bluuebunny/crossref_metadata_2025 huggingface dataset:
Quasilinear modelling of collisional trapped electron modes
Authors: Stephens C.D. , Citrin J. , van de Plassche K.L. , Bourdelle C. , Tala T. , Salmi A. , Jenko F.
Published: December 2024

The simplification of collision operators is necessary for quasilinear turbulence modelling used with integrated modelling frameworks, such as the gyrokinetic code QuaLiKiz. The treatment of collisions greatly impacts the accuracy of trapped electron mode (TEM) modelling, which is necessary to predict the electron heat flux and the balance between inward and outward particle fluxes. In particular, accurate particle flux predictions are necessary to successfully model density peaking in the tokamak core. We explored two ways of improving collisional TEM model reduction for tokamak core plasmas. First, we carried out linear GENE simulations to study the complex interplay between collisions and trapped electrons. We then used these simulations to define an effective trapped fraction to characterize the collisional TEM based on two key parameters, the local inverse-aspect ratio

$\epsilon$

and the collisionality

$\nu ^\ast$

. One aspect missing from analytical TEM research is that the collisional frequency and the bounce-transit frequency are both velocity dependent; this effective trapped fraction takes both into account. In doing so, we determined that two parameters are not enough to model the collisional TEM, as an additional third free parameter was necessary. We determined that this model, as currently formulated, is not suitable for integrated modelling purposes. Second, we directly improved QuaLiKiz's Krook operator, which relies on two free parameters. We determined that these parameters required adjustments against higher-fidelity collisional models. In order to improve density profile predictions when paired with integrated models, we refined the Krook operator by using GENE simulations as a higher-fidelity point of comparison. We then demonstrate strong improvement of density peaking predictions of QuaLiKiz within the integrated modelling framework JETTO.
Supramolecular transparent plastic engineering via covalent-and-supramolecular polymerization
Authors: Zhang Yunfei , Cai Changyong , Guo Zhiyuan , Li Xing , Zhao Gai , Dong Shengyi
Published: December 2024

Inspired by the toughening phenomena in biological systems, a synergistic covalent-and-supramolecular polymerization strategy was applied to construct mechanically strong transparent materials.
Predictors of Concordance between Patient-Reported and Provider-Documented Symptoms in the Context of Cancer and Multimorbidity
Authors: Gilbertson-White Stephanie , Albashayreh Alaa , Ji Yuwen , Bandyopadhyay Anindita , Zeinali Nahid , Cherwin Catherine
Published: December 2024

Background The integration of patient-reported outcomes (PROs) into clinical care, particularly in the context of cancer and multimorbidity, is crucial. While PROs have the potential to enhance patient-centered care and improve health outcomes through improved symptom assessment, they are not always adequately documented by the health care team.

Objectives This study aimed to explore the concordance between patient-reported symptom occurrence and symptoms documented in electronic health records (EHRs) in people undergoing treatment for cancer in the context of multimorbidity.

Methods We analyzed concordance between patient-reported symptom occurrence of 13 symptoms from the Memorial Symptom Assessment Scale and provider-documented symptoms extracted using NimbleMiner, a machine learning tool, from EHRs for 99 patients with various cancer diagnoses. Logistic regression guided with the Akaike Information Criterion was used to identify significant predictors of symptom concordance.

Results Our findings revealed discrepancies in patient and provider reports, with itching showing the highest concordance (66%) and swelling showing the lowest concordance (40%). There was no statistically significant association between multimorbidity and high concordance, while lower concordance was observed for women, patients with advanced cancer stages, individuals with lower education levels, those who had partners, and patients undergoing highly emetogenic chemotherapy.

Conclusion These results highlight the challenges in achieving accurate and complete symptom documentation in EHRs and the necessity for targeted interventions to improve the precision of clinical documentation. By addressing these gaps, health care providers can better understand and manage patient symptoms, ultimately contributing to more personalized and effective cancer care.
Anti-Interference High-Speed Modulation Decoder for Quantum Key Distribution
Authors: Xu 许 Hua-Xing 华醒 , Wang 王 Shao-Hua 少华 , Wang 王 Chang-Lei 昌雷 , Zhang 张 Ping 平
Published: December 2024

Quantum key distribution is increasingly transitioning toward network applications, necessitating advancements in system performance, including photonic integration for compact designs, enhanced stability against environmental disturbances, higher key rates, and improved efficiency. In this letter, we propose an orthogonal polarization exchange reflector Michelson interferometer model to address quantum channel disturbances caused by environmental factors. Based on this model, we designed a Sagnac reflector-Michelson interferometer decoder and verified its performance through an interference system. The interference fringe visibility exceeded 98% across all four coding phases at 625 MHz. These results indicate that the decoder effectively mitigates environmental interference while supporting high-speed modulation frequencies. In addition, the proposed anti-interference decoder, which does not rely on magneto-optical devices, is well-suited for photonic integration, aligning with the development trajectory for next-generation quantum communication devices.
Differences in severity of reticulo-rumen pH drop in primiparous Holstein cows fed the same diet during transition and early lactation: effects on performance, energy balance, blood metabolites, and reproduction
Authors: Castillo-Lopez Ezequias , Hartinger Thomas , Farghaly Mohsen M , Reisinger Nicole , Lang Claudia , Klambauer Laura , Huber Johann , Zebeli Qendrim
Published: December 2024

We recently reported factors leading to different severity of ruminal pH drop in primiparous cows fed the same diet during transition and early lactation. The present study evaluates the effects of those severities on performance and several blood and balance parameters in the same 24 primiparous cows from 3 wk before calving until week 10 in lactation. The dietary concentrate was increased for all cows from 32 before calving to 60% dry matter (DM) basis over the first week in lactation, resulting in a diet with 40% non-fiber carbohydrates (NFC), and 14.4% physically effective fiber [peNDF > 8]. Ruminal pH was monitored with indwelling systems in all cows during the study; then several indices of duration and magnitude of pH change were used as indicators of the severity of ruminal pH drop. Accordingly, as reported in the companion paper, the cows were classified as either higher pH drop (HIGH; n = 9), moderate (MOD; n = 9), or lower (LOW; n = 6) severity of pH drop. In the present report, body weight, body condition score, and back fat thickness decreased but rumen mucosa thickness increased after calving in all cows (P < 0.05). Post-partum daily energy intake in HIGH was greater (P < 0.05) than in the other categories. In addition, there were 5.6 kg extra of energy-corrected milk in HIGH (P < 0.05). Independent of the severity of pH drop, blood glucose, non-esterified fatty acids, beta-hydroxybutyrate, bilirubin, and cortisol were higher, whereas triglycerides, total protein, globulin, albumin, urea nitrogen, cholesterol, calcium, and phosphorous were lower at calving (P < 0.05). Blood cholesterol was greater in HIGH than the other pH categories (P < 0.05); insulin and reproductive variables were not affected by the severity of the pH drop. Overall, primiparous cows fed the same diet showed different severity of ruminal pH drop, but the individual variation in ruminal pH depression was not related to a negative impact on milk yield, energy balance, or blood metabolites during the study. This indicates that the impact of low ruminal pH on the animals may depend not only on the severity of the pH drop (average of 403 min/d of pH < 5.8 over 13 wk) but also on diet characteristics. Specifically, drops of ruminal pH can be tolerated by primiparous cows during the first 10 wk in milk consuming a diet containing 40% NFC and 14.4% peNDF > 8. It would be worth studying the severity of ruminal pH drop in a larger sample size during the entire lactation and if the severity is sustained on the next lactation.
Opposition or Acquiescence to Neoliberal Hegemony? A Sociological Analysis of the Use of Human Rights Frames in UK Social Movements
Authors: Duncan John
Published: December 2024

Building on recent work in the field of sociology of rights which emphasizes the ‘social life of rights’ and the interaction between micro-level social constructions via social movement action, and macro-level systemic forces, this paper constructs a counter-hegemonic theory of human rights. By drawing on both Gramscian theories and a Social Reproduction Theory framework, a novel view of neoliberal hegemony is described. The role of human rights as part of this hegemony is then clarified as an essential element of the production of consent to hegemony. This hegemonic form of human rights is contrasted against a counter-hegemonic construction which is grounded in data generated from 10 in-depth qualitative interviews conducted with social movement activists in the UK. Three findings generated from the data are described. The activists interviewed 1) consistently rejected hegemonic, legal/non-governmental organization human rights structures; 2) used human rights as an introduction to their activism and a base upon which further critiques are built; and 3) frequently used human rights to contest the commodification of socially reproductive goods. Considering these findings, the role of contesting hegemonic constructions of human rights in resisting wider neoliberal hegemony is considered. While counter-hegemonic rights are not considered to have produced the level of social movement action required to overcome deeply embedded neoliberalism, counter-hegemonic human rights hold the potential to contribute to challenging the production of both consent and coercion to neoliberalism in the UK.
Intestinal stem cells in intestinal homeostasis and colorectal tumorigenesis
Authors: Shi Gaoli , Li Yang , Shen Haihong , He Qiankun , Zhu Pingping
Published: December 2024

Colorectal cancer (CRC), one of the most common tumors in the world, is generally proposed to be generated from intestinal stem cells (ISCs). Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5)-positive ISCs are located at the bottom of the crypt and harbor self-renewal and differentiation capacities, serving as the resource of all intestinal epithelial cells and CRC cells as well. Here we review recent progress in ISCs both in non-tumoral and tumoral contexts. We summarize the molecular mechanisms of ISC self-renewal, differentiation, and plasticity for intestinal homeostasis and regeneration. We also discuss the function of ISCs in colorectal tumorigenesis as cancer stem cells and summarize fate dynamic, competition, niche regulation, and remote environmental regulation of ISCs for CRC initiation and propagation.
A phase II trial of larotrectinib in tumors with NTRK fusions or extremes of NTRK mRNA overexpression identified by comprehensive genomic profiling
Authors: Thavaneswaran Subotheni , Sim Hao-Wen , Grady John , Espinoza David , Huang Min Li , Lin Frank , McGrath Margaret , Desai Jayesh , Charakidis Michail , Brown Michael , Kansara Maya , Simes John , Thomas David
Published: December 2024

Background

TRK-inhibitors have demonstrated efficacy across several cancers with NTRK fusions. Their activity in cancers with NTRK overexpression remains unclear.

Methods

This trial enrolled patients with advanced cancers harboring NTRK fusions or extreme mRNA overexpression, defined as NTRK1/2/3 expression by RNA profiling >5 SDs for a given cancer type. The primary endpoint was objective response rate (ORR), with secondary endpoints including time-to-progression (TTP) ratio [TTP on study to TTP on previous systemic therapy (TTP1)], progression-free survival (PFS), and overall survival (OS). Initially planned for 2 non-comparator groups: primary central nervous system (CNS) and non-CNS tumours with NTRK fusions, the protocol was amended to permit NTRK overexpression.

Results

Seventeen patients were treated with larotrectinib: one glioblastoma with a SPECC1L::NTRK2 fusion (group 1), and a peripheral nerve sheath tumor with a TPM3::NTRK1 fusion and 15 patients with overexpression (group 2). The ORR was 6%. An additional 3 of 12 (25%) TTP1-evaluable patients achieved a TTP ratio ≥1.3 and 2 of 5 without an evaluable TTP1 had a PFS >6 months. Median PFS and OS were 3.5 (95% CI, 1.4-6.0) and 15.9 months (95% CI, 6.4-NR), respectively.

Conclusion

Unlike its efficacy in NTRK-fusion positive cancers, larotrectinib did not demonstrate a signal of efficacy among tumors with NTRK overexpression.
Making responsible research and innovation meaningful in citizen science
Authors: Tauginienė Loreta , Butkevičienė Eglė , Heinisch Barbara , Massetti Luciano , Ugolini Francesca , Popov Snežana
Published: December 2024

This study aims to explore what aspects of citizen science (CS) make the involvement of researchers (implementing CS projects) meaningful in terms of Responsible Research and Innovation (RRI) principles. Using constructivist grounded theory, we analysed semi-structured interviews conducted with 20 CS projects in terms of sensemaking and sensegiving. In terms of sensemaking, researchers of CS projects tend to implicitly self-incorporate RRI principles into work and among these principles, public engagement and inclusion are key aspects motivating researchers into CS projects. In terms of sensegiving, researchers prioritize open access and science education over other RRI principles. The lack of acknowledgment of RRI’s importance in the current research culture proves to be a significant barrier to implementing these principles in a sustained manner. Likewise, experiential learning was widely practised; however, CS projects encountered different concerns and dilemmas. Therefore, tailored training on RRI is necessary for researchers involved in CS projects.
Cardiovascular diseases in patients with cancer: A comprehensive review of epidemiological trends, cardiac complications, and prognostic implications
Authors: Alshahrani Ali A. , Kontopantelis Evangelos , Morgan Catharine , Ravindrarajah Rathi , Martin Glen P. , Mamas Mamas A.
Published: December 2024

This article provides an overview of the current evidence on the epidemiology, overlapping risk factors, and pathophysiology of cardiovascular disease (CVD) in patients with cancer. It explores the cardiotoxic effects of anticancer therapy and their impact on prognosis. Although cancer survival rates have improved over the last two decades, the risk of CVD has risen over time in patients with cancer. CVD and cancer share similar risk factors and a common pathophysiology involving inflammation. Many chemotherapeutic agents used to treat cancer are associated with cardiovascular complications (such as heart failure, myocardial infarction, and thrombosis). Current evidence indicates a significant burden of CVD in patients with cancer, particularly in the first year following cancer diagnosis, with elevated risk persisting beyond this period. This short- and long-term risk of CVD may vary depending on the cancer type and treatment regimen. Early identification of potential cardiovascular risk in patients with cancer, can lead to more favorable clinical and survival outcomes. Given the acute and long-term consequences, patients with cancer require increased cardiovascular care and lifestyle optimization. This article offers valuable insights into the cardiovascular burden and needs of patients with cancer. It is intended for a general medical research readership interested in the intersection of cardiology and oncology.
Design of semi-open prosthetic socket with constant force for lower limb
Authors: Wang Minghui , Song Jianguo , Nong Qingjun , Qian Yu , Yan Xianbo , Yu Hongliu
Published: December 2024

Background:

Prosthetic socket is a key component of the prosthesis for clinical application; its performance directly affects the adaptation of the residual limb to the prosthetic socket. There are long-term and short-term volume fluctuation of the residual limb. The volume fluctuation of the residual limb will lead to the pressure mismatch at the interface of the residual limb and the prosthetic socket, which will cause a series of skin and fit problems. The volume fluctuation of the residual limb is considered a key factor for the successful application of the prosthetic socket; its solution is imminent. The purpose of this paper is to design a prosthetic socket with a constant force unit to solve the problem of volume fluctuation of the residual limb.

Methods:

Constant force extrusion for the residual limb is proposed to solve the problem in this paper. A constant force unit is designed based on the superelasticity of shape memory alloy, and a semi-open prosthetic socket embedded in the constant force unit is designed. The constant force property of prosthetic socket is optimized and verified by finite element analysis.

Results:

The constant force unit obtains a maximum constant force region of 9.36 mm at 13 mm applied displacement, and the minimum stress amplitude is 0.0264%.

Conclusions:

The semi-open prosthetic socket may achieve constant pressure at the interface between the residual limb and prosthetic socket within a certain range of the residual limb volume change, and it has a lightweight, good heat dissipation, size adjustability, and constant interface pressure.
Validity and reliability of Glittre activities of daily living test in lower-limb prosthetic users
Authors: Çiftçi Özge , Yurt Yasin , Koltak Cansu , Eker Levent
Published: December 2024

Background:

Functional capacity assessments have an important role in determining the level of mobility in lower-limb prosthetic users.

Objectives:

Our aim was to investigate the reliability and validity of the Glittre activities of daily living (ADL) test in lower-limb prosthetic users.

Study design:

A cross-sectional study.

Methods:

The study included 66 people over the age of 18 years who had used a lower-limb prosthesis for at least 6 months and could walk at least 30 m independently. For construct validity, the correlation of the Glittre ADL test with the 2-min walk test, timed up and go test, and functional reach test was examined, and Bland-Altman agreement analysis was performed. Intra-rater reliability was examined with 2 tests performed by the same physiotherapist on different days, and inter-rater reliability was examined with a test performed by a second physiotherapist on a different day.

Results:

The reliability of the Glittre ADL test was found to be excellent for intra-rater (intraclass correlation coefficient = 0.940, 95% confidence interval = 0.903–0.963, standard error of measurement = 26.03, minimal detectable change = 72.31) and good for inter-rater (intraclass correlation coefficient = 0.890, 95% confidence interval = 0.806–0.936, standard error of measurement = 36.80, minimal detectable change = 102.06, p < 0.001). There was a strong negative correlation between Glittre ADL test and 2-min walk test (r = −0.785), a strong positive correlation with timed up and go (r = 0.805), and a weak negative correlation with functional reach test (r = −0.266, p < 0.05). Bland-Altman plots showed 95% agreement for both validity and reliability measurements.

Conclusions:

The Glittre ADL test is a valid and reliable test that can be used in the assessment of functional capacity in lower extremity prosthesis users.
Effects of dynamic elastomeric fabric orthoses in children with cerebral palsy: A single-blind randomized controlled trial
Authors: Bezgin Sabiha , Novak Iona , Çobanoğlu Gamze , Elbasan Bülent
Published: December 2024

Background:

The dynamic elastomeric fabric orthoses (DEFOs) are made of neoprene material, providing the right biomechanical alignment and afferent input in the trunk, pelvis, and extremities, potentially allowing individuals to actively participate in daily life.

Objective:

The aim of this study was to investigate the effects of DEFOs applied to the lower trunk and pelvis, on balance, gait parameters, and pelvic symmetry in children with cerebral palsy (CP).

Study Design:

An evaluator-blinded randomized controlled trial.

Methods:

Twenty-two children (7 girls, 15 boys) aged 4–10 years, with spastic CP, Gross Motor Function Classification System levels 1 and 2 were included. Thirteen children were randomly assigned to the control group (group 1) and 13 to the orthosis group (group 2), but 4 withdrew before treatment commenced. There were 10 children in group 1 and 12 in group 2. Both groups received a physiotherapy and rehabilitation program twice a week for 8 weeks. Children in group 2 received lower body and pelvis DEFOs in addition to physiotherapy and rehabilitation sessions. Dynamic elastomeric fabric orthoses wearing tolerance was gradually built up over the first week, until the child was wearing the DEFO 8 h per day. The pediatric balance scale and timed up and go test were used to assess balance, while gait parameters and pelvic kinematic values were evaluated using the BTS G-Walk, a wireless mini digital gait analysis system. All of the measurement tools used were validated for CP.

Results:

Only stride length among the gait parameters changed in the group using DEFO compared with the group not using it (p = 0.035). There was no change in gait speed and cadence nor were there any differences in the balance scores between the groups. However, the pelvic tilt in the frontal plane of the pelvis improved significantly in the group using DEFOs compared with the group not using it (p = 0.014).

Conclusions:

Dynamic elastomeric fabric orthoses used in the lower body and pelvis conferred superior stride length and the pelvic tilt in the frontal plane to conventional physiotherapy. All other outcomes were equally effective between groups.
Designing equipment to allow high-level pararowing for a person with bilateral transfemoral amputation: A case report
Authors: Janvier Guillaume , Cotinat Maëva , Viton Jean-Michel , Timsit Michele , Bensoussan Laurent , Prieur-Blanc Nicolas
Published: December 2024

Rowing requires both the upper and lower body to be active for balance, steering, and propulsion, constituting a real challenge for athletes with disabilities. To our knowledge, adapted setups allowing pararowing for people with bilateral transfemoral amputation have not yet been described. This case report describes the adapted setup for Mr S, 24 years old, who underwent bilateral transfemoral amputation in 2019 after a motorcycle accident. He walks with 2 prostheses and practices high-level para-rowing in the Para-Rowing 2 single sculls category. We designed 2 prostheses consisting of a liner (Iceross Seal-In® X5 TF), an adapted socket, a knee (aqua-knee 3WR95), and a prosthetic foot (RushHiPro). We also designed a seat made of Plastazote and thermoplastic polymer foot rests. This equipment allows Mr S to wear his prostheses, which helps him to stabilize in the boat and to use maximum trunk amplitude during the rowing movement. However, the weight of the current equipment limits Mr S’s performance. This case study demonstrates that it is possible to adapt equipment to allow an individual with double transfemoral amputation to perform pararowing at competition level.
demres: An R package to study time-varying demographic resilience
Authors: Louvrier Julie , Courtiol Alexandre , White Ella W. , Clark Adam T. , Benhaiem Sarah , Radchuk Viktoriia
Published: December 2024

Quantifying the resilience of populations to disturbances is essential to assess how threatened populations are. Demographic resilience has been defined as the ability of populations to resist and recover from alterations in their demographic structures. Resilience metrics are typically obtained by applying transient analyses to matrix population models. Until now, the questions of how demographic resilience can change over time, how to quantify such temporal variation and when it is important to account for it have not yet been studied. However, since demographic rates fluctuate over time, it is essential to evaluate whether and under what conditions the assumption of time-constant demographic resilience remains appropriate.

In this study we introduce demres - an R package that offers functions to quantify time- varying and time-constant demographic resilience metrics, including time to convergence, damping ratio, inertia, maximum amplification, maximum attenuation and reactivity. The package also allows the comparison of these two approaches, both visually and by means of distance metrics.

We use a case study to illustrate the versatility of demres and demonstrate how this tool can be readily used by conservation biologists, managers and others to assess the time- varying resilience of wildlife populations using long-term demographic data. Our framework facilitates standardised comparisons of demographic resilience metrics, for example by means of comparative studies across populations and species.
A multiscale electro-metabolic model of a rat neocortical circuit reveals the impact of ageing on central cortical layers
Authors: Farina Sofia , Cattabiani Alessandro , Mandge Darshan , Shichkova Polina , Isbister James B. , Jacquemier Jean , King James G. , Markram Henry , Keller Daniel
Published: December 2024

The high energetic demands of the brain arise primarily from neuronal activity. Neurons consume substantial energy to transmit information as electrical signals and maintain their resting membrane potential. These energetic requirements are met by the neuro-glial-vascular (NGV) ensemble, which generates energy in a coupled metabolic process. In ageing, metabolic function becomes impaired, producing less energy and, consequently, the system is unable to sustain the neuronal energetic needs. We propose a multiscale model of electro-metabolic coupling in a reconstructed rat neocortex. This combines an electro-morphologically reconstructed electrophysiological model with a detailed NGV metabolic model. Our results demonstrate that the large-scale model effectively captures electro-metabolic processes at the circuit level, highlighting the importance of heterogeneity within the circuit, where energetic demands vary according to neuronal characteristics. Finally, in metabolic ageing, our model indicates that the middle cortical layers are particularly vulnerable to energy impairment.
When does sexual selection through mate choice deplete versus exaggerate genetic variation: is there a lek paradox?
Authors: Xu Kuangyi , Servedio Maria R.
Published: December 2024

The evolution of female preferences for male display traits relies on females receiving indirect benefits from their choice of mate. This requires substantial genetic variation in display traits or male quality. Nevertheless, sexual selection through mate choice has been assumed to deplete this genetic variation and thus ultimately diminish strong preferences. In fact, sexual traits often have higher genetic variation than non-sexual traits. The puzzle presented by this pattern, and, relatedly, how costly preferences and display traits are maintained, is known as the “lek paradox”. Using infinitesimal models, we show that, contrary to prior suppositions, sexual selection through mate choice may exaggerate genetic variance in male display traits and female preferences, provided that the variance of female preferences relative to the male trait at the stage of mate choice is not too small and preferences are not too weak. In fact, even if preference variation is substantially smaller than trait variation, trait variation can still increase over the case of random mating, as long as selection on the trait is sufficiently strong compared to that on preferences. When trait variation does decrease, we find this reduction to be generally slight. It is under situations such as lekking, in which females can simultaneously choose from many males so that mate discrimination tends to be effectively strong and the cost of choice weak, that sexual selection through mate choice should be expected to be the most powerful in exaggerating genetic variance in male displays.

Significance statement

The “lek paradox” – how variation in sexual display traits can be maintained, and mating preferences persist, over evolutionary time – has been one of the most enduring mysteries of the sexual selection literature. We clarify the multiple pathways by which sexual selection via mate preferences alters the genetic variance in display traits and female preferences. Using a mathematical model, we show that the lek paradox is built upon a false premise. We find a wide range of realistic conditions under which sexual selection will increase or minimally reduce variation in display traits, allowing mating preferences to be maintained in a population.
Mu-opioid receptor activation potentiates excitatory transmission at the habenulo-peduncular synapse
Authors: Singhal Sarthak M. , Szlaga Agata , Chen Yen-Chu , Conrad William S. , Hnasko Thomas S.
Published: December 2024

The continuing opioid epidemic poses a huge burden on public health. Identifying the neurocircuitry involved and how opioids modulate their signaling is essential for developing new therapeutic strategies. The medial habenula (MHb) is a small epithalamic structure that projects predominantly to the interpeduncular nucleus (IPN) and represents a mu-opioid receptor (MOR) hotspot. This habenulo-peduncular (HP) circuit can regulate nicotine and opioid withdrawal; however, little is known about the physiological impact of MOR on its function. Using MOR-reporter mice, we observed that MORs are expressed in a subset of MHb and IPN cells. Patch-clamp recordings revealed that MOR activation inhibited action potential firing in MOR+MHb neurons and induced an inhibitory outward current in IPN neurons, consistent with canonical inhibitory effects of MOR. We next used optogenetics to stimulate MOR+MHb axons to investigate the effects of MOR activation on excitatory transmission at the HP synapse. In contrast to its inhibitory effects elsewhere, MOR activation significantly potentiated evoked glutamatergic transmission to IPN. The facilitatory effects of MOR activation on glutamate co-release was also observed from cholinergic-defined HP synapses. The potentiation of excitatory transmission mediated by MOR activation persisted in the presence of blockers of GABA receptors or voltage-gated sodium channels, suggesting a monosynaptic mechanism. Finally, disruption of MOR in the MHb abolished the faciliatory action of DAMGO, indicating that this non-canonical effect of MOR activation on excitatory neurotransmission at the HP synapse is dependent on pre-synaptic MOR expression. Our study demonstrates canonical inhibitory effects of MOR activation in somatodendritic compartments, but non-canonical faciliatory effects on evoked glutamate transmission at the HP synapse, establishing a new mode by which MOR can modulate neuronal function.
Combined deletion of ZFP36L1 and ZFP36L2 drives superior cytokine production in T cells at the cost of cell fitness
Authors: Zandhuis Nordin D. , Bradarić Antonia , van der Zwaan Carmen , Hoogendijk Arie J. , Popović Branka , Wolkers Monika C.
Published: December 2024

A key feature of cytotoxic CD8+T cells for eliminating pathogens and malignant cells is their capacity to produce pro-inflammatory cytokines, which includes TNF and IFNγ. Provided that these cytokines are highly toxic, a tight control of their production is imperative. RNA-binding proteins (RBPs) are essential for the fine-tuning of cytokine production. The role of the RBP ZFP36L1 and its sister protein ZFP36L2 herein has been established, however, their relative contribution to cytokine production is not well known. We here compared the effect of ZFP36L1 and ZFP36L2 single and double deficiency in murine effector CD8+T cells. Whereas single deficient T cells significantly increased cytokine production, double deficiency completely unleashed the cytokine production. Not only the TNF production was substantially prolonged in double-deficient T cells. Also, the production of IFNγ reached unprecedented levels with >90% IFNγ–producing T cells compared to 3% in WT T cells, even after 3 days of continuous activation. This continuous cytokine production by double-deficient T cells was also observed in tumor-infiltrating lymphocytes in vivo, however, with no effect on tumor growth. Rather, ZFP36L1 and ZFP36L2 double deficiency resulted in decreased cell viability, impaired STAT5 signaling, and dysregulated cell cycle progression. In conclusion, while combined deletion in ZFP36L1 and ZFP36L2 can drive continuous cytokine production even under chronic activation, safeguards are in place to counteract such super-cytokine producers.
Doublet decoding of tRNASer3demonstrates plasticity of ribosomal decoding center
Authors: Krishnaswamy Shruthi , Akbar Shirin , Larsson Daniel S. D. , Chen Yang , Selmer Maria
Published: December 2024

Frameshifts can be caused by specific combinations of tRNA and mRNA. The wildtype AGC-decodingE. colitRNASer3GCUwas in the 1980s shown to induce -1 ribosomal frameshifting on GCA alanine codons, and proposed to read a two-base codon instead of a canonical triplet. It has remained unclear whether this type of non-cognate decoding can be accommodated by the ribosome. We here performed single-particle cryo-EM reconstructions onE. coli70S ribosomes with the frameshift-inducing tRNASer3bound to the non-cognate GCA codon or the cognate AGC codon in the ribosomal A site. The structures demonstrate that doublet-decoding is made possible when A1493, the conserved monitoring base in 16S rRNA, mimics a first codon base, forming a Hoogsteen base pair with U36 from the anticodon and stacking with the mRNA. This interaction pushes the first two bases of the A-site codon in position for base pairing with C35 and G34 of the anticodon.
EnzymeCAGE: A Geometric Foundation Model for Enzyme Retrieval with Evolutionary Insights
Authors: Liu Yong , Hua Chenqing , Zeng Tao , Rao Jiahua , Zhang Zhongyue , Wu Ruibo , Coley Connor W , Zheng Shuangjia
Published: December 2024

Enzyme catalysis is fundamental to life, driving the chemical transformations that sustain biological processes and support industrial applications. However, unraveling the intertwined relationships between enzymes and their catalytic reactions remains a significant challenge. Here, we present EnzymeCAGE, a catalytic-specific geometric foundation model trained on approximately 1 million structure-informed enzyme-reaction pairs, spanning over 2,000 species and encompassing an extensive diversity of genomic and metabolic information. EnzymeCAGE features a geometry-aware multi-modal architecture coupled with an evolutionary information integration module, enabling it to effectively model the nuanced relationships between enzyme structure, catalytic function, and reaction specificity. EnzymeCAGE supports both experimental and predicted enzyme structures and is applicable across diverse enzyme families, accommodating a broad range of metabolites and reaction types. Extensive evaluations demonstrate EnzymeCAGE’s state-of-the-art performance in enzyme function prediction, reaction de-orphaning, catalytic site identification, and biosynthetic pathway reconstruction. These results highlight its potential as a transformative foundation model for understanding enzyme catalysis and accelerating the discovery of novel biocatalysts.
Higher-Order Interactions in Neuronal Function: From Genes to Ionic Currents in Biophysical Models
Authors: Reva Maria , Arnaudon Alexis , Zbili Michael , Markram Henry , Goaillard Jean-Marc , Van Geit Werner
Published: December 2024

Neuronal firing patterns are the consequence of precise variations in neuronal membrane potential, which are themselves shaped by multiple ionic currents. In this study, we use biophysical models, statistical methods, and information theory to explore the interaction between these ionic currents and neuron electrophysiological phenotype. We created numerous electrical models with diverse firing patterns using Monte Carlo Markov Chain methods. By analyzing these models, we identified intricate relationships between model parameters and electrical features. Our findings show that neuronal features are often influenced by multiple ionic currents sharing synergistic relationships. We also applied our methods to single-cell RNAseq data, discovering gene expression modules specific to certain interneuron types. This research sheds light on the complex links between biophysical parameters and neuronal phenotypes.
No time to waste: A synthesis of evidence on time reallocation following water, sanitation and hygiene interventions
Authors: Sharma Waddington Hugh , Dickin Sarah K , Basak Kishore , Mohandas Saranya , Macura Biljana
Published: December 2024

Large amounts of time are wasted globally by households who need access to improved water for domestic uses and sanitation. The burden of inadequate access mainly affects women and girls in low- and middle-income countries. We conducted a systematic review and meta-analysis based on evidence mapping initiatives. The evidence synthesis found mean reductions of 15 minutes per trip for water supply, and 3 minutes per trip for sanitation interventions, adding up to around 8 hours per week and 3.5 hours per week respectively at the household level. Time savings from improvements in water supplies were very large, whether improved water supplies were provided at the household or community level. In contrast, studies on water treatment reported small time increases, and there were no studies that reported time following hygiene interventions. We found limited evidence on time reallocation to other activities, but disaggregated data showed girls were significantly more likely to attend school following WASH interventions. This policy-relevant evidence synthesis contributes to the case for increasing investments in appropriate water supply and sanitation interventions.
Large language models for conducting systematic reviews: on the rise, but not yet ready for use – a scoping review
Authors: Lieberum Judith-Lisa , Töws Markus , Metzendorf Maria-Inti , Heilmeyer Felix , Siemens Waldemar , Haverkamp Christian , Böhringer Daniel , Meerpohl Joerg J. , Eisele-Metzger Angelika
Published: December 2024

Background

Machine learning (ML) promises versatile help in the creation of systematic reviews (SRs). Recently, further developments in the form of large language models (LLMs) and their application in SR conduct attracted attention.

Objective

To provide an overview of ML and specifically LLM applications in SR conduct in health research.

Study design

We systematically searched MEDLINE, Web of Science, IEEEXplore, ACM Digital Library, Europe PMC (preprints), Google Scholar, and conducted an additional hand search (last search: 26 February 2024). We included scientific articles in English or German, published from April 2021 onwards, building upon the results of a mapping review with a related research question. Two reviewers independently screened studies for eligibility; after piloting, one reviewer extracted data, checked by another.

Results

Our database search yielded 8054 hits, and we identified 33 articles from our hand search. Of the 196 included reports, 159 described more traditional ML techniques, 37 focused on LLMs. LLM approaches covered 10 of 13 defined SR steps, most frequently literature search (n=15, 41%), study selection (n=14, 38%), and data extraction (n=11, 30%). The mostly recurring LLM was GPT (n=33, 89%). Validation studies were predominant (n=21, 57%). In half of the studies, authors evaluated LLM use as promising (n=20, 54%), one quarter as neutral (n=9, 24%) and one fifth as non-promising (n=8, 22%).

Conclusions

Although LLMs show promise in supporting SR creation, fully established or validated applications are often lacking. The rapid increase in research on LLMs for evidence synthesis production highlights their growing relevance.

HIGHLIGHTS

Machine learning (ML) offers promising support for systematic review (SR) creation.

GPT was the most commonly used large language model (LLM) to support SR production.

LLM application included 10 of 13 defined SR steps, most often literature search.

Validation studies predominated, but fully established LLM applications are rare.

LLM research for SR conduct is surging, highlighting the increasing relevance.
Release strategies affect the freshwater residence and survival of hatchery-reared juvenile Chinook Salmon
Authors: Balfour Thomas J. B. , Hurwitz David J. A. , Atkinson Jamieson B. , Martins Eduardo G.
Published: December 2024

Objective

This study investigated the effects of size, location and timing of release on the freshwater residence and survival hatchery-reared Chinook Salmon (Oncorhynchus tshawytscha) in the Toquaht River, BC.

Methods

Juvenile salmon were PIT tagged and released on three separate dates (May 23, June 9 and 19, 2021) and three distinct locations within the river (lower river [below lake], lake, and upper river [above lake]). Fish were detected near the river mouth using a PIT array, and detection data were analyzed with an integrated model of freshwater residence and capture-recapture using Bayesian inference.

Result

The median duration of freshwater residence was 13.8 days and was longer for fish released in the lake and upper river earlier in the study. The median survival probability was 0.35 and it was higher for fish released in the lake and upper river later in the study. Both freshwater residence time and survival declined with fish size at release.

Conclusion

These findings highlight that hatchery release strategies can significantly influence survival and freshwater residence times, underscoring the need for adaptable management practices.

Impact statement

Juvenile Chinook Salmon survival during freshwater residence and outmigration is strongly influenced by hatchery release strategies, thus optimizing these strategies is key for hatcheries to support the recovery of salmon populations.
Phage-displayed synthetic library and screening platform for nanobody discovery
Authors: Xia Baolong , Kim Ah-Ram , Liu Feimei , Han Myeonghoon , Stoneburner Emily , Makdissi Stephanie , Cara Francesca Di , Mohr Stephanie E. , Ring Aaron M. , Perrimon Norbert
Published: December 2024

Nanobodies, single-domain antibodies derived from camelid heavy-chain antibodies, are known for their high affinity, stability, and small size, which make them useful in biological research and therapeutic applications. However, traditional nanobody generation methods rely on camelid immunization, which can be costly and time- consuming, restricting their practical feasibility. In this study, we present a phage- displayed synthetic library for nanobody discovery. To validate this approach, we screened nanobodies targeting variousDrosophilasecreted proteins. The nanobodies identified were suitable for applications such as immunostaining and immunoblotting, supporting the phage-displayed synthetic library as a versatile platform for nanobody development. To address the challenge of limited accessibility to high-quality synthetic libraries, this library will be openly available for non-profit use.
Understanding genetic architecture overcomes tradeoffs between seed quality and insect resistance
Authors: White Joseph R. , McNellie James P. , Keepers Kyle G. , Smart Brian C. , Portlas Zoe M. , Marcus Zach E. , Kane Nolan C. , Prasifka Jarrad R. , Hulke Brent S.
Published: December 2024

The sunflower (Helianthus annuus) pericarp protects the seed within from both abiotic and biotic stresses. Achenes with stronger pericarps are less susceptible to damage from insect feeding. Complicating the genetic improvement of pericarp strength is the negative correlation between pericarp thickness (a component of strength) and oil content. As breeding efforts have increased oil content, there has been a concomitant decrease in pericarp thickness. A logical sunflower improvement goal is to improve oil content while preserving pericarp strength through genetic mechanisms independent of the tradeoffs with pericarp thickness. To determine the genetic basis of oil content, pericarp strength, and thickness, we identified QTL in two populations; the Sunflower Association Mapping panel (Mandel et al., 2011) and a recombinant inbred line (RIL) population derived from a thin pericarp oilseed inbred (HA 467) crossed to a thick pericarp open pollinated variety from Türkiye (PI 170415). A region on chromosome 15 was associated with neighboring QTL for banded moth resistance, oil content, and pericarp thickness, partially underlying the trade-offs among these traits. Additional QTL on chromosome 5 and 14 for pericarp strength provide fewer trade-offs with oil content. QTL for pericarp strength on chromosome 5 and pericarp thickness on chromosome 16 were associated with large structural variants, with candidate gene presence/absence variation between the haplotypes on chromosome 5. Understanding the origin and nature of phenotypic tradeoffs is beneficial to plant biologists and sunflower breeders as they seek to understand the origin and genetic architecture of adaptive and maladaptive traits.
A single main-chain hydrogen bond required to keep GABAAreceptors closed
Authors: Borghese Cecilia M. , Galpin Jason D. , Lidbrink Samuel Eriksson , Zhuang Yuxuan , Desai Netrang G. , Howard Rebecca J. , Lindahl Erik , Ahern Christopher A. , Goldschen-Ohm Marcel P.
Published: December 2024

GABAAreceptors are the primary inhibitory neurotransmitter receptors throughout the central nervous system. Despite significant progress understanding their three-dimensional structure, a critical gap remains in determining the molecular basis for channel gating. We recently identified M2-M3 linker mutations that suggest linker flexibility has asymmetric subunit-specific correlations with channel opening. Here we use non-canonical amino acids (ncAAs) to investigate the role of main-chain H-hydrogen bonds (H-bonds) that may stabilize the M2-M3 linkers. We show that a single main-chain H-bond within the β2 subunit M2-M3 linker inhibits pore opening and is required to keep the unliganded channel closed. Furthermore, breaking this H-bond during channel opening accounts for approximately one third of the activation energy derived from GABA binding. In contrast, the analogous H-bond in the α1 subunit has no effect on gating. Our observations suggest that channel opening involves state-dependent breakage/disruption of a specific main-chain H-bond within the β2 subunit M2-M3 linker.