bluuebunny/crossref_metadata_2025 huggingface dataset:
Homoplantaginin alleviates high glucose‐induced vascular endothelial senescence by inhibiting mtDNA–cGAS–STING pathway via blunting DRP1–mitochondrial fission–VDAC1 axis
Authors: Wang Lei , Zhang Xueying , Huang Xi , Sha Xiaotong , Li Xulu , Zheng Jianmei , Li Shitong , Wei Zhifeng , Wu Feihua
Published: October 2024

Vascular endothelial senescence is a major risk factor for diabetic vascular complications. Abnormal mitochondrial fission by dynamically related protein 1 (DRP1) accelerates vascular endothelial cell senescence. Homoplantaginin (Hom) is a flavonoid in Salvia plebeia R. Br. with protecting mitochondrial and repairing vascular properties. However, the relevant mechanism of Hom against diabetic vascular endothelial cell senescence remains unclear. Here, we used db/db mice and high glucose (HG)‐treated human umbilical vein endothelial cells (HUVECs) to assess the anti‐vascular endothelial cell senescence of Hom. We found that Hom inhibited senescence‐associated β‐galactosidase activity, decreased the levels of senescence markers, and senescence‐associated secretory phenotype factors. Additionally, Hom inhibited the expression of cGAS–STING pathway and downstream inflammatory factors. STING inhibitor H‐151 delayed endothelial senescence, whereas STING overexpression attenuated the anti‐endothelial senescence effect of Hom. Furthermore, we observed that Hom reduced mitochondrial fragmentation and inhibited abnormal mitochondrial fission using transmission electron microscopy. Importantly, Hom has a stronger effect on mitochondrial fission protein than mitochondrial fusion protein, especially downregulated the expression of DRP1. DRP1 inhibitor Mdivi‐1 suppressed cGAS‐STING pathway and vascular endothelial senescence, yet DRP1 agonist FCCP attenuated the effect of Hom. Surprisingly, Hom blunted abnormal mitochondrial fission mediated by DRP1 mitochondrial localization, suppressed interaction of DRP1 with VDAC1 and prevented VDAC1 oligomerization, which was necessary for mtDNA escape and subsequent cGAS–STING pathway activation. These results revealed a previously unrecognized mechanism that Hom alleviated vascular endothelial senescence by inhibited mtDNA–cGAS–STING signaling pathway via blunting DRP1–mitochondrial fission–VDAC1 axis.
Socioeconomic Status, Smoking, and Lung Cancer: Mediation and Bias Analysis in the SYNERGY Study
Authors: Hovanec Jan , Kendzia Benjamin , Olsson Ann , Schüz Joachim , Kromhout Hans , Vermeulen Roel , Peters Susan , Gustavsson Per , Migliore Enrica , Radoi Loredana , Barul Christine , Consonni Dario , Caporaso Neil E. , Landi Maria Teresa , Field John K. , Karrasch Stefan , Wichmann Heinz-Erich , Siemiatycki Jack , Parent Marie-Elise , Richiardi Lorenzo , Simonato Lorenzo , Jöckel Karl-Heinz , Ahrens Wolfgang , Pohlabeln Hermann , Fernández-Tardón Guillermo , Zaridze David , McLaughlin John R. , Demers Paul A. , Świątkowska Beata , Lissowska Jolanta , Pándics Tamás , Fabianova Eleonora , Mates Dana , Schejbalova Miriam , Foretova Lenka , Janout Vladimír , Boffetta Paolo , Forastiere Francesco , Straif Kurt , Brüning Thomas , Behrens Thomas
Published: October 2024

Background:

Increased lung cancer risks for low socioeconomic status (SES) groups are only partially attributable to smoking habits. Little effort has been made to investigate the persistent risks related to low SES by quantification of potential biases.

Methods:

Based on 12 case–control studies, including 18 centers of the international SYNERGY project (16,550 cases, 20,147 controls), we estimated controlled direct effects (CDE) of SES on lung cancer via multiple logistic regression, adjusted for age, study center, and smoking habits and stratified by sex. We conducted mediation analysis by inverse odds ratio weighting to estimate natural direct effects and natural indirect effects via smoking habits. We considered misclassification of smoking status, selection bias, and unmeasured mediator–outcome confounding by genetic risk, both separately and by multiple quantitative bias analyses, using bootstrap to create 95% simulation intervals (SI).

Results:

Mediation analysis of lung cancer risks for SES estimated mean proportions of 43% in men and 33% in women attributable to smoking. Bias analyses decreased the direct effects of SES on lung cancer, with selection bias showing the strongest reduction in lung cancer risk in the multiple bias analysis. Lung cancer risks remained increased for lower SES groups, with higher risks in men (fourth vs. first [highest] SES quartile: CDE, 1.50 [SI, 1.32, 1.69]) than women (CDE: 1.20 [SI: 1.01, 1.45]). Natural direct effects were similar to CDE, particularly in men.

Conclusions:

Bias adjustment lowered direct lung cancer risk estimates of lower SES groups. However, risks for low SES remained elevated, likely attributable to occupational hazards or other environmental exposures.
The mediating role of kinesiophobia in pain intensity, physical function, and physical activity level in inflammatory arthritis
Authors: Medrado Larissa Nakahata , Oliveira-Junior Silvio Assis de , Martinez Paula Felippe
Published: October 2024

Pain is the main symptom of inflammatory arthritis and it can impair physical functional performance and physical activity level. Some individuals can develop kinesiophobia and experience a vicious circle of worsening health. This study aimed to investigate the association between pain and physical functional performance/physical activity and determine whether kinesiophobia mediates this association. This was a cross-sectional study with individuals diagnosed with inflammatory arthritis (rheumatoid arthritis or spondyloarthritis) treated at a Rheumatology Outpatient Clinic. We assessed pain (Visual Analogue Scale), physical activity (International Physical Activity Questionnaire – long form), kinesiophobia (Tampa Scale for Kinesiophobia), and physical functional performance (Handgrip Strength Dynamometry, 30-second Sit-to-Stand test, Static Muscular Endurance test, and Timed Up and Go test). The mediating effect of kinesiophobia on the relationship between pain intensity and physical functional performance/physical activity was analyzed, and the significance of the mediating effect (kinesiophobia) was tested through a bootstrap approach. Thirty-three individuals with inflammatory arthritis (mean age: 48 ± 12 years) participated in the study. Kinesiophobia mediates the relationship between pain intensity and physical functional performance analyzed by the 30-second Sit-to-Stand test [indirect effect (IE)overall = −0.343, bootstrap 95% confidence interval (CI): −0.698 to −0.002] and by knee flexion at 90º of the dominant limb (IEoverall = −1.55, bootstrap 95% CI: −3.43 to −0.237). In conclusion, pain intensity can affect physical functional performance through kinesiophobia in individuals with inflammatory arthritis.
Improving Patient Care Through Collaborative Re-envisioning of the Model of Critical Care
Authors: Hickin Sharon , Hudniuk Heather , Gyorfi Sarah
Published: October 2024

Purpose

Advanced medical therapies enable people to live longer with multiple comorbidities, increasing the acuity and complexity of care required upon admission into the intensive care unit. This, coupled with the shift toward a less experienced nursing workforce as skilled nurses retire or leave the critical care environment, prompted the need to re-envision how critical care is delivered. The purpose of this quality improvement project was to embed the values of staff and patient partners in a re-envisioned critical care model, which aligns the provision of high-quality care with staff skill mix and patient needs.

Methods

Through a series of clinical nurse specialist–led engagement sessions with patients, families, and the members of the healthcare team who work in this environment every day, we talked about what is important in critical care. We used their words and thoughts to inform and shape a new sustainable model of critical care.

Outcome

The 4 components identified as essential to achieving this vision include an acuity-complexity–based approach to care, a transition from separate high-acuity and intensive care areas to integrated units, development of a career pathway to advance practice, and exploration of opportunities to optimize the scope of the interprofessional team.

Conclusion

Embedding the values and experience of the people directly connected with providing and/or experiencing critical care increases the likelihood of success in developing, implementing, and sustaining a new model of care. This multifaceted approach resulted in 4 distinct components with achievable outcomes that support this re-envisioned patient-centered sustainable model of critical care.
Addressing US Military Transgender Care Inequalities
Authors: Vendramel Santos Weeks Luana , Linder Julie Michelle
Published: October 2024

Purpose/Objectives

There are more than 130 000 US veterans and more than 12 500 active-duty service members who identify as transgender. Lack of training in transgender and gender-affirming care among healthcare providers in the military is still reported. The article aims to explore and advocate for the unique role of advanced practice registered nurses, especially clinical nurse specialists, in providing culturally sensitive and evidence-based care to the transgender population within the US military.

Description of the Project/Program

The clinical nurse specialists’ pivotal role in policy advocacy and translation of evidence to improve the quality of care and patient outcomes for transgender service members is highlighted. The article also explores the historical journey of transgender care in the US military, addressing discriminatory policies and the implications of the ever-evolving regulations in military transgender healthcare.

Outcome

The article aims to create awareness of clinical nurse specialist utilization in US military healthcare services to improve the care of transgender individuals in the military.

Conclusion

The uncertain future for transgender service members highlights the ongoing commitment needed to navigate complex military healthcare policies and foster inclusive, evidence-based practices. Therefore, the clinical nurse specialist plays a pivotal role in shaping the future of transgender healthcare within the US military.
Telesurgery a Systematic Literature Review and Future Directions
Authors: Reddy Sumeet Kumar , Saikali Shady , Gamal Ahmed , Moschovas Marcio Covas , Rogers Travis , Dohler Mischa , Marescaux Jacques , Patel Vipul
Published: October 2024

Objective:

To undertake a systematic review of the medical literature on telesurgery, with a key focus on identifying the key technical and non-technical themes searched in medical articles and to analyze gaps in the current knowledge base on telesurgery.

Background:

It has now been over two decades since the first successful case of telesurgery and since this time there have been significant technological and telecommunications advancements.

Methods:

A systematic review of the literature was completed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Details of the protocol for this systematic review were registered on PROSPERO (CRD42024511530).

Results:

In total, 102 unique references which were allocated into five categories; technical, cybersecurity, ethical, financial, regulatory considerations to discuss key themes. The vast majority of references were related to technical considerations which have demonstrated the feasibility of telesurgery. The non-technical considerations have a paucity of literature and a lack of guidance on telesurgery which appears to still be the major barriers to telesurgery.

Conclusions:

Telesurgery presents many interdisciplinary challenges, encompassing both important technical and non-technical (such as cybersecurity, ethical, financial, and regulatory) considerations. Further research, collaboration between stakeholders, collaborative community of experts, and the development of comprehensive consensus frameworks are essential steps toward the widespread adoption of telesurgery.
The COMPARE Study: Comparing Perioperative Outcomes of Oncologic Minimally Invasive Laparoscopic, Da Vinci Robotic, and Open Procedures
Authors: Ricciardi Rocco , Seshadri-Kreaden Usha , Yankovsky Ana , Dahl Douglas , Auchincloss Hugh , Patel Neera M. , Hebert April E. , Wright Valena
Published: October 2024

Objective:

To assess 30-day outcomes of da Vinci robotic-assisted (dV-RAS) versus laparoscopic/thoracoscopic (lap/VATS) or open oncologic surgery.

Summary Background Data:

Complex procedures in deep/narrow spaces especially benefit from dV-RAS. Prior procedure-specific comparisons are not generalizable.

Methods:

PubMed, Scopus and EMBASE were systematically searched (latest: 11/17/2023) following PRISMA and PROSPERO (Reg#CRD42023466759). Randomized, prospective, and database studies were pooled as odds ratios (OR) or mean differences (MD) in R using fixed-effect or random-effects (heterogeneity significant). ROBINS-I/RoB 2 were used to assess bias.

Results:

Of 56,314 unique references over 12 years from 22 countries, 230 studies (34 randomized, 74 prospective, 122 database) comparing dV-RAS to lap/VATS or open surgery across 7 procedures, 4 specialties, representing 1,194,559 dV-RAS; 1,095,936 lap/VATS and 1,625,320 open cases were included. Operative time for dV-RAS was longer than lap/VATS (MD:17.73min [9.80,25.67], P<0.01) and open surgery (MD:40.92min [28.83,53.00], P<0.01), whereas hospital stay was shorter (lap/VATS MD:-0.51d [-0.64,-0.38], P<0.01; open MD:-1.85d [-2.09,-1.62], P<0.01) and blood loss was less versus open (MD:-293.44ml [-359.53,-227.35]). There were fewer dV-RAS conversions (OR:0.44 [0.40,0.49], P<0.01), transfusions (OR:0.79 [0.72,0.88], P<0.01), postoperative complications (OR:0.90 [0.84,0.96], P<0.01), readmissions (OR:0.91 [0.83,0.99], P=0.04), and deaths (OR:0.86 [0.81,0.92], P<0.01) versus lap/VATS, and fewer transfusions (OR:0.25 [0.21,0.30], P<0.01), postoperative complications (OR:0.56 [0.52,0.61], P<0.01), readmissions (OR:0.71 [0.63,0.81], P<0.01), reoperations (OR:0.89 [0.81,0.97], P<0.01), and deaths (OR:0.54 [0.47,0.63], P<0.01) versus open surgery. Blood loss (MD:-12.26mL [-29.44,4.91], P=0.16) and reoperations (OR:1.03 [0.95,1.11], P=0.48) were similar for dV-RAS and lap/VATS. There was significant heterogeneity.

Conclusions:

Da Vinci-RAS confers benefits across oncological procedures and study designs. These results provide clinical evidence to multi-specialty-care decision-makers considering dV-RAS.
Prevention of Trafficking in Organs, Tissues, and Cells
Authors: Martin Dominique E. , Capron Alexander M. , Fadhil Riadh A. S. , Forsythe John L. R. , Padilla Benita , Pérez-Blanco Alicia , Van Assche Kristof , Bengochea Milka , Cervantes Lilia , Forsberg Anna , Gracious Noble , Herson Marisa R. , Kazancioğlu Rümeyza , Müller Thomas , Noël Luc , Trias Esteve , López-Fraga Marta
Published: October 2024

Trafficking in human organs, cells, and tissues has long been a source of concern for health authorities and professionals, and several international ethical guidance documents and national laws have affirmed the prohibition of trade in these substances of human origin (SoHOs). However, despite considerable attention to the issue of organ trafficking, this remains a substantial and widespread problem internationally. In contrast, trafficking in cells, tissues, and medical products derived from SoHOs has received comparatively little attention, and the extent and nature of such trafficking remain largely unknown. Consequently, as part of the 2023 Global Summit on Convergence in Transplantation held in Santander, Spain, an ethics working group was assigned the task of formulating actionable recommendations to support the prevention of trafficking in all SoHOs. In reporting on this work, we review factors that may influence the persistent trafficking of SoHOs, explore the potential difficulties associated with the collection and reporting of data about suspected trafficking activities, and argue that more practical and consistent guidance, training, and regulatory frameworks are needed internationally to support effective reporting, sharing of data, and collaborative responses to suspected trafficking cases. We also discuss the importance of psychosocial evaluation of living donors as a strategy to detect and prevent organ trafficking and strive to advance the implementation of this well-established recommendation by outlining minimum standards for psychosocial evaluation of living donors.
Risk Stratification for Chronic Kidney Disease After Liver Transplant for Metabolic Dysfunction-associated Steatohepatitis (MASH) Cirrhosis: Results From the NailMASH Consortium
Authors: Satapathy Sanjaya K. , Elwir Saleh , Brandman Danielle , Smith Coleman , Jiang Yu , Vanatta Jason , Ha Nghiem B. , Cheung Amanda C. , Bhat Mamatha , Patel Pratik , Siddiqui Mohammad S. , Rinella Mary E. , Watt Kymberly D.
Published: October 2024

Background.

Chronic kidney disease (CKD) is a well-recognized complication in patients undergoing liver transplantation (LT), particularly those with metabolic dysfunction-associated steatohepatitis (MASH), a leading cause of cirrhosis in the modern era. This study sought to refine risk stratification for CKD events post-LT in cirrhosis patients with MASH by leveraging baseline renal function at transplant.

Methods.

A total of 717 MASH cirrhosis patients who had LT (1997–2017) at 7 US centers (NailMASH Consortium) were analyzed. Patients were categorized by estimated glomerular filtration rate (eGFR) at transplant: low (LGFR, eGFR ≤30 mL/min/1.73 m²), medium (MGFR, eGFR >30–≤60 mL/min/1.73 m²), and high (HGFR, eGFR >60 mL/min/1.73 m²). Time-related eGFR intercepts, slopes, and assessments of advanced-stage CKD (aCKD) events, defined as 2 eGFR levels <30 mL/min/1.73 m² separated by ≥90 d, were examined.

Results.

Post-LT, LGFR group showed increased eGFR, whereas the HGFR group experienced a decline. The 3-mo mark was identified as a “reset point,” signifying a new reference level, beyond which a different rate of decline was observed. After 3 mo, mean eGFRs of the LGFR group approached MGFRs, whereas the mean eGFR of the HGFR group continued to decrease but remained higher than other groups during a 60-mo follow-up. LGFR patients had significantly higher aCKD probability than MGFR and HGFR groups. Subanalysis at 3 mo post-LT revealed more aCKD events in the LGFR group compared with MGFR and HGFR groups (P < 0.0001).

Conclusions.

The study underscores renal impact of LT in MASH cirrhosis, indicating unique eGFR trajectories post-LT tied to baseline eGFR, with a reset point at 3 mo. Monitoring post-LT renal function, especially in those at aCKD risk, is crucial. Renal-sparing immunosuppression may help, regardless of baseline eGFR. Further studies are needed for interventions addressing renal dysfunction of patients with MASH post-LT.
Zebrafish reveal new roles for Fam83f in hatching and the DNA damage-mediated autophagic response
Authors: Jones Rebecca A. , Cooper Fay , Kelly Gavin , Barry David , Renshaw Matthew J. , Sapkota Gopal , Smith James C.
Published: October 2024

The FAM83 (
Fam
ily with sequence similarity
83
) family is highly conserved in vertebrates, but little is known of the functions of these proteins beyond their association with oncogenesis. Of the family, FAM83F is of particular interest because it is the only membrane-targeted FAM83 protein. When overexpressed, FAM83F activates the canonical Wnt signalling pathway and binds to and stabilizes p53; it therefore interacts with two pathways often dysregulated in disease. Insights into gene function can often be gained by studying the roles they play during development, and here we report the generation of
fam83f
knock-out (KO) zebrafish, which we have used to study the role of Fam83f
in vivo
. We show that endogenous
fam83f
is most strongly expressed in the hatching gland of developing zebrafish embryos, and that
fam83f
KO embryos hatch earlier than their wild-type (WT) counterparts, despite developing at a comparable rate. We also demonstrate that
fam83f
KO embryos are more sensitive to ionizing radiation than WT embryos—an unexpected finding, bearing in mind the previously reported ability of FAM83F to stabilize p53. Transcriptomic analysis shows that loss of
fam83f
leads to downregulation of phosphatidylinositol-3-phosphate (PI(3)P) binding proteins and impairment of cellular degradation pathways, particularly autophagy, a crucial component of the DNA damage response. Finally, we show that Fam83f protein is itself targeted to the lysosome when overexpressed in HEK293T cells, and that this localization is dependent upon a C’ terminal signal sequence. The zebrafish lines we have generated suggest that Fam83f plays an important role in autophagic/lysosomal processes, resulting in dysregulated hatching and increased sensitivity to genotoxic stress
in vivo
.
Young sanctuary-living chimpanzees produce more communicative expressions with artificial objects than with natural objects
Authors: Gibson Violet , Taylor Derry , Salphati Sarah , Somogyi Eszter , Nomikou Iris , Davila-Ross Marina
Published: October 2024

In humans, interactions with objects are often embedded in communicative exchanges. Objects offer unique affordances to explore, carry functions and hold cultural relevance, which can shape children’s interactions and communication. Research indicates that the use of artificial objects, such as certain toys, helps promote pre-linguistic communication, consequently impacting language development. Given that chimpanzees use objects extensively compared to other great apes, and considering the differences between chimpanzees and bonobos in intrinsic motivation for tool use and the extended developmental period during which they learn to use objects, it is reasonable to expect that objects may influence chimpanzees’ communication. Here, we examined interactions of 31 immature sanctuary-living chimpanzees with non-novel artificial and natural objects and tested their vocal and facial expressions, applying methods previously designed for children. Our results showed an increase in these expressions associated with artificial objects. These findings provide the first empirical evidence that chimpanzee communicative expressions may be influenced by inherent properties of objects, potentially promoting varied communication, comparable to the impact distinctive objects have on pre-linguistic children. By exploring this connection between object-centric interactions and communication, this study reveals deep phylogenetic roots where objects may have shaped great ape communication and possibly evolutionary foundations of language.
Investigating the impact of environmental feedback on the optional prisoner’s dilemma for insights into cyclic dominance and evolution of cooperation
Authors: Fahimur Rahman Shuvo Md. , Kabir K. M. Ariful
Published: October 2024

This study incorporates environmental feedback into the optional prisoner’s dilemma and rock–paper–scissors games to examine the mutual influence of eco-evolutionary outcomes and strategy dynamics. A novel game-theoretic model is developed that integrates the optional prisoner’s dilemma and rock–paper–scissors games by incorporating an environmental state variable. By adjusting feedback parameters, chaos, oscillations and coexistence are observed that surpass the usual outcomes of social dilemmas when the environment transitions between depleted and replenished states. Defection is no longer advantageous in evolution; cooperation, abstention and cyclic dominance arise. The observed transitions align with natural economics, ecology and sociology phenomena. The inclusion of abstention options and environmental feedback has a significant impact on collective outcomes when compared with conventional games. This has important implications for studying adaptation and decision-making in situations with ecological constraints.
A phenotypic drug discovery approach by latent interaction in deep learning
Authors: Yu Tat Wai Billy
Published: October 2024

Contemporary drug discovery paradigms rely heavily on binding assays about the bio-physicochemical processes. However, this dominant approach suffers from overlooked higher-order interactions arising from the intricacies of molecular mechanisms, such as those involving
cis
-regulatory elements. It introduces potential impairments and restrains the potential development of computational methods. To address this limitation, I developed a deep learning model that leverages an end-to-end approach, relying exclusively on therapeutic information about drugs. By transforming textual representations of drug and virus genetic information into high-dimensional latent representations, this method evades the challenges arising from insufficient information about binding specificities. Its strengths lie in its ability to implicitly consider complexities such as epistasis and chemical–genetic interactions, and to handle the pervasive challenge of data scarcity. Through various modeling skills and data augmentation techniques, the proposed model demonstrates outstanding performance in out-of-sample validations, even in scenarios with unknown complex interactions. Furthermore, the study highlights the importance of chemical diversity for model training. While the method showcases the feasibility of deep learning in data-scarce scenarios, it reveals a promising alternative for drug discovery in situations where knowledge of underlying mechanisms is limited.
On the effect of the maximal proper acceleration in the inertia
Authors: Gallego Torromé Ricardo
Published: October 2024

The effect of a hypothetical maximal proper acceleration on the mass of a charged particle is investigated in the context of particle accelerators. In particular, it is shown that maximal proper acceleration implies an increase in the kinetic energy of the particle being accelerated with respect to the relativistic energy. Such an increase in kinetic energy leads to a reduction of the luminosity of the bunches with respect to the expected luminosity in the relativistic models of the bunches. This relative loss in luminosity is of the order 10
−3
to 10
−5
for the Large Hadron Collider (LHC) bunches and can be of order up to 10
−3
for certain laser-plasma accelerator facilities. Although the effect is small, it increases with the square of the bunch population.
DeepVul: A Multi-Task Transformer Model for Joint Prediction of Gene Essentiality and Drug Response
Authors: Jararweh Ala , Arredondo David , Macaulay Oladimeji , Dicome Mikaela , Tafoya Luis , Hu Yue , Virupakshappa Kushal , Boland Genevieve , Flaherty Keith , Sahu Avinash
Published: October 2024

Despite their potential, current precision oncology approaches benefit only a small fraction of patients due to their limited focus on actionable genomic alterations. To expand its applicability, we propose DeepVul, a multi-task transformer-based model designed to predict gene essentiality and drug response from cancer transcriptome data. DeepVul aligns gene expressions, gene perturbations, and drug perturbations into a latent space, enabling simultaneous and accurate prediction of cancer cell vulnerabilities to numerous genes and drugs. Benchmarking against existing precision oncology approaches revealed that DeepVul not only matches but also complements oncogene-defined precision methods. Through interpretability analyses, DeepVul identifies underlying mechanisms of treatment response and resistance, as demonstrated with BRAF vulnerability prediction. By leveraging wholegenome transcriptome data, DeepVul enhances the clinical actionability of precision oncology, aiding in the identification of optimal treatments across a broader range of cancer patients. DeepVul is publicly available athttps://github.com/alaaj27/DeepVul.git.
IDH-mutant gliomas arise from glial progenitor cells harboring the initial driver mutation
Authors: Park Jung Won , Kwak Jiehoon , Kim Keon-Woo , Jung Saehoon , Nam Chang Hyun , Kim Hyun Jung , Lee Sang Mee , Park Ji-Hyung , Yoo Jihwan , Shim Jin-Kyoung , Kim Chungyeul , Ahn Sangjeong , Pusch Stefan , von Deimling Andreas , Chang Jong Hee , Kim Se Hoon , Ju Young Seok , Kang Seok-Gu , Lee Jeong Ho
Published: October 2024

Discovering the cell-of-origin harboring the initial driver mutation provides a fundamental basis for understanding tumor evolution and development of new treatments. For isocitrate dehydrogenase (IDH)-mutant gliomas – the most common malignant primary brain tumors in adults under 50 – the cell-of-origin remains poorly understood. Here, using patient brain tissues and genome-edited mice, we identified glial progenitor cells (GPCs), including oligodendrocyte progenitor cells (OPCs), as the glioma-originating cell type harboring the IDH mutation as the initial driver mutation. We conducted comprehensive deep sequencing, including droplet digital PCR and deep panel and amplicon sequencing to 128 tissues from 62 patients (29 IDH-mutant gliomas and 33 IDH-negative controls) comprising tumors, normal cortex or normal subventricular zone (SVZ), and blood. Surprisingly, low-level IDH mutation was found in the normal cortex away from the tumor in 38.5% (10 of 26) of IDH-mutant glioma patients, whereas no IDH mutation was detected in the normal SVZ. Furthermore, by analyzing cell-type–specific mutations, the direction of clonal evolution, the single-cell transcriptome from patient brains and novel mouse model of IDH-mutant glioma arising from mutation-carrying OPCs, we determined that GPCs, including OPCs, harboring the initial driver mutation are responsible for the development and evolution of IDH-mutant gliomas. In summary, our results demonstrate that GPCs containing the IDH mutation are the cells-of-origin harboring the initial driver mutation in IDH-mutant gliomas.
Bitter Taste Receptor Agonists Induce Apoptosis in Papillary Thyroid Cancer
Authors: Wei Kimberly , Hill Brianna L. , Miller Zoey A. , Mueller Arielle , Thompson Joel C. , Lee Robert J. , Carey Ryan M.
Published: October 2024

Background

Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, with a 20% recurrence rate. Bitter taste receptors (T2Rs) and their genes (TAS2Rs) may regulate survival in solid tumors. This study examined T2R expression and function in PTC cells.

Methods

Three PTC cell lines (MDA-T32, MDA-T68, MDA-T85) were analyzed for expression using RT-qPCR and immunofluorescence. Live cell imaging measured calcium responses to six bitter agonists. Viability and apoptosis effects were assessed using crystal violet and caspase 3/7 activation assays. Genome analysis of survival was conducted.

Results

TAS2R14was consistently highly expressed in all cell lines. Five bitter agonists produced significant calcium responses across all cell lines. All bitter agonists significantly decreased viability and induced apoptosis. HigherTAS2R14expression correlated with better progression-free survival in patients (p<0.05).

Conclusions

T2R activation by bitter agonists induces apoptosis and higherTAS2Rexpression is associated with survival, suggesting potential therapeutic relevance in thyroid cancer management.
Moving towards more holistic machine learning-based approaches for classification problems in animal studies
Authors: Christensen Charlotte , Ferreira André C. , Cherono Wismer , Maximiadi Maria , Nyaguthii Brendah , Ogino Mina , Herrera C Daniel , Farine Damien R.
Published: October 2024

Machine-learning (ML) is revolutionizing field and laboratory studies of animals. However, a challenge when deploying ML for classification tasks is ensuring the models are reliable. Currently, we evaluate models using performance metrics (e.g., precision, recall, F1), but these can overlook the ultimate aim, which is not the outputs themselves (e.g. detected species or individual identities, or behaviour) but their incorporation for hypothesis testing. As improving performance metrics has diminishing returns, particularly when data are inherently noisy (as human-labelled, animal-based data often are), researchers are faced with the conundrum of investing more time in maximising metrics versus doing the actual research. This raises the question: how much noise can we accept in ML models? Here, we start by describing an under-reported factor that can cause metrics to underestimate model performance. Specifically, ambiguity between categories or mistakes in labelling validation data produces hard ceilings that limit performance metrics. This likely widespread issue means that many models could be performing better than their metrics suggest. Next, we argue and show that imperfect models (e.g. low F1 scores) can still be useable. Using a case study on ML-identified behaviour from vulturine guineafowl accelerometer data, we first propose a simulation framework to evaluate robustness of hypothesis testing using models that make classification errors. Second, we show how to determine the utility of a model by supplementing existing performance metrics with ‘biological validations’. This involves applying ML models to unlabelled data and using the models’ outputs to test hypotheses for which we can anticipate the outcome. Together, we show that effects sizes and expected biological patterns can be detected even when performance metrics are relatively low (e.g., F1: 60-70%). In doing so, we provide a roadmap for validation approaches of ML classification models tailored to research in animal behaviour, and other fields with noisy, biological data.

Highlights

Evaluating machine learning (ML) models must go beyond performance metrics

Mislabels in validation data leads to underestimation of model’s performance

Underestimated metrics can cause research delays despite models being useful

We propose simulations and biological validations to evaluate model performance

Models with low standard metrics can still be powerful for hypothesis testing
The combined effect of viral infection and temperature on the gene response of melon and zucchini plants with different levels of temperature tolerance
Authors: De Moya-Ruiz C. , Rabadán M.P. , Gómez P.
Published: October 2024

Biotic and abiotic environmental factors shape plant responses. As such the interplay between viral infection and heat-stress can trigger specific physiological and metabolic plant responses that lead to gene-specific changes in defense and development. However, although plant gene expression patterns have been thoroughly studied under a single stress, the extent to which the combination of both stressors could modulate common or exclusive signaling pathways remains unclear. In this study, we examined the effects of watermelon mosaic virus infection and diurnal temperature variations (20/14 °C, 26/20 °C, and 32/24 °C) on the gene responses of two plant species (melon and zucchini), each with high- and low-temperature tolerance, using a differential 3’mRNA-seq approach. The WMV load was much greater in zucchini than in melon plants, and was also dependent on the temperature conditions and tolerance of each plant species. Our comparative RNA-seq analysis revealed that the percentage of differentially expressed genes (DEGs) was higher in the thermo-susceptible plants of both species under the combination of WMV infection and low temperatures (20 °C). Among these significantly regulated genes, between 37 % and 45 % were related to biotic and/or abiotic stress. Furthermore, we found that 30 GO terms were involved in the response to both combined stress from low temperatures and 23 GO terms for high temperatures, which were exclusive to the thermotolerant varieties. Together, these findings allowed the identification of two unique orthologous genes linked to temperature and virus infection in melon and zucchini plants. Understanding the effects of biotic and abiotic factors on plant responses is essential for unraveling the complexity of plant-pathogen-environment interactions and developing strategies to enhance plant resilience and productivity under changing climatic conditions.
Exact Continuous Spiking Rate Inference
Authors: Stern Merav
Published: October 2024

Many cognitive functions involve multiple brain areas simultaneously processing, distributing, and sharing information. The wide-field imaging technique can record such brain-wide activity since it offers a unique combination of simultaneous recordings from a wide field of view at a high rate. This unique combination is achieved by using a single-photon camera, which is set to capture, from a large area, neural activity-driven light emission generated by calcium indicators. Adequately analyzing this captured data requires inferring the underlying neural activity from the recorded fluorescence, a challenging mathematical problem. The challenge arises from the calcium indicator dynamics, which distort the neural dynamics as it transforms the neural activity into light emission and from the presence of noise. The wide-field setting adds a distinctive challenge. Its wide field of view recordings at a high rate constrains the spatial resolution to be limited. As a result, each fluorescence trace captured by each camera’s pixel originates from many neuron activities and not a single neuron as typical of other recording techniques. No previous, rigorously studied analytic solution exists for inferring neural activity from recorded fluorescence in the wide-field setting. Here, we phrase the inference problem arising from wide-field recordings as an optimization problem and solve it exactly. To ensure the robustness of our solution and provide a solid foundation for its application, we rigorously verify it using real data. We further suggest a novel approach for the optimization problem parameter-tuning. Beyond recovering the neural dynamics, our inference will allow future studies to retrieve accurate, correlation-based analyses of brain-wide activity.
Longitudinal Microbiome-based Interpretable Machine Learning for Identification of Time-Varying Biomarkers in Early Prediction of Disease Outcomes
Authors: Dai Yifan , Qian Yunzhi , Qu Yixiang , Guan Wyliena , Xie Jialiu , Wang Duan , Butler Catherine , Dashper Stuart , Carroll Ian , Divaris Kimon , Liu Yufeng , Wu Di
Published: October 2024

Information generated from longitudinally-sampled microbial data has the potential to illuminate important aspects of development and progression for many human conditions and diseases. Identifying microbial biomarkers and their time-varying effects can not only advance our understanding of pathogenetic mechanisms, but also facilitate early diagnosis and guide optimal timing of interventions. However, longitudinal predictive modeling of highly noisy and dynamic microbial data (e.g., metagenomics) poses analytical challenges. To overcome these challenges, we introduce a robust and interpretable machine-learning-based longitudinal microbiome analysis framework, LP-Micro, that encompasses: (i) longitudinal microbial feature screening via a polynomial group lasso, (ii) disease outcome prediction implemented via machine learning methods (e.g., XGBoost, deep neural networks), and (iii) interpretable association testing between time points, microbial features, and disease outcomes via permutation feature importance. We demonstrate in simulations that LP-Micro can not only identify incident disease-related microbiome taxa but also offers improved prediction accuracy compared to existing approaches. Applications of LP-Micro in two longitudinal microbiome studies with clinical outcomes of childhood dental disease and weight loss following bariatric surgery yield consistently high prediction accuracy. The identified critical early predictive time points are informative and aligned with clinical expectations.
Nanoscale curvature of the plasma membrane regulates mechanoadaptation through nuclear deformation and rupture
Authors: Francis Emmet A. , Sarikhani Einollah , Patel Vrund , Meganathan Dhivya Pushpa , Jahed Zeinab , Rangamani Padmini
Published: October 2024

Nuclear translocation of the transcription regulatory proteins YAP and TAZ is a critical readout of cellular mechanotransduction. Recent experiments have demonstrated that cells on substrates with well-defined nanotopographies exhibit an altered mechanical and signaling response when compared to those on flat substrates, demonstrating mechanoadaptation to geometric constraints. Specifically, such cells show lower rates of focal adhesion formation, resulting in lower amounts of YAP/TAZ nuclear translocation. In this study, we investigate how the crosstalk between substrate nanotopography and mechanotransduction affects cytoskeletal activity and the nuclear transport of YAP/TAZ. We develop a biophysical model that incorporates plasma membrane (PM) curvature-dependent inhibition of integrin-mediated signaling, PM curvature-sensitive actin assembly, and stretch-induced opening of nuclear pore complexes (NPCs) upon indentation of the nuclear envelope (NE) by nanopillars. Our model predicts lower levels of cytoskeletal activation on nanopillar substrates, consistent with experiments. We demonstrate that this effect can be partially compensated for by increasing the indentation of the NE, leading to local cytoskeletal accumulation and enhanced YAP/TAZ transport through stretched NPCs. Nuclear deformation and cytoskeletal arrangement in our model agree well with experimental fluorescence images and electron micrographs of cells on nanopillar substrates. We then use our model to predict the effects of NE rupture on YAP/TAZ nuclear abundance, showing that if nuclear entry is favored over export through these rupture-induced pores, YAP/TAZ accumulates in the nucleus. We confirm this prediction experimentally, showing that nuclear YAP/TAZ increases in cells with ruptured NEs.
Usage-inspired Interactive Digital Pathology System for Pathology Instruction in Indonesia
Authors: Dwianingsih Ery Kus , Adyaksa Dewa Nyoman Murti , Walczysko Petr , Kusumastuti Auliana Hayu , Burel Jean-Marie , Swedlow Jason R
Published: October 2024

Background COVID-19 shifted Indonesian education to remote learning. The Gadjah Mada University (UGM) Faculty of Medicine Public Health and Nursing (UGM FMPHN) struggled with studying tumor images remotely due to resource shortages. In parallel, the University of Dundee's (UoD) OME team created OMERO for image management, inspiring UGM to use OMERO to develop GamaPath for web-based image viewing. This report details its implementation, effectiveness, and potential expansion to practical sessions and workshops in Indonesia. Methods Teaching slides were scanned in Indonesia and imported into OMERO at UoD. UGM students, residents, and clinicians used GamaPath for anatomical pathology training for several sessions between 2022 and 2024. GamaPath was also used for national continuing education sessions for pathologists held through 2023. Experiences and evaluations were collected via online surveys and results were assessed by modified MARuL scores. Results The UoD-UGM collaboration produced an application satisfying the initial need for remote teaching during COVID lockdown. However, after returning to in-person teaching, access to interactive training materials online was considered to be an essential part of effective instruction by students and faculty. The GamaPath application provided flexible access to interactive materials that enhanced the educational experience. Of 256 survey respondents, mean modified MARuL score for GamaPath web app was 40.92 (SD = 10.73) with a median of 41 (IQR = 34-50). Among the 107 pathologists who used GamaPath for national continuing education, the majority gave it the highest possible rating for functionality, ease of use, and overall experience. Conclusions UGMs FMPHN collaborated with UoD to create a digital pathology platform based on OMERO, improving image analysis and feedback for practical sessions and workshops using GamaPath.
Social contact patterns and their impact on the transmission of respiratory pathogens in rural China
Authors: Liang Yuxia , Zhang Juanjuan , You Qian , Wang Qianli , Yang Xiaohong , Zhong Guangjie , Dong Kaige , Zhao Zeyao , Liu Nuolan , Yan Xuemei , Lu Wanying , Peng Cheng , Zhou Jiaxin , Lin Jiqun , Litvinova Maria , Jit Mark , Ajelli Marco , Yu Hongjie
Published: October 2024

Introduction

Social contact patterns significantly influence the transmission dynamics of respiratory pathogens. Previous surveys have quantified human social contact patterns, yielding heterogeneous results across different locations. However, significant gaps remain in understanding social contact patterns in rural areas of China.

Methods

We conducted a pioneering study to quantify social contact patterns in Anhua County, Hunan Province, China, from June to October 2021, when there were minimal coronavirus disease-related restrictions in the area. Additionally, we simulated the epidemics under different assumptions regarding the relative transmission risks of various contact types (e.g., indoor versus outdoor, and physical versus non-physical).

Results

Participants reported an average of 12.0 contacts per day (95% confidence interval: 11.3–12.6), with a significantly higher number of indoor contacts compared to outdoor contacts. The number of contacts was associated with various socio-demographic characteristics, including age, education level, income, household size, and travel patterns. Contact patterns were assortative by age and varied based on the type of contact (e.g., physical versus non-physical). The reproduction number, daily incidence, and infection attack rate of simulated epidemics were remarkably stable.

Discussion

We found many intergenerational households and contacts that pose challenges in preventing and controlling infections among the elderly in rural China. Our study also underscores the importance of integrating various types of contact pattern data into epidemiological models and provides guidance to public health authorities and other major stakeholders in preparing and responding to infectious disease threats in rural China.
Competitive interactions shape brain dynamics and computation across species
Authors: Luppi Andrea I , Sanz Perl Yonatan , Vohryzek Jakub , Mediano Pedro A.M. , Rosas Fernando E , Milisav Filip , Suarez Laura Estefany , Gini Silvia , Gutierrez-Barragan Daniel , Gozzi Alessandro , Misic Bratislav , Deco Gustavo , Kringelbach Morten L
Published: October 2024

Adaptive cognition relies on cooperation across anatomically distributed brain circuits. However, specialised neural systems are also in constant competition for limited processing resources. How does the brain's network architecture enable it to balance these cooperative and competitive tendencies? Here we use computational whole-brain modelling to examine the dynamical and computational relevance of cooperative and competitive interactions in the mammalian connectome. Across human, macaque, and mouse we show that the architecture of the models that most faithfully reproduce brain activity, consistently combines modular cooperative interactions with diffuse, long-range competitive interactions. The model with competitive interactions consistently outperforms the cooperative-only model, with excellent fit to both spatial and dynamical properties of the living brain, which were not explicitly optimised but rather emerge spontaneously. Competitive interactions in the effective connectivity produce greater levels of synergistic information and local-global hierarchy, and lead to superior computational capacity when used for neuromorphic computing. Altogether, this work provides a mechanistic link between network architecture, dynamical properties, and computation in the mammalian brain.