bluuebunny/crossref_metadata_2025 huggingface dataset:
Early versus delayed laparoscopic cholecystectomy for gallbladder perforation
Authors: Wu Renqing , Dumas Ryan P. , Nomellini Vanessa
Published: November 2024

BACKGROUND

Gallbladder perforation occurs in 2% to 11% of patients with acute cholecystitis, with associated mortality estimated to be at 12% to 42%. Because of its low incidence, the data on management remain sparse. There is a lack of evidence to suggest whether early or delayed cholecystectomy is superior in the treatment of perforated cholecystitis. We hypothesize that an early definitive operation is associated with decreased total hospital length of stay (THLOS).

METHODS

Using the National Surgical Quality Improvement Program database from the American College of Surgery, we identified patients who underwent laparoscopic cholecystectomy for gallbladder perforation on an urgent or emergent basis from 2012 to 2021. We divided them into those who underwent early (<2 days from the date of admission to the date of operation) and delayed cholecystectomy (≥2 days from the date of admission to the date of operation). Our primary outcome was the THLOS. We created multivariate regression models to assess for the association of early versus delayed operation and THLOS.

RESULTS

The THLOS was found to be 2.94 days longer in the delayed group compared with the early group (p < 0.05). In those who did not present with sepsis on admission, the THLOS was noted to be 4.71 days longer in the delayed group compared with the early group (p < 0.05). Early versus delayed operation was not associated with a difference in the postoperative length of stay, 30-day postoperative complications, rate of readmission, and reoperation, regardless of preoperative sepsis status.

CONCLUSION

Early laparoscopic cholecystectomy for gallbladder perforation is associated with decreased THLOS, and there were no other differences in outcomes compared with delayed laparoscopic cholecystectomy. Patients with gallbladder perforation would likely benefit from an early operation within 2 days of admission.

LEVEL OF EVIDENCE

Therapeutic/Care management; Level III.
Short-Latency Trigeminocervical Reflex Obtained Without Muscle Activation: Topographic Distribution and Methodological Approach
Authors: Melo Denise Lima Medeiros de , Comerlato Enio Alberto , Tavares Eduardo Santos , Pinheiro Denise Spinola , Manzano Gilberto Mastrocola
Published: November 2024

Purpose:

Electrical stimulation of trigeminal nerve branches elicits early and late reflex responses in the cervical muscles, known as the trigeminocervical reflex (TCR). This study aimed to evaluate the neurophysiological aspects, stimulation patterns, and topographic distribution of short-latency TCR components in humans in the absence of voluntary muscle activation.

Methods:

This prospective observational study included 30 participants. Trigeminocervical reflex responses were simultaneously recorded from the bilateral sternocleidomastoid, trapezius, and splenius capitis muscles (without voluntary muscle activation), after electrical stimulation of the supraorbital and infraorbital nerves. Two different stimulation protocols were evaluated: a 3 Hz stimulation protocol (using averaging) and a single-pulse stimulation protocol.

Results:

Using a 3 Hz stimulation protocol, short-latency TCR responses were recorded in the sternocleidomastoid, trapezius, and splenius capitis muscles, ipsilateral and/or contralateral, but with variable recordability depending on the recording site. The most reliable response was obtained in ipsilateral sternocleidomastoid muscle. To the best of our knowledge, this is the first study to demonstrate the elicitation of short-latency TCR components in the sternocleidomastoid muscle in the absence of voluntary muscle activation in humans without craniocervical junction disorders or lower brainstem abnormalities.

Conclusions:

The choice of an appropriate stimulation protocol is particularly relevant for recording short-latency TCR components, considering that the visualization of early or late responses seems to be facilitated by different stimulation methodologies.
A feminine advantage in the domain of harm: a review and path forward
Authors: Graso Maja , Reynolds Tania
Published: November 2024

Despite well-documented disparities disadvantaging women (e.g. discrepancies between men and women in salaries and leadership roles), we argue that there are contexts in which disparities disadvantage men. We review the literature suggesting harm to women is perceived as more severe and unacceptable than identical harm to men, a bias potentially rooted in evolutionary, base rate, stereotype-based and cultural shift explanations. We explore how these biases manifest in protective responses toward women and harsher judgements toward men, particularly in contexts of victimization and perpetration. Our review aims to complement the existing literature on gender biases by presenting a balanced view that acknowledges men and women face unique challenges. By understanding these biases, we hope to foster a more equitable discourse on gender and harm, encouraging empathy and validation of suffering irrespective of gender. This holistic approach aims to de-escalate gender-based conflicts and promote effective interventions for both men and women.
An endoplasmic reticulum localized acetyl-CoA transporter is required for efficient fatty acid synthesis in
Toxoplasma gondii
Authors: Qin Biyun , Fan Bolin , Li Yazhou , Wang Yidan , Shen Bang , Xia Ningbo
Published: November 2024

Toxoplasma gondii
is an obligate intracellular parasite that can infect humans and diverse animals. Fatty acids are critical for the growth and proliferation of
T. gondii
, which has at least two pathways to synthesize fatty acids, including the type II de novo synthesis pathway in the apicoplast and the elongation pathway in the endoplasmic reticulum (ER). Acetyl-CoA is the key substrate for both fatty acid synthesis pathways. In the apicoplast, acetyl-CoA is mainly provided by the pyruvate dehydrogenase complex. However, how the ER acquires acetyl-CoA is not fully understood. Here, we identified a putative acetyl-CoA transporter (TgAT1) that localized to the ER of
T. gondii
. Deletion of TgAT1 impaired parasite growth and invasion
in vitro
and attenuated tachyzoite virulence
in vivo
. Metabolic tracing using
13
C-acetate found that loss of TgAT1 reduced the incorporation of
13
C into certain fatty acids, suggesting reduced activities of elongation. Truncation of AT1 was previously reported to confer resistance to the antimalarial compound GNF179 in
Plasmodium falciparum
. Interestingly, GNF179 had much weaker inhibitory effect on
Toxoplasma
than on
Plasmodium
. In addition, deletion of AT1 did not affect the susceptibility of
Toxoplasma
to GNF179, suggesting that this compound might be taken up differently or has different inhibitory mechanisms in these parasites. Together, our data show that TgAT1 has important roles for parasite growth and fatty acid synthesis, but its disruption does not confer GNF179 resistance in
T. gondii
.
Fair voting outcomes with impact and novelty compromises? Unravelling biases in electing participatory budgeting winners
Authors: Maharjan Sajan , Majumdar Srijoni , Pournaras Evangelos
Published: November 2024

Participatory budgeting, as a paradigm for democratic innovations, engages citizens in the distribution of a public budget to projects, which they propose and vote for implementation. So far, voting algorithms have been proposed and studied in social choice literature to elect projects that are popular, while others prioritize a proportional representation of voters’ preferences, for instance, the rule of equal shares. However, the anticipated impact and novelty in the broader society by the winning projects, as selected by different algorithms, remains totally under-explored, lacking both a universal theory of impact for voting and a rigorous unifying framework for impact and novelty assessments. This article tackles this grand challenge towards new axiomatic foundations for designing effective and fair voting methods. This is through new and striking insights derived from a large-scale analysis of biases over 345 real-world voting outcomes, characterized for the first time by a novel portfolio of impact and novelty metrics. We find strong causal evidence that equal shares comes with impact loss in several infrastructural projects of different cost levels that have been so far over-represented. However, it also comes with a novel, yet over-represented, impact gain in welfare, education and culture. We discuss the broader implications of these results and how impact loss can be mitigated at the stage of campaign design and project ideation.

This article is part of the theme issue ‘Co-creating the future: participatory cities and digital governance’.
Computational diplomacy: how ‘hackathons for good’ feed a participatory future for multilateralism in the digital age
Authors: Maillart Thomas , Gomez Lucia , Lombard Ewa , Nolte Alexander , Pisano Francesco
Published: November 2024

This article explores the role of
hackathons for good
in building a community of software and hardware developers focused on addressing global sustainable development goal (SDG) challenges. We theorize this movement as computational diplomacy: a decentralized, participatory process for digital governance that leverages collective intelligence to tackle major global issues. Analysing Devpost and GitHub data reveals that 30% of hackathons since 2010 have addressed SDG topics, employing diverse technologies to create innovative solutions. Hackathons serve as crucial kairos moments, sparking innovation bursts that drive both immediate project outcomes and long-term production. We propose that these events harness the neurobiological basis of human cooperation and empathy, fostering a collective sense of purpose and reducing interpersonal prejudice. This bottom–up approach to digital governance integrates software development, human collective intelligence and collective action, creating a dynamic model for transformative change. By leveraging kairos moments, computational diplomacy promotes a more inclusive and effective model for digital multilateral governance of the future.

This article is part of the theme issue ‘Co-creating the future: participatory cities and digital governance’.
Mapping sidewalk accessibility with smartphone imagery and Visual AI: a participatory approach
Authors: Morra Diego , Zhu Xiaosheng , Liu Chang , Fu Kyle , Duarte Fábio , Mora Simone , He Zhengbing , Ratti Carlo
Published: November 2024

Evaluating sidewalk accessibility is conventionally a manual and time-consuming task that requires specialized personnel. While recent developments in Visual AI have paved the way for automating data analysis, the lack of sidewalk accessibility datasets remains a significant challenge. This study presents the design and validation of Sidewalk AI Scanner, a web app that enables quick, crowdsourced and low-cost sidewalk mapping. The app enables a participatory approach to data collection through imagery captured using smartphone cameras. Subsequently, dedicated algorithms automatically identify sidewalk features such as width, obstacles or pavement conditions. Though not a replacement for high-resolution sensing methods, this method leverages data crowdsourcing as a strategy to produce a highly scalable, city-level dataset of sidewalk accessibility, offering a novel perspective on the city’s inclusivity; fostering community empowerment and participatory planning.

This article is part of the theme issue ‘Co-creating the future: participatory cities and digital governance’.
Resisting technological inevitability: Google Wing’s delivery drones and the fight for our skies
Authors: Zenz Anna , Powles Julia
Published: November 2024

Efforts to realize on-demand delivery drone networks present a stark example of how the technology industry seeks to dominate new markets, regardless of societal consequences. Analyzing the most advanced of these efforts—Google Wing’s operations in Australia since 2017—we identify the instrumental role of narratives of technological inevitability (of tech expansion, and societal adaptation) in catalyzing new sky-based commerce. Yet the interest of this case study lies in a twist. Google Wing’s rollout in Australia’s capital, Canberra, initially proceeded as a textbook example of tech expansion. However, citizen engagement and public governance dramatically intervened and, we argue, disrupted the logic of technological inevitability. This article is the first to analyze these dynamics, many of which originated with Bonython Against Drones (BAD), a community action group forged from those who first lived under Google’s food delivery drones. The article exposes the flawed logic of technological inevitability as the enabling force of tech expansion; characterizes the governance failures that help install corporate visions for public goods; animates the potentialities of communities living with new technologies; and identifies the sky itself, as both a public commons and a vital, living habitat, as a key future locus for participatory governance.

This article is part of the theme issue ‘Co-creating the future: participatory cities and digital governance’.
Participatory design based on opinion pooling
Authors: Batty Michael , Shao Tianqu , Lopane Fulvio D.
Published: November 2024

We focus here on methods for locating future urban development, ranging from entire towns to site designs. These methods articulate the urban design problem in terms of a series of factors pertaining to different measures of land suitability that are represented as spatial surfaces or maps. In realistic problems, these factors inevitably conflict with one another, and we thus define various design methods that enable us to select optimal locations for development based on weighting these factors in different ways. We begin with methods for resolving conflicts between the suitability maps using simple averaging with equal weights and then introduce methods for representing the interactions between the factors as a hierarchy for how these factors can be related to each other following an order for their differential weighting. We then generalize this method to ways in which a variety of individual experts can pool their knowledge of the problem to achieve a consensus solution using a process of group dynamics. The implication is that these kinds of dynamics might be used to enable effective public participation where conflicts between opinions can be resolved collectively. We are currently exploring this through methods of geodesign where networks of stakeholders, planners and designers can be brought together to solve these problems both empirically as well as formally.

This article is part of the theme issue ‘Co-creating the future: participatory cities and digital governance’.
Pan-cancer study on transition of signaling systems from primary to metastatic tumors
Authors: Zhou Wenjia , Zhang Junhua
Published: November 2024

Metastatic progression is responsible for the majority of cancer-related deaths. A better understanding of the underlying molecular mechanisms driving metastasis therefore remains of utmost importance. Here we take efforts to excavate mutant driver factors of metastases in the level of signaling pathways. We introduce two models, EntCDP and ModSDP, to detect the similarity and specificity of pathways in a pan-cancer context. The simulation studies confirm their feasibility and identification accuracy. Using mutation profiles of 17 cancer types with primary and metastatic cohorts from MSK-IMPACT, we apply the two models to investigate the transition of signaling systems from primary to metastatic tumors mainly from five perspectives. 1) We initially perform a comprehensive comparison of 15 primary-metastatic cancer pairs. Nearly all shared common driver genes or pathways, while specific driver gene sets of primary or/and metastatic tumors can be seen for almost each pair, except for breast cancer. 2) We use ModSDP to identify the specificity of metastases with the same primary site and highlight calcium signaling in breast cancer with bone metastasis, FoxO signaling for melanoma/lung lymph node metastasis, etc. 3) Oppositely, we use EntCDP to identify common factors yielding three frequently metastatic sites (liver, lung and brain), and recognized cushing syndrome, microRNAs in cancer and MAPK signaling pathway, separately. 4) Regarding high-tropism metastatic patterns, we investigated the relationship between the metastatic tumor and primary tumors in both locations. In the typical pattern of colorectal cancer metastasis to the liver, we detected hepatic signals in primary colorectal cancer. 5) Finally, we focused on the common and specific characteristics of relevant cancer types, such as gender-related cancers and gastrointestinal cancers. Study on gynecologic tumors suggest endocrine hormone change and virus infection as their common risk factors, while for male we highlight hedgehog signaling and EPH-related receptors as invasive potential of prostate cancer. Multiple interesting findings revealed by this study may be helpful for the understanding of the extent of signal changes during tumor metastasis. We expect that this study will provide a valuable resource for transforming our knowledge about signals in cancer metastasis into alternative clinical practice for advanced patients.
GRIP: physics-informed neural network for gradient retention time prediction in liquid chromatography
Authors: George Kevin , Haeckl F.P. Jake , Großmann Gerrit , Gurevich Alexey , Tagirdzhanov Azat
Published: November 2024

Gradient liquid chromatography has numerous applications in life sciences. Retention time prediction remains challenging due to complex underlying physical processes and highly variable chromatographic conditions. Here, we present GRIP, a physics-informed neural network for gradient retention time prediction that explicitly uses experimental setup parameters. GRIP demonstrates zero-shot generalization to unseen chromatographic systems while being on par or out-performing the transfer learning-based baseline. This approach can computationally guide the experimental setup configuration tailored to specific compounds of interest.
Trained innate immunity attenuates macrophage efferocytosis of cancer cells
Authors: Chatzis Alexandros , Lukaszonek Jakub , Lagos Dimitris , Boucher Dave , Kourtzelis Ioannis
Published: November 2024

Macrophage phagocytosis has been implicated in regulating anti-tumour immunity. Trained innate immunity (TII), inducedviamodulation of mature myeloid cells or their bone marrow progenitors, mediates sustained increased responsiveness to secondary challenges. Despite the advances in the study of TII-mediated anti-tumour activity, the impact of TII on the orchestration of phagocytosis in the tumour setting requires further elucidation. Here, we investigated whether macrophage phagocytosis of tumour cells can be modulated through induction of TII.

To this end, mice were pre-treated with β-glucan, a fungal-derived agonist of TII, and bone marrow was isolated for macrophage differentiation. Macrophages were then co-cultured with tumour cells that were either apoptotic or opsonised with an antibody recognising a tumour antigen, to mimic efferocytosis and antibody-dependent cellular phagocytosis (ADCP), respectively.

While TII did not have any impact in the modulation of ADCP, efferocytosis was decreased in trained macrophages. Along the same line, gene expression analysis demonstrated that mRNA levels of molecules promoting efferocytosis were downregulated in trained macrophages. Trained macrophages exerted decreased levels of active caspase-1 and produced decreased levels of interleukin-1β upon efferocytosis of tumour cells.

Our findings reveal a hitherto unknown role of TII in the regulation of anti-tumour immunity and may set the stage for designing new cancer immunotherapeutic approaches targeting macrophage efferocytosis.
Reconciling conflicting selection pressures in the plant collaborative non-self recognition self-incompatibility system
Authors: Jangid Amit , Erez Keren , Feldheim Ohad Noy , Friedlander Tamar
Published: November 2024

How do complex biological systems reconcile conflicting selection pressures acting on their components? We study this question in the context of the collaborative non-self recognition selfincompatibility, a system that inhibits self-fertilization in plants. Self-incompatibility relies on specific molecular recognition between proteins, expressed in female and male reproductive organs. These proteins co-evolved to enable fertilization between individuals and disable self-fertilization simultaneously. We study the impact of these opposing selection pressures on the amino acid frequencies in these proteins’ recognition domain. We construct a theoretical framework enabling promiscuous recognition between proteins and multiple partners each, as found empirically, and employ stochastic simulations. We find asymmetric responses to selection affecting mostly the female, but not the male protein composition. Using large deviations theory, we well-approximate the simulated frequencies and find agreement with genomic data. We expect our methodology to be broadly applicable to analyze the balance between conflicting pressures in additional biological systems.
Melanin concentrating hormone projections to the nucleus accumbens enhance the reward value of food consumption and do not induce feeding or REM sleep
Authors: Furman Katherine L. , Baron Lorelei , Lyons Hannah C. , Cha Timothy , Evans Jack R. , Manna Jayeeta , Zhu Limei , Mattis Joanna , Burgess Christian R.
Published: November 2024

Regulation of food intake and energy balance is critical to survival. Hunger develops as a response to energy deficit and drives food-seeking and consumption. However, motivations to eat are varied in nature, and promoted by factors other than energy deficit. When dysregulated, non-homeostatic drives to consume can contribute to disorders of food intake, adding to the increasing prevalence of restrictive eating disorders and obesity. Melanin-concentrating hormone (MCH) neurons have been implicated in the regulation of feeding behavior, in addition to a number of other fundamental behaviors including sleep, anxiety, and maternal behavior. Several studies suggest that MCH peptide increases food consumption, while studies of MCH neurons show effects only on cued feeding, and others show no effect of MCH neuron manipulation on feeding. MCH neurons have widespread projections to diverse downstream brain regions yet few studies have investigated the function of specific projections or differentiated the behaviors they regulate. Here we use optogenetics, in combination with different behavioral paradigms, to elucidate the role of MCH projections to the nucleus accumbens (NAc) in sleep and feeding behavior. We show that MCH neurons projecting to the NAc do not induce changes in baseline feeding or REM sleep, but do enhance the preference for a food paired with optogenetic stimulation. Furthermore, this effect is diminished in female mice relative to males, in line with previous results suggesting sex differences in the functional role of MCH neurons. These results suggest that MCH projections to the NAc can enhance the rewarding value of consumed food.

Significance Statement

While feeding is often driven by hunger, there are non-homeostatic reasons why animals consume food. Melanin-concentrating hormone (MCH) neurons have been implicated in the regulation of many fundamental behaviors, including feeding, sleep and reward. They project broadly throughout the brain, suggesting that they may mediate this diverse set of behaviors independently via specific projections to downstream regions. We used optogenetic activation of MCH neurons and their projections to the nucleus accumbens (NAc) in combination with complex behavioral paradigms to demonstrate that MCH projections to the NAc do not induce baseline feeding or increases in REM sleep but do enhance the value of a paired food. These results suggest that MCH neurons contribute to non-homeostatic consumption via projections to the NAc.
Assessing the quality of generative artificial intelligence for science communication in environmental research
Authors: Worden David , Richards Daniel
Published: November 2024

The adoption of Generative Artificial Intelligence (GenAI) tools is drastically changing the way that researchers work. While debate on the quality of GenAI outputs continues, there is optimism that GenAI may help human experts to address the most significant environmental challenges facing society. No previous research has quantitatively assessed the quality of GenAI outputs intended to inform environmental management decisions. Here we surveyed 98 environmental scientists and used their expertise to assess the quality of human and GenAI content relevant to their discipline. We analysed the quality and relative preference between human and GenAI content across three use cases in environmental science outreach and communication. Our results indicate that the GenAI content was generally deemed adequate in quality by human experts, with an average of 82% of respondents indicating a quality of “adequate” or better across the three use cases. Respondents exhibited strong preferences for GenAI over human-only content when using GenAI imageery of future park management scenarios. For the use cases of generating a wetland planting guide and answering a question about invasive species management, preferences were heterogeneous amongst respondents. Our findings raise substantive questions about GenAI content as a complement to human expertise when research is transferred to public audiences.
Acute Inhibition of Adipose Triglyceride Lipase by NG497 Dysregulates Insulin and Glucagon Secretion from Human Islets
Authors: Kim Lucy B , Liu Siming , Richtsmeier Syreine , Górniak Michał , Vikram Anamika , Imai Yumi
Published: November 2024

Adipose triglyceride lipase (ATGL), which catalyzes the breakdown of triglycerides in lipid droplets (LDs), plays a critical role in releasing fatty acids to support insulin secretion in pancreatic beta cells. Based on genetic downregulation of ATGL in beta cells, multiple mechanisms are proposed that acutely or chronically regulate insulin secretion. Currently, the contribution of acute versus chronic mechanisms in the regulation of insulin secretion is unclear. Also, little is known whether ATGL affects alpha cell function. Using the human-specific ATGL inhibitor, NG497, this study investigates the impact of acute inhibition of ATGL on hormone secretion from human islets. When lipolysis by ATGL was assessed via morphological differences in LDs in confocal images of beta and alpha cells, beta cells exposed to NG497 showed notable increases in LD size and number under glucose-sufficient culture. The effect of NG497 on LD accumulation in alpha cells was more prominent under fasting-simulated conditions than glucose-sufficient conditions, pointing toward a critical role for ATGL lipolysis under conditions that stimulate hormone secretion in beta and alpha cells. When exposed to NG497 acutely, human islets reduced glucose-stimulated insulin secretion mildly, particularly first-phase insulin secretion, to an extent less pronounced than the impacts of chronic ATGL downregulation. Thus, chronic mechanisms play a predominant role in reducing insulin secretion when ATGL is downregulated. Acute exposure of human islets to NG497 significantly reduced glucagon secretion at low glucose concentration, highlighting an important potential role of ATGL lipolysis in promoting hormone secretion acutely from alpha cells.
TLL1 knockdown attenuates prostate cancer progression by enhancing antitumor immunity
Authors: Hao Jing-Lan , He Jia-Qi , Hu Hang , Wu Xiao-Yu , Zhu Zi-Heng , Zhao Xi , Li Lan , Ruan Yong-Tong , Yang Juan , Fu Ming , Zhang Kai , Gao Ping , Dong Xiao-Ming
Published: November 2024

Due to the inevitable progression to castration-resistant prostate cancer (CRPC) following treatment with androgen deprivation therapy (ADT), it is essential to develop novel treatment approaches for managing CRPC. Here we showed that metalloproteinase TLL1 was positively associated with prostate cancer aggressiveness. Mechanistically, TLL1 promoted prostate cancer cells migration and metastasis through cleaving latent TGF-β1 to activate TGF-β signaling pathway. Moreover,LINC01179interacted with Miz1 to attenuate TLL1 expression andLINC01179impaired prostate cancer cell proliferation and migration ability by suppressing TLL1 expression to deactivate TGF-β signaling activity. Meanwhile, we observed that TLL1 increased the expression of PD-L1 by activating TGF-β signaling pathway and TLL1 depletion enhanced the antitumor efficacy by anti-PD-1 antibody via augmenting the infiltration proportions of CD8+T cells in tumors. In addition, T cell-specific overexpression of TLL1 disrupted T cell development in the thymus. TLL1 overexpression in T cells accelerated RM-1 prostate tumor growth in mice by decreasing the infiltration of CD8+T cells into tumors. Collectively, our results revealed that TLL1 may be a potential therapeutic target to alter prostate cancer progression.
TCR-TRANSLATE: Conditional Generation of Real Antigen Specific T-cell Receptor Sequences
Authors: Karthikeyan Dhuvarakesh , Raffel Colin , Vincent Benjamin , Rubinsteyn Alexander
Published: November 2024

The paradoxical nature of T-cell receptor (TCR) specificity, which requires both precise recognition and adequate coverage of antigenic peptide-MHCs (pMHCs), poses a fundamental challenge in immunology. Efforts at modeling this complex many-to-many mapping have been greatly impeded by a severe lack of experimental data. To address this, we present TCR-TRANSLATE, a novel framework that adapts low-resource machine translation techniques to the TCR:pMHC specificity domain. Here, we explore sequence-to-sequence (seq2seq) modeling with various training strategies, including semi-synthetic data augmentation and multi-task objectives to generate antigen specific TCR sequences for a given target of interest. We benchmark twelve model variants derived from the BART and T5 model architectures on a target-rich validation set of well-studied pMHCs, finding an optimal model, TCRT5, that generated validated antigen-specific CDR3β sequences for previously unseen antigens. While current limitations include a narrow validation set and a focus on the CDR3β loop, our approach demonstrates the potential of seq2seq models in rapidly generating antigen-specific TCR repertoires, offering a promising avenue for increasing throughput in precision immunotherapies. Our findings highlight both the capabilities and limitations of sequence-based conditional TCR design, emphasizing the need for experimental validation to bridge the gaps between predictions, metrics, and functional capacity.
Neutralization of recent SARS-CoV-2 variants by genetically and structurally related mAbs of the pemivibart lineage
Authors: Powers Colin , Williams Braedon , Kreher Alex , Gao Feng , West Brandyn , Chupp Daniel , Allen Robert
Published: November 2024

Pemivibart is a monoclonal antibody therapy currently under Emergency Use Authorization for the for the pre-exposure prophylaxis of coronavirus disease 2019 (COVID-19) in adults and adolescents over 12 years of age with certain immunocompromised conditions. As a part of the overall monitoring strategy for the activity of pemivibart, the antibody is regularly evaluated against emerging variants of SARS-CoV-2 using pseudovirus neutralization assays. Recent clinical data from Invivyd demonstrates that the PhenoSense pseudovirus assays carried out at Monogram Biosciences have been a reliable and consistent predictor of continued pemivibart clinical activity against SARS-COV-2 variants that have predominated across the timespan that includes the CANOPY clinical trial and the post-EUA authorization period. Additionally, new potential antibodies based upon the structural framework of pemivibart are continuously under evaluation. Fifteen of these yeast-produced “pemivibart-like” antibodies were tested for neutralization activity against recent variants KP.3 and KP.3.1.1. Like pemivibart, all 15 maintained activity against KP.3.1.1, with the change in IC50averaging 2.51-fold +/-0.7 compared to KP.3. Four pemivibart-like antibodies were also tested against the XEC variant, with the change in IC50averaging 3.01-fold compared to KP.3. These data suggest continued activity for pemivibart and pemivibart-like antibodies against KP.3.1.1 and XEC, recent variants containing N-terminal domain modifications.
Ventilatory Burden Predicts Change in Sleepiness Following Positive Airway Pressure in Sleep Apnea
Authors: Staykov Eric , Mann Dwayne L. , Kainulainen Samu , Leppänen Timo , Töyräs Juha , Azarbarzin Ali , Sands Scott A. , Terrill Philip I.
Published: November 2024

Rationale

Excessive daytime sleepiness, an important symptom of obstructive sleep apnea (OSA), is commonly quantified using the Epworth Sleepiness Scale score (ESS). Baseline OSA severity measures (ventilatory burden, flow limitation, and hypoxemia) provide insights into OSA pathophysiology and could predict changes in sleepiness (i.e. change-in-ESS) following continuous positive airway pressure (CPAP) treatment.

Objectives

We hypothesized that change-in-ESS following CPAP treatment can be predicted from baseline polysomnography.

Methods

Associations between OSA severity measures and ESS were evaluated in 2332 participants, adjusting for age, sex, BMI, and total sleep time. Change-in-ESS prediction was evaluated using 213 CPAP treatment studies (HomePAP, BestAIR, and ABC) in three steps: severity measures were compared (adjusted regression,n=64), a prediction model was developed using baseline ventilatory burden and baseline ESS (n=139), and then evaluated in holdout participants (n=74).

Measurements and Main Results

In cross-sectional analysis, ESS was associated with ventilatory burden (0.45 points/SD; 95% CI 0.23−0.67), hypoxic burden (0.39; 0.17−0.62), the apnea-hypopnea index (AHI) (0.36; 0.14−0.59), and flow limitation severity (0.22; 0.01−0.43). Comparison analysis revealed that change-in-ESS was most strongly associated with baseline ventilatory burden (-1.08 points/SD; -2.13 to -0.05) and baseline ESS (-2.75; -3.83 to -1.69); the AHI association was weaker (-0.97; -2.01−0.05). Predicted change-in-ESS and actual change-in-ESS were correlated in holdout participants (adjustedR²=0.313); median [IQR] actual change-in-ESS of predicted responders (≥2-point ESS improvement,n=54, 73.0%) was -5.0 [-10.0 to -2.0] and non-responders was 0.0 [-1.0−1.0] (P<0.001).

Conclusions

Baseline ventilatory burden and baseline ESS were independently associated with change-in-ESS and could be used together to inform clinicians whether CPAP treatment will likely improve a patient’s sleepiness.
MUSCLE: Muscle Understanding through Synthetic Computation and Lesion Evaluation A Semi-Synthetic Dataset for Hamstring Injury Prediction Using Electrical Impedance
Authors: Youssef Baby Lea , Shehayib Reem , Maalouf Noel
Published: November 2024

Hamstring Injuries (HSIs) are common among athletes and necessitate extended rehabilitation before Return to Sport (RTS). Post-injury, athletes undergo physical examinations, which often fall short in assessing injury severity or guiding rehabilitation. Therefore, imaging techniques such as Magnetic Resonance Imaging (MRI) are used to evaluate the injury more comprehensively, aiding in the assessment of optimal rehabilitation and RTS timelines. Given the significant impact of HSIs on athletic careers, early prediction is essential. This article investigates the use of Electrical Impedance Tomography (EIT) for HSI prediction. EIT, a noninvasive method, involves injecting a current or voltage into the affected area to detect property changes, allowing for real-time monitoring and supporting its role in HSI prediction. A semi-synthetic dataset was created using MRI scans of patients with hamstring injuries. The dataset was developed by mapping the boundaries of the hamstring muscles (semimembranosus, semitendinosus, and biceps femoris) with Electrical Impedance Tomography and Diffuse Optical Tomography Reconstruction Software (EIDORS). EIDORS generated EIT voltage measurements by defining muscle boundaries and setting appropriate properties, forming the basis for the dataset. Machine Learning (ML) models were then employed to validate the dataset by distinguishing between injured and healthy hamstrings. The best-performing model, Random Forest (RF), achieved an accuracy of 98%, demonstrating the potential of EIT in predicting HSIs.

Abstract Figure

Figure 1:

Graphical Abstract
Usefulness of apparent diffusion coefficient values and magnetic resonance imaging histogram analysis for identifying histological types of preoperative testicular tumors
Authors: Yasuda Yuka , Osaka Akiyoshi , Izumi Keita , Iwahata Toshiyuki , Nakayama Akinori , Kubota Kazunori , Saito Kazutaka
Published: November 2024

This study aimed to evaluate the ability of magnetic resonance imaging (MRI), including diffusion-weighted imaging with apparent diffusion coefficient values, to differentiate histological types of testicular tumors. Of 156 testicular tumors diagnosed at our hospital between January 2010 and July 2023, 65 cases with MRI were included. Tumors were categorized as seminoma, non-seminoma, and malignant lymphoma. Apparent diffusion coefficient values were calculated and analyzed using the ratio to normal testes and histograms according to tumor subtypes. Among the 65 cases, 46 were seminomas, 14 non-seminomas, and 5 malignant lymphomas. The apparent diffusion coefficient value ratio of seminomas was significantly higher than that of malignant lymphomas (p = 0.013). Additionally, the apparent diffusion coefficient value ratio of non-seminomas was significantly higher than that of seminomas and malignant lymphomas (p = 0.0013 and p < 0.001, respectively). On apparent diffusion coefficient histograms, malignant lymphomas had significantly higher values of kurtosis and skewness than seminomas. Normal testes and non-seminomas had significantly higher kurtosis and skewness values than that of malignant lymphomas and seminomas. A scoring model for seminomas and malignant lymphomas, developed with age and apparent diffusion coefficient value ratios, discriminated against the probability of seminoma and malignant lymphomas. MRI using apparent diffusion coefficient values and histogram analysis may aid the histological typing of seminomas, non-seminomas, malignant lymphomas.
Monandrous flies do remate: plastic and evolutionary consequences of heat exposure on mating behaviour and fertility in Drosophila subobscura
Authors: Grandela Afonso , Antunes Marta A , Santos Marta A , Quina Ana S , Costa Isabel R , Borges Guilherme , Matos Margarida , Rodrigues Leonor R , Simoes Pedro
Published: November 2024

Recent work has reinforced the importance of fertility in predicting population persistence under global warming, especially male fertility. However, most studies on mating and reproductive performance have used as model organism polyandrous species, remaining unclear if and how will monandrous species respond. This is unfortunate as one could expect monandrous species to be particularly susceptible, given their inability to use sperm from multiple males to prevent reduced progeny production due to male sterility. It could be that monandrous females can overcome this toll in fertility by plastically changing their mating rate, or that monandrous populations evolve the ability to remate upon repeated exposure to heat. To test this, we studied the real-time evolution as well as the thermal plastic response of two geographically distinct populations of the monandrous species Drosophila subobscura after 45 generations evolving under a warming scenario. We assessed the impact of heat on male mating behaviour and fertility, as well as the impact of reduced male fertility on female mating behaviour and fertility. We found that in males the toll in mating behaviour due to heat can be recovered with time, whereas that in reproductive success cannot. On the other hand, females exposed to heat-stressed males significantly increased their remating rate, allowing to recover considerably their own reproductive success. Interestingly, most responses were plastic, with no striking effect of adaptation to warming nor of geographical origin. Our work brings new insights into the effects of heat on monandrous species and establishes a model to study how a shift in mating system may affect species' ability to respond to climate change.
ER Ca2+-levels control neuromodulator secretion by regulating L-type Ca2+-channel activity
Authors: Hoogstraaten Rein I. , Toonen Ruud F. , Verhage Matthijs
Published: November 2024

Regulated secretion typically depends on activity-induced Ca2+influx. However, in invertebrates, the endoplasmic reticulum (ER) plays a distinct role, particularly in the release of neuromodulators from dense-core vesicles (DCVs). Here, we investigated the role of the neuronal ER as a Ca2+source for neuromodulator secretion in primary mouse neurons by directly monitoring ER and cytosolic Ca2+dynamics, along with DCV exocytosis at single vesicle resolution. During neuronal activity, neurons with a low initial [Ca2+]ERtook up Ca2+into the ER, while those with a high initial [Ca2+]ERreleased ER Ca2+. These latter neurons showed more DCV exocytosis. Acute ER Ca2+release by caffeine or thapsigargin application, resulted in minute increases in bulk cytosolic free Ca2+that did not trigger DCV exocytosis. Remarkably, following ER Ca2+depletion levels, activity-dependent Ca2+influx and DCV exocytosis were reduced by 50-90%, while synaptic vesicle (SV) exocytosis was unaffected. L-type Ca2+-channel inhibition by nimodipine reduced DCV exocytosis and Ca2+influx by 80-90 % without affecting SV exocytosis, a phenocopy of ER store depletion. In addition, introducing L-type channels lacking STIM1 interaction sites restored DCV fusion following ER store depletion. We conclude that the ER functions as a dynamic Ca2+store serving both as a Ca2+source or sink. Moreover, ER depletion activates a feedback loop that controls L-type Ca2+channel activity, essential for DCV exocytosis.
Stakeholder perspectives on the effectiveness of the Ifakara-Lupiro-Mang’ula Wildlife Management Area in Southern Tanzania
Authors: Tarimo Lucia J. , Kavishe Deogratius R. , Butler Fidelma , Killeen Gerry F. , Mombo Felister
Published: November 2024

In Tanzania, Wildlife Management Areas (WMAs) are established on village lands, usually adjacent to centrally managed core protected areas like national parks and game reserves, and managed in a devolved manner by local village authorities. WMAs are intended to conserve wildlife outside such core protected areas, while also providing opportunities for local communities to derive tangible benefits from wildlife and other natural resources. This study evaluates the perceived effectiveness of the Ifakara-Lupiro-Mang’ula (ILUMA) WMA in southern Tanzania among various stakeholders, focusing on its conservation, livelihoods and community development functions. Based on thematic analysis of perspectives shared by stakeholders at national, regional, district and village levels through in-depth interviews, focus group discussions and a public stakeholders meeting, the WMA was considered to have succeeded to only a very modest extent in achieving its intended goals. Essentially all participants narrated that the area is heavily encroached by human activities, including livestock grazing, agriculture, illegal fishing, meat poaching, deforestation, charcoal burning, timber harvesting and even permanent settlements. Contributing factors include a recently growing influx of agro-pastoralist immigrants, top-down political interference, financial constraints, financial mismanagement, limited resources for operations, lack of conservation education, investors or government support, and recent displacement of encroachment pressure from newly upgraded, centrally-managed protected areas nearby. To ensure future success and sustainability of the WMA, participants recommended enhancing stakeholder involvement and community participation in WMA management, improved collaboration with nearby centrally-managed protected areas for implementing operations, overhaul of the WMA constitution to reflect current best practices, building capacity among relevant village leaders and elected WMA representatives and initiating conservation education initiatives for the local community. Overall, the WMA should explore alternative income sources beyond tourism, to ensure direct benefits for the community member through sustainable, carefully-regulated access to natural resources, and resolve ongoing conflict over land use between the long-established villages that govern ILUMA and agro-pastoralists immigrants who have moved into the area more recently.
Influenza A virus transcription generates capped cRNAs that activate RIG-I
Authors: Elshina Elizaveta , Pitre Emmanuelle , Mendes Marisa , Schweibenz Brandon , Fan Rebecca L.Y. , French Hollie , Park Ji Woo , Wang Wei , Poon Leo L.M. , Marcotrigiano Joseph , Russell Alistair B. , te Velthuis Aartjan J.W.
Published: November 2024

During influenza A virus (IAV) infection, host pathogen receptor retinoic acid-inducible gene I (RIG-I) detects the partially complementary, 5ʹ-triphosphorylated ends of the viral genome segments and non-canonical replication products. However, it has also been suggested that innate immune responses may be triggered by viral transcription. In this study, we investigated whether an immunostimulatory RNA is produced during IAV transcription. We show that the IAV RNA polymerase can read though the polyadenylation signal during transcription termination, generating a capped complementary RNA (ccRNA), which contains the 5ʹ cap of an IAV mRNA and the 3ʹ terminus of a cRNA instead of a poly(A) tail. ccRNAs are detectablein vitroand in both ribonucleoprotein reconstitution assays and IAV infections. Mutations that disrupt polyadenylation enhance ccRNA synthesis and increase RIG-I-dependent innate immune activation. Notably, while ccRNA itself is not immunostimulatory, it forms a RIG-I agonist by hybridizing with a complementary negative-sense viral RNA. These findings thus identify a novel non-canonical IAV RNA species and suggest an alternative mechanism for RIG-I activation during IAV infection.
Identification of a novel begomovirus betasatellite and occurrence of a viral complex associated with leaf curl disease in Bhut Jolokia in Assam
Authors: Saikia Richita , Paswan Ricky Raj , Borah Basanta Kumar
Published: November 2024

Bhut Jolokia (Capsicum chinenseJacq.) is one of the hottest chillies and an economically important crop in the northeastern regions of India. A major problem in the cultivation of Bhut Jolokia is the occurrence of leaf curl disease, which causes huge annual economic losses. The present study reveals the viral complex associated with the leaf curl disease in Bhut Jolokia collected from different geographical locations in Assam. A novel begomovirus betasatellite component was identified in two Bhut Jolokia samples, which was phylogenetically distinct from known begomovirus betasatellites. DAS-ELISA and PCR analysis confirmed the presence of multiple plant viruses including Chilli leaf curl virus (ChiLCV), Cucumber mosaic virus (CMV), Potato virus Y (PVY) and Tomato leaf curl virus (ToLCV) in most of the naturally infected Bhut Jolokia samples. Phylogenetic analysis revealed that thecoat protein(CP) gene of ChiLCVs and ToLCVs were highly conserved compared to theCPof CMV.