bluuebunny/crossref_metadata_2025 huggingface dataset:
Phenolic, antioxidant capacity and antinutritional compounds in different Australian acacia seeds
Authors: Chong Wei Shan Cassandra , Tilbrook Dale , Pereira Gavin , Dykes Gary A , George Nicholas , Coorey Ranil
Published: February 2025

The polyphenols, antioxidant activities and antinutrients in Acacia seeds of different species, growing locations and harvest years were characterised in this study. The main phenolic compounds were 6-hydroxy-2-methylindole and 2,2′-methylenebis(6-tert-butyl-methylphenol). The total phenolic and total flavonoid contents of the free polyphenol fractions were positively correlated, while the total phenolic content and ABTS, DPPH and ORAC of the bound fractions were negatively correlated. There were no differences in trypsin and chymotrypsin inhibition activities across all seed batches. The lowest phytate (11.1038 ± 0.006 mg/g) and tannin contents (2.0323 ± 0.7462%) were found in Acacia retinodes Amphitheatre 2020 and A. retinodes Firgrove 2022, respectively. The highest saponin (45.4578 ± 12.2990%) and oxalate contents (4.2396 ± 0.7949%) were found in A. retinodes Grampians 2020 and A. retinodes Firgrove 2020, respectively. The results of this study showed differences in antioxidant activities and antinutrients content which implies that compositional values should not be extrapolated between different species and harvest years.
Food loss and waste reduction by using industry 4.0 technologies: examples of promising strategies
Authors: Arshad Rai Naveed , Abdul-Malek Zulkurnain , Parra-López Carlos , Hassoun Abdo , Qureshi Muhammad Imran , Sultan Aysha , Carmona-Torres Carmen , Waal Jennifer Mignonne , Jagtap Sandeep , Garcia-Garcia Guillermo
Published: February 2025

Food loss and waste represent a significant global issue, posing a threat to food sustainability on a worldwide scale. Approximately one-third of the food produced for human consumption is wasted, resulting in substantial environmental impact and economic loss. However, the growing awareness among consumers and the development of emerging technologies driven by the 4th Industrial Revolution (Industry 4.0) present numerous opportunities to reduce food loss and waste. This article provides a comprehensive examination of recently developed strategies for reducing food loss and waste. The role of Industry 4.0 technologies, such as the Internet of Things, artificial intelligence, cloud computing, blockchain, and big data, is highlighted through examples of various promising initiatives. The results of this analysis show that the application of digital technologies to address the issue of food loss and waste is on the rise globally, with Industry 4.0 technologies revolutionizing many sectors, including the food sector. This article could assist scholars and industry leaders in comprehending the urgency and significance of implementing Industry 4.0 in the food sector. Further research is necessary, and closer collaboration between producers, distributors, consumers, and other actors involved in the food supply chain is still required to reduce food loss and waste further.
Pricing weather derivatives and managing weather risks under regime switching
Authors: Li Peng , Wang Funing , Wang Limei , Liu Keying , Shen Jianwei , Zhong Weizhou
Published: February 2025

Accepted by: Aris Syntetos

A large number of empirical studies have shown that regime switching is an important characteristic of temperature processes. Thus, this work develops an efficient finite difference scheme with one-sided difference to price weather derivatives with the partial differential equations (PDEs) of regime-switching temperature models. For management purposes, an initial management model framework is then proposed to manage portfolios incorporating weather derivatives. This work also performs statistical analysis on the temperature dataset from Toronto, Canada and recalibrates the regime-switching temperature models, as one parameter value is found incorrect in the literature. Numerical experiments indicate that the finite difference scheme is much more competitive than the Monte Carlo simulations and the lattice approaches. The PDEs pricing approach has great potential to be used in practical portfolio management problems involving weather risks.
Life history strategies complement niche partitioning to support the coexistence of closely related Gilliamella species in the bee gut
Authors: Yang Chengfeng , Han Benfeng , Tang Junbo , Hu Jiawei , Qiu Lifei , Cai Wanzhi , Zhou Xin , Zhang Xue
Published: February 2025

The maintenance of bacterial diversity at both species and strain levels is crucial for the sustainability of honey bee gut microbiota and host health. Periodic or random fluctuation in diet typically alters the metabolic niches available to gut microbes, thereby continuously reshaping bacterial diversity and interspecific interactions. It remains unclear how closely related bacteria adapt to these fluctuations and maintain coexistence within the bee gut. Here, we demonstrate that the five predominant Gilliamella species associated with Apis cerana, a widely distributed Asiatic honey bee, have diverged in carbohydrate metabolism to adapt to distinct nutrient niches driven by dietary fluctuation. Specifically, the glycan-specialists gain improved growth on a pollen-rich diet, but are overall inferior in competition to non-glycan-specialist on either a simple sugar or sugar-pollen diet, when co-inoculated in the bee host and transmitted across generations. Strikingly, despite of their disadvantage in a high-sugar condition, the glycan-specialists are found prevalent in natural A. cerana guts. We further reveal that these bacteria have adopted a life history strategy characterized by high biomass yield on a low-concentration sugar diet, allowing them to thrive under poor nutritional conditions, such as when the bee hosts undergo periodical starvation. Transcriptome analyses indicate that the divergence in life history strategies is attributed to gene expression programming rather than genetic variation. This study highlights the importance of integrative metabolic strategies in carbohydrate utilization, which facilitate the coexistence of closely related Gilliamella species in a changing bee gut environment.
Factors associated with impaired physical functionality in x-linked hypophosphatemia
Authors: Ivanovic-Zuvic Danisa , Madison Annette , Jiménez Macarena , Oyanadel María Lorena , Gattini Natalia , Guzmán Carolina , Cifré Manuela , Silvestre Rony , García Cristián , Contreras Oscar , Collins Michael T , Florenzano Pablo
Published: February 2025

X-linked hypophosphatemia (XLH) is a rare inherited disorder characterized by elevated levels of fibroblast growth factor-23 (FGF23), chronic hypophosphatemia, impaired bone mineralization and chronic long-term manifestations. Treatment for XLH has been mainly focused on normalizing its biochemical abnormalities. Despite treatment, patients with XLH often present impaired physical function and decreased quality of life (QoL). We hypothesize that physical functionality and QoL is more strongly associated with chronic pain and decreased muscle mass than persistent biochemical abnormalities or exposure to conventional treatment. We conducted an observational, cross-sectional study with patients with XLH. Clinical records and biochemical parameters were assessed. QoL surveys SF36v.2 and WOMAC were applied. Functional status was measured by a physiatrist and an occupational therapist. Appendicular lean mass (ALM) was measured and compared to age and sex-matched healthy controls. Enthesopathies and osteoarthritis were evaluated. Pain was assessed using the Brief Pain Inventory, the Visual Analog Scale and the Doleur Neuropathique-4 scales. Muscle strength was evaluated by the Quadriceps Muscle isometric Strength (QMS) and physical performance with the 6-minute walk test (6MWT) and the Functional Independence Measure (FIM) scale. A total of 30 patients were included: 21 females; median age of 32 years. All participants had significant functional deficits, chronic pain and reduced QoL. Limitations in daily activities were significantly associated with higher severity of pain, decreased ALM, lower QMS, and less distance in 6MWT (P<.05). Neither FIM scale, phosphate levels, FGF23, nor the lifetime exposure to conventional treatment were associated with these functional variables. In conclusion, impaired physical functionality in patients with XLH was associated with lower muscle mass, lower muscle strength and severe chronic pain. These findings highlight the importance of, in addition to optimizing the biochemical control of the disease, expanding patient care including pain prevention and management as well as comprehensive physical therapy and rehabilitation.
Proteomic analysis and effects on osteogenic differentiation of exosomes from patients with ossification of the spinal ligament
Authors: Nakajima Hideaki , Johnson William E B , Kamitani Mikiko , Watanabe Shuji , Honjoh Kazuya , Kubota Arisa , Matsumine Akihiko
Published: February 2025

Ossification of the spinal ligament (OSL), including ossification of the posterior longitudinal ligament (OPLL) and ossification of the ligamentum flavum (OLF), is a multifactorial disease that includes genetic predisposition. The association between the rate of ossification in the spinal canal and the severity of myelopathy symptoms is well known, but the degree of progression varies widely among patients. Although many candidate genes and biomarkers have been reported, there are no definitive and quantitative conclusions to date, probably because of low reproducibility due to individual differences. In this study, we focused on exosomes secreted by ossified spinal ligament cells. Exosomes are crucial for intercellular communication during development and progression of disease. In a co-culture study of non-OLF cells with OLF cells, there was increased osteogenic differentiation, including Runx2 and Wnt3a expression, with use of exosome-penetrating filters (1.2 μm) compared to exosome-non-penetrating filters (0.03 μm). Dose-dependent increases in alkaline phosphatase activity and mineral deposition were observed in non-OLF cells treated with OLF-derived exosomes. These results support the hypothesis that OLF-derived exosomes are involved in regulation of osteogenic differentiation. In comparative proteomics analysis, 32 factors were increased and 40 were decreased in OLF-derived exosomes compared to non-OLF-derived exosomes. Molecular network analysis of these 72 factors indicated 10 significant pathways, including the MMP signaling, mTOR signaling, Wnt signaling and VDR-associated pathways. Among the upregulated exosomal membrane proteins in OLF samples, COL IV, FMNL3, mTORC2, and PIP4K showed increased expression with greater ossification, suggesting they may serve as biomarkers of disease activity and therapeutic targets. These factors are involved in the PI3K/Akt/mTOR signaling pathway, and particularly mTOR is known to regulate osteogenic and chondrogenic differentiation. In contrast, FABP5, several KRT family proteins, S100A8, SERPINB3, and TGM, were significantly downregulated in OLF-derived exosomes. These findings provide novel insights into the molecular mechanisms underlying OSL pathogenesis.
Minimally invasive solutions for ischiofemoral impingement: case analysis and evolving surgical strategies
Authors: Palma Inês , Nave Afonso , Torres Tiago , Neto Ana Luísa , Campos Martins José , Seco António
Published: February 2025

Variations in the femoral version are increasingly recognized as a cause of coxalgia due to impingement or instability. The true prevalence of these variations remains unknown. The authors report a case of bilateral ischiofemoral impingement (IFI) caused by excessive femoral anteversion treated with a subtrochanteric femoral derotational osteotomy and long intramedullary nailing. We report the case of a 22-year-old female patient with deep left hip pain, consistent with IFI, refractory to conservative treatment. Imaging revealed an ischiofemoral space (IFS) of 16 mm and a femoral anteversion of 34°. A subtrochanteric femoral derotational osteotomy stabilized with a long intramedullary nail was performed. At 18 months, the same surgical procedure was performed due to similar symptoms on the right side, with an IFS of 14 mm and femoral anteversion of 35°. Joint mobility was restored bilaterally, and the symptoms were resolved. Lesser trochanter resection has been reported as a surgical option for IFI in small case series. While conventional subtrochanteric femoral derotational osteotomy with plate fixation shows good functional outcomes, pseudarthrosis remains a concern. The authors’ minimally invasive technique using the backstroke technique for osteotomy site compression helps prevent this complication while preserving the iliopsoas insertion. In this case study, a subtrochanteric femoral derotational osteotomy effectively treated bilateral IFI associated with increased femoral anteversion. The patient achieved excellent clinical outcomes with complete symptom resolution following successful consolidation of both osteotomies, though subsequent implant removal was performed to facilitate potential future surgeries.
Current status of cancer genome medicine for pancreatic ductal adenocarcinoma
Authors: Doi Toshifumi , Ishikawa Takeshi , Moriguchi Michihisa , Itoh Yoshito
Published: February 2025

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis; however, advancements in cancer genome profiling using next-generation sequencing have provided new perspectives. KRAS mutations are the most frequently observed genomic alterations in patients with PDAC. However, until recently, it was not considered a viable therapeutic target. Although KRAS G12C mutations for which targeted therapies are already available are infrequent in PDAC, treatments targeting KRAS G12D and pan-KRAS are still under development. Similarly, new treatment methods for KRAS, such as chimeric antigen receptor T-cell therapy, have been developed. Several other potential therapeutic targets have been identified for KRAS wild-type PDAC. For instance, immune checkpoint inhibitors have demonstrated efficacy in PDAC treatment with microsatellite instability-high/deficient mismatch repair and tumor mutation burden–high profiles. However, for other PDAC cases with low immunogenicity, combination therapies that enhance the effectiveness of immune checkpoint inhibitors are being considered. Additionally, homologous recombination repair deficiencies, including BRCA1/2 mutations, are prevalent in PDAC and serve as important biomarkers for therapies involving poly (adenosine diphosphate-ribose) polymerase inhibitors and platinum-based therapies. Currently, olaparib is available for maintenance therapy of BRCA1/2 mutation-positive PDAC. Further therapeutic developments are ongoing for genetic abnormalities involving BRAF V600E and the fusion genes RET, NTRK, NRG, ALK, FGFR2, and ROS1. Overcoming advanced PDAC remains a formidable challenge; however, this review outlines the latest therapeutic strategies that are expected to lead to significant advancements.
Validation of five prognostic models treated with axitinib beyond first-line nivolumab plus ipilimumab therapy for metastatic renal cell carcinoma: a Japanese multicenter retrospective study
Authors: Kikuchi Hiroshi , Osawa Takahiro , Matsushita Yuto , Kojima Takahiro , Sazuka Tomokazu , Hatakeyama Shingo , Goto Keisuke , Numakura Kazuyuki , Yamana Kazutoshi , Kandori Shuya , Ueda Kosuke , Tanaka Hajime , Kurahashi Toshifumi , Bando Yukari , Kimura Takahiro , Nishiyama Naotaka , Kato Takuma , Hara Hiroaki , Ito Yoichi , Kitamura Hiroshi , Miyake Hideaki , Shinohara Nobuo
Published: February 2025

Objective

To validate multiple prognostic models in metastatic renal cell carcinoma patients who received second-line axitinib following first-line nivolumab plus ipilimumab therapy.

Methods

Five prognostic models (ACL, albumin, C-reactive protein, and lactate dehydrogenase; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; MSKCC, Memorial Sloan Kettering Cancer Center; ATP, axitinib treatment prediction; JMRC, Japanese metastatic renal cancer) to predict overall survival (OS) were validated and compared using data from 86 metastatic renal cell carcinoma patients who received second-line axitinib therapy following first-line nivolumab plus ipilimumab therapy at 34 hospitals affiliated with the Japan Urologic Oncology Group.

Results

The Karnofsky performance status, time from initial diagnosis to first-line therapy, and hemoglobin, platelet, albumin, and C-reactive protein levels correlated with OS in univariate Cox regression analyses. Among these factors, only albumin had a significant impact on OS in the multivariate analysis. The integrated area under the curve (AUC) of the ACL, IMDC, MSKCC, ATP, and JMRC models were 0.78, 0.76, 0.76, 0.69, and 0.70, respectively. The ACL model showed a higher value than the others in the time-dependent AUC.

Conclusions

The accuracy of the five prognostic models (ACL, IMDC, MSKCC, ATP, and JMRC) created in the pre–immuno-oncology (IO) treatment cohort was maintained in the second-line axitinib group after nivolumab plus ipilimumab therapy. The ACL model demonstrated moderate accuracy in predicting OS with the fewest number of clinical variables.
Real-world clinical usage and efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer: a multi-institutional study in the CsJUC
Authors: Tohi Yoichiro , Kobayashi Keita , Daizumoto Kei , Sekino Yohei , Fukuhara Hideo , Niigawa Heima , Katayama Satoshi , Shimizu Ryutaro , Takamoto Atsushi , Nishimura Kenichi , Nagami Taichi , Hayashida Yushi , Hirama Hiromi , Shiraishi Koji , Tomida Ryotaro , Kobatake Kohei , Inoue Keiji , Miyaji Yoshiyuki , Bekku Kensuke , Morizane Shuichi , Miura Noriyoshi , Wada Koichiro , Sugimoto Mikio ,   Chu-shikoku Japan Urological Consortium, Inoue Keiji , Yamamoto Shinkuro , Shiraishi Koji , Miyaji Yoshiyuki , Hinata Nobuyuki , Furukawa Junya , Araki Motoo , Kawada Tatsushi , Takenaka Atsushi , Saika Takashi , Wada Koichiro , Tohi Yoichiro , Kato Takuma , Naito Hirohito , Fukuhara Hideo , Kobayashi Keita , Ohira Shin , Daizumoto Kei , Sasaki Yutaro , Tomida Ryotaro , Katayama Satoshi , Shimizu Ryutaro , Nishimura Kenichi , Watanabe Ryuta , Nagami Taichi , Takamoto Atsushi , Niigawa Heima , Sekino Yohei , Kobatake Kohei , Sugimoto Mikio
Published: February 2025

Objective

To evaluate the real-world clinical usage and effectiveness of apalutamide in men with nonmetastatic castration-resistant prostate cancer (nmCRPC).

Methods

We retrospectively reviewed the data of 186 men who received apalutamide across 17 institutions. The primary outcomes were the clinical usage of apalutamide for nmCRPC: prior usage of other androgen receptor signaling inhibitors (ARSIs), prior radical treatment, and the distribution of the prostate-specific antigen (PSA) doubling time (PSA-DT) at the initial administration of apalutamide. The secondary outcomes were the efficacy of apalutamide: PSA response (50% or 90% decline), progression-free survival, and skin-adverse events (AEs).

Results

We identified 75 patients with nmCRPC. A total of 31 (41.3%) patients received prior treatment with other ARSIs. A total of 42 men (56%) did not receive any prior radical treatment. The PSA-DT was <3.0, 3.0–5.9, 6.0–10, and > 10 months in 34.7%, 40%, 14.7%, and 10.6% of the patients, respectively. Patients receiving prior treatment with other ARSIs showed a significantly lower PSA response (PSA 50% decline, 88.4% vs. 18.8%; PSA 90% decline, 60.5% vs. 6.2%, P < .001, respectively) and significantly shorter progression-free survival (median: 37 months vs. 4 months; log-rank P < .001) than those without prior ARSI treatment, although cancer status did not differ between the groups. Skin-AEs were observed in 42.7%.

Conclusions

This real-world study revealed that apalutamide was used for the treatment after other ARSIs in >40% of patients with nmCRPC and showed limited efficacy in this context, although the effectiveness of apalutamide without prior other ARSI treatment was comparable with that reported in clinical trial results.
Celebrating World Neglected Tropical Diseases Day: A Global Call to Unite, Act, and Eliminate Neglected Tropical Diseases
Authors: Wilder-Smith Annika B , Fuller L C , Parajuli Niraj
Published: February 2025

World Neglected Tropical Diseases (NTD) Day on January 30th, with the theme ‘Unite. Act. Eliminate.’, emphasizes the global fight against NTDs, underlining efforts to address the inequalities that perpetuate NTDs. This article explores the milestones and calls for sustained collaboration to achieve a healthier, more equitable future for vulnerable populations.
The single-berry metabolomic clock paradigm reveals new stages and metabolic switches during grapevine berry development
Authors: Tavernier Flora , Savoi Stefania , Torregrosa Laurent , Hugueney Philippe , Baltenweck Raymonde , Segura Vincent , Romieu Charles
Published: February 2025

Asynchronicity causes metabolic chimerism in usual grapevine phenological stages, calling for a revisit of berry development at the individual fruit scale. To reveal the dynamics of metabolite composition in grapevine berries without phenological a priori, a dataset of 9,256 ions was obtained on 125 fruits at different stages by non-targeted ultra-performance liquid chromatography coupled to high-resolution mass spectrometry. This large metabolomic dataset was submitted to an analysis workflow combining classification and dimension reduction tools. This led to the clustering of metabolites into 12 specific kinetic patterns and a metabolome-based definition of the pericarp intrinsic clock outperforming expert timing procedures. Such increased temporal resolution enabled the identification of metabolite clusters that are annunciative of the onset of ripening, noticeably characterized by transient lipidic changes and the start of ABA accumulation. We also highlighted a cluster of stilbenes that accumulate during terminal fruit shriveling, after the arrest of phloem unloading. This non-targeted approach enables a more precise characterization of grapevine berry development through the concept of metabolomic clock. The discovery of new metabolic milestones of berry development paves the way toward a better assessment of the impact of environmental changes on the metabolism of non-climacteric fruit, in different genotypes.
Red deer resequencing reveals the importance of sex chromosomes for reconstructing Late Quaternary events
Authors: de Jong Menno J , Anaya Gabriel , Niamir Aidin , Pérez-González Javier , Broggini Camilla , Membrillo del Pozo Alberto , Nebenfuehr Marcel , de la Peña Eva , Ruiz-Olmo Jordi , Seoane Jose Manuel , Vedel Giovanni , Barboiron Aurelie , Bartoš Luděk , Buzan Elena , Carden Ruth F , Darchiashvili Giorgi , Dragan Gačić , Frantz Alain C , Gérard Adrien , Gort-Esteve Araceli , Guillaumat Etienne , Hantschmann Anja , Hemami Mahmoud-Reza , Höglund Jacob , de Jong Joost F , Kerdikoshvili Niko , Kern Christian , Konjevic Dean , Koubek Petr , Karaiskou Nikoleta , Pellerin Maryline , Krojerová-Prokešová Jarmila , McDevitt Allan D , Merker Stefan , Pfenninger Markus , Røed Knut H , Saint-Andrieux Christine , Sarigol Fatih , Sykut Maciej , Triantafyllidis Alexandros , Pemberton Josephine , Saarma Urmas , Iacolina Laura , Niedziałkowska Magdalena , Zachos Frank E , Carranza Juan , Janke Axel
Published: February 2025

Sex chromosomes differ in their inheritance properties from autosomes, and hence may encode complementary information about past demographic events. We compiled and analysed a range-wide resequencing dataset of the red deer (Cervus elaphus), one of the few Eurasian herbivores of the Late Pleistocene megafauna still found throughout much of its historic range. Our analyses of 144 whole genomes reveal striking discrepancies between the population clusters suggested by autosomal and X-chromosomal data. We postulate that the genetic legacy of Late Glacial population structure is better captured and preserved by the X chromosome than by autosomes, for two reasons. First, X chromosomes have a lower Ne and hence lose genetic variation faster during isolation in glacial refugia, causing increased population differentiation. Second, following postglacial recolonisation and secondary contact, immigrant males pass on their X chromosomes to female offspring only, which effectively halves the migration rate when gene flow is male-mediated. Our study illustrates how a comparison between autosomal and sex chromosomal phylogeographic signals unravels past demographic processes which otherwise would remain hidden.
Are women with disabilities more at risk of intimate partner violence?
Authors: Hervé Justine , Theiss Katherine , Mitra Sophie
Published: February 2025

Women with disabilities may face heightened risks of intimate partner violence (IPV) given the discrimination and barriers they face in society. While some country-specific studies explore the link between disability and IPV, cross-country research remains limited. Using internationally comparable data for women aged 15–49 from eleven countries (Cambodia, Haiti, Kenya, Mali, Mauritania, Pakistan, Rwanda, Senegal, South Africa, Timor-Leste, and Uganda), we assess whether women with disabilities consistently face higher IPV risks. Controlling for socioeconomic and demographic factors, women with disabilities have a 6-percentage-point higher risk of IPV compared to those without (P < .05) in the pooled sample. At the country level, this association is significant in five countries. The link between disability and IPV also varies by type, with stronger associations for severe physical IPV (seven countries) and weaker associations for sexual IPV (two countries). Logit decomposition analysis in the five countries where the disability gap in exposure to IPV is significant shows that observed differences in characteristics account for part of the gap. However, unobserved factors, such as stigma, also play a significant role in driving the disparity. Additionally, our results suggest that the lack of consistent findings across countries may result from data limitations, such as small sample sizes, measurement errors, and reporting biases. This underscores the importance of developing evidence-based approaches to better measure disability and IPV in household surveys.
Layover start timing predicts layover sleep quantity and timing on Long-Range and Ultra-Long-Range trips
Authors: Rempe Michael J , Rasmussen Ian , Gregory Kevin , Johnson Cheyenne , Hsin Matthew , Flynn-Evans Erin , Hilditch Cassie J , Lamp Amanda
Published: February 2025

Study Objectives

Airline pilot sleep during layover is an important factor for alertness on subsequent flights. Assessing pilots’ sleep on layover is an important first step in helping them obtain the most recuperative sleep possible on layover. Here we investigate the quantity and timing of sleep during layovers and determine predictors for layover sleep.

Methods

Sleep was assessed in 256 pilots flying a total of 473 long-range (LR; flight time 12-16h) or ultra-long-range (ULR; flight time > 16h) trips. Sleep was assessed using actigraphy. We employed linear mixed-effects models with layover sleep characteristics as the outcomes. The predictor variables included operational factors and sleep history.

Results

Overall, pilots averaged 7.2 hours of sleep per 24 hours of layover, which was significantly less than their daily sleep before or after the trip. Layover start time (relative to home base time) was the most salient predictor of sleep timing and quantity during both shorter (∼24-h) and the first 24h of longer (∼48-h) layovers. During the last 24h of longer layovers, crew type predicted sleep quantity.

Conclusions

Although average sleep quantity during layovers was within the margins of recommended sleep duration, it was still less than pre- and post-trip sleep duration, suggesting modest sleep loss on layovers. Layover start timing was the strongest predictor of layover sleep quantity and timing and, thus, may be a modifiable factor to protect circadian-aligned sleep opportunities during layover.
Local urothelial cell-driven detrusor contractions
Authors: Alom Firoj , Ratcliff Kyle Joseph , Mickle Aaron D
Published: February 2025

Signaling molecules released from the urothelium by mechanical stretch are known to play a sensory role in bladder contractions via neuronal signaling. It is also theorized that these molecules released from the urothelium could act locally to induce urothelial cell-mediated local bladder contractions. In this study, we specifically stimulated the urothelial cells using optogenetics to investigate how the urothelial released signaling molecules can influence bladder contractions locally. Using anex-vivowhole bladder preparation, we stimulated the urothelial cells by activating channelrhodopsin-2 (ChR2) with blue light and initiated the urothelial cell-mediated local bladder contractions. The P2X receptor antagonist, PPADS, nearly abolished the contractions. The muscarinic receptor antagonist, atropine, significantly inhibited the contractions. Nifedipine, which blocks extracellular Ca2+entry, abolished the contractions. G protein-coupled receptor inhibitor YM-254890 significantly inhibited the contractions. Hemichannel inhibitor carbenoxolone disodium and the exocytotic pathway of transmitter release inhibitor brefeldin A also showed significant inhibition of the contractions. In conclusion, we validated the previous hypothesis that urothelial release factors can influence bladder contractions locally without the need for signaling from the central nervous system. Further studies are needed to determine the relevance of this signaling pathway in normal bladder physiology and pathophysiologic conditions.
B cell subsets have different capacities for phagocytosis and subsequent presentation of antigen to cognate T cells
Authors: Morelli Daniel M , Langille Morgan , Zhang Richard , Craig Heather C , Shooshtari Parisa , Heit Bryan , Kerfoot Steven M
Published: February 2025

B cells have been shown to be phagocytic under some circumstances. However, the phagocytic capacity of different B cell subsets and how this is linked to Antigen (Ag) presentation or other functions has not been characterized. To address this, we developed 2 µm phagocytic Ag conjugated bead targets that target phagocytic pathways including the BCR, scavenger, Fc, and complement receptors to study potential pathways by which B cells phagocytose both cognate and non-cognate Ags. We found that while follicular B2 (Fo B), marginal zone, and B1 B cells are highly phagocytic of BCR-engaging targets through their BCR, only peritoneal cavity B1 cells could uptake non-cognate Ag-coated beads or bacteria. Despite this, B1 cells were not effective at presenting Ag to activate cognate T cells or at killing phagocytosed bacteria. Finally, analysis of scRNA-seq data revealed that these differences in phagocytic capacity could not be explained by differential expression of relevant phagocytic receptors, implying that there is likely some form of regulation in place preventing non-cognate Ag uptake by Fo B cells. Our work will help contribute to a better understanding of non-classical Ag uptake mechanisms employed by B cells and their relevance to inflammation.
ECD co-operates with ERBB2 to promote tumorigenesis through upregulation of unfolded protein response and glycolysis
Authors: Kennedy Benjamin B. , Raza Mohsin , Mirza Sameer , Rajan Asher Rajkumar , Oruji Farshid , Storck Matthew M. , Lele Subodh M. , Reznicek Timothy E. , Li Lusheng , Rowley M. Jordan , Wan Shibiao , Mohapatra Bhopal C. , Band Hamid , Band Vimla
Published: February 2025

The ecdysoneless (ECD) mRNA and protein are overexpressed in breast cancer (BC), and its overexpression correlates with poor prognosis and short patient survival, particularly in ERBB2/HER2-positive BC. This study investigates the co-operative oncogenic mechanism of ECD and ERBB2 by deriving transgenic mice overexpressing ECD and/or ERBB2 (huHER2) in mammary epithelium under MMTV promoter, as well as human mammary immortal epithelial cell lines (hMECs) overexpressing ECD and/or ERBB2. WhilehuHER2Tg mice developed more homogenous solid nodular carcinomas, double transgenic mice (ECD;huHER2Tg) developed heterogenous and histologically aggressive mammary tumors with basal-like phenotype and epithelial mesenchymal transition (EMT) features, likeECDTg tumors, resembling more to patient tumors. Importantly, transcriptomic profile ofECD;huHER2Tg tumors revealed upregulation of two major oncogenic pathways, unfolded protein response (UPR) and glycolysis. Similarly, hMECs expressing both ECD and ERBB2 as compared to single gene expressing cells showed increase in oncogenic traits, and RNA-seq analysis showed a significant upregulation of glycolysis and UPR pathways. ECD is an RNA binding protein, and directly associates with three key glycolytic enzymes (LDHA,PKM2andHK2) and mRNA of a major UPR regulated gene GRP78, that results in increased mRNA stability. Lastly, we show an increase in glucose uptake and enhanced glycolytic rate in ECD+ERBB2-overexpressing cells as compared to ECD− or ERBB2-overexpressing hMECs. Taken together, our findings support a co-operative role of ECD and ERBB2 in oncogenesis by enhancing two major oncogenic pathways, UPR and glycolysis.

Significance

This study provides mechanistic insights that overexpression of ECD in ERBB2+ breast cancer patients correlates with shorter patient survival, by identifying direct ECD binding to mRNAs for UPR and glycolysis pathways.
Allosteric inhibition rescues hydrocephalus caused by catalytically inactive Shp2
Authors: Makrides Neoklis , Sun Emily , Mir Hilal , Jiang Ziyuan , Wu Yihua , Serra Carlos , Cardoso Wellington V , Shah Neel H. , Zhang Xin
Published: February 2025

SHP2, a protein tyrosine phosphatase (PTP) crucial in Ras-MAPK signaling, is associated with various human congenital diseases and cancers. Here, we show that the catalytically inactiveShp2C459Smutation results in communicating hydrocephalus, similar to the catalytically activatingShp2E76KandMek1DDmutants. Unlike previous mutants, however,Shp2C459S/+mutation uniquely affects ciliary development rather than neurogenesis, leading to reduced cilia density and impaired ciliary motility. Differential scanning fluorimetry revealed thatSHP2C459S, SHP2E76KandSHP2C459S/E76Kmutations all induce an open SHP2 conformation, but onlySHP2C459Sleads to aberrant GAB1 phosphorylation in cells expressing wild-type SHP2. This distinctive signaling pattern correlates with our observations in brain ventricular tissues ofShp2C459S/+mice, where Erk and Stat3 activities remain normal but Gab1 phosphorylation is elevated. Critically, we show that the hydrocephalus phenotype inShp2C459Smice can be mitigated by allosteric inhibition of Shp2. These findings suggest thatShp2-associated hydrocephalus is driven by conformational changes rather than altered catalytic activity. Our results underscore the therapeutic potential of conformation-specific allosteric inhibitors in targeting both catalytically active and inactiveSHP2mutants.
A small lipidated peptide targeting NaV1.8 channels attenuates osteoarthritic pain behavior and prevents bone erosion
Authors: Rodriguez Raider , Kuechle Joseph B. , Bhattacharjee Arin
Published: February 2025

Chronic pain is a major concern for patients with osteoarthritis (OA). Current treatments for OA-related pain often fail and may worsen the disease. The sodium channel subtype NaV1.8 has emerged as a potential target for treating pain, leading to the development of NaV1.8 inhibitors in clinical trials. We previously identified Magi-1, a WW domain-containing scaffold protein, as a regulator of NaV1.8 at the plasma membrane of nociceptive neurons. Disrupting the interaction between NaV1.8 and Magi-1 facilitated channel degradation in neurons, reducing pain behavior in multiple animal models. In this study, we investigated the impact of disrupting NaV1.8 scaffolding on an animal model of OA pain using genetic and pharmacological approaches. Genetic Magi-1 knockdown effectively attenuated established OA pain in mice. Pharmacological targeting of the NaV1.8-Magi-1 interaction in rats with a lipidated NaV1.8 WW binding domain decoy peptide inhibited pain behavior for multiple weeks. MicroCT imaging revealed minimal alterations in subchondral bone remodeling in animals injected with the lipidated decoy peptide compared to those receiving scrambled peptide-control animals. This suggested that the NaV1.8 peptidomimetic not only alleviated OA pain but also delayed joint degeneration. Our preclinical studies indicate that intraarticular injection of lipidated peptides capable of disrupting ion channel scaffolding in neurons can provide effective and sustained analgesia for several weeks after a single administration.
Esophageal adenocarcinoma relapse after chemoradiation is dominated by a basal-like subtype
Authors: Hoppe Sascha , Noseir Soha , Yazbeck Ali , Zaburannyi Nestor , Großbach Jan , Lyu Su Ir , Camacho Oscar Velazquez , Müller Stefan , Gebauer Florian , Richartz Vanessa , Holz Barbara , Berg Johannes , Achter Viktor , Altmüller Janine , Becker Kerstin , Arolt Christoph , Meder Lydia , Zhao Yue , Schlößer Hans , Baus Wolfgang W. , Kamp Florian , Baues Christian , Beyer Andreas , Odenthal Margarete , Quaas Alexander , Buettner Reinhard , Hillmer Axel M.
Published: February 2025

Neoadjuvant chemoradiation therapy (RCT) is a frequently used treatment regimen for esophageal adenocarcinoma (EAC); however, the response varies dramatically, and resistance is a clinical challenge. We aimed to identify the molecular mechanisms underlying RCT resistance. We established a mouse xenograft RCT model with human EAC cell lines representing different response groups, and tested enhanced genomic instability as a potential evolutionary modulator by reducingBRCA2function. Xenografts that relapsed after RCT displayed upregulation of stress response keratins, includingKRT6andKRT16connected with a basal-like transcriptomic/ proteomic phenotype. We screened our cohort of 728 patients with EAC and found significantly shorter overall survival for patients with KRT6-high tumors, driven by patients receiving neoadjuvant treatment. Overall, we identified a basal-like cell state in EAC that reflects RCT relapse. The basal-like subtype is a marker of treatment failure, providing a new avenue for translational research to overcome RCT resistance.
Database-Augmented Transformer-Based Large Language Models Achieve High Accuracy in Mapping Gene-Phenotype Relationships
Authors: Suhardi Nicolas Matthew , Oktarina Anastasia , Bostrom Mathias P.G. , Yang Xu , Suhardi Vincentius Jeremy
Published: February 2025

Transformer-based large language models (LLMs) have demonstrated significant potential in the biological and medical fields due to their ability to effectively learn from large-scale, diverse datasets and perform a wide range of downstream tasks. However, LLMs are limited by issues such as information processing inaccuracies and data confabulation, which hinder their utility for literature searches and other tasks requiring accurate and comprehensive extraction of information from extensive scientific literature. In this study, we evaluated the performance of various LLMs in accurately retrieving peer-reviewed literature and mapping correlations between 102 genes and four phenotypes: bone formation, cartilage formation, fibrosis, and cell proliferation. Our analysis included standard transformer-based LLMs (ChatGPT4o and Gemini1.5 Pro), fine-tuned LLMs with dedicated custom databases containing peer-reviewed articles (SciSpace and ScholarAI), and fine-tuned LLMs without dedicated databases (PubMedGPT and ScholarGPT). Using human-curated gene-to-phenotype mappings as the ground truth, we found that fine-tuned LLMs with dedicated databases (SciSpace and ScholarAI) achieved high accuracy (>80%) in gene-to-phenotype mapping. Additionally, these models were able to provide relevant peer-reviewed publications supporting each gene-to-phenotype correlation. These findings underscore the importance of database augmentation and finetuning in enhancing the reliability and utility of LLMs for biomedical research applications.
DyAb: sequence-based antibody design and property prediction in a low-data regime
Authors: Lin Joshua Yao-Yu , Hofmann Jennifer L. , Leaver-Fay Andrew , Liang Wei-Ching , Vasilaki Stefania , Lee Edith , Pinheiro Pedro O. , Tagasovska Natasa , Kiefer James R. , Wu Yan , Seeger Franziska , Bonneau Richard , Gligorijevic Vladimir , Watkins Andrew , Cho Kyunghyun , Frey Nathan C.
Published: February 2025

Protein therapeutic design and property prediction are frequently hampered by data scarcity. Here we propose a new model, DyAb, that addresses these issues by leveraging a pair-wise representation to predict differences in protein properties, rather than absolute values. DyAb is built on top of a pre-trained protein language model and achieves a Spearman rank correlation of up to 0.85 on binding affinity prediction across molecules targeting three different antigens (EGFR, IL-6, and an internal target), given as few as 100 training data. We employ DyAb in two design contexts: as a ranking model to score combinations of known mutations, and combined with a genetic algorithm to generate new sequences. Our method consistently generates novel antibody candidates with high binding rates, including designs that improve on the binding affinity of the lead molecule by more than ten-fold. DyAb represents a powerful tool for engineering therapeutic protein properties in low data regimes common in early-stage drug development.
SCGclust: Single Cell Graph clustering using graph autoencoders integrating SNVs and CNAs
Authors: Potu Teja , Hu Yunfei , Khan Rituparna , Dharani Srinija , Ni Jingchao , Zhang Liting , Zhou Xin Maizie , Mallory Xian
Published: February 2025

Intra-tumor heterogeneity (ITH) is a compounding factor for cancer prognosis and treatment. Single-cell DNA sequencing (scDNA-seq) provides cellular resolution of the variations in a cell and has been widely used to study cancer progression and responses to drug and treatment. While the low coverage scDNA-seq technologies typically provides a large number of cells, accurate cell clustering is essential for effectively characterizing ITH. Existing cell clustering methods typically are based on either single nucleotide variations (SNV) or copy number alterations (CNA), without leveraging both signals together. Since both SNVs and CNAs are indicative of the cell subclonality, in this paper, we designed a robust cell clustering tool that integrates both signals using a graph autoencoder. Our model co-trains the graph autoencoder and a graph convolutional network (GCN) to guanrantee meaningful clustering results and to prevent all cells from collapsing into a single cluster. Given the low dimensional embedding generated by the autoencoder, we adopted a Gaussian Mixture Model to further cluster cells. We evaluated our method on eight simulated datasets and a real cancer sample. Our results demonstrate that our method consistently achieves higher V-measure scores compared to SBMClone, a SNV-based method, and a K-means method, which relies solely on CNA signals. These findings highlight the advantage of integrating both SNV and CNA signals within a graph autoencoder framework for accurate cell clustering. SCGclust is publicly available athttps://github.com/compbio-mallory/cellClustering_GNN.
A unique two-excipient heat stable tablet formulation of oral insulin: preliminary results
Authors: Lai Manshun , Zhu Changcheng , Delarosa Jaclyn , Lal Manjari
Published: February 2025

We report a novel formulation approach for development of a thermostable oral insulin tablet. Using freeze drying to form a heat stable tablet in a single-step process, we demonstrate hydroxypropyl beta cyclodextrin (HP-β-CD) encapsulated lipophilic ion-pair complex of insulin using bile salt achieves intestinal absorption and sustained glucose levels. The tablets produced using this simple approach with only two excipients offer protection from enzymatic and stomach acid degradation and facilitate insulin uptake, without any need for specialized drug manufacturing or enteric coating. Insulin in this innovative formulation is thermotolerant, capable of maintaining stability even under heat stress at 30-40°C/65-75% RH. The convenient presentation of insulin as a thermostable oral tablet presents a low-cost scalable manufacturing method that simplifies the logistics of storage, transport, and distribution in any setting, including areas where cold storage maybe limited or unavailable.

Graphical Abstract

Our unique formulation approach protects insulin from stomach and temperature induced degradation, improves intestinal permeability providing a sustained release of insulin for glycemic control. The freeze dried tablet product format is easily scalable and flexible, increasing accessibility across all populations.
Latitudinal gradients in stable hydrogen isotopes of North American trees
Authors: Keppler Frank , Berger Lars , Greule Markus , Esper Jan , Wieland Anna
Published: February 2025

Stable hydrogen isotopes (δ2H values) of plant matter provide information about ambient climate conditions and physiological processes.δ2H values of tree stem wood methoxy groups (δ2HTM) are increasingly used to reconstruct the isotope composition of precipitation (δ2Hprecip) and temperature variability in mid latitudes regions. However, empirical evidence of the basic latitudinal gradients in North America and their inter-continental context are still missing. We sampled 104 tree cores in 13 North American sites ranging from 38°-69°N and investigated the relationship betweenδ2HTMandδ2Hprecipvalues. Recordedδ2HTMvalues are highly depleted in2H relative to meteoric water and align closely with predictions from a biochemical model. Reconstructed temperature changes, derived fromδ2HTMvalues, agree well with instrumental data in North American since 1932. Our results reveal that the latitudinal gradients ofδ2HTMvalues closely resembleδ2Hprecipvalues across North America. When combining these spatial patterns withδ2HTMandδ2Hprecipdata from Europe a strong correlation (R2= 0.94, p < 0.001) and a consistent fractionation of –193 ± 13 mUr, representative for Northern Hemisphere mid-to-high latitude sites, is established. The validation across North American and European transects serves as a foundational basis for advancing applications in biogeochemistry and paleoclimate research.
Managing risks and trade-offs in multispecies fisheries: the role of trophic control and price asymmetry
Authors: Villain Théo , Poggiale Jean-Christophe , Loeuille Nicolas
Published: February 2025

Ecosystem-based fisheries management (EBFM) aims to balance ecological and economic goals while employing precautionary measures to address uncertainties in knowledge and management. This study investigates fishing strategies to achieve this balance while minimizing the associated risks. Using a simplified prey-predator model, we explored various scenarios reflecting the diversity of global fisheries. The model integrates key ecological dynamics (bottom-up and top-down forces), economic factors (price structures), and aggregates the diversity of fishing practices by distributing fishing mortality across species. Our findings reveal that predators are always more affected by fishing than prey, regardless of the effort distribution. High yields are achieved by reducing predator densities—either maximizing predator catches when they are highly valued or reducing predation pressure to enhance prey harvests when prey prices are high. Such strategies result in significant ecological impacts, leading to systematic trade-offs. Elevated prey prices and top-down controlled systems intensify these trade-offs, increasing ecological risks. Regarding uncertainties, we demonstrate that maximizing yields poses risks to both biodiversity and profitability. Reconciliation is challenging but feasible when both species are fished. This balance can be achieved only in bottom-up controlled systems where prey valuation is not disproportionately high compared to predator prices.