bluuebunny/crossref_metadata_2025 huggingface dataset:
The value of the combined MR imaging features and clinical factors Nomogram model in predicting intractable postpartum hemorrhage due to placenta accreta
Authors: Lu Xian , Zhang Haibo , Wu Xianhua , Chen Xianfeng , Zhang Qin , Song Wei , Jin Yanqi , Yuan Mingming
Published: March 2024

To explore the value of the combined MR imaging features and clinical factors Nomogram model in predicting intractable postpartum hemorrhage (IPH) due to placenta accreta (PA). We conducted a retrospective study with 270 cases of PA patients admitted to our hospital from January 2015 to December 2022. The clinical data of these patients were analyzed, and they were divided into 2 groups: the IPH group and the non-IPH group based on the presence of IPH. The differences in data between the 2 groups were compared, and the risk factors for IPH were analyzed. A Nomogram model was constructed using independent high-risk factors, and the predictive value of this model for IPH was analyzed. The results of multivariable binary Logistic regression analysis showed higher number of cesareans, placenta previa, placenta accreta type (implantation, penetration), low signal strip on T2 weighted image (T2WI) were independent high-risk factor for IPH (P < .05). ROC analysis and Hosmer-Lemeshow goodness-of-fit test showed the Nomogram predictive model constructed with the high-risk factor has good discrimination and calibration. Decision curve analysis (DCA) showed that when the probability threshold for the Nomogram model’s prediction was in the range from 0.125 to 0.99, IPH patients could obtain more net benefits, making it suitable for clinical application. The higher number of cesareans, placenta previa, placental accreta type (implantation, penetration), and low signal strip on T2WI are independent high-risk factor for IPH. The Nomogram predictive model constructed with the high-risk factor demonstrates good clinical efficacy in predicting the occurrence of IPH due to PA.
The key determinants of low back pain among lifestyle behaviors in adolescents: A cross-sectional study from Saudi Arabia
Authors: Alotaibi Mazyad A. , Alfaifi Reem M. , Alhowimel Ahmed S. , Alodaibi Faris A. , Alzahrani Hosam , Alenazi Aqeel M. , Alqahtani Bader A. , Elnaggar Ragab K.
Published: March 2024

Establishing preventive measures and treatment strategies for adolescents with low back pain (LBP) may be greatly enhanced by fully grasping the complex interaction between LBP and lifestyle behaviors. The key objective of this study was to explore the possible associations between lifestyle behaviors and LBP among adolescents in Saudi Arabia. A cross-sectional study was conducted among high school students from 5 major regions in Saudi Arabia. Participants were enlisted for the research project between May and November 2021. To evaluate the presence/severity of LBP, physical activity, sedentary duration, sleep quality, nutrition, health responsibility, interpersonal relationships, spiritual growth, and stress management, a well-established web-based survey was employed. A total of 2000 students participated, with 57.9% reporting LBP. Students with LBP had lower scores on overall health-promoting lifestyle behaviors and all subscales, including physical activity, compared to those without LBP. Linear regression analysis revealed significant associations between sedentary duration and global sleep quality with pain severity among students with LBP. This study highlights the association between lifestyle behaviors and LBP among adolescents in Saudi Arabia. Promoting physical activity, reducing sedentary behavior, and improving sleep quality may be crucial in preventing and managing LBP in this population. Comprehensive strategies targeting lifestyle behaviors should be implemented to improve the well-being of adolescents and reduce the burden of LBP. Further research is needed to better understand the underlying mechanisms and develop effective preventive and treatment strategies for LBP among adolescents.
Comparative effectiveness between two types of head-mounted magnification modes using a smartphone-based virtual display
Authors: Chun Robert , Deemer Ashley , Fujiwara Kyoko , Deremeik James , Bradley Christopher K. , Massof Robert W. , Werblin Frank S.
Published: March 2024

SIGNIFICANCE

This work shows the benefits of using two different magnification strategies to improve the reading ability of low-vision patients using a head-mounted technology.

PURPOSE

The aim of this study was to conduct a comparative clinical trial evaluating the effectiveness of two magnification strategies in a head-mounted virtual reality display.

METHODS

Eighty-eight eligible low-vision subjects were randomized into two arms: (1) the full-field magnification display or (2) the virtual bioptic telescope mode. Subjects completed baseline testing and received training on how to use the device properly and then took the device home for a 2- to 4-week intervention period. An adaptive rating scale questionnaire (Activity Inventory) was administered before and after the intervention (home trial) period to measure the effect of the system. A Simulator Sickness Questionnaire was also administered. Baseline and follow-up results were analyzed using Rasch analysis to assess overall effectiveness of each magnification mode for various functional domain categories.

RESULTS

Both magnification modes showed a positive effect for reading, visual information, and the overall goals functional domain categories, with only reading reaching statistical significance after correction for multiple comparisons. However, there were no significant between-group differences between the two modes. The results of the Simulator Sickness Questionnaire showed that the magnification modes of the head-mounted display device were overall well tolerated among low-vision users.

CONCLUSIONS

Both the full-field and virtual bioptic magnification strategies were effective in significantly improving functional vision outcomes for self-reported reading ability.
Frequency and Reporting of Complications after Dupuytren Contracture Interventions: A Systematic Review and Meta-Analysis
Authors: Raval Parag , Kulkarni Kunal , Johnson Nicholas , Divall Pip , Nevill Clareece , Sutton Alex , Dias Joseph
Published: March 2024

Background:

Numerous complications are reported following interventions for Dupuytren contracture; however, their incidence, management, and outcomes remain poorly reported. The aims of this review were to report the proportions of complications, compare likelihood of complications between interventions, and evaluate reporting.

Methods:

Patient demographics, interventions, complications, their management, and outcomes were extracted. Analysis of descriptive data enabled review of reporting. Meta-analysis (MA) of noncomparative data sets enabled estimation of proportions of patients experiencing complications. Network meta-analysis (NMA) of comparative studies estimated the relative occurrence of complications between interventions.

Results:

Twenty-six studies, comprising 10,831 patients, were included. Interventions included collagenase injection, percutaneous needle fasciotomy (PNF), limited fasciectomy (LF), open fasciotomy (OF), and dermofasciectomy (DF). Overall quality and consistency of outcomes reporting was poor. MA enabled estimates of probabilities for 3 common complications across all interventions; the reported rates for LF were 4.5% for infection, 3% for nerve injury, and 3.3% for CRPS. LF, the most common intervention, was used as the reference intervention for comparison of the most common complications via NMA, including hematoma (OF odds ratio, 0.450 [95% CI, 0.277 to 0.695]; PNF odds ratio, 0.245 [95% CI, 0.114 to 0.457]), infection (PNF odds ratio, 0.2 [95% CI, 0.0287 to 0.690]; DF odds ratio, 2.02 [95% CI, 1.02 to 3.74]), and neurapraxia [PNF odds ratio, 0.0926 [95% CI, 0.00553 to 0.737]).

Conclusions:

There was limited reporting of complication occurrence, management, and outcomes, contributing to a gap in information for informed patient consent. MA was possible for reporting of proportions for infection, nerve injury, and CRPS. NMA enabled direct comparison of the 6 most common complications between interventions. Improving consistency and quality in complications reporting aids counseling of patients regarding the true rates and consequences of the risks of interventions, which can guide selection.
GalT Knockout Porcine Nerve Xenografts Support Axonal Regeneration in a Rodent Sciatic Nerve Model
Authors: King Nicholas C. , Tsui Jane M. , Bejar-Chapa Maria , Marshall Michael S. , Kogosov Ann S. , Fan Yingfang , Hansdorfer Marek A. , Locascio Joseph J. , Randolph Mark A. , Winograd Jonathan M.
Published: March 2024

Background:

Nerve xenografts harvested from transgenic α1,3-galactosyltransferase knockout pigs lack the epitope responsible for hyperacute rejection in pig-to-primate transplants. It is unknown whether these cold-preserved nerve grafts support axonal regeneration in another species during and after immunosuppression. The authors compared outcomes between autografts and cold-preserved xenografts in a rat sciatic model of nerve gap repair.

Methods:

Fifty male Lewis rats had a 1-cm sciatic nerve defect repaired using autograft and suture (n = 10); 1-week or 4-week cold-preserved xenograft and suture (n = 10 per group); or 1-week or 4-week cold-preserved xenograft and photochemical tissue bonding using a human amnion wrap (n = 10 per group). Rats with xenografts were given tacrolimus until 4 months postoperatively. At 4 and 7 months, rats were killed and nerve sections were harvested. Monthly sciatic functional index (SFI) scores were calculated.

Results:

All groups showed increases in SFI scores by 4 and 7 months. The autograft suture group had the highest axon density at 4 and 7 months. The largest decrease in axon density from 4 to 7 months was in the group with 1-week cold-preserved photochemical tissue bonding using a human amnion wrap. The only significant difference between group SFI scores occurred at 5 months, when both 1-week cold-preserved groups had significantly lower scores than the 4-week cold-preserved suture group.

Conclusions:

The results suggest that α1,3-galactosyltransferase knockout nerve xenografts may be viable alternatives to autografts. Further studies of long-gap repair and comparison with acellular nerve allografts are needed.

Clinical Relevance Statement:

This proof-of-concept study in the rat sciatic model demonstrates that cold-preserved α1,3-galactosyltransferase knockout porcine xenografts support axonal regeneration and viability following immunosuppression withdrawal. These results further suggest a role for both cold preservation and photochemical tissue bonding in modulating the immunological response at the nerve repair site.
Prognostic factors associated with venous thromboembolism following traumatic injury: A systematic review and meta-analysis
Authors: Tran Alexandre , Fernando Shannon M. , Rochwerg Bram , Hameed Morad S. , Dawe Phillip , Hawes Harvey , Haut Elliott , Inaba Kenji , Engels Paul T. , Zarychanski Ryan , Siegal Deborah M. , Carrier Marc
Published: March 2024

INTRODUCTION

Trauma patients are at increased risk of venous thromboembolism (VTE), including deep venous thrombosis and/or pulmonary embolism. We conducted a systematic review and meta-analysis summarizing the association between prognostic factors and the occurrence of VTE following traumatic injury.

METHODS

We searched the Embase and Medline databases from inception to August 2023. We identified studies reporting confounding adjusted associations between patient, injury, or postinjury care factors and risk of VTE. We performed meta-analyses of odds ratios using the random-effects method and assessed individual study risk of bias using the Quality in Prognosis Studies tool.

RESULTS

We included 31 studies involving 1,981,946 patients. Studies were predominantly observational cohorts from North America. Factors with moderate or higher certainty of association with increased risk of VTE include older age, obesity, male sex, higher Injury Severity Score, pelvic injury, lower extremity injury, spinal injury, delayed VTE prophylaxis, need for surgery, and tranexamic acid use. After accounting for other important contributing prognostic variables, a delay in the delivery of appropriate pharmacologic prophylaxis for as little as 24 to 48 hours independently confers a clinically meaningful twofold increase in incidence of VTE.

CONCLUSION

These findings highlight the contribution of patient predisposition, the importance of injury pattern, and the impact of potentially modifiable postinjury care on risk of VTE after traumatic injury. These factors should be incorporated into a risk stratification framework to individualize VTE risk assessment and support clinical and academic efforts to reduce thromboembolic events among trauma patients.

LEVEL OF EVIDENCE

Systematic Review and Meta-Analysis; Level III.
Nonadherence to Immunosuppressant Therapy of Kidney Transplant Candidate Patients: External Validation of the KATITA-25 Scale
Authors: de Medeiros Oliveira Luana Cristina Lins , Martins Rand Randall , de Oliveira Renata Borges , da Nóbrega Ítala Morgânia Farias , de Medeiros Batista Lorena , Moreira Francisca Sueli Monte , de Andrade Cinthya Cavalcante , Tavares Raquel Padilha Martins , de Vasconcelos Alan Lucena , Oliveira Antonio Gouveia
Published: March 2024

Background.

The self-administered Kidney AlloTransplant Immunosuppressive Therapy Adherence (KATITA-25) questionnaire is a multidimensional scale for use in the pretransplant setting that evaluates the predisposition to nonadherence of patients who are candidates to kidney transplant. The scale has shown adequate internal consistency and test–retest reliability. This study presents the results of an external validation study of the KATITA-25 scale.

Methods.

Patients >18 y old scheduled for kidney transplant were included in this multicenter study. The KATITA-25 scale was administered before surgery and then at 3-mo posttransplantation for evaluation of scale sensitivity to change. At this time, 2 validated medication adherence scales were applied for assessment of concurrent validity. For evaluation of predictive validity, nonadherence to immunosuppressive medication was assessed at 6 and 12 mo after transplantation by 3 independent methods: patient self-report of nonadherence using the Morisky-Green-Levine Medication Assessment Questionnaire scale, serum trough levels of immunosuppressants, and pharmacy refills.

Results.

Three twenty-two patients were available for evaluation of concurrent validity and 311 patients of predictive validity. After kidney transplant, the median KATITA-25 score decreased from 20 to 8 (P < 0.001), demonstrating scale sensitivity to change, and the KATITA-25 score showed correlation with the Basel Assessment of Adherence to Immunosuppressive Medication Scale score (Spearman’s ρ 0.18, P = 0.002) and the Cuestionario para la Evaluación de la Adhesión al Tratamiento Antiretroviral scores (ρ −0.17, P = 0.002), confirming concurrent validity. The nonadherence rate was 57.6%. The scale predictive validity was demonstrated by the area under the receiver operating characteristics curve (0.68), sensitivity (59.8%), specificity (68.2%), and positive predictive value (71.8%).

Conclusions.

This external validation study of KATITA-25 scale provided evidence of sensitivity to change, and structural, criterion, and predictive validity.
Aquablation: An overview of a novel, minimally invasive surgical modality to treat benign prostatic hyperplasia
Authors: Scholtz David J. , Hooshyari Ali , Vermeulen Lodewikus Petrus , Burns Timothy , Ordones Flavio , Gilling Peter
Published: March 2024

Benign prostatic hyperplasia (BPH) is a highly prevalent condition among aging men with significant negative impacts on quality of life. Although multiple surgical treatment modalities exist, there is an ongoing search for minimally invasive techniques to reduce hospital stays and adverse effects without compromising good functional outcomes. Aquablation is a novel minimally invasive surgical technique that combines robotic precision with heat-sparing ablation of obstructing prostate tissue. We describe the setup and mechanism of action of aquablation. A comprehensive literature search for clinical trials and recent meta-analyses was conducted and functional outcomes and adverse effects across multiple studies are summarized here. Aquablation produces comparable (if not superior) outcomes in terms of reduced International Prostate Symptom Score, improved Qmax (comparison of maximum flow velocity), and lower postvoid residuals to transurethral resection of the prostate. These findings are consistently reproduced across multiple clinical trials, including those conducted in the private sector. One major benefit of aquablation is that the risk of injury to the ejaculatory ducts appears to be significantly lower, as evident from the low percentage of cases of postoperative anejaculation issues. Adverse effects are rare, and the most significant one to mention is blood loss requiring transfusion. At present, the overall cost of aquablation is still higher than other methods of treating BPH and this is due to intraoperative and equipment costs. Postoperative care is no more expensive than other methods of BPH treatment. In conclusion, aquablation is a safe and effective surgical modality for the treatment of BPH. It can be offered as an alternative to other surgical modalities for those who wish to spare ejaculatory function. The procedure itself can be easily taught. With further development of this novel technology and increased availability, there is the potential for it to become a much more cost-effective method for surgical treatment of BPH.
Correlation of the Endoscopic Gastroesophageal Flap Valve with Pathologic Reflux
Authors: Manasa Morgan , Galvin Katie , Fazl Alizadeh Reza , Ruhi-Williams Perisa , Choi Alyssa , Samarasena Jason , Chang Kenneth , Nguyen Ninh T
Published: March 2024

BACKGROUND:

The Hill classification characterizes the geometry of gastroesophageal junction and Hill grades (HGs) III and IV have a high association with pathologic reflux. This study aimed to understand the use of the Hill classification and correlate the prevalence of pathologic reflux across different HGs.

STUDY DESIGN:

A retrospective review of 477 patients who underwent upper endoscopy and BRAVO pH monitoring between August 2018 and October 2021 was performed. These charts were reviewed for endoscopic findings for hiatal hernia and association of HGs with pathologic reflux, defined as an abnormal esophageal acid exposure time (AET) of ≥4.9%.

RESULTS:

Of 477 patients, 252 (52.8%) had an HG documented on the endoscopy report. Of the 252 patients, 61 had HG I (24.2%), 100 had HG II (39.7%), 61 had HG III (24.2%), and 30 had HG IV (11.9%). The proportion of patients with abnormal AET increases with increasing HGs (p < 0.001) as follows: I (39.3%), II (52.5%), III (67.2%), and IV (79.3%). The mean overall AET is as follows: HG I (5.5 ± 6%), HG II (7.0 ± 5.9%), HG III (10.2 ± 10.3%), and HG IV (9.5 ± 5.5%). The proportion of patients with hiatal hernia was 18% for HG I, 28% for HG II, 39.3% for HG III, and 80% for HG IV.

CONCLUSIONS:

Use of the Hill classification in clinical practice is low. There is an association of increasing HGs with increasing proportion of patients with abnormal AET. There is a high proportion of patients within HGs I and II with documented pathologic reflux and the presence of a hiatal hernia as observed on endoscopic examination. Our study suggests that endoscopic grading of the gastroesophageal junction may not adequately differentiate between normal vs abnormal reflux status, particularly for HGs I and II.
Development of a First-in-Class RIPK1 Degrader to Enhance Antitumor Immunity
Authors: Yu Xin , Lu Dong , Qi Xiaoli , Lin Hanfeng , Holloman Bryan L. , Jin Feng , Xu Longyong , Ding Lang , Peng Weiyi , Wang Meng C. , Chen Xi , Wang Jin
Published: March 2024

The scaffolding function of receptor interacting protein kinase 1 (RIPK1) confers intrinsic and extrinsic resistance to immune checkpoint blockades (ICBs) and has emerged as a promising target for improving cancer immunotherapies. To address the challenge posed by a poorly defined binding pocket within the intermediate domain, we harnessed proteolysis targeting chimera (PROTAC) technology to develop a first-in-class RIPK1 degrader, LD4172. LD4172 exhibited potent and selective RIPK1 degradation bothin vitroandin vivo. Degradation of RIPK1 by LD4172 triggered immunogenic cell death (ICD) and enriched tumor-infiltrating lymphocytes and substantially sensitized the tumors to anti-PD1 therapy. This work reports the first RIPK1 degrader that serves as a chemical probe for investigating the scaffolding functions of RIPK1 and as a potential therapeutic agent to enhance tumor responses to immune checkpoint blockade therapy.
Spatial and temporal characteristics of laboratory-inducedAnopheles coluzziiswarms: shape, structure and flight kinematics
Authors: Poda Bèwadéyir Serge , Cribellier Antoine , Feugère Lionel , Fatou Mathurin , Nignan Charles , Hien Domonbabele François de Sale , Müller Pie , Gnankiné Olivier , Dabiré Roch Kounbobr , Diabaté Abdoulaye , Muijres Florian T. , Roux Olivier
Published: March 2024

Anophelesmosquitoes mate at sunset in aerial swarms. The development of mating-based methods for effective malaria vector control requires a good knowledge of the flight behaviour ofAnophelesspecies in mating swarms. However, the process of how swarms are formed and maintained remains poorly understood. Here, we characterized the three-dimensional spatial and temporal flight kinematics ofAnopheles coluzziimales swarming above a ground marker. We observed that the location, shape and volume of swarms were highly stereotypic, consistent over the swarming duration, regardless of the number of individuals in the swarm. The swarm had an elliptical cone shape, and we observed a differential spatial distribution of flight kinematics parameters within the swarm volume. Among these parameters, only swarm density varied with swarm size. Using a sensory system-informed model, we show that swarm location and shape can accurately be modelled based on visual perception of the marker. To control swarm height, swarming individuals maintain an optical angle of the marker ranging from 24° to 55°. Limiting the viewing angle deviation to 4.5% of the maximum value results in the observed elliptical cone swarm shape. We discuss the implications of these finding in mating success, speciation and for vector control.
py_ped_sim - A flexible forward genetic simulator for complex family pedigree analysis
Authors: Guardado Miguel , Perez Cynthia , Jackson Shalom , Magaña Joaquín , Campana Sthen , Samperio Emily , Rojas Berenice Chavez , Hernandez Selena , Syas Kaela , Hernandez Ryan , Zavala Elena I. , Rohlfs Rori
Published: March 2024

Background

Large-scale family pedigrees are commonly used across medical, evolutionary, and forensic genetics. These pedigrees are tools for identifying genetic disorders, tracking evolutionary patterns, and establishing familial relationships via forensic genetic identification. However, there is a lack of software to accurately simulate different pedigree structures along with genomes corresponding to those individuals in a family pedigree. This limits simulation-based evaluations of methods that use pedigrees.

Results

We have developed a python command-line-based tool called py_ped_sim that facilitates the simulation of pedigree structures and the genomes of individuals in a pedigree. py_ped_sim represents pedigrees as directed acyclic graphs, enabling conversion between standard pedigree formats and integration with the forward population genetic simulator, SLiM. Notably, py_ped_sim allows the simulation of varying numbers of offspring for a set of parents, with the capacity to shift the distribution of sibship sizes over generations. We additionally add simulations for events of misattributed paternity, which offers a way to simulate half-sibling relationships. We validated the accuracy of our software by simulating genomes onto diverse family pedigree structures, showing that the estimated kinship coefficients closely approximated expected values.

Conclusions

py_ped_sim is a user-friendly and open-source solution for simulating pedigree structures and conducting pedigree genome simulations. It empowers medical, forensic, and evolutionary genetics researchers to gain deeper insights into the dynamics of genetic inheritance and relatedness within families.
Systematic Evaluation of Cell Type Deconvolution Methods for Plasma Cell-free DNA
Authors: Sun Tongyue , Yuan Jinqi , Zhu Yacheng , Yang Shen , Zhou Junpeng , Ge Xinzhou , Qu Susu , Li Wei , Li Jingyi Jessica , Li Yumei
Published: March 2024

Plasma cell-free DNA (cfDNA) is derived from cellular death in various tissues. Investigating the origin of cfDNA through tissue/cell type deconvolution allows us to detect changes in tissue homeostasis that occur during disease progression or in response to treatment. Consequently, cfDNA has emerged as a valuable noninvasive biomarker for disease detection and treatment monitoring. Although there are numerous methylation-based methods of cfDNA cell type deconvolution available, a comprehensive and systematic evaluation of these methods has yet to be conducted. In this study, we thoroughly benchmarked five previously published methods: MethAtlas, cfNOMe, CelFiE, CelFEER, and UXM. Utilizing deep whole-genome bisulfite sequencing data from 35 human cell types, we generated cfDNA mixtures with known ground truth to assess the deconvolution performance under various scenarios. Our findings indicate that different factors, including sequencing depth, reference marker selection, and reference completeness, influence cell type deconvolution performance. Notably, omitting cell types present in a mixture from the reference leads to suboptimal results. Despite each method exhibited distinct performances under various scenarios, CelFEER and UXM exhibit overall superior performance compared to the others. In summary, we comprehensively evaluated factors influencing methylation-based cfDNA cell type deconvolution and proposed general guidelines to maximize the performance.
Aging-associated long non-coding RNA boosts longevity and reduces the ribosome content of non-dividing fission yeast cells
Authors: Anver Shajahan , Sumit Ahmed Faisal , Sun Xi-Ming , Hatimy Abubakar , Thalassinos Konstantinos , Marguerat Samuel , Alic Nazif , Bähler Jürg
Published: March 2024

Genomes produce widespread long non-coding RNAs (lncRNAs) of largely unknown functions. We characterizeaal1(aging-associated lncRNA) which is induced in quiescent cells of fission yeast. Deletion ofaal1shortens the chronological lifespan of non-dividing cells, while ectopic overexpression ofaal1prolongs their lifespan, indicating that this lncRNA actsin trans. The overexpression ofaal1leads to the repression of ribosomal protein genes and inhibition of cell growth, andaal1genetically interacts with coding genes functioning in protein translation. Theaal1RNA localizes to the cytoplasm and associates with ribosomes. Notably,aal1deletion or overexpression is sufficient to increase or decrease the cellular ribosome content. Therpl1901mRNA, encoding a ribosomal protein, is a binding target ofaal1.The levels ofrpl1901are reduced ∼2-fold byaal1,which is critical and sufficient to extend the lifespan. Remarkably, the expression ofaal1lncRNA inDrosophilatriggers an extension of fly lifespan. We propose thataal1reduces the ribosome content by decreasing the levels of Rpl1901, thus attenuating protein translation and promoting longevity. Although theaal1lncRNA itself is not conserved, its effect in flies raises the possibility that animals feature related mechanisms that modulate aging, based on the conserved translational machinery.
Mechanical cues of extracellular matrix determine tumor innervation
Authors: Jiang Shu-Heng , Zhang Shan , Cai Zhiwei , Yu Min-Hao , Li Hui , Jiang Luju , Cai Shuqi , Zhu Yuheng , Wang Hao , Huo Rui-Xue , Xia Xiang , Yao Hong-Fei , Zhu Lei , Zhang Xue-Li , Hu Li-Peng , Li Qing , Li Jun , Huo Yan-Miao , Hua Rong , Xue Junli , Jiang Chongyi , Sun Yong-Wei , Zhang Jun-Feng , Zhang Zi-Zhen , Liu De-Jun , Xiao Gary Gui-Shan , Zhang Zhi-Gang
Published: March 2024

Peripheral tumors can establish local autonomic and sensory nerve networks, termed as tumor innervation (TIN), to support tumorigenesis and metastasis. While nerve dependence in cancers is well-established, the mechanisms governing TIN remain unclear. Here, we report that extracellular matrix (ECM) stiffness, a major mechanical abnormality in the tumor microenvironment (TME), is an essential contributor of TIN. In preclinical models, reducing lysyl oxidase-mediated ECM crosslinking lowers tissue stiffness and TIN in pancreatic cancer, while inflammation-induced matrix stiffening boosts the hyperinnervation of the pancreatic precursor lesions. Mechanistically, β1-containing integrins sense the mechanical cues exerted by ECM stiffness, and the translational co-activator YAP1 acts as an essential nuclear relay to induce the expression of neurotropic genes, particularly brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). 3D imaging of the whole cleared pancreas reveals that blockade of mechanosensor integrin β1 or pharmacological inhibition of the mechanotransducer YAP1 effectively reduces TIN. In clinical settings, tumor samples with a dense, crosslinked, and stiffened ECM exhibit significant TIN. In summary, these findings identify ECM stiffness as an important driver of TIN and suggest that targeting integrin β1/YAP1-dependent mechanotransduction may counteract TIN.
IFNγ-dependent remodelling of the myeloid landscape underlies control of IFNγ-insensitive tumours
Authors: Lau Vivian W.C. , Mead Gracie , Mazet Julie M. , Krishnan Anagha , Roberts Edward W. , Prota Gennaro , Gileadi Uzi , Cerundolo Vincenzo , Gérard Audrey
Published: March 2024

Loss of IFNγ-sensitivity by tumours is thought to be a mechanism enabling evasion, as some cancers lacking IFNγ-signalling demonstrate resistance to checkpoint immunotherapy. However, recent studies demonstrated that IFNγ-resistant tumours are well-controlled and sensitized for immunotherapy. The underlying mechanism leading to enhanced immune responses in those patients is unknown. Using IFNγ-insensitive melanoma tumours which were well-controlled by the endogenous anti-tumour response, we found that despite low basal MHC class I expression by tumours, CD8+T cell infiltration was not hindered and, unexpectedly, their production of IFNγ was still important for tumour control. Mechanistically, IFNγ triggers pro-inflammatory remodelling of IFNγ-insensitive tumours, affecting the differentiation of myeloid cells. Predominantly, immunosuppressive macrophages are inhibited, while inflammatory phenotypes of monocytes and ‘mono-macs’ are preserved in IFNγ-insensitive tumours. This is supported by a co-dependency between CD8+T cells and monocyte/macrophages, as depletion of one resulted in loss of the other. Our work demonstrates an important mechanistic understanding of how IFNγ resistance does not preclude failure of anti-tumour responses. Importantly, immune remodelling appears to be dominant in IFNγ-sensitive and IFNγ-insensitive mixed tumours, and is enriched in humans with tumours mutated in the IFNγ pathway, suggesting this may be leveraged for therapy in the future.
Notch3is a genetic modifier of NODAL signalling for patterning asymmetry during mouse heart looping
Authors: Bønnelykke Tobias Holm , Chabry Marie-Amandine , Perthame Emeline , Desgrange Audrey , Meilhac Sigolène M.
Published: March 2024

The TGFβ secreted factor NODAL is a major left determinant required for the asymmetric morphogenesis of visceral organs, including the heart. Yet, when this signalling is absent, shape asymmetry, for example of the embryonic heart loop, is not fully abrogated, indicating that there are other factors regulating left-right patterning. Here, we used a tailored transcriptomic approach to screen for genes asymmetrically expressed in the field of heart progenitors. We thus identifyNotch3as a novel left-enriched gene and validate, by quantitative in situ hybridization, its transient asymmetry in the lateral plate mesoderm and node crown, overlapping withNodal. In mutant embryos, we analysed the regulatory hierarchy and demonstrate thatNodalin the lateral plate mesoderm amplifiesNotch3asymmetric expression. The function ofNotch3was uncovered in an allelic series of mutants. In single neonate mutants, we observe thatNotch3is required with partial penetrance for the development of ventricles, in addition to its known role in coronary arteries. In compound mutants, we reveal thatNotch3acts as a genetic modifier ofNodal, able to modulate heart looping direction and the curvature of the outflow tract. WhereasNotch3was previously associated with the CADASIL syndrome, its contribution to asymmetric organogenesis is now relevant to severe laterality defects such as the heterotaxy syndrome.
Teaching deep networks to see shape: Lessons from a simplified visual world
Authors: Jarvers Christian , Neumann Heiko
Published: March 2024

Deep neural networks have been remarkably successful as models of the primate visual system. One crucial problem is that they fail to account for the strong shape-dependence of primate vision. Whereas humans base their judgements of category membership to a large extent on shape, deep networks rely much more strongly on other features such as color and texture. While this problem has been widely documented, the underlying reasons remain unclear. We design simple, artificial image datasets in which shape, color, and texture features can be used to predict the image class. By training networks to classify images with single features and feature combinations, we show that some network architectures are unable to learn to use shape features, whereas others are able to use shape in principle but are biased towards the other features. We show that the bias can be explained by the interactions between the weight updates for many images in mini-batch gradient descent. This suggests that different learning algorithms with sparser, more local weight changes are required to make networks more sensitive to shape and improve their capability to describe human vision.

Author summary

When humans recognize objects, the cue they rely on most is shape. In contrast, deep neural networks mostly use local features like color and texture to classify images. We investigated how this difference arises, using images of simple shapes like rectangles and the letters L and T, combined with color and texture features. By testing different feature combinations, we show that some networks are generally unable to learn about shape, whereas others could learn to recognize shapes in isolation, but ignored shape if another feature was present. We show that this bias for color and texture arises from the way in which networks are trained: by averaging the learning signal over many images, the training algorithm favors simple features that are relatively similar in many images and removes sparser, more varied shape features. These insights can help build networks that are more sensitive to shape and work better as models of human vision.
Astrocytes mediate two forms of spike timing-dependent depression at entorhinal cortex-hippocampal synapses
Authors: Martínez-Gallego Irene , Coatl-Cuaya Heriberto , Rodríguez-Moreno Antonio
Published: March 2024

The entorhinal cortex (EC) connects to the hippocampus sending different information from cortical areas that is first processed at the dentate gyrus (DG) including spatial, limbic, and sensory information. Excitatory afferents from lateral (LPP) and medial (MPP) perforant pathways of the EC connecting to granule cells of the DG play a role in memory encoding and information processing and are deeply affected in humans suffering Alzheimeŕs disease and temporal lobe epilepsy, contributing to the dysfunctions found in these pathologies. The plasticity of these synapses is not well known yet, as are not known the forms of long-term depression (LTD) existing at those connections. We investigated whether spike timing-dependent long-term depression (t-LTD) exists at these two different EC-DG synaptic connections in mice, and whether they have different action mechanisms. We have found two different forms of t-LTD, at LPP- and MPP-GC synapses and characterised their cellular and intracellular mechanistic requirements. We found that both forms of t-LTD are expressed presynaptically and that whereas t-LTD at LPP-GC synapses does not require NMDAR, t-LTD at MPP-GC synapses requires ionotropic NMDAR containing GluN2A subunits. The two forms of t-LTD require different group I mGluR, mGluR5 LPP-GC synapses and mGluR1 MPP-GC synapses. In addition, both forms of t-LTD require postsynaptic calcium, eCB synthesis, CB1R, astrocyte activity, and glutamate released by astrocytes. Thus, we discovered two novel forms of t-LTD that require astrocytes at EC-GC synapses.
Water position prediction with SE(3)-Graph Neural Network
Authors: Park Sangwoo
Published: March 2024

Most protein molecules exist in a water medium and interact with numerous water molecules. Consideration of interactions between protein molecules and water molecules is essential to understanding the functions of the protein. In computational studies on protein functions, either implicit solvation or explicit solvation methods are used to consider the effect of water on the protein. Implicit solvation methods consider water as a continuous solvent and have lower computational costs than explicit methods that consider water as a collection of individual water molecules. However, some water molecules have specific interactions with protein molecules, which are critical to protein function and require explicit treatment to consider these specific interactions. Thus, as a compromise between computational cost and consideration of specific interactions, hybrid methods use explicit consideration of water molecules with specific interaction with protein molecules while considering other water molecules implicitly. Prediction of the water positions having specific interaction is required to perform such hybrid methods, where various water position prediction methods have been developed. However, currently developed water position prediction methods still require considerable computational cost. Here, we present a water position prediction method with low computational cost and state-of-the-art prediction performance by utilizing SE(3)-an equivariant graph neural network. The introduction of a graph neural network enabled the consideration of the atom as a single data point, which makes computational costs less than our previous water prediction method using a convolutional neural network, which considers an atom as multiple data points. Our new water position prediction method, WatGNN, showed an average computation time of 1.86 seconds while maintaining state-of-the-art prediction performance. The source code of this water prediction method is freely available athttps://github.com/shadow1229/WatGNN.
Neurovascular unit adjustments following chronic distress explain motivational deficits in mice
Authors: Cabeza Lidia , Mor Damien , Ramadan Bahrie , Benhora-Chabeaux Guillaume , Houdayer Christophe , Haffen Emmanuel , Peterschmitt Yvan , Etievant Adeline , Bourasset Fanchon
Published: March 2024

Background

The neurovascular unit (NVU) represents the structural and functional relationship between the neural tissue and the blood. Neurovascular dysfunction has been highlighted in neuropsychiatric afflictions, but whether it is a cause or a consequence of the pathology remains to be elucidated. Thus, to elucidate the role of the NVU on the emergence of emotional-cognitive dysfunction, it is necessary to study how its individual components associate. This study therefore aims at investigating whether the development of depressive-related loss of motivation is grounded on NVU adjustments impacting the permeability of the blood-brain barrier (BBB) and in particular, of the structural scaffolding of microvessels.

Methods

Adult male C57BL/6jRj mice chronically treated with corticosterone (CORT) and showing severe motivational deficits in an operant progressive ratio (PR) schedule of reinforcement task, presented altered neural activation assessed through FosB expression in key brain regions involved in motivational processing (anterior insular cortex, basolateral amygdala, bed nucleus of the stria terminalis and ventral tegmental area). We evaluated NVU modifications through immunofluorescence staining targeting specific markers of microglia (IBA-1), endothelial tight junctions (ZO-1) and astrocytes (GFAP). The effect of chronic CORT administration on mice BBB permeability was evaluated throughin vivoperfusion of fluorescent 40 kDa Dextran.

Results

Our results highlight that where sustained neuronal activation failed, NVU modifications predict behavioural deficits in CORT-treated animals. Notably, our analyses show that NVU modifications within the ventral tegmental area are essential to understand effort-based related behavioural performance in mice, and most particularly, that the key element of microvessels’ tight junctions ZO-1 plays a pivotal role on motivation-related behavioural output.

Conclusions

Our results confirm a direct role of neurovascular adaptations on emotional and cognitive behavioural performance in mice, and therefore place the NVU in a key position in the research of the biological substrate at the origin of neuropsychiatric disorders.
Functional states of prelimbic and related circuits during the acquisition of a GO/noGO task in rats
Authors: Muñoz-Redondo Carmen , Parras Gloria G. , Andreu-Sánchez Celia , Martín-Pascual Miguel Ángel , Delgado-García José M. , Gruart Agnès
Published: March 2024

GO/noGO tasks enable assessing decision-making processes and the ability to suppress a specific action according to the context. Here, rats had to discriminate between two visual stimuli (GO or noGO) shown on an iPad screen. The execution (for GO) or non-execution (for noGO) of the selected action (to touch or not the visual display) were reinforced with food. The main goal was to record and to analyze local field potentials (LFPs) collected from cortical and subcortical structures when the visual stimuli were shown on the touch screen and during the subsequent activities. Rats were implanted with recording electrodes in the prelimbic cortex, primary motor cortex, nucleus accumbens septi, basolateral amygdala, dorsolateral and dorsomedial striatum, hippocampal CA1, and mediodorsal thalamic nucleus. Spectral analyses of the collected data demonstrate that the prelimbic cortex was selectively involved in the cognitive and motivational processing of the learning task but not in the execution of reward-directed behaviors. In addition, the other recorded structures presented specific tendencies to be involved in these two types of brain activity in response to the presentation of GO or noGO stimuli. Spectral analyses, spectrograms, and coherence between the recorded brain areas indicate their specific involvement in GO vs. noGO tasks.
The Genetic Puzzle of Multicopy Genes: Challenges and Troubleshooting
Authors: Partida Vania Gabriela Sedano , Dias Henrique Moura , Portes Maria Teresa , Van Sluys Marie-Anne
Published: March 2024

Background

Studies with multicopy genes impose challenges related to gene redundancy and sequence similarity among copies. Recent advances in molecular biology and genomics tools associated with dedicated databases facilitate their study. Thus, the present work emphasizes the need for rigorous methodologies and standardized approaches to interpret RT-qPCR results accurately.

Results

The present work inPhyscomitrium patensprovides a comprehensive five-step protocol, using thiamine thiazole synthase (THI1) and sucrose 6-phosphate phosphohydrolase (S6PP)genes as proof of concept, to showcase a systematic workflow for studying multicopy genes. Beyond examining genes of interest, we highlight the critical role of choosing appropriate internal controls in the analytical process for accurately interpreting gene expression patterns. We emphasized the importance of identifying the most relevant orthologous gene, recognizing the inherent challenges in determining the most functional copy for subsequent studies. Our objective is to enhance comprehension of gene redundancy by dissecting multicopy genes’ genomic landscape and its characteristics. Furthermore, we address the decision-making process surrounding the quantification of expression levels of multicopy genes.

Conclusions

The study of multicopy genes discloses early events of functional adaptation. We emphasize the significance of multicopy genes in plant biology and provide a practical protocol for their study. Plant systems are strongly influenced by light/dark cycles, and the challenges inherent to this process are acknowledged. In conclusion, our comprehensive approach aims to advance the understanding of multicopy gene dynamics, offering practical methodologies and contributing valuable insights to the scientific community.
Human long noncoding RNA,VILMIR,is induced by major respiratory viral infections and modulates the host interferon response
Authors: John Kristen , Huntress Ian , Smith Ethan , Chou Hsuan , Tollison Tammy S. , Covarrubias Sergio , Crisci Elisa , Carpenter Susan , Peng Xinxia
Published: March 2024

Long noncoding RNAs (lncRNAs) are a newer class of noncoding transcripts identified as key regulators of biological processes. Here we aimed to identify novel lncRNA targets that play critical roles in major human respiratory viral infections by systematically mining large-scale transcriptomic datasets. Using bulk RNA-sequencing (RNA-seq) analysis, we identified a previously uncharacterized lncRNA, named virus inducible lncRNA modulator of interferon response (VILMIR), that was consistently upregulated afterin vitroinfluenza infection across multiple human epithelial cell lines and influenza A virus subtypes.VILMIRwas also upregulated after SARS-CoV-2 and RSV infectionsin vitro. We experimentally confirmed the response ofVILMIRto influenza infection and interferon-beta (IFN-β) treatment in the A549 human epithelial cell line and found the expression ofVILMIRwas robustly induced by IFN-β treatment in a dose and time-specific manner. Single cell RNA-seq analysis of bronchoalveolar lavage fluid (BALF) samples from COVID-19 patients uncovered thatVILMIRwas upregulated across various cell types including at least five immune cells. The upregulation ofVILMIRin immune cells was further confirmed in the human T cell and monocyte cell lines, SUP-T1 and THP-1, after IFN-β treatment. Finally, we found that knockdown ofVILMIRexpression reduced the magnitude of host transcriptional responses to IFN-β treatment in A549 cells. Together, our results show thatVILMIRis a novel interferon-stimulated gene (ISG) that regulates the host interferon response and may be a potential therapeutic target for human respiratory viral infections upon further mechanistic investigation.

IMPORTANCE

Identifying host factors that regulate the immune response to human respiratory viral infection is critical to developing new therapeutics. Human long noncoding RNAs (lncRNAs) have been found to play key regulatory roles during biological processes, however the majority of lncRNA functions within the host antiviral response remain unknown. In this study, we identified that a previously uncharacterized lncRNA,VILMIR, is upregulated after major respiratory viral infections including influenza, SARS-CoV-2, and RSV. We demonstrated thatVILMIRis an interferon-stimulated gene that is upregulated after interferon-beta (IFN-β) in several human cell types. We also found that knockdown ofVILMIRreduced the magnitude of host transcriptional responses to IFN-β treatment in human epithelial cells. Our results reveal thatVILMIRregulates the host interferon response and may present a new therapeutic target during human respiratory viral infections.