bolcato Sofia , Nyaguthii Brendah , Aplin Lucy M
Published: August 2024

Animal tracking has opened the door to address many fundamental questions in ecology and conservation. While historically animals have been tracked as a means to understand their large-scale movements, such as migration, there is now a greater focus on using tracking to study movements over smaller scales, individual variation in movement, or how movements shape social network structure. With this shift in focus also comes different tracking needs, including the need to track larger numbers of individuals. Tracking studies all face some technological limitations. For example, GPS and other active tracking solutions can collect fine-scale movement data, but have a high cost per tag, limiting the number of individuals that can be followed. They also have high energy costs of data acquisition and download, limiting time periods over which data can be collected. Low-energy passive (e.g. PIT) or active (e.g. reverse GPS) tags can overcome these limitations, but instead require animals to remain within a bounded study area or to come into close proximity to detectors. Here we describe one solution that can overcome many current limitations by employing the massive global network of personal mobile phones as gateways for tracking animals using Bluetooth low energy (BLE) beacons. In areas with medium to high density of people, these simple-to-make beacons can provide regular updates of position over long time periods (battery life 1-3 years). We describe how to use off-the-shelf components to produce BLE beacons that weigh c. 5-6 g and cost < $7USD. Using field testing, we then show that beacons are capable of producing high-frequency tracking data that can be used to build home ranges or to detect spatio-temporal co-occurrences among individuals. BLE beacons are a low cost, low energy solution for studying organisms (e.g. birds, mammals, and reptiles) living and moving in urban landscapes. Their low weight and small size makes them particularly well-suited for tracking smaller species. When combined with fixed gateways, their use can also be extended to non-urban habitats. Their high accessibility is likely to make them an attractive solution for many research projects.
A model-informed target product profile for population modification gene drives for malaria control
Authors: Mondal Agastya , Sanchez Castellanos Hector Manuel , Marshall John Macky
Published: August 2024

As reductions in malaria transmission in sub-Saharan Africa stagnate, gene drive-modified mosquitoes represent one of the most promising novel tools for continued disease control. In order to advance from the laboratory to the field, gene drives will be assessed against target product profiles, planning tools that list minimum criteria products should satisfy as they progress through the development pipeline. Here, we use an eco-epidemiological model to investigate parameter values for population modification gene drives that satisfy two previously-discussed target outcomes: a 50% reduction in clinical malaria incidence for a duration (window-of-protection) of at least three years, and a time-to-impact of less than one year. We consider two African settings, Burkina Faso and Kenya, where gene drive mosquitoes are currently being researched, and consider three transmission intensities at each. For the gene drive product, we explore rates of homing and resistance allele generation, fitness costs associated with gene drive and non-functional resistance alleles, and the efficacy of the effector gene(s) at reducing mosquito-to-human transmission. We find that when the window-of-protection criterion is satisfied, the time-to-impact criterion also is. Target outcomes are most influenced by the fitness cost associated with the gene drive allele and effector gene efficacy. Resistance allele parameters are also highly influential on target outcomes, and determine how long the gene drive allele persists in the population after most available wild-type alleles have been cleaved. Low rates of functional resistance allele generation are preferred, while costly non-functional resistance alleles will allow the drive allele to outcompete them. Homing rates already achieved for Anopheles gene drives do not need to be improved upon. A conundrum exists whereby the most important product parameters for predicting field efficacy are those that can only be reliably measured in the field, which presents a challenge for assessment of product readiness.
A novel role for Neurog2 in MYCN driven neuroendocrine plasticity of prostate cancer
Authors: Walke Prachi , Price Jared D.W. , Vizeacoumar Frederick S. , Joseph Nickson , Maranda Vincent , Chowdhury Bari , Patel Jay , Zhang Yue , Dong He , New Lara , Ganapathysamy Ashtalakshmi , Gong Li Hui , Elhasasna Hussain , Bhanumathy Kalpana K. , Wu Yuliang , Freywald Andrew , Krishnan Anand , Vizeacoumar Franco J.
Published: August 2024

Neuroendocrine prostate cancer (NEPC) presents a formidable clinical challenge owing to its aggressive progression and resistance to conventional therapies. A key driver of NEPC is the overexpression ofMYCN, a well-established oncogene associated with neuroendocrine tumors. However, efforts to directly inhibit the N-Myc protein encoded by this gene have resulted in limited success, thereby hindering therapeutic advancements. To overcome this obstacle, we conducted unbiased genome-wide screening using isogenic prostate cancer cell lines to identify the synthetic vulnerabilities ofMYCN. Among the identified candidates,NEUROG2emerged as a significant candidate. Neurog2 is a proneural transcription factor (PTF) known for its role in developmental processes and trans-differentiation of adult cells. Our findings demonstrate that Neurog2 depletion does not affect non-malignant cells, but significantly suppresses the growth ofMYCN-overexpressing cells and tumors in orthotopic NEPC models. Furthermore, our observations indicate that the Neurog2-mediated regulation of PTFs can facilitate NEPC development. Thus, targeting Neurog2 holds promise as an effective therapeutic strategy forMYCN-overexpressing NEPC.
14-3-3 promotes sarcolemmal expression of cardiac CaV1.2 and nucleates isoproterenol-triggered channel super-clustering
Authors: Spooner Heather C. , Costa Alexandre D. , González Adriana Hernández , Ibrahimkhail Husna , Yarov-Yarovoy Vladimir , Horne Mary , Dickson Eamonn J. , Dixon Rose E.
Published: August 2024

The L-type Ca2+channel (CaV1.2) is essential for cardiac excitation-contraction coupling. To contribute to the inward Ca2+flux that drives Ca2+-induced-Ca2+-release, CaV1.2 channels must be expressed on the sarcolemma; thus the regulatory mechanisms that tune CaV1.2 expression to meet contractile demand are an emerging area of research. A ubiquitously expressed protein called 14-3-3 has been proposed to affect Ca2+channel trafficking in non-myocytes, however whether 14-3-3 has similar effects on CaV1.2 in cardiomyocytes is unknown. 14-3-3 preferentially binds phospho-serine/threonine residues to affect many cellular processes and is known to regulate cardiac ion channels including NaV1.5 and hERG. Altered 14-3-3 expression and function have been implicated in cardiac pathologies including hypertrophy. Accordingly, we tested the hypothesis that 14-3-3 interacts with CaV1.2 in a phosphorylation-dependent manner and regulates cardiac CaV1.2 trafficking and recycling. Confocal imaging, proximity ligation assays, super-resolution imaging, and co-immunoprecipitation revealed a population of 14-3-3 colocalized and closely associated with CaV1.2. The degree of 14-3-3/CaV1.2 colocalization increased upon stimulation ofβ-adrenergic receptors with isoproterenol. Notably, only the 14-3-3-associated CaV1.2 population displayed increased cluster size with isoproterenol, revealing a role for 14-3-3 as a nucleation factor that directs CaV1.2 super-clustering. 14-3-3 overexpression increased basal CaV1.2 cluster size and Ca2+currents in ventricular myocytes, with maintained channel responsivity to isoproterenol. In contrast, isoproterenol-stimulated augmentation of sarcolemmal CaV1.2 expression and currents in ventricular myocytes were abrogated by 14-3-3 inhibition. These data support a model where 14-3-3 interacts with CaV1.2 in a phosphorylation-dependent manner to promote enhanced trafficking/recycling, clustering, and activity duringβ-adrenergic stimulation.

Significance Statement

The L-type Ca2+channel, CaV1.2, plays an essential role in excitation-contraction coupling in the heart and in part regulates the overall strength of contraction during basal and fight- or-flightβ-adrenergic signaling conditions. Proteins that modulate the trafficking and/or activity of CaV1.2 are interesting both from a physiological and pathological perspective, since alterations in CaV1.2 can impact action potential duration and cause arrythmias. A small protein called 14-3-3 regulates other ion channels in the heart and other Ca2+channels, but how it may interact with CaV1.2 in the heart has never been studied. Examining factors that affect CaV1.2 at rest and duringβ-adrenergic stimulation is crucial for our ability to understand and treat disease and aging conditions where these pathways are altered.
Trade-offs beget trade-offs: Causal analysis of mammalian population dynamics
Authors: Bergman Juraj , Pedersen Rasmus Ø. , Lundgren Erick J. , Trepel Jonas , Pearce Elena A. , Czyżewski Szymon , Tietje Melanie , Lemoine Rhys T. , Macià Moisès Coll , Schierup Mikkel H. , Svenning Jens-Christian
Published: August 2024

Survival and reproduction strategies in mammals are determined by trade-offs between life history traits. In turn, the unique configuration of traits that characterizes mammalian species gives rise to species-specific population dynamics. The dependence of population dynamics on life history has been primarily studied as the relationship between population density and size-related traits. With the recent accumulation of genomic data, the effective population size (number of breeding individuals;Ne) over the last 100-800 kya has become quantifiable for a large proportion of mammals. Using phylogenetic path analysis, we compared the dependence of population density andNeon eleven traits that characterize mammalian allometry, diet and reproduction. We found variable trait impacts on these two metrics of population dynamics across different phylogenetic, ecological and conservation classifications of mammals. Brain size had a negative effect on density but a positive effect onNe, especially in primates and carnivores. Diet specialization had a negative effect on both density andNe. The relationship betweenNe(but not density) and several traits showed biome-related gradients. We found that critically endangered species have life history strategies that impede population recovery, as reflected by the strong positive dependence of both density andNeon generation length. Our findings demonstrate that trade-offs characterizing life history evolution are not only trait-specific, but are also present between different metrics of population dynamics. This challenges the static nature of the “energetic equivalence” rule and has major implications for selecting the appropriate population metric in species conservation and restoration strategies.

Significance statement

Trade-offs are an essential component of trait evolution, underlying various strategies used by species to mitigate environmental pressures and ensure their survival. We investigated how traits affect mammalian population-level parameters, including population density and effective population size (number of breeding individuals;Ne). We found that the impact of traits on these two measures of population dynamics was variable. For example, both density andNedecreased in species with larger body size, while brain size was negatively related to population density but positively related toNe. We therefore show that evolutionary trade-offs are not limited to traits, but are also present between population-level parameters, which can have important implications for future conservation and restoration efforts.
Spatial Immunophenotyping from Whole-Slide Multiplexed Tissue Imaging Using Convolutional Neural Networks
Authors: Yosofvand Mohammad , Edmiston Sharon N. , Smithy James W. , Peng Xiyu , Kostrzewa Caroline E. , Lin Bridget , Ehrich Fiona , Reiner Allison , Miedema Jayson , Moy Andrea P. , Orlow Irene , Postow Michael A. , Panageas Katherine , Seshan Venkatraman E. , Callahan Margaret K. , Thomas Nancy E. , Shen Ronglai
Published: August 2024

The multiplexed immunofluorescence (mIF) platform enables biomarker discovery through the simultaneous detection of multiple markers on a single tissue slide, offering detailed insights into intratumor heterogeneity and the tumor-immune microenvironment at spatially resolved single cell resolution. However, current mIF image analyses are labor-intensive, requiring specialized pathology expertise which limits their scalability and clinical application. To address this challenge, we developed CellGate, a deep-learning (DL) computational pipeline that provides streamlined, end-to-end whole-slide mIF image analysis including nuclei detection, cell segmentation, cell classification, and combined immuno-phenotyping across stacked images. The model was trained on over 750,000 single cell images from 34 melanomas in a retrospective cohort of patients using whole tissue sections stained for CD3, CD8, CD68, CK-SOX10, PD-1, PD-L1, and FOXP3 with manual gating and extensive pathology review. When tested on new whole mIF slides, the model demonstrated high precision-recall AUC. Further validation on whole-slide mIF images of 9 primary melanomas from an independent cohort confirmed that CellGate can reproduce expert pathology analysis with high accuracy. We show that spatial immuno-phenotyping results using CellGate provide deep insights into the immune cell topography and differences in T cell functional states and interactions with tumor cells in patients with distinct histopathology and clinical characteristics. This pipeline offers a fully automated and parallelizable computing process with substantially improved consistency for cell type classification across images, potentially enabling high throughput whole-slide mIF tissue image analysis for large-scale clinical and research applications.
Serum metabolomics signatures after an acute bout of combined traditional or high-intensity tactical training in young males and females
Authors: Graham Zachary Aaron , PATHAK KHYATIBEN V , Garcia-Mansfield Krystine , Lavin Kaleen , Torres Anakaren , McAdam Jeremy , Broderick Timothy , Pirrotte Patrick , Bamman Marcas
Published: August 2024

Exercise is a multipotent stimulus that results in large-scale dynamic changes to the systemic molecular profile. Alternative exercise prescriptions and doses would be expected to result in distinct signatures due to differences in duration and intensity. We tested two novel combined endurance and resistance exercise regimens to better understand how differing prescriptions alter the acute metabolomics response at multiple timepoints up to 24h post-exercise. Serum metabolomics for n=37 untrained individuals was analyzed for participants completing traditional combined exercise [TRAD; n = 20 (11M/9F)] or high-intensity tactical training [HITT; n= 17 (9M/8F)] before exercise (pre), and immediately (h0), 3 and 24 h post-exercise (h3 and h24, respectively). We found minimal metabolites had a group by time interaction (2 with FDR < 0.10; 31 with nominal p < 0.05;), but both stimuli resulted in large-scale within-group changes to the circulating metabolome. TRAD consistently had greater numbers of differentially abundant metabolites (FDR < 0.10) as compared to HITT at h0 (431 vs. 333), h3 (435 vs. 331) and h24 (168 vs. 76). The major metabolite classes altered were related to key energy substrates for both groups at h0 (e.g., glucose, pyruvate) and energy replenishment for h3 and h24 (e.g., 12,13 diHOME, palmitylcarnitine, free fatty acids). In summary, our data are the first to describe the acute changes in the circulating metabolome following combined endurance and resistance exercise. Additionally, we show the two distinct doses of combined exercise led to generally similar patterns of responses, with the longer duration TRAD dose resulting in a higher magnitude of change.
Identifying unmeasured heterogeneity in microbiome data via quantile thresholding (QuanT)
Authors: Lu Jiuyao , Satten Glen A. , Meyer Katie A. , Launer Lenore J. , Ling Wodan , Zhao Ni
Published: August 2024

Microbiome data, like other high-throughput data, suffer from technical heterogeneity stemming from differential experimental designs and processing. In addition to measured artifacts such as batch effects, there is heterogeneity due to unknown or unmeasured factors, which lead to spurious conclusions if unaccounted for. With the advent of large-scale multi-center microbiome studies and the increasing availability of public datasets, this issue becomes more pronounced. Current approaches for addressing unmeasured heterogeneity in high-throughput data were developed for microarray and/or RNA sequencing data. They cannot accommodate the unique characteristics of microbiome data such as sparsity and over-dispersion. Here, we introduce Quantile Thresholding (QuanT), a novel non-parametric approach for identifying unmeasured heterogeneity tailored to microbiome data. QuanT applies quantile regression across multiple quantile levels to threshold the microbiome abundance data and uncovers latent heterogeneity using thresholded binary residual matrices. We validated QuanT using both synthetic and real microbiome datasets, demonstrating its superiority in capturing and mitigating heterogeneity and improving the accuracy of downstream analyses, such as prediction analysis, differential abundance tests, and community-level diversity evaluations.
Evaluating the predictive accuracy of ion channel models using data from multiple experimental designs
Authors: Shuttleworth Joseph G , Lei Chon Lok , Windley Monique J , Hill Adam P , Preston Simon P , Mirams Gary R
Published: August 2024

Mathematical models are increasingly being relied upon to provide quantitatively accurate predictions of cardiac electrophysiology. Many such models concern the behaviour of particular subcellular components (namely, ion channels) which, together, allow the propagation of electrical signals through heart-muscle tissue - namely, the firing of action potentials. In particular, IKr, a voltage-sensitive potassium ion-channel current, is of interest owing to its central pore's propensity for blockage by various small molecules. We use newly collected data obtained from an ensemble of voltage-clamp experiments to validate the predictive accuracy of various dynamical models of IKr. To do this, we fit models to each protocol individually, and quantify the error in the resultant model predictions. This allows the comparison of predictive accuracy for IKrmodels under a diverse collection of previously unexplored dynamics. Our results highlight heterogeneity between parameter estimates obtained from different cells, suggesting the presence of latent effects not yet accounted for in our models. This heterogeneity has a significant impact on our parameter estimates and suggests routes for model improvement.
Intercellular compartmentation of trehalose 6-phosphate metabolism inSetaria viridisleaves
Authors: Tonetti Tomas , Rojas Bruno E , Lucero Leandro E , Feil Regina , Calace Paula , Saigo Mariana , Arrivault Stephanie , Stitt Mark , Lunn John E , Figueroa Carlos M
Published: August 2024

Trehalose 6-phosphate (Tre6P) is a signal metabolite that links carbon metabolism with plant development. Our current understanding of Tre6P metabolism and signalling is predominantly based on studies in Arabidopsis thaliana. Some features could be adapted to the specific physiology, anatomy, and life cycle of this C3 eudicot model species, and thus might not be representative of other angiosperms. To better understand the regulation of carbon metabolism by Tre6P in monocot C4 species we used Setaria viridis, which has been widely adopted as a model for the major C4 NADP-malic enzyme subtype crop species, such as maize (Zea mays), sorghum (Sorghum bicolor) and sugarcane (Saccharum officinarum). In this work, we analysed the levels of transcripts encoding Tre6P-related enzymes in different tissues and cell types from S. viridis. The TREHALOSE-6-PHOSPHATE SYNTHASE1 transcript, its encoded protein (TPS1, the enzyme responsible for Tre6P synthesis) and Tre6P were mainly located in bundle sheath cells of S. viridis. Our results show that Tre6P is predominately synthesized and located in bundle sheath and associated cells, where it could play a fundamental role in the regulation of sucrose levels by modulating phloem loading.
Runx3 Acts as Homodimeric Chromatin Binding Factor Regulating Heterochromatin-Mediated Cancerous Phenotype
Authors: Mahmoud Salma Awad , Bonne Isabelle , Sim Aik Yong , Abuelenain Gehan Labib
Published: August 2024

The recent paradoxical dual citizenships of Runt-related transcription factor 3 (Runx3) in tumorigenesis remains poorly characterized. Here, we report the oncogenic capacity of Runx3 as chromatin modulator in metastatic gastric cancer model. Runx3 exists as homodimer and binds cooperatively to modified nucleosomes. Additionally, we detected a synergistic functional enhancement of octamer transfer, nucleosome sliding and stochiometric integrity of SWI/SNF by Runx3. We found that Runx3 depletion increased nucleosomes occupancy and promoted chromatin silencing by heterochromatin condensation and HP1 oligomerization. ATAC-seq analysis revealed differential accessibility per chromosome due to Runx3 null expression with dysregulation of multiple inflammatory response and DNA repair pathways. Mechanistically, these modulations resulted in aberrant DNA damage repair response, which is rescued by RUNX3 overexpression. These findings reveal a new paradigm in Runx3 biology as dynamic chromatin regulatory element vital for the maintenances of cancerous phenotype.